PREDICTION OF RISK OF PRE-ECLAMPSIA

Abstract

A method of early detection of risk of pre-eclampsia in a pregnant woman comprises the steps of determining the blood pressure and body mass index (BMI) of the pregnant woman, and optionally sex of the fetus, at 8 to 24 weeks of pregnancy, comparing the BMI with a reference BMI, and comparing the blood pressure input with a reference blood pressure, and providing a risk of pre-eclampsia and in particular term or pre-term pre-eclampsia based on the comparison.

Claims

1. A method of screening a pregnant woman for risk of the pregnant woman subsequently developing pre-eclampsia and to differentiate the risks for developing preterm and term preeclampsia, comprising the steps of: determining the blood pressure and body mass index (BMI) of the pregnant woman and the sex of the fetus at 13 to 19 weeks of pregnancy, in which the fetal sex is determined by an in-vitro diagnostic method; comparing the BMI with a reference BMI; and comparing the blood pressure input with a reference blood pressure, wherein: when the woman exhibits blood pressure higher than the reference blood pressure, a BMI lower than the reference BMI, and the fetal sex is female, the woman is predicted to be at elevated risk of developing pre-term pre-eclampsia; and/or when the woman exhibits blood pressure higher than the reference blood pressure and a BMI higher than the reference BMI, and the fetal sex is male, the woman is predicted to be at elevated risk of developing term pre-eclampsia.

2. A method according to claim 1, in which the determined blood pressure is mean arterial pressure (MAP).

3. A method according to claim 1 or 2, in which the reference BMI is 25.

4. A method according to any preceding claim, in which the pregnant woman is considered low risk for developing pre-eclampsia.

5. A method according to any preceding claim, in which the BMI is compared with a reference BMI first to determine if the BMI is higher or lower than a reference BMI, wherein: when the BMI is determined to be higher than a reference BMI, a reference blood pressure for a high BMI pregnant woman (high BMI reference blood pressure) is employed in the blood pressure comparison step, and wherein when the BMI is determined to be lower than a reference BMI, a reference blood pressure for a low BMI pregnant woman (low BMI reference blood pressure) is employed in the blood pressure comparison step.

6. A method according to any preceding claim, in which the method employs a computer processor configured to: receive as inputs the blood pressure, BMI (or height and weight parameters) of the pregnant woman, and the sex of the fetus; optionally calculate the BMI from the height and weight parameter inputs; compare the BMI with a reference BMI; compare the blood pressure input with a reference blood pressure; and provide an output based on the comparison.

7. A method according to claim 6, in which the output based on the comparison comprises: when the blood pressure input is higher than the reference blood pressure, the calculated BMI is lower than the reference BMI, and the fetal sex is female, the output is that the pregnant woman is at elevated risk of subsequently developing pre-term pre-eclampsia; and/or when the blood pressure input is higher than the reference blood pressure, the calculated BMI is higher than the reference BMI, and the fetal sex is male, the output is that the pregnant woman is at elevated risk of subsequently developing term pre-eclampsia.

8. A system to determine risk of pre-eclampsia in a pregnant woman and to differentiate the risks for developing preterm and term preeclampsia, comprising a computer processor configured to: receive as inputs the blood pressure and body mass index (BMI) of the pregnant woman at 13 to 19 weeks of pregnancy, compare the BMI with a reference BMI; comparing the blood pressure input with a reference blood pressure, and output a risk of term or pre-term pre-eclampsia based on the comparison, wherein: when the woman exhibits blood pressure higher than the reference blood pressure and a BMI lower than the reference BMI, the output is a prediction of an elevated risk of the pregnant woman subsequently developing pre-term pre-eclampsia; when the woman exhibits blood pressure lower than the reference blood pressure and a BMI lower than the reference BMI, the output is a prediction that the pregnant woman is not at elevated risk of subsequently developing pre-term pre-eclampsia; when the woman exhibits blood pressure higher than the reference blood pressure and a BMI higher than the reference BMI, the output is a prediction of an elevated risk of the pregnant woman subsequently developing term pre-eclampsia; or when the woman exhibits blood pressure lower than the reference blood pressure and a BMI higher than the reference BMI, the output is a prediction that the pregnant woman is not at elevated risk of subsequently developing term pre-eclampsia.

9. A system according to claim 8, in which the computer processor is configured to receive the height and weight of the pregnant woman and calculate the BMI of the pregnant woman.

10. A system according to claim 8 or 9, in which the computer processor is configured to: compare the BMI of the pregnant woman with a reference BMI to determine if the BMI of the pregnant woman is higher or lower than a reference BMI, and: when the BMI is determined to be higher than a reference BMI, compare the blood pressure of the pregnant woman with a reference blood pressure for a high BMI pregnant woman; or when the BMI is determined to be lower than a reference BMI, compare the blood pressure of the pregnant woman with a reference blood pressure for a low BMI pregnant woman.

11. A system according to any of claims 8 to 10, in which the computer processor is configured to: receive as an additional input the fetal sex, compare the BMI with a reference BMI; comparing the blood pressure input with a reference blood pressure, and output a risk of term or pre-term pre-eclampsia based on the comparison.

12. A system according to claim 11, in which: when the woman exhibits blood pressure higher than the reference blood pressure, a BMI lower than the reference BMI, and the fetal sex is female, the output is a prediction of elevated risk of the pregnant woman subsequently developing pre-term pre-eclampsia; and/or when the woman exhibits blood pressure higher than the reference blood pressure, a BMI higher than the reference BMI, and the fetal sex is male, the output is a prediction of elevated risk of the pregnant woman subsequently developing term pre-eclampsia.

13. A system according to any of claims 8 to 12, comprising a blood pressure measurement apparatus, height measurement apparatus, and weight measurement apparatus operatively coupled to the computer processor.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0081] FIG. 1: AU-ROC and box plots for cases and controls for all pregnant women

[0082] Prediction of All PE (FIG. 1A)

[0083] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop PE and women who will not develop PE later in their pregnancy.

[0084] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0085] Prediction of Preterm PE (FIG. 1B)

[0086] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0087] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0088] Prediction of Term PE (FIG. 1C)

[0089] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0090] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0091] FIG. 2: AU-ROC and box plots for cases and controls for low BMI pregnant women

[0092] Prediction of All PE (FIG. 2A)

[0093] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop PE and women who will not develop PE later in their pregnancy

[0094] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0095] Prediction of Preterm PE (FIG. 2B)

[0096] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0097] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0098] Prediction of Term PE (FIG. 2C)

[0099] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0100] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0101] FIG. 3: AU-ROC and box plots for cases and controls for high BMI pregnant women

[0102] Prediction of All PE (FIG. 3A)

[0103] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop PE and women who will not develop PE later in their pregnancy

[0104] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0105] Prediction of Preterm PE (FIG. 3B)

[0106] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0107] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0108] Prediction of Term PE (FIG. 3C)

[0109] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0110] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0111] FIG. 4: AU-ROC and box plots for cases and controls for pregnant women carrying a female fetus

[0112] Prediction of All PE (FIG. 4A)

[0113] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop PE and women who will not develop PE later in their pregnancy

[0114] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0115] Prediction of Preterm PE (FIG. 4B)

[0116] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0117] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0118] Prediction of Term PE (FIG. 4C)

[0119] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0120] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0121] FIG. 5: AU-ROC and box plots for cases and controls for pregnant women carrying a male fetus

[0122] Prediction of All PE (FIG. 5A)

[0123] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop PE and women who will not develop PE later in their pregnancy

[0124] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0125] Prediction of Preterm PE (FIG. 5B)

[0126] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0127] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0128] Prediction of Term PE (FIG. 5C)

[0129] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0130] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0131] FIG. 6: AU-ROC and box plots for cases and controls for low BMI pregnant women further stratified according to fetal sex

[0132] Prediction of Preterm PE in women carrying a female fetus (FIG. 6A)

[0133] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0134] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0135] Prediction of Preterm PE in women carrying a male fetus (FIG. 6B)

[0136] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0137] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0138] Prediction of Term PE in women carrying a female fetus (FIG. 6C)

[0139] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0140] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0141] Prediction of Term PE in women carrying a male fetus (FIG. 6D)

[0142] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0143] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0144] FIG. 7: AU-ROC and box plots for cases and controls for high BMI pregnant women further stratified according to fetal sex

[0145] Prediction of Preterm PE in women carrying a female fetus (FIG. 7A)

[0146] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0147] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0148] Prediction of Preterm PE in women carrying a male fetus (FIG. 7B)

[0149] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop preterm PE and women who will not develop PE later in their pregnancy

[0150] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing preterm PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0151] Prediction of Term PE in women carrying a female fetus (FIG. 7C)

[0152] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0153] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

[0154] Prediction of Term PE in women carrying a male fetus (FIG. 7D)

[0155] Receiver operating curve for MAP—If P is small (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore MAP has the ability to distinguish between women who will develop term PE and women who will not develop PE later in their pregnancy

[0156] Notched box and whisker graphs comparing the distribution of MAP in pregnant women not developing PE (0) and women developing term PE (1) later in their pregnancies. The central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median (in-box whiskers: 95% Cl for median). Whiskers: lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences).

DETAILED DESCRIPTION OF THE INVENTION

[0157] All publications, patents, patent applications and other references mentioned herein are hereby incorporated by reference in their entireties for all purposes as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference and the content thereof recited in full.

Definitions and General Preferences

[0158] Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

[0159] Unless otherwise required by context, the use herein of the singular is to be read to include the plural and vice versa. The term “a” or “an” used in relation to an entity is to be read to refer to one or more of that entity. As such, the terms “a” (or “an”), “one or more,” and “at least one” are used interchangeably herein.

[0160] As used herein, the term “comprise,” or variations thereof such as “comprises” or “comprising,” are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers. Thus, as used herein the term “comprising” is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.

[0161] As used herein, the term “disease” is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.

[0162] As used herein, the term “treatment” or “treating” refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s) (for example, the reduction in accumulation of pathological levels of lysosomal enzymes). In this case, the term is used synonymously with the term “therapy”.

[0163] Additionally, the terms “treatment” or “treating” refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term “prophylaxis”.

[0164] As used herein, an effective amount or a therapeutically effective amount of an agent defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition. The amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate “effective” amount in any individual case using routine experimentation and background general knowledge. A therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement. A therapeutic result need not be a complete cure.

[0165] In the context of treatment and effective amounts as defined above, the term subject (which is to be read to include “individual”, “animal”, “patient” or “mammal” where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; and rodents such as mice, rats, hamsters and guinea pigs. In preferred embodiments, the subject is a human.

[0166] Unless otherwise required by context, the use of the terms “AUROC” and “AUC” are used interchangeably herein.

[0167] As used herein, the term “at risk of developing pre-term pre-eclampsia” should be understood to mean a risk that is higher than the general population (or sub-population) of pregnant woman. Likewise, the term “at risk of developing term pre-eclampsia” should be understood to mean a risk that is higher than the general population (or sub-population) of pregnant woman. For a pregnant woman that is identified by the method or system of the invention as being at risk of term or pre-term PE, the level of risk increases proportionally with the elevation in blood pressure. Thus, the more the woman's blood pressure is elevated compared with the reference blood pressure, the greater the risk. Likewise, for a pregnant woman that is identified by the method or system of the invention as being not at risk of term or pre-term PE, the reduction of risk decreases proportionally with the elevation in blood pressure.

[0168] In one embodiment, the term implies an AUROC predictive performance of at least 0.65. In one embodiment, the term implies an AUROC predictive performance of at least 0.70. In one embodiment, the term implies an AUROC predictive performance of at least 0.75. In one embodiment, the term implies an AUROC predictive performance of at least 0.80. In one embodiment, the term implies an AUROC predictive performance of at least 0.85. In one embodiment, the term implies an AUROC predictive performance of at least 0.90.

[0169] As used herein, the term “early detection of risk of pre-eclampsia” means detection of risk prior to the appearance of symptoms of the syndrome, for example during the second trimester of pregnancy (or late first trimester or early third trimester), for example from 8 to 24 weeks, or from 10 and 22 weeks, and ideally about 16 weeks (+/−2 or 3 weeks) gestation. The term “early stage of pregnancy” means prior to the appearance of clinical symptoms of the syndrome, for example during the second trimester of pregnancy, for example from 8 to 24 weeks or from 10 to 22 weeks or from 11 to 19 weeks, and ideally about 16 weeks (+/−2, 3, 4 or 5 weeks).

[0170] A pregnant woman is diagnosed with preeclampsia when the woman has gestational hypertension (systolic BP≥140 mmHg and/or diastolic BP≥90 mmHg (Korotkoff V) on at least 2 occasions 4 h apart after 20 weeks' gestation, but before the onset of labour or postpartum systolic BP≥140 mmHg and/or diastolic BP≥90 mmHg on at least 2 occasions 4 h apart with any of the following new-onset conditions: [0171] proteinuria (≥300 mg/24 h or spot urine protein:creatinine ratio≥30 mg/mmol creatinine, or urine dipstick protein>=++). [0172] Other maternal organ dysfunction, including: Acute kidney Injury (creatinine>=90 micromol/L or >=1 mg/dL); Liver involvement (elevated transaminases, eg, alanine aminotransferase or aspartate aminotransferase>40 IU/L) with or without right upper quadrant or epigastric abdominal pain; Neurological complications (examples include eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, and persistent visual scotomata); Hematological complications (thrombocytopenia-platelet count; <150 000/μL, disseminated intravascular coagulation, hemolysis) [0173] Or Uteroplacental dysfunction (such as fetal growth restriction, abnormal umbilical artery [UA] Doppler wave form analysis, or stillbirth) [13].

[0174] As used herein, the term “pre-term pre-eclampsia” should be understood to mean, a pre-eclampsia diagnosis which is made pre-term, e.g. before (<) 37 weeks of gestation and which warrants for the pre-term delivery of the baby, e.g. before (<) 37 weeks of gestation.

[0175] As used herein, the term “term pre-eclampsia” should be understood to mean, a pre-eclampsia diagnosis which is made and whereby for delivery of the baby is term, e.g. at or after (≥) 37 weeks of gestation.

[0176] As used herein, the term “BMI” or “body mass index” as applied to a pregnant woman should be understood to mean the woman's height (m)×weight (kg) taken early in pregnancy, e.g. at 8-24 weeks pregnancy.

[0177] As used herein, the term “reference BMI” should be understood to mean an average BMI for pregnant women in a given population. For European women, this would be 25.

[0178] As used herein, the term “blood pressure” may be maternal diastolic or maternal systolic blood pressure, or mean arterial pressure (MAP) which is estimated as follows: MAP=[⅔ (diastolic bp)+⅓ (systolic bp)].

[0179] As used herein, the term “reference blood pressure” should be understood to mean an average blood pressure for pregnant women in a given population. The methods and systems of the invention may optionally use a reference blood pressure for all pregnant women, a sub-population of pregnant women, or a reference blood pressure for high BMI pregnant women (i.e. when the pregnant woman is determined to have a high BMI) or a reference blood pressure for low BMI pregnant women (i.e. when the pregnant woman is determined to have a low BMI).

[0180] As used herein, the term “fetal sex” refers to the sex of the fetus carried by the pregnant woman. Fetal sex is generally determined early in pregnancy, at or around the same time as the BMI and blood pressure is determined. Fetal sex can be established by ultrasound.

[0181] Ultrasound has been the traditional method used for fetal sex determination. In the second and third trimesters, it is accurate in >99% of cases with normal genitalia. Early ultrasound (12-14 weeks) is also a reliable option when performed at specialized centers. Invasive testing, either using chorionic villus sampling from 11 weeks or amniocentesis from 15 weeks is also an option. More preferably, fetal sex can be determined by fetal sex determination using cell-free fetal DNA as available in the maternal blood stream during pregnancy, for example using, but not limited to, DNA sequencing or PCR technology. In one embodiment, the fetal sex is determined by an in-vitro diagnostic method.

[0182] As used herein, the term “pre-eclampsia drug” refers to a therapeutic intervention for pregnant women to prevent development of pre-eclampsia typically during the second or third trimester of pregnancy. An Example of therapeutic intervention for preterm pre-eclampsia includes Aspirin. Examples of therapeutic intervention for term pre-eclampsia and/or preeclampsia in the high bmi group include: Low Molecular Weight Heparin; Restriction of weight gain by either caloric intake reduction or life style changes; Interventions to lower the glycemic index, including but not restricted to, insulin, glycemic index lowering probiotics; Citrulline; Antioxidants, including but not limited to, antioxidant vitamins (e.g., ascorbic acid, -tocopherol, -carotene), inorganic antioxidants (e.g., selenium), and a plant-derived polyphenols, antioxidants to mitochondria, including but not limited to, Mito VitE and ergothioneine; statins, including but not limited to, Pravastin. Therapies involving the use of anti-inflammatory or immunosuppressive agents like, but not limited to, tacrolimus, or sulfalazine. In addition, one can easily envision preferred therapeutic combinations like, but not limited to, aspirin and metformin; or metformin and sulfalazine.

[0183] As used herein, the term “metformin treatment” refers to treatment with Metformin (GLUCOPHAGE) or a combination therapy comprising Metformin and an addition drug, for example aspirin, thiazolidinediones, DPP-4 inhibitors, sulfonylureas, and meglitinide.

[0184] The embodiments in the invention described with reference to the drawings comprise a computer apparatus and/or processes performed in a computer apparatus. However, the invention also extends to computer programs, particularly computer programs stored on or in a carrier adapted to bring the invention into practice. The program may be in the form of source code, object code, or a code intermediate source and object code, such as in partially compiled form or in any other form suitable for use in the implementation of the method according to the invention. The carrier may comprise a storage medium such as ROM, e.g. CD ROM, or magnetic recording medium, e.g. a floppy disk or hard disk. The carrier may be an electrical or optical signal which may be transmitted via an electrical or an optical cable or by radio or other means.

Exemplification

[0185] The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only: they are not intended to be limiting in any way to the scope of the monopoly claimed or to the invention described. These examples constitute the best mode currently contemplated for practicing the invention.

[0186] In a cohort of case-control study constituting 1336 pregnant women, blood pressure measurements were taken early in pregnancy. Within this group, 123 women developed preeclampsia and 1213 did not. The 1231 who did not develop preeclampsia were a representative cross-section of all other pregnancies: other complications of pregnancy like spontaneous preterm birth, gestational diabetes, fetal growth restriction etc. . . . occurred in the control group. From the 123 women who developed preeclampsia, 32 developed preterm preeclampsia and 91 did develop term preeclampsia. The pregnancy population considered was deemed “low risk” for developing preeclampsia from a clinical perspective: the following women were excluded from the study: women with essential hypertension treated pre-pregnancy, women who had moderate-severe hypertension at booking (BP>160/100 mmHg), i.e., the first time they were seen in their pregnancies; women with diabetes, women with renal disease, women with systemic Lupus Erythematosus. Women with Anti-phospholipid syndrome, women with sickle cell disease, women who were treated with low-dose aspirin or heparin/low molecular weight heparin, women with a previous pregnancy.sup.4.

[0187] Other characteristics of the study population are summarised in below Table 1:

TABLE-US-00001 Controls (Non-PE) PE Number N = 1213 N = 123 Maternal Age, Yrs Mean (SD) 29.591 (4.499) 29.837 (4.866) median (Q1, Q3) 30.00 (27.00, 33.00) 30.00 (26.00, 33.00) BMI missing data (n) 2 — Mean (SD) 24.879 (4.116) 26.486 (4.660) median (Q1, Q3) 24.000 (22.000, 26.900) 25.700 (22.900, 29.700) bmi < 25 (n, (%))/bmi >= 25 (n, (%))    733 (60.53)/478 (39.47%) 55 (44.72%)/68 (55.28)   bmi < 30 (n, (%))/bmi >= 30 (n, (%)) 1076 (88.85%)/135 (11.15%) 91 (78.86%)/26 (21.14%) Fetal Sex data unavailable (n, (%)) 16 (1.32%) — Female Fetus (n, (%)) 563 (46.41%) 56 (45.53%) Male Fetus (n, (%)) 634 (52.27%) 67 (54.47%) 2.sup.nd MAP (mm Hg) mean (SD) 83.719 (7.862) 89.509 (8.912) median (Q1, Q3) 83.000 (78.333, 88.667) 89.000 (83.667, 95.167) Delivery (weeks) Mean (SD) 39.837 (2.006) 37.780 (3.399) median (Q1, Q3) 40.286 (39.143, 41.000) 38.857 (36.857, 40.00) Preterm Delivery (n, ((%) 61 (5.03%) 32 (26.02%) Preterm PE Term PE Number N = 32 N = 91 Maternal Age, Yrs Mean (SD) 30.343 (5.147) 29.6593 (4.780) median (Q1, Q3) 30 (27.00, 32.25) 30 (26.00, 33.00) BMI missing data (n) — — Mean (SD) 26.334 (3.530) 26.540 (5.014) median (Q1, Q3) 26.450 (23.450, 28.475) 25.500 (22.750, 29.700) bmi < 25 (n, (%))/bmi >= 25 (n, (%)) 13 (40.63%)/19 (59.38)  42 (46.15%)/49 (53.85%) bmi < 30 (n, (%))/bmi >= 30 (n, (%)) 26 (81.25%)/6 (18.75%) 71 (78.02%)/20 (21.98%) Fetal Sex data unavailable (n, (%)) — — Female Fetus (n, (%)) 12 (37.5%) 44 (48.35%) Male Fetus (n, (%)) 20 (62.5%) 47 (51.65%) 2.sup.nd MAP (mm Hg) mean (SD) 90.521 (8.352) 89.154 (9.118) median (Q1, Q3) 88.83 (85.250, 95.750) 89.000 (83.500, 95.000) Delivery (weeks) Mean (SD) 33.103 (3.228) 39.425 (1.247) median (Q1, Q3) 34.00 (31.857, 35.857) 39.429 (38.429, 40.429) Preterm Delivery (n, ((%) 32 (100%) 0 (0%) Preeclampsia was diagnosed as follows: Preeclampsia (PE) was defined as gestational hypertension (systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg (Korotkoff V) on at least 2 occasions 4 h apart after 20 weeks' gestation, but before the onset of labour or postpartum systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg on at least 2 occasions 4 h apart with proteinuria (≥300 mg/24 h or spot urine protein:creatinine ratio ≥ 30 mg/mmol creatinine, or urine dipstick protein > = ++)

[0188] At about 15 weeks of gestation (14+0 to 16+6 weeks'), the following maternal measurements were performed: weight, height, blood pressure and entered in a database. A pregnant woman's status at the time of delivery was also recorded in a database. Information about pregnancy complications will also be recorded. All participants who developed pre-eclampsia had detailed clinical, laboratory and outcome data collected. All women consented to be part of this study..sup.4

[0189] Fetal sex can be established by ultrasound. Ultrasound has been the traditional method used for fetal sex determination. In the second and third trimesters, it is accurate in >99% of cases with normal genitalia..sup.5 Early ultrasound (12-14 weeks) is also a reliable option when performed at specialized centers..sup.6 Invasive testing, either using chorionic villus sampling from 11 weeks or amniocentesis from 15 weeks is also an option.sup.7,8. More preferably, fetal sex can be determined by fetal sex determination using cell-free fetal DNA as available in the maternal blood stream during pregnancy, for example using, but not limited to, DNA sequencing or PCR technology.sup.9,10.

[0190] The discriminative performance of Mean Arterial Pressure (MAP) was quantified using the area under the receiver operating curve (AUROC).sup.11. An AUROC of 0.5 or lower indicates an absence of predictive power for the outcome. The exact Binomial Confidence Interval for the Area Under the Curve was calculated. Mean Arterial Pressure is considered a predictor if its AUROC was significantly higher than 0.5 (p<0.05). The Mean Arterial Pressure as calculated from the second set of blood pressure measurements taken is used. In total there were three set of blood pressure measurements taken, each consisting out of a diastolic and systolic reading. Mean Arterial Pressures as calculated from the 1.sup.st, 2.sup.nd and 3.sup.rd readings did not differ significantly; the Mean Arterial Pressure as calculated from the 2.sup.nd set of blood pressure readings was therefore arbitrarily taken for reporting.

[0191] The added value of refining pre-eclampsia prediction by sub-typing the pregnancy in terms of the maternal characteristic “BMI”, or/and the fetal characteristic “fetal sex” and sub-typing the pre-eclampsia outcome in terms of gestational age at pre-eclampsia indicated delivery was quantified by calculating the absolute difference in AU ROC for preeclampsia prediction in the sub-types created, whereby the following criteria were applied [0192] Absolute Delta AUROC>=0.1: distinct added value of sub-typing (bold in tables) [0193] 0.1>Absolute Delta AUROC>=0.05: some added value of sub-typing (Italic in tables)

[0194] From the following table 2 (FIG. 1), it is clear that the classic risk predictor blood pressure (MAP) has some predictive performance for predicting preeclampsia in this population [AUROC=0.69]; as well known. When assessing the predictive performance of MAP to predict either outcome sub-types preterm PE or term PE in the whole population, the predictive performance remains largely the same; only some minor prediction refinement is achieved (cf. Delta AUROC=0.05) However, when one uses the height (in meter) and weight (in kg) to calculate the pregnant woman's BMI, and uses this information to classify women in either a low BMI group or a high BMI group, blood pressure allows to differentially predict preterm PE and term PE. It is found that MAP (as a representative blood pressure measurement) has exceptional preterm PE prediction performance in the low BMI group [AUROC>0.80], yet no meaningful predictive performance for preterm PE in the high BMI group. Conversely, MAP is a poor predictor for term PE in the low BMI group and an average predictor for term PE in the high BMI group [AUROC>0.70]; Table 3 and Appendix 1—FIGS. 2 and 3.

[0195] Alternatively, when one takes into consideration the fetal characteristic, fetal sex (Female or Male), the refinement of preeclampsia risk prediction for preeclampsia or the preeclampsia outcome subtypes preterm preeclampsia or term preeclampsia, is either negligible (Prediction of PE and Prediction of term PE) or minor. For preterm preeclampsia, incorporating fetal sex information delivers some minor prediction refinement (cf. Delta AUROC=0.079), with improved preterm preeclampsia prediction for women carrying a female fetus [AUC>0.75]. See also table 4 and Appendix 1—FIGS. 4 and 5.

[0196] However, when one uses the height (in meter) and weight (in kg) to calculate the pregnant woman's BMI, uses this information to classify women in either a low BMI group or a high BMI group, and then further stratify the women in function of the sex of the fetus they carry, prediction of preeclampsia and its subtypes preterm preeclampsia and term preeclampsia using blood pressure can be further refined.

[0197] It is found that the exceptional preterm PE prediction performance in the low BMI group of MAP (as a representative blood pressure measurement) is accentuated further in women carrying a female fetus [AUROC>0.9] compared to women carrying a male fetus [AUROC<0.80]. The lack of preterm preeclampsia prediction using MAP is maintained in the high BMI group irrespective of using fetal sex information.

[0198] Whereas MAP appears a poor predictor for term PE in the low BMI group [AUROC=0.615], additional sub-typing based on fetal sex information reveals that MAP does have some prediction performance for term PE in women carrying a female fetus [AUROC>0.65] compared to women carrying a male fetus [AUROC<0.60]. Conversely, in the women in the high BMI group, additional sub-typing based on fetal sex improves prediction of term preeclampsia carrying a male fetus [AUROC>0.75] compared to women carrying a female fetus [AUROC<0.70]; Table 5 and Appendix 1—FIGS. 6 and 7

TABLE-US-00002 TABLE 2 controls (non PE) PE Cases Prediction (AUROC) Mean Mean AUROC p- n MAP (SD) n MAP (SD) AUROC 95% CI value Prediction of PE All Pregnancies 1213 83.719 (7.862) 123 89.509 (8.912) 0.691 0.665-0.716 <0.001 Δ AUROC Prediction of All Pregnancies 1213 83.719 (7.862) 32 90.521 (8.352) 0.726 0.700-0.750 <0.001 0.055 preterm PE Prediction of All Pregnancies 1213 83.719 (7.862) 91 89.154 (9.118) 0.671 0.652-0.704 <0.001 term PE

TABLE-US-00003 TABLE 3 controls (non PE) PE Cases Prediction (AUROC) Mean Mean AUROC p- n MAP (SD) n MAP (SD) AUROC 95%CI value Prediction All Pregnancies 1213 83.719 (7.862) 123 89.509 (8.912) 0.691 0.665-0.716 <0.001 Δ AUROC of PE Pregnancies BMI <25 733 81.819 (7.457) 55 86.297 (7.785) 0.667 0.632-0.699 <0.001 0.016 Pregnancies BMI >=25 478 86.614 (7.584) 68 92.108 (8.969) 0.683 0.642-0.722 <0.001 Prediction of All Pregnancies 1213 83.719 (7.862) 32 90.521 (8.352) 0.726 0.700-0.750 <0.001 Δ AUROC preterm PE Pregnancies BMI <25 733 81.819 (7.457) 13 90.462 (4.879) 0.834 0.806-0.860 <0.001 0.238 Pregnancies BMI >=25 478 86.614 (7.584) 19  90.561 (10.218) 0.596 0.551-0.639 0.18 Prediction All Pregnancies 1213 83.719 (7.862) 91 89.154 (9.118) 0.671 0.652-0.704 <0.001 Δ AUROC of term PE Pregnancies BMI <25 733 81.819 (7.457) 42 85.008 (8.103) 0.615 0.579-0.649 0.014 0.102 Pregnancies BMI >=25 478 86.614 (7.584) 49 92.707 (8.477) 0.717 0.677-0.755 <0.001

TABLE-US-00004 TABLE 4 controls (non PE) PE Cases Prediction (AUROC) Mean Mean AUROC p- n MAP (SD) n MAP (SD) AUROC 95% CI value Prediction All Pregnancies 1213 83.719 (7.862) 123 89.509 (8.912) 0.691 0.665-0.716 <0.001 Δ AUROC of PE & female fetus 563 83.355 (7.665) 56 88.118 (8.904) 0.698 0.660-0.734 <0.001 0.013 & male fetus 634 84.028 (8.048) 67 89.836 (8.972) 0.685 0.649-0.719 <0.001 Prediction of All Pregnancies 1213 83.719 (7.862) 32 90.521 (8.352) 0.726 0.700-0.750 <0.001 Δ AUROC preterm PE & female fetus 563 83.355 (7.665) 12 91.028 (7.213) 0.773 0.737-0.807 <0.001 0.079 & male fetus 634 84.028 (8.048) 20 90.217 (9.134) 0.694 0.657-0.729 <0.001 Prediction All Pregnancies 1213 83.719 (7.862) 91 89.154 (9.118) 0.671 0.652-0.704 <0.001 Δ AUROC of term PE & female fetus 563 83.355 (7.665) 44 88.598 (9.316) 0.678 0.639-0.715 <0.001 0.004 & male fetus 634 84.028 (8.048) 47 89.674 (8.997) 0.682 0.645-0.716 <0.001

TABLE-US-00005 TABLE 5 controls (non PE) PE Cases Prediction (AUROC) Mean Mean AUROC p- n MAP (SD) n MAP (SD) AUROC 95% CI value Prediction All Pregnancies 1213 83.719 (7.862) 123 89.509 (8.912) 0.691 0.665-0.716 <0.001 Δ AUROC of PE & female fetus 563 83.355 (7.665) 56 88.118 (8.904) 0.698 0.660-0.734 <0.001 0.013 & male fetus 634 84.028 (8.048) 67 89.836 (8.972) 0.685 0.649-0.719 <0.001 Pregnancies BMI <25 733 81.819 (7.457) 55 86.297 (7.785) 0.667 0.632-0.699 <0.001 Δ AUROC & female fetus 334 81.300 (7.112) 25 87.347 (8.431) 0.713 0.663-0.759 <0.001 0.086 & male fetus 391 82.194 (7.692) 30 85.167 (7.231) 0.627 0.578-0.673 <0.001 Pregnancies BMI >=25 478 86.614 (7.584) 68 92.108 (8.969) 0.683 0.642-0.722 <0.001 Δ AUROC & female fetus 228 86.349 (7.483) 31 90.548 (8.151) 0.643 0.581-0.701 0.011 0.068 & male fetus 243 86.978 (7.739) 37 93.414 (8.722) 0.711 0.654-0.763 <0.001 Prediction of All Pregnancies 1213 83.719 (7.862) 32 90.521 (8.352) 0.726 0.700-0.750 <0.001 Δ AUROC preterm PE & female fetus 563 83.355 (7.665) 12 91.028 (7.213) 0.773 0.737-0.807 <0.001 0.079 & male fetus 634 84.028 (8.048) 20 90.217 (9.134) 0.694 0.657-0.729 <0.001 Pregnancies BMI <25 733 81.819 (7.457) 13 90.462 (4.879) 0.834 0.806-0.860 <0.001 Δ AUROC & female fetus 334 81.300 (7.112) 4 93.583 (3.604) 0.94 0.901-0.963 <0.001 0.167 & male fetus 391 82.194 (7.692) 9 89.074 (4.879) 0.773 0.729-0.813 <0.001 Pregnancies BMI >=25 478 86.614 (7.584) 19  90.561 (10.218) 0.596 0.551-0.639 0.18 Δ AUROC & female fetus 228 86.349 (7.483) 8 89.750 (8.402) 0.602 0.536-0.665 0.36 0.014 & male fetus 243 86.978 (7.739) 11  91.152 (11.719) 0.588 0.523-0.649 0.38 Prediction of All Pregnancies 1213 83.719 (7.862) 91 89.154 (9.118) 0.671 0.652-0.704 <0.001 Δ AUROC term PE & female fetus 563 83.355 (7.665) 44 88.598 (9.316) 0.678 0.639-0.715 <0.001 0.004 & male fetus 634 84.028 (8.048) 47 89.674 (8.997) 0.682 0.645-0.716 <0.001 Pregnancies BMI <25 733 81.819 (7.457) 42 85.008 (8.103) 0.615 0.579-0.649 0.014 Δ AUROC & female fetus 334 81.300 (7.112) 21 86.159 (8.608) 0.67 0.618-0.719 0.017 0.106 & male fetus 391 82.194 (7.692) 21 83.857 (7.597) 0.564 0.514-0.612 0.298 Pregnancies BMI >=25 478 86.614 (7.584) 49 92.707 (8.477) 0.717 0.677-0.755 <0.001 Δ AUROC & female fetus 228 86.349 (7.483) 23 90.826 (9.561) 0.657 0.595-0.712 0.014 0.106 & male fetus 243 86.978 (7.739) 26 94.372 (7.169) 0.763 0.708-0.812 <0.001

EQUIVALENTS

[0199] The foregoing description details presently preferred embodiments of the present invention. Numerous modifications and variations in practice thereof are expected to occur to those skilled in the art upon consideration of these descriptions. Those modifications and variations are intended to be encompassed within the claims appended hereto.

REFERENCES

[0200] 1. Steegers, E. a P., von Dadelszen, P., Duvekot, J. J. & Pijnenborg, R. Pre-eclampsia. Lancet 376, 631-44 (2010). [0201] 2. Wright, D. et al. Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin on length of stay in the neonatal intensive care unit. Am. J. Obstet. Gynecol. 218, 612.e1-612.e6 (2018). [0202] 3. Syngelaki, A. et al. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. N. Engl. J. Med. 374, 434-43 (2016). [0203] 4. Navaratnam, K. et al. A multi-centre phase IIa clinical study of predictive testing for preeclampsia: improved pregnancy outcomes via early detection (IMPROvED). BMC Pregnancy Childbirth 13, 226 (2013). [0204] 5. Emerson, D. S., Felker, R. E. & Brown, D. L. The sagittal sign. An early second trimester sonographic indicator of fetal gender. J. Ultrasound Med. 8, 293-297 (1989). [0205] 6. Efrat, Z., Akinfenwa, O. O. & Nicolaides, K. H. First-trimester determination of fetal gender by ultrasound. Ultrasound Obstet. Gynecol. 13, 305-307 (1999). [0206] 7. Alfirevic, Z., Mujezinovic, F. & Sundberg, K. Amniocentesis and chorionic villus sampling for prenatal diagnosis. in Cochrane Database of Systematic Reviews (ed. Alfirevic, Z.) 148-156 (John Wiley & Sons, Ltd, 2003). doi:10.1002/14651858.CD003252 [0207] 8. Hackett, G. A. et al. Early amniocentesis at 11-14 weeks' gestation for the diagnosis of fetal chromosomal abnormality—a clinical evaluation. Prenat. Diagn. 11, 311-315 (1991). [0208] 9. Mazloom, A. R. et al. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat. Diagn. 33, 591-597 (2013). [0209] 10. Costa, J. M. et al. First-trimester fetal sex determination in maternal serum using real-time PCR. Prenat. Diagn. 21, 1070-4 (2001). [0210] 11. Zweig, M. H. & Campbell, G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin. Chem. 39, 561-77 (1993). [0211] 12. Catalano, P. M. & Shankar, K. Obesity and pregnancy: Mechanisms of short term and long term adverse consequences for mother and child. BMJ 356, 1-37 (2017). [0212] 13. Brown et al (Hypertensive disorders of Pregnancy, Hypertension, 2018; 72: 24-43).