Over half a century ago, Deckmann and Micheal reported that preeclamptic women showed an elevated pressor response to vasopressin. Although the performance of the test had a 77%sensitivity and 95% specificity in 1973, The largest most recent study of 494 healthy nulliparous women found a disappointing sensitivity of 22% with a specificity of 85% for prediction of pregnancy induced hypertensive disorders..The disappointing results of recent studies raises doubts about usefulness as a continuing test.(6)

Urine albumin excretion rate was the best predictive value for preeclampsia in hypertensive patient when blood for fibronectin, anthithrombin 3,alpha 1 microglobulin, U-N acetyl-beta-glucosominidase ,uric acid and albumin excretion rate was studied in 68 non pregnancy induced hypertensive and 40 chronic hypertensive, positive predictive value and specificity being 87.5 and 98.9 respectively.(7)

Elevated serum uric acid levels were associated with clinical severity of preeclampsia and perinatal outcomes. Despite a good amount of studies, not of all studies suggest that the serum uric acid levels may begin to rise before the onset of hypertension and proteinuria. Hyperuricaemia, an early sign of renal involvement in preeclampsia, is the result of reduced renal clearance due to altered tubular processing of uric acid preceding glomerular affliction, which will cause albminuria. However results from recent studies show that despite its long history of use, the discriminatory value of serum uric acid as a predictor of preeclampsia remains to be proven.(8,9) Microproteinuria levels above 375mg/l may be significant and thus could be utilized as a screening test for the early detection of a woman at risk of developing preeclampsia. Serum uric acid and creatinine had no predictive value. Rodriques and Susuki showed that in women with a low levels of calcium/creatinine ratio and high microalbuminuria, 84% developed PE.(10,11) Martinez , however says there is no diagnostic value of microalbuminuria and the calcium/creatinine ratio when used alone (13)

When clinical utility of urinary soluble endoglin was compared with soluble fms-like tyrosine kinase 1 to placental growth factor (PIGF)ratio, soluble endoglin levels were significantly raised in preterm preeclampsia .However urinary endoglin has limitations to determine the severity of preeclampsia, and to differentiate between preeclampsia and chronic hypertension (14)

Women with preeclampsia appear to present a unique urine proteomic fingerprint composed of SERPINA1 and albumin fragments that predicts preeclampsia in need of mandated delivery with highest accuracy. This characteristic proteomic profile also has the ability to distinguish preeclampsia from other hypertensive or proteinuric disorders in pregnancy.(!5)

Urine levels of inhibin A showed the greatest discrimination between severe preeclampsia and pregnant control women, when there was cut off of 45pg/mg. for urine creatinine Women with greater than 90pg/mg urinary creatinine had a 17 fold relative risk of a clinically indicated delivery due to preeclampsia. (16)

Measurement of urinary kallikrein(IUK)to creatinine ratio(IUK:ck) between 16-20 weeks of gestation is a simple and practical test for the determining the risk of developing subsequent preeclampsia, with a sensitivity and specificity comparable to those reports as ascertained by other investigators using the well recognized, but less practical, angiotensin II sensitivity test(17)

Urinary microtransferrinuria levels in pregnant women who subsequently developed preeclampsia and eclampsia where significantly higher than those pregnant women who remained normotensive. Microtranferrinuria as a predictor for preeclampsia had a sensitivity 93.5%,specificity 65%,positive predictive value of 83% and a negative predictive value of 98.4%,whereas these values for microalbimunria were50%,58%,50% and 91% respectively. Hence Microtranferrinuria is potentially a more sensitive predictor of preeclampsia than microalbuminuria.(18)

The urinary excretion of N-acetyl-beta-glucosaminidine, a lysosomal enzyme of the renal tubular cells, was increased in normal pregnant women and in woman with transient hypertension when compared to non pregnant healthy controls. In preeclampsia women, the increase was much higher than corresponding to their gestational age. (19)

Inhibin–A was determined as a more sensitive marker for the prediction of preeclampsia than hCG. Addition of hCG data to inhibin did not improve the screening efficiency for preeclampsia suggesting that inhibin-A and hCG are markers of the same underling pathological process.(20)

Despite using multivariable second trimester clinical factors and biomarkers like history of preeclampsia, elevated mean arterial pressure, low unconjugated serum oestriol, the addition of human chorionic gonadotrophin and alpha-fetoprotein biochemical markers did not enhance the model’s predicative value for severe preeclampsia (21)

Midtrimester beta-hCG levels alone correlated significantly with the severity of preeclampsia. However the combination of MShCG levels, body mass index(BMI),parity and age as a predictive test for preeclampsia was far superior to MShCG alone. This multi-factorial model could identify preeclampsia with a sensitivity of 70% and a specificity of 71 %.( 22)

Even after incorporating the strongest risk factors such as nulliparity, history of preeclampsia, elevated mean arterial pressure, low unconjugated serum oestriol concentration, and in addition of hCG and α -fetoprotein did not improve the predictive value for severe pre-eclampsia(23)

Plasma tumor necrosis factor was measured in the first, second and third trimester prospectively. Although the plasma TNF-alpha levels were higher in preeclamptics compared with normotensives,the levels cannot be used in the first, second trimester as a specific marker however may be useful in the early third trimester.(24)

Plasma fibronectin was assessed to see if it could predict the onset of preeclampsia. This study showed that with increased fibronectin levels the sensitivity, specificity, positive and negative predictive values were 37.5%(95%CI=3.3-71.7),96.6%(95%CI=93.7-99.6),37.5%(95%CI=3.3-71,3)and 96.6%(95%CI-93.7-99.6) .Its sensitivity has to be improved for it to a specific marker for preeclampsia however its negative predictive value strongly argues against the development of preeclampsia within the next 4 weeks of blood sampling(27)

However platelet angiotensin ll receptors measurement is not a clinical useful marker in the prediction of preeclampsia.

Serum thrombomodulin antigen levels were measured in patients with preeclampsia, gestational hypertension and chronic hypertension. Levels were higher in preeclampsia than those with gestational hypertension or chronic hypertension. Thrombomodulin may serve as a clinical marker to differentiate preeclampsia from other disorders of pregnancy.(28)

In obstetrics the low levels of SHBG in the first half of pregnancy were reported as a promising early risk marker of the later development of preeclampsia (29).When controls were compared with those who developed preeclampsia, serum testerone, sex hormone binding globulin and dehydroepiandrosterone sulphate were measured and compared. As compared to normotensives controls, preeclamptic women exhibited no statically significant differences in the median levels of total testerone, free androgen index, sex hormone binding globulin or dehysroepiandrosterone. (30)

Levels of CA125, has been historically a valuable parameter as a marker of ovarian carcinoma but also in other fields of obstetrics and gynecology. To date, most of the studies dealing with the CA125 and preeclampsia remain experimental and their clinical usefulness is not widely acknowledged (31)

Lipoprotein a concentration in women with preeclampsia and healthy pregnancies was assessed to determine the usefulness as a prognostic factor in preeclampsia. The results show that the determination of lipoprotein (a) levels in preeclampsia may be a significant predictor of Eclampsia (32)

Hypertension and proteinuria, may be due to an excess of circulating anti-angiogenic growth factors, most notably soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng).(33)

sFlt1 is an endogenous protein that is produced by the placenta. sFlt1 is able to bind to the angiogenic growth factors vascular endothelial growth factor and placental growth factor, thereby neutralizing their functions. Soluble endoglin was found to cooperate with the soluble form of vascular endothelial growth factor receptor 1 in the pathogenesis of preeclampsia by inducing endothelial cell dysfunction.(34). High serum concentrations of sFlt1 and low concentrations of free vascular endothelial growth factor and free placental growth factor were evident clinically prior to clinical manifestation of preeclampsia. The excessive production of these two anti-angiogenic proteins induces endothelial dysfunction by preventing circulating proangiogenic factors such as the placental growth factor, the vascular endothelial growth factor but also the transforming growth factor-beta. Despite numerous placental factors having been experimented, none has been able to reproduce a typical phenotype of preeclampsia.(35) More recently, serum levels of sEng were also significantly elevated in preeclamptic women and levels of sEng correlated strongly with severity of the disease process. Thus, measurement of sFlt1 and sEng in the maternal circulation may be a useful diagnostic and screening tool for preeclampsia and would have significant impact in current obstetrical care by reducing preeclampsia-induced morbidity and mortality. (36). Changes in the maternal plasma concentration of s-Eng, sVEGFR-1, and PlGF precede the clinical presentation of PE(37)) The combined PlGF/sEng ratio and its delta and slope had an excellent predictive performance for the prediction of early-onset preeclampsia, with very high likelihood ratios for a positive test result and very low likelihood ratios for a negative test result(38)(39).Masuyama and colleagues in 2009 have shown that there is sufficient data to suggest that there are different profiles of angiogenic factors and adipocytokines between women who develop early and late onset preeclampsia.(40,)

This discovery has two potential effects. Firstly, the possibility, in measuring these surrogates markers in the blood or urine to predict the onset of preeclampsia before its clinical manifestations. Secondly the postulated possibility of reversing the angiogenic imbalance state of preeclamspsia by correcting the maternal syndrome by transiently adding exogenous proangiogenic factor.(41,42)

Serum levels of collagen synthesis, procollagen I, carboxy-terminal peptide (PICP) and procollagen111 amino-terminal peptide (PIIIP), in patients with preeclampsia and controls. The markers were mildly elevated in preeclampsia, but unlikely to be useful in the prediction of preeclampsia. (49)

Midtrimester amniotic fluid cytokinase may reflect the maternal immune system in the maternal fetal interface and thus be predictive of preeclampsia, concentrations of interleukin (IL)-6, IL8, IL10, IL11, IL12, Il15, tumor necrosis factor (TGF)-alpha and transforming growth factor (TGF)-beta in the amniotic fluid at 14-16 weeks gestation from women with normal pregnancies and from those who subsequently developed severe preeclampsia. The concentrations of cytokinase did not significantly differ between patients and controls.(50)

The current development of powerful mass spectrometry-based proteomic techniques capable of identifying and characterizing multiple proteins simultaneously has added a new insights into the field of biomedical research. Application of these methodologies with more conventional techniques in pregnancy-related research has begun to provide a new perspective on the biochemical blueprint of pregnancy and its related disorders. This enables the identification of proteins specific to a disease process; proteomics is likely to contribute, not only to the comprehension of the underlying pathophysiologies, but also to the clinical diagnosis of multifactorial pregnancy disorders. The technology to pregnancy research is in its infancy, identification of the cellular proteome, and it’s of functional networks and disease biomarkers can be expected to significantly improve maternal healthcare outcomes in the near future. (51)Proteomics alterations in pre-eclampsia suggest that possible cellular battle against mitochondria-originated oxidative stress test resulting in recovery or apoptosis. The over expression of chaperonin 60, GST, VDAC, Erp29 and cathespin D in pre-eclampsia makes it a ideal marker of predicting preeclampsia (52, 53)