WO2014055849A1 - Procédés permettant de diagnostiquer et de pronostiquer un dysfonctionnement placentaire et une pré-éclampsie - Google Patents

Procédés permettant de diagnostiquer et de pronostiquer un dysfonctionnement placentaire et une pré-éclampsie Download PDF

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WO2014055849A1
WO2014055849A1 PCT/US2013/063434 US2013063434W WO2014055849A1 WO 2014055849 A1 WO2014055849 A1 WO 2014055849A1 US 2013063434 W US2013063434 W US 2013063434W WO 2014055849 A1 WO2014055849 A1 WO 2014055849A1
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pigf
female
level
p1gf
days
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Paul R. SHEARD
Kenneth Kupfer
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Alere San Diego, Inc.
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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
    • G01N33/74—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
    • G01N2333/475—Assays involving growth factors
    • 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

Definitions

  • Pre-eclampsia is a serious multisystem disorder, presenting in mild and severe forms, that occurs in pregnant women. Pre-eclampsia is defined as hypertension
  • eclampsia can rapidly progress to a convulsive phase termed eclampsia, if undetected or not delivered.
  • Pre-eclampsia affects approximately 3-5% of pregnancies worldwide (WHO. 2005. World Health Report: Make Every Mother and Child Count. Geneva: World Health Organization). Overall, 15-25% of women with gestational hypertension progress to pre- eclampsia (Saudan P et al. Does gestational hypertension become pre-eclampsia? BJOG (1998) 105: 1177-84).
  • Hypertension in pregnancy is usually defined as systolic blood pressure of at least 140 mmHg and/or diastolic blood pressure of at least 90 mmHg.
  • Proteinuria during pregnancy is defined as 300 mg of protein, or more, in a 24-hour urine collection (which correlates with 30 mg/dL or a spot ratio of 30 mg/mmol) (Brown MA et al. The
  • the severity of hypertension in pre-eclampsia can vary widely, from mild blood pressure elevations, to severe hypertension resistant to multiple medications, often associated with headache and visual changes.
  • the placenta plays a central role in the pathogenesis of pre-eclampsia, as evidenced by the rapid disappearance of clinical signs and symptoms of pre-eclampsia following delivery of the placenta (McMaster MT et al. Abnormal placentation and the syndrome of pre-eclampsia. Semin. Nephrol. (2004) 24:540-7).
  • pre-eclampsia Although the origins of pre-eclampsia remain unclear, a major cause is the failure to develop an adequate blood supply to the placenta, leading to placental oxidative stress (Redman, CWG. Pre-eclampsia, the Placenta and the Maternal Systemic Inflammatory Response-A Review. Placenta (2003) 24, Supplement A, Trophoblast Research 17: S21- S27).
  • Placental growth factor is made by the placenta and circulates at high concentration in normal pregnancy.
  • PIGF placental growth factor
  • pre-eclampsia there is increased expression of soluble fins-like tyrosine kinase- 1 (sFltl) which binds to circulating PIGF (Maynard S et al. Excess placental soluble fms-like tyrosine kinase 1 (sFltl) may contribute to endothelial dysfunction, hypertension, and proteinuria in pre-eclampsia. J. Clin. Invest. (2003) 111 : 649-658; Ahmad S et al.
  • Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in pre-eclampsia. Circ. Res. (2004) 95:884-91; Kendall RL et al. Inhibition of vascular endothelial cell growth factor (VEGF) activity by an VEGF receptor-1
  • PIGF concentrations peak at 26 to 30 weeks and then decline as term approaches (Tidwell SC et al. Low maternal serum levels of placenta growth factor as an antecedent of clinical pre-eclampsia. Am. J. Obstet. Gynecol. (2001) 184:1267-72).
  • PIGF levels are abnormally low in women with preeclampsia compared to women with a healthy pregnancy of approximately the same gestational age and PIGF is lower in severe pre-eclampsia compared with mild preeclampsia (Robinson CJ, Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe pre-eclampsia, Am. J. Obstet. Gynecol. (2006) 195, 255-9; Ghosh S et al. Serum PIGF as a potential biomarker for predicting the onset of preeclampsia. Arch Gynecol Obstet (2011).
  • soluble fms-like tyrosine kinase- 1 bind to PIGF and thus significantly lower the levels of maternal circulating PIGF (Levine RJ., et al. N EnglJMed. (2004) 350(7):672-83).
  • Pregnant women with suspected or confirmed preterm pre-eclampsia and a low circulating level of PIGF are at increased risk for adverse maternal and perinatal outcome (Rana S et al. Angiogenic factors and the risk of adverse outcomes in women with suspected pre-eclampsia. Circulation. (2012) 125:911-919; Chaiworapongsa T et al. Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia. J. Matern. Fetal. Neonatal. Med. (2011) 24(10): 1187-207; Ahola T et al.
  • pre-eclampsia is diagnosed by late, non-specific markers, delaying clinical management decisions.
  • Pre-eclampsia is a complicated clinical syndrome and women may experience any one or more of a range of signs and symptoms which do not follow a specific pattern or time course. Because the appearance of diagnostic markers is late in the disease process and variable, severe pre-eclampsia can develop rapidly and unpredictably during pregnancy. Clinical assessment of pre-eclampsia is limited by the poor accuracy and reliability of available diagnostic markers. While current clinical practice defines pre-eclampsia as the presence of new onset hypertension and proteinuria, the appearance of these features is late in the disease process and is not consistent between pregnant women.
  • the present invention relates to methods for determining placental dysfunction (also known as placental insufficiency) in a female suspected of having placental dysfunction, who has been pregnant for less than or equal to about 35 weeks.
  • One method involves the step of detecting the amount of placental growth factor (P1GF) present in an appropriate sample obtained from the female suspected of having placental dysfunction or pre- eclampsia.
  • the sample may comprise blood, plasma, serum, or urine. If the level of P1GF is less than or equal to about 25 pg/mL, then the female is diagnosed with having placental dysfunction or pre-eclampsia.
  • an appropriate sample obtained from the female diagnosed with placental dysfunction or pre-eclampsia can be detected at least one day after the initial detection and re-assayed for the amount of P1GF. If the level of P1GF is in the range of about 26 pg/mL to about 79 pg/mL, then the female is diagnosed as potentially having placental dysfunction or pre-eclampsia.
  • an appropriate sample may be obtained from that female about 2, 3 or 4 days later and re-assayed for the amount of P1GF. If the level of P1GF is about 80 pg/mL or higher, then the female is diagnosed as not having placental dysfunction or pre-eclampsia. Thereafter, an appropriate sample may be obtained from the female about 7 days later and re-assayed for the amount of P1GF. Also provided herein are methods for determining placental dysfunction in a female suspected of having preeclampsia. Other methods are for assigning a prognosis of a future complication associated with pregnancy in a female suspected of having placental dysfunction. Methods for assigning a likelihood of pre-term delivery in a female suspected of having placental dysfunction or pre-eclampsia are also disclosed.
  • the information obtained by measuring the protein levels of PIGF in a pregnant woman at various points in her pregnancy, alone or in conjunction with other clinical information, can not only aid in the diagnosis of placental dysfunction or preterm preeclampsia, but also aid in the prognosis, for example, to determine whether a more conservative or radical approach to therapy should be pursued.
  • Figure 1 is a clinical management algorithm using the Alere Triage® PIGF in women presenting with suspected placental dysfunction or pre-eclampsia before 35 weeks gestation.
  • Figure 2 is a graph showing individual PIGF concentrations in normal healthy pregnancies.
  • FIG. 3 is a Receiver Operator Characteristic (ROC) curve of PIGF concentrations
  • Figure 4 is a Kaplan-Meier survival curves of the proportion of women undelivered as a function of gestational age (weeks) for each of the three PIGF categories for women presenting prior to 35+0 weeks of gestation.
  • Figure 5 compares the results obtained by testing patient samples with the Alere
  • Triage® PIGF test as opposed to the Perkin Elmer Delfia test.
  • a "biological sample” refers to a sample of biological material obtained from a subject, preferably a pregnant female. Examples include blood, plasma, serum, or urine. Severely hemolyzed specimens should be avoided. When a sample appears to be severely hemolyzed, another specimen should be obtained and tested. In certain embodiments, plasma samples may be prepared using EDTA as the anticoagulant. In certain
  • the sample may be treated to minimize the interference of any heterophile antibodies.
  • it may be desirable to treat a biological sample prior to measuring the level of P1GF.
  • one or more cells may be isolated from the biological sample. Fractions of the sample may be prepared. In other cases, proteins or specific proteins may be isolated or purified from an ititial sample.
  • a "patient” refers to a pregnant female human.
  • the pregnant female may be less than about 40+6 weeks pregnant. In certain embodiments, the pregnant female may be between about 9+0 to about 40+6 weeks pregnant.
  • Pre-eclampsia refers to the presence of new onset hypertension (>140mmHg systolic or >90mmHg diastolic) and proteinuria ( 0.3g protein in a 24h urine sample or equivalent). Pre-eclampsia may be regarded as severe in the presence of multiorgan involvement such as pulmonary oedema, seizures, oliguria (500 mL per day),
  • thrombocytopenia platelet count 100,000 per L
  • abnormal liver enzymes associated with persistent epigastric or right upper-quadrant pain or persistent and severe CNS symptoms (eg, altered mental status,
  • Atypical pre-eclampsia refers to gestational proteinuria in the absence of gestational hypertension, with other diagnostic findings (or vice versa), chronic proteinuria plus gestational hypertension, or chronic hypertension plus at least one abnormal laboratory test (low platelets or elevated liver enzymes).
  • “Severe pre-eclampsia” refers to a blood pressure > 160 mmHg systolic or > 110 mmHg diastolic; proteinuria of at least 5 g/24 h; medical complications (pulmonary edema, acute renal insufficiency, cerebral edema, hematoma hepatic, HELLP syndrome), oliguria, fetal growth restriction or oligohydramnios, or symptoms suggesting significant end-organ involvement, such as headache, visual disturbances, epigastric pain, tinnitus, (see, e.g, Vigil-De Gracia et al.
  • Superimposed pre-eclampsia refers to females with hypertension and no proteinuria early in pregnancy ( ⁇ 20 weeks' gestation). The following characteristics may be seen: sudden increase in blood pressure, new onset-proteinuria, defined as the urinary excretion of >0.3 g protein in a 24-h specimen; thrombocytopenia (platelet count ⁇ 100,000 cells/mm 3 ), and or with headache, scotomata, or epigastric pain.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • “Mild pre-eclampsia” refers to mild hypertension, normal platelet count, liver enzymes and absent maternal symptoms, (see, e.g., Zamorski et al. American Family Physician (2001) 64(2): 263-270).
  • P1GF identifies a placental problem and predicts a pregnancy complication. For example, the cause of pre-term pre-eclampsia originates in the placenta.
  • an appropriate sample may be obtained and contacted with at least one labelled antibody directed against placental growth factor (PIGF) in an appropriate immunoassay, for example, the Alere Triage® PIGF test as described herein.
  • PIGF placental growth factor
  • an immunoassay comprises at least one solid phase on which the assay occurs.
  • solid phase is used to describe a range of surfaces, including but not limited to, the surface of a particle, such as a latex particle, a magnetically susceptible particle, a colloidal sol particle (such as colloidal gold, colloidal silver), the surface of a microtiter plate, the surface of a test tube, the surface of a glass slide.
  • the solid phase may be used to support at least one antibody used to detect the target of interest
  • PIGF protein or degradation product thereof qualitatively or quantitatively the presence of PIGF protein or degradation product thereof, or the presence of any biological molecule or product that may be indicative of PIGF expression, or degradation product thereof.
  • the amount of labelled antibody detected in the assay will then provide an indication of the level of PIGF in the pregnant female.
  • Any antibody, whether natural or synthetic or phage-display produced, full length or a fragment thereof, monoclonal or polyclonal, that binds sufficiently strongly and specifically to the PIGF to be detected, e.g., human PIGF, may be used in the immunoassay.
  • An antibody may have a Kd of at most about 10 "6 M, 10 "7 M, 10 "8 M, 10 "9 M, 10 "10 M, 10 "U M, 10 "12 M.
  • house keeping proteins or other proteins whose expression level do not vary may be used as internal controls and controls across experiments.
  • the control may be isolated PIGF purified protein and nucleotide sequences encoding for such a protein as set forth set forth in U.S. Patent no. 5,919,899 (Persico M et al .
  • the control samples may be standardized quantities of synthetic PIGF protein.
  • Housekeeping proteins, such as actin, from biological samples of the same type obtained from normal pregnant females based on maternal age, gestational age, matching prior medical history, same pre- exising medical or psychological conditions, blood type, ethnicity, racial background, genetic make-up, such as homogeneous genotype or phenotype, and environmental or sociological background may be used.
  • the expression level of PIGF present in a biological sample may be compared with one or a range of PIGF levels normally found in biological samples (of the same type) of normal pregnant females as set forth above.
  • pregnant females suspected of placental dysfunction or pre-eclampsia can be matched with normal pregnant females based on maternal age ( ⁇ 1, 2, 3, 4, 5 years) and gestational age ( ⁇ 1, 2, 3, 4, 5 weeks).
  • the female test patients may be matched with females recruited consecutively or from a heterogeneous population of women with suspected placental dysfunction or pre-eclampsia.
  • a control When comparing a PIGF level to a control level, a control may be a value that corresponds to the level of PIGF in a normal pregnant female's biological sample of the same type as that from which a sample was obtained.
  • a control may also be an average or mean value of at least 2, 5, 10 or more values of levels of PIGF in normal pregnant females.
  • a control may also be a value obtained from standardized measurement of synthetic PIGF protein, DNA, or RNA.
  • a normal control sample can also be a standard sample that contains the same concentration of PIGF that is normally found in a biological sample of the same type and that is obtained from a healthy pregnant female patient or a pregnant female who does not have placental dysfunction or pre-eclampsia.
  • the relative expression levels of P1GF may be normalized by the amount of the control in each lane, i.e., the value of the P1GF signal is divided by the value of the control signal.
  • P1GF protein expression may be considered to be elevated (and therefore predictive of a good prognosis) when the value of PIGF/control is more than 1, e.g., about 1.1 , 1.2, 1.3, 1.4, 1.5., 2, 2.5, 3, 5, 10, 30, 100 or depressed (and therefore predictive of an unfavorable prognosis) 0, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8.
  • a poor prognosis may be concluded from the presence of at least about 2 fold, 5 fold, 10 fold, 30 fold, 50 fold, 100 fold or less P1GF in the sample of the subject compared to the control value.
  • Higher or lower levels of P1GF in a sample from a pregnant female suspected of placental dysfunction or pre-eclampsia relative to a control value of a healthy pregnant female refers to a level that is statistically significant or significantly above or below levels found in the control value or tissue from the healthy pregnant female.
  • the term “statistically significant” or “significantly” refers to statistical significance and generally means a two standard deviation (2SD) above normal, or higher, concentration of the marker.
  • the levels of P1GF can be represented by arbritary units, for example as units obtained from a densitometer, luminometer, or an ELISA plate reader. Ratios or differences in number of units from a pregnant female's sample and number of units from a control sample, may be used to determine the prognosis, and subsequent treatment, of the patient from whom the samples were taken.
  • a pregnant female's prior measurements may be compared to her subsequent measurements.
  • the prior measurement in the same pregnant female may be any measurement made during the time period of about 9+0 to about 40+6 weeks, about 20+0 to about 40+6 weeks pregnant, or any increments thereof.
  • a value obtained from a pregnant female may be compared to other values, e.g., control values, present in computer readable form.
  • a value obtained from a pregnant female may be entered into an algorithm as illustrated in Figure 1 or a software program comprising one or more values, e.g., control values, and values from positive or negative placental dysfunction or pre-eclampsia, and a comparison can be effected by the software program.
  • a software program may also provide a conclusion based on the comparison. ii.
  • Methods diagnostic and prognostic of placental dysfunction or pre-eclampsia Measuring the protein levels of PIGF in a pregnant female suspected of having placental dysfunction or pre-eclampsia at various points in her pregnancy enables a caregiver to mitigate risk.
  • the method may be performed in a female suspected of having placental dysfunction or pre-eclampsia, who is between 20 to 40 weeks pregnant (i.e. 140- 280 days.
  • the assay is particularly informative when performed on subjects, who have been pregnant less than or equal to about 35 weeks (245 days)).
  • Any of the methods of the present invention may be utilized in a pregnant female who is less than or equal to about 40+6 weeks pregnant, a pregnant female who is between about 9+0 to about 40+6 weeks pregnant, or any increments thereof.
  • a PIGF level of less than or equal to about 25 pg/mL indicates that the female has severe placental dysfunction or pre-eclampsia and thus an increased likelihood of preterm delivery. The female risks a worsening of disease progression and an adverse outcome preterm. A future measurement of PIGF should be scheduled. For example, a female whose PIGF level is 25 pg/mL or less may have her PIGF level re -measured every day from the date of the first measurement- particularly if the female shows signs or symptoms of placental dysfunction or pre-eclampsia.
  • Pre-eclampsia signs and symptoms can include: proteinuria, new onset or worsening hypertension (pre-existing or gestational), scotomata, epigastric pain, fetal growth restriction and a small for gestational age (SGA) fetus.
  • a female whose PIGF level is 25 pg/mL or less, with or without pre-eclampsia signs and symptoms, may be monitored closely for the development of complications of preeclampsia, including HELLP syndrome, fetal growth restriction, stillbirth, eclampsia.
  • Such women are more likely to require anti-hypertensive therapy, anticonvulsants, steroids, or magnesium sulphate.
  • the patient may be treated with pre-term delivery, to reduce the risk of such pregnancy complications.
  • a PIGF level of about 26 pg/mL to about 79 pg/mL indicates that the female may have placental dysfunction or pre-eclampsia and thus a potentially increased likelihood for pregnancy complications, as described above, and for preterm delivery.
  • the female's PIGF level may be re-measured, for example every fourth day from the date of the first measurement to assess disease progression and severity, and to determine the likely time of required preterm delivery.
  • a PIGF level of about 80 pg/mL or higher indicates that the female does not have placental dysfunction or pre-eclampsia, that her signs and symptoms are likely to be from other causes, and is unlikely to progress to delivery within 14 days after the test.
  • the PIGF level of this female may be measured once every week or once every other week after the date of the first measurement to detect onset of disease.
  • Re -measurement of PIGF levels may be performed after successive incremental days, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, etc. days after the first measurement.
  • Any of the methods presented herein may comprise a PIGF level ranging from successive increments of 0 pg/mL to about 3000 pg/mL.
  • a measured amount of PIGF in the sample of less than or equal to 25 pg/mL may indicate a 94% positive predictive value for pre-term delivery.
  • a measured amount of PIGF in the sample of greater than 80 pg/mL may indicate a 96% positive predictive value that delivery will not occur within the next 14 days.
  • a high level of PIGF expression such as 80 pg/mL or higher, may be indicative of a good prognostic outlook and a greater potential for no placental dysfunction or pre- eclampsia, while a very low or undetectable level, such as from 0 pg/mL to about 25 pg/mL, may be indicative of a poor prognostic outlook and a greater potential for an adverse outcome.
  • An intermediate level of PIGF expression such as from about 26 pg/mL to about 80 pg/mL, may be indicative of placental dysfunction or pre-eclampsia.
  • a fold decrease ranging from about a 2- to about a 70- fold difference from the first to second, second to third, third to fourth, fourt to fifth, etc. measurement may indicate presence of or worsening placental dysfunction, confirming the suspicion of a diagnosis of pre-eclampsia and indicating an increased likelihood for preterm delivery, or any complication of placental dysfunction.
  • placental dysfunction may absence of placental dysfunction, removing the suspicion of a diagnosis of pre-eclampsia and indicating a reduced likelihood for preterm delivery, delivery within 14 days, or any complication of placental dysfunction.
  • a decrease of PIGF in a pregnant female indicates that the female has an increased risk of developing placental dysfunction, pre-eclampsia, fetal growth restriction, or worsening placental dysfunction, pre-eclampsia, fetal growth restriction, and is susceptible to an adverse outcome preterms
  • An increase of PIGF in a pregnant female indicates that the female has a lower risk of developing placental dysfunction, pre- eclampsia, fetal growth restriction, or worsening placental dysfunction, pre-eclampsia, fetal growth restriction, and is unlikely to be susceptible to an adverse outcome preterm.
  • P1GF levels may be monitored after a female is diagnosed with placental dysfunction or pre-eclampsia or fetal growth restriction and treated. For example, a reference reading can be taken before and after subsequent treatment, and subsequent readings taken at regular intervals.
  • a fall in P1GF level, greater than predicted by the expected level in a normal healthy pregnancy indicates that the treatment may be ineffective.
  • P1GF is less than or equal to about 25 mg/mL
  • An aggressive therapy may include bed rest, pre-term delivery, antihypertensive therapy, an agent that increases P1GF levels, or a combination thereof.
  • the treatment may then be followed by monitoring of P1GF levels using any of the
  • the methods described herein when used alone or in conjunction with other clinical information can not only aid in the diagnosis of placental dysfunction, but also aid in the prognosis of, for example, preterm pre-eclampsia, severe, mild, superimposed preeclampsia, fetal growth restriction, and to determine whether a more conservative or radical approach to therapy should be taken.
  • P1GF levels may be measured in conjunction with other diagnostic information or medical history of the pregnant female.
  • the female also tests positive for proteinuria, hypertension, scotomata, epigastric pain, fetal growth restriction, low estimated fetal weight, small for gestational age (SGA), altered maternal blood chemistry (including but not limited to hyperuricaemia, low platelets, raised plasma transaminases, chronic proteinuria) or risk factors for the development of placental dysfunction and pre-eclampsia including anti-phospholipid syndrome, first pregnancy, chronic HTN disease, diabetes, renal disease, and protein S deficiency.
  • SGA small for gestational age
  • the methods of the present invention may be used in conjunction with determining the presence or level of other prognostic factors selected from the group consisting of anti-angiogenic factor, angiogenic factor, creatinine, aspartate transaminase, soluble fms-like tyrosine kinase-1, BNP, NGAL, soluble Endoglin, or vascular endothethial growth factor using the methods of the present invention set forth above. Incorporation by reference
  • Alere Triage® P1GF Test and related test devices may be obtained and operated based on the manufacturer's instructions. Briefly, the test procedure involves the addition of several drops of an EDTA anticoagulated plasma specimen to the sample port on the Alere Triage® Test Device. After addition of the specimen, the specimen reacts with fluorescent antibody conjugates and flows through the Test Device by capillary action. Complexes of the fluorescent antibody conjugate are captured on a discrete zone, which comprises a second antibody specific to the analyte. The assay thus follows the principles of a sandwich immunoassay. The Test Device is inserted into the Alere Triage ® Meter (hereafter referred to as Meter). The Meter is programmed to perform the analysis after the specimen has reacted with the reagents within the Test Device.
  • Meter the Alere Triage ® Meter
  • the analysis is based on the amount of fluorescence the Meter detects within a measurement zone on the Test Device.
  • the concentration of the analyte in the specimen is directly proportional to the fluorescence detected.
  • the results are displayed on the Meter screen in approximately 15 minutes from the addition of specimen. All results are stored in the Meter memory to display or print when needed. If connected, the Meter can transmit results to the lab or hospital information system.
  • P1GF 12-3000 pg/mL. Values below 12 pg/mL are reported as ⁇ 12 pg/mL. Values above the measurable range are reported as > 3000 pg/mL.
  • Hook effect was evaluated using samples containing P1GF concentrations significantly higher than the upper limit of the measurable range. No hook effect was observed up to 15,000 pg/mL.
  • compositions The following drugs, Atenolol, Magnesium Sulfate, and Nifedipine, were evaluated for potential cross-reactivity and interference using the methods provided in CLSI EP7-A. Each drug was added to a plasma pool containing approximately 98 pg/mL PIGF. Each drug was tested at the concentration recommended by CLSI EP7-A or at a concentration at least equivalent to the maximum therapeutic level. None of the drugs influenced the accuracy of measurement of the PIGF concentration.
  • Proteins The following proteins were tested for analytical specificity:
  • Plasma samples were obtained from 287 pregnant women recruited into a multi- center, prospective serial sample collection study. Of these, 247 women met inclusion criteria (no diagnosis of pre-eclampsia and no maternal, fetal, or neonatal adverse outcome). The total number of samples collected was 1366 over up to six serial draws per subject, sampled at three to five week intervals from 20+0 to 40+6 weeks' gestation.
  • SGA Small for gestational age
  • the distributions of PIGF concentrations within each gestational age (GA) interval were characterized by percentiles as shown in Table 4, below. Table 4. Normal reference range percentiles of PIGF by GA interval.
  • Plasma samples were obtained from 625 pregnant women with suspected preeclampsia recruited into a multi-center, prospective study. Study inclusion criteria were age 16 years or greater, pregnancy between 20+0 and 40+0 weeks gestation, and signs, or symptoms of pre-eclampsia. Women with 3 or more viable fetuses at the time of enrollment were excluded. Written informed consent was required for all study participants. Plasma samples were collected at the time of study enrollment, upon first suspicion of preeclampsia. Samples were frozen and shipped to a central laboratory where they were subsequently tested on a single lot of Alere Triage® PIGF. There were 287 (out of 625) pregnant women with suspected pre-eclampsia who presented prior to 35+0 weeks of gestation.
  • Diagnosis of atypical forms of pre-eclampsia required a combination of features to co-exist with proteinuria or hypertension, including maternal laboratory biochemistry abnormalities, fetal growth restriction, or the presence of new onset and persistent symptoms (e.g., severe headache and/or scotomata and/or epigastric pain and/or right upper quadrant pain).
  • Women with isolated SGA, mild gestational hypertension, isolated chronic hypertension, isolated gestational proteinuria or chronic proteinuria, or transient hypertension did not meet criteria for traditional or expanded definitions of pre-eclampsia.
  • the Receiver Operator Characteristic (ROC) curve for diagnosis of preterm preeclampsia is shown in Figure 3 for pregnant women presenting prior to 35+0 weeks of gestation (167 Non-PE versus 120 PE).
  • the AUC is 0.862 (95%CI 0.818, 0.907).
  • the ROC curve shows one cutoff of 100 pg/mL, which is constant and independent of gestational age. Diagnostic performance is evaluated at this cutoff (P1GF ⁇ 100 pg/mL, Test Positive) (results in Table 9).
  • Table 9 The Receiver Operator Characteristic
  • the sensitivity and specificity of P1GF with a cutoff of 100 pg/mL for a diagnosis of preterm pre-eclampsia was 90.0% (108 of 120) and 65.3%> (109 of 167), respectively, with an NPV of 90.1% (109 out of 121 women with P1GF > 100 pg/mL did not have preterm pre-eclampsia).
  • P1GF results ⁇ 100 pg/mL are considered abnormal and suggestive of patients with placental dysfunction and, in conjunction with other signs and symptoms, support a diagnosis of preterm pre-eclampsia.
  • Prognostic performance of P1GF was evaluated prospectively for delivery within a 14-day interval of P1GF evaluation in women presenting prior to 35+0 weeks of gestation.
  • Kaplan-Meier survival curves in Figure 4 show the proportion of women undelivered as a function of gestational age (weeks) for the three discrete categories of PIGF concentration.
  • a Cox proportional hazards model was fit to this data to predict the time interval between sample collection (at presentation) and delivery up to 14 days after sample collection. Delivery beyond 14 days was censored and hazard ratios were calculated relative to the reference group (PIGF High) also adjusted for the gestational age at sample collection (which was not statistically significant). The adjusted hazard ratios were 6.78 (95%CI 2.59, 17.71) and 26.94 (95%CI 10.69, 67.86) for PIGF Medium and Low, respectively.
  • Prognostic performance is evaluated at both the lower cutoff (PIGF Low) and the upper cutoff (PIGF High) (results in Table 10).
  • Prognostic Performance (Clinical Sensitivity, Specificity, NPV, and PPV with 95% confidence intervals) for prognosis of delivery within 14 days of presentation and preterm in women presenting prior to 35+0 weeks of gestation. Two cutoffs are evaluated, PIGF ⁇ 12 pg/mL (PIGF Low, Test Positive) and PIGF > 100 pg/mL (PIGF High, Test Negative).
  • the PPV for preterm delivery was 94.2% (65 of 69 women with PIGF ⁇ 12 pg/mL delivered preterm).
  • the NPV for delivery within the next 14 days was 95.9% (116 of 121 with PIGF >100 pg/mL did not deliver within the next 14 days).
  • the NPV improved to 97.5% (118 of 121 women with PIGF >100 pg/mL) when considering the more restrictive endpoint of preterm PE delivered within 14 days.
  • PIGF results ⁇ 12 pg/mL are considered highly abnormal and suggestive of patients with severe placental dysfunction and at increased likelihood for preterm delivery.
  • PIGF results of > 100 pg/mL are considered normal and suggestive of patients without placental dysfunction and unlikely to progress to delivery within 14 days of the test.
  • New onset hypertension 32+6 120/73
  • Return 37+3 121/81
  • New onset proteinuria 32+6 (2+, 330mg 24h)
  • TTD time to delivery
  • Example 7 Comparative Studies of the Alere Triage® PIGF test to other PIGF tests
  • Figure 5 shows a comparison of the Alere Triage® PIGF test to the Roche Elecsys® PIGF test.
  • the Roche assay was unable to correctly diagnose preeclampsia.
  • Alere Triage® had higher sensitivity, without loss of specificity, in the diagnosis of early onset preeclampsia compared to Elecsys®.
  • Figure 6 showing a comparison of the Alere Triage® P1GF test (plasma) to the Perkin Elmer Delfia Xpress P1GF (serum).
  • Alere Triage® had higher sensitivity, without loss of specificity, than the Perkin Elmer Delfia test.
  • the Triage assay reports lower levels of P1GF in women with placental dysfunction or its complications, pre-eclampsia and intrauterine growth restriction.
  • the Roche Elecsys or Perkin Elmer Delfia assay provide disease discrimination sufficient to enable accurate risk discrimination adequate for clinical management.
  • the Alere Triage test categorises pregnant women with suspected placental dysfunction and pre-eclampsia into low, medium, high risk groups sufficient to direct clinical management.
  • Alere Triage® P1GF accurately identifies women with pre-eclampsia before 34+6 weeks.
  • PIGF pg/ml 334 (203-289) 248 (73-531) 256 (130-781)
  • Figueras (Figueras F., et al. Abstract submitted for FIGO 2012)
  • Example 8 Evaluation of PIGF in women presenting between 35 and 37 weeks gestation with suspected preeclampsia
  • PIGF The analytical performance of PIGF was further evaluated using samples collected from women presenting at clinic between 35+0 and 37+0 weeks of gestation, with suspected preeclampsia. Data from a ROC curve for prognosis of preterm delivery resulting from suspected or confirmed pre-eclampsia in women presenting between 35+0 and 37+0 weeks of gestation (expanded definition, delivering prior to 40+0 weeks) is shown in the following table.
  • the data indicate that where the measured level of PIGF is > 100 pg/mL, the probability of preterm delivery following measurement of PIGF is low: (i) 97% of women with PIGF >100 pg/mL are unlikely to experience preterm delivery; and (ii) 97% of women with a diagnosis of pre-eclampsia requiring preterm delivery have PIGF ⁇ 100 pg/mL, thereby providing assurance to the clinician that women with PIGF >100 pg/mL do not have placental dysfunction, do not have preterm pre-eclampsia, and are unlikely to suffer from a pregnancy complication associated with these conditions.

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Abstract

La présente invention se rapporte à des procédés permettant de déterminer un dysfonctionnement placentaire chez une femme pour laquelle on suspecte un dysfonctionnement placentaire ou une pré-éclampsie par évaluation de l'expression du facteur de croissance du placenta P1GF dans un échantillon biologique d'une patiente qui est enceinte de moins de 35 semaines. De même, la présente invention se rapporte à des procédés permettant d'établir un pronostic pour une future complication associée à la grossesse d'une femme pour laquelle on suspecte un dysfonctionnement placentaire et qui est enceinte de moins de 35 semaines. L'invention se rapporte en outre à des procédés permettant de gérer et d'atténuer les risques des femmes enceintes pour lesquelles on suspecte un dysfonctionnement placentaire ou une pré-éclampsie afin de surveiller l'état de santé et le bien-être du bébé et de la maman. Lesdits procédés peuvent être utilisés au moment de l'évaluation initiale pour diagnostiquer une suspicion de dysfonctionnement placentaire ou de pré-éclampsie afin d'identifier un groupe de femmes enceintes souffrant d'un dysfonctionnement placentaire ou de pré-éclampsie et afin de déterminer la probabilité de développer des complications en cas de dysfonctionnement placentaire ou de pré-éclampsie. Par conséquent, les procédés peuvent non seulement fournir des informations de pronostic très utiles pour les patientes mais également aider les cliniciens à sélectionner une patiente enceinte candidate pour avoir des chances de bénéficier d'une prise en charge thérapeutique de la pré-éclampsie précoce et sévère.
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RU2707095C1 (ru) * 2019-03-27 2019-11-22 Федеральное государственное бюджетное научное учреждение "Дальневосточный научный центр физиологии и патологии дыхания" Способ диагностики степени тяжести хронической плацентарной недостаточности у серопозитивных к цитомегаловирусу женщин

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