Predictive test for pre-eclampsia

Details Predictive test for pre-eclampsia Predictive test for pre-eclampsia

2001-06-06

2004-05-11

Brusca, John S. (Department: 1631)

Data processing: measuring, calibrating, or testing

Measurement system in a specific environment

Biological or biochemical

C424S009100

Reexamination Certificate

active

06735529

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a test which can be used to predict pre-eclampsia in pregnant women.
2. Related Art
Pre-eclampsia is a disorder of human pregnancy. Which affects around 5 to 10% of pregnancies. The underlying cause of pre-eclampsia remains unclear in spite of extensive clinical and basic research. Pre-eclampsia is the definition given to the condition in pregnancy in which elevated blood pressure is associated with proteinuria. Pre-eclampsia is distinct from eclampsia which is additionally associated with convulsions. Pre-eclampsia is defined in Souhami & Moxham
Textbook of Medicine
, Second edition, Churchill Livingstone (1994), as an abnormal rise in blood pressure between the first and second halves of pregnancy of ≦30/20 mmHg, with abnormal urate levels of >0.35 mmol/l at 32 weeks or >0.4mmol/l thereafter, associated with proteinuria, impaired renal function and clotting disorders. The consequences of pre-eclampsia are serious and include reduced uteroplacental perfusion, foetal growth retardation, pre-term birth, and increased foetal and maternal morbidity and mortality.
There have been many attempts to provide a reliable predictive test for pre-eclampsia. Previous suggestions have involved assays for the levels of circulating biochemical markers in the mother's blood but to date the scientific literature on this issue is contradictory and inconclusive. The following hormones have all been identified as possible markers in an elevation of levels might be predictive of pre-eclampsia in maternal plasma: progesterone, oestradiol, total human chorionic gonadotrophin (hCG), corticotrophin-releasing factor (CRF), adrenocorticotrophin (Muller et al
Am. J. Obst. Gynecol
. 175 37-40 (1996); Ashour et al
Am. J. Obst. Gynecol
. 176 438-444 (1997); Hsu et al
Am. J. Obst. Gynecol
. 170 1135-1138 (1994); Wenstrom et al
A. J. Obst. Gynecol
. 171 1038-1041 (1994)). Conversely, levels of oestriol, human placental lactogen and cortisol are unchanged or decreased. Whilst circulating CRF has been proposed as a prognostic marker for pre-eclampsia, treatment of hypertension does not influence maternal CRF levels and nor has any correlation been found between CRF levels and mean blood pressure.
Other possible markers which have been suggested are Activin A and Inhibin A. Activin is a hypophysiotrophic factor produced by the placenta which is know to act as a growth factor having activity in modulating cell growth and differentiation. Currently, there are three forms of activin which are recognised to exist as homodimeric proteins: Activin A (&bgr;
A
&bgr;
A
). Activin AB (&bgr;
A
&bgr;
B
) and Activin B (&bgr;
B
&bgr;
B
) in which the subunits are linked by disulphide bridges. Inhibins are heterodimeric proteins consisting of &agr;&bgr;
A
(Inhibin A) and &agr;&bgr;
B
(Inhibin B) subunits also linked by disulphide bridges. Additionally monomeric Inhibin &agr; subunits are present in the circulation and follicular fluid. Inhibin is thought to have an endocrine role which inhibits pituitary production of follicle-stimulating hormone (FSH). Muttikrishna et al (
The Lancet
349 1285-1288 (1997)) have proposed that Activin A and Inhibin A might be suitable markers for the onset of pre-eclampsia. These proteins were suggested because they were thought to be more sensitive markers than hCG or corticotrophin-releasing hormone where there is a considerable overlap in elevated hormone levels between control and pre-eclamptic women.
BRIEF SUMMARY OF THE INVENTION
However, it has now been found that a predictive test for pre-eclampsia which is based on levels of free &bgr;-human chorionic gonadotrophin (free &bgr;-hCG) and Inhibin A can in fact provide a surprisingly improved level of predictiveness over previously known tests. The present invention describes a system of screening for pre-eclampsia, in which a single risk estimate is derived from measurements carried out on biochemical samples obtained during pregnancy.
DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect of the invention there is provided a method of predicting the risk of pre-eclampsia in a pregnant woman, the method comprising the steps of:
(a) obtaining a sample of blood from the woman;
(b) subsequently assaying the sample for the levels of free &bgr;-human chorionic gonadotrophin (free &bgr;-hCG) and Inhibin A present in the sample; and
(c) determining the risk of pre-eclampsia using the measured levels of free &bgr;-human chorionic gonadotrophin (free &bgr;-hCG) and Inhibin A present in the sample.
Methods according to the present invention are carried out ex vivo. In the step (a), the sample of blood may be collected by any suitable means from the pregnant woman. The species free &bgr;-human chorionic gonadotrophin (free &bgr;-hCG) is distinct from the intact or total form of the molecule which is referred to simply as hCG or total hCG. The assay of the sample in step (b) for the levels of free &bgr;-human chorionic gonadotrophin (free &bgr;-hCG) and Inhibin A present in the sample may be carried out using standard protocols e.g. those based on ELISA (Enzyme-Linked ImmnoSorbent Assay) or RIA (RadioImmunoAssay), or commercially available kits, e.g. free &bgr;-human chorionic gonadotrophin (free &bgr;-hCG) can be measured using the solid phase, two site fluoroimmunometric assay based on a direct sandwich technique as described by Stevenson et al (
Ann. Clin. Biochem
. 30 99-100 (1993)) and Spencer et al (
Ann. Clin. Biochem
. 29 506-518 (1992)). Inhibin A can be measured according to the solid phase sandwich ELISA assay described by Groome et al (
J. Immunol. Methods
165 167-176 (1993);
Clin. Endocrinol
., 40 717-723 (i994)). In particular embodiments of the present invention, the assay may also comprise an analysis of the levels of unconjugated oestriol (uE
3
), which can be measured using the solid phase, time resolved fluoroimmunoassay described in U.S. Pat. No. 4,565,790 and U.S. Pat. No. 4,808,541. Additionally, since free &bgr;-hCG and total hCG are known to be highly correlated in pregnancy, total hCG may also be used as a screening marker for pre-eclampsia in a method according to the present invention as an alternative to free &bgr;-hCG. The intact hCG molecule (total hCG) can be measured directly using exactly the same method as for the free &bgr;-subunit with AFP, i.e. sold phase, two-site fluoroimmunometric assay based on a direct sandwich technique. Preferably, the markers used are free &bgr;-hCG and Inhibin A measured after 20 weeks of pregnancy, and particularly at the end of the second trimester and the beginning of the third trimester.
In step (c), the determination of the risk of pre-eclampsia can be undertaken by comparing the levels of free &bgr;-human chorionic gonadotrophin (free &bgr;-hCG) and Inhibin A present in the sample with those in a control sample, or the median level in a group of control samples, i.e. samples from unaffected pregnancies, to provide a prediction of the probability of the onset of pre-eclampsia in the woman. The determination of risk nay comprise deriving the likelihood ratio using a multivariate analysis based on distribution parameters from a set of reference data.
Calculation of risk from the measured marker levels is based on the observed relative frequency distribution of marker levels in (a) pre-eclamptic and (b) unaffected pregnancies. Any of the known statistical techniques may be used. Preferably the multivariate Gaussian model is used, which is appropriate where the observed distributions are reasonably Gaussian. Such multivariate Gaussian analysis is in itself known, for example from Wald N J, Cuckle H S, Densem J W, et al (1988); Maternal serum screening for Down's syndrome in early pregnancy. BMJ 297, 883-887 and Royston P, Thompson S G (1992); Model-based screening by risk with application to Down's syndrome. Stat Med 11, 256-268.
In a preferred method, two Gaussian heights are calculated, (a) one for the pre-eclamptic distribution and (b) the other for the u

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