Back ground: PET a disease of theories of unknown particular cause characterized by hypertensive disorder, protein excretion in urine that additionally could be accompanied or not by organ dysfunction. CA125 is an antigen measured by radioimmunoassay. Its physiological and molecular significance in obstetric diseases is not fully clarified most research trials are made on this antigen in obstetric research field to explore and investigate its role as a marker in various diseases.

Aim:

The current research was performed to evaluate and correlate the correlation between CA125 serum level in normal gestations and gestations affected by PET.

Methodology: The current research study is composed of 300 singleton gestations. The study subjects were divided into 3 research groups: control research group (n = 100), mild PET research group (n = 100) and severe PET research group (n = 100). The three research groups were statistically alike as regards variables such as maternal age, gestational age and BMI.The research study was conducted at a private hospital in Jeddah, KSA, United Doctors Hospital. over 3 years from April 2014 to April 2017.

Results: The current research study results displayed that no statistical significant difference existed between the research study groups concerning age, BMI, parity, smoking, GA and serum creatinine. On the other hand SBP, DBP, serum urea, serum CA125, urine protein, and NICU admission were statistically significantly lowest in control research group followed by mild PET research group and statistically significantly highest in severe PET research group. Interestingly it has been revealed in the current research findings that platelets count was statistically significantly lowest in severe PET research group with no statistically significant difference between control and mild groups. The current research study have evaluated in addition diagnostic performance of laboratory investigations performed between research study groups displayed the following  Serum BUN, serum CA125 and proteinuria had  statistically significant high diagnostic performance and features in discriminating  between PET from normal (highest in urine protein).On the other hand Serum BUN had statistically significant moderate diagnostic performance and features , whereas serum CA125 and urine protein had statistically significant high diagnostic performance  and features in discriminating severe from mild PET (highest in urine protein).

 Conclusion: Our research group came to the conclusion that serum CA125 level in maternal serum is directly correlated to PET presence and its degree of severity i.e CA-125 is a Biological marker mirroring the disease severity .Additionally it has the privilege of being. More readily available and considered less costly in comparison to other biological markers, It could be used as a screening tool for PET. However larger sample size should be considered in future research studies and consideration should be made for ethnic and racial difference that could aid in future met analysis performance.

Hypertensive disorders of gestation  is one of the common issues leading to maternal mortality  globally. It  is responsible  for  around 12% of maternal mortalities worldwide . Roughly 5% of gestations   develop  PET, Which makes it one of the chief gestational medical Disorders . The WHO statistically guessed  that  above 100,000 females pass away from PET every  year  all over the world, the issue is more prominent in developing countries in comparison to developed countries [1-5]. Maternal and fetal morbidity is great , particularly  in developing  nations having a prevalence range  around 2% to 17%. As preseclampsia is a disease of theories having no well demarcated etiology Featured clinically  by hypertensive disorder, protein excretion in urine, +/- Organ function affection. In vast majority of case scienarios , pathological examination reveales  Microscopic evidence  of placental vascular  insufficiency  correlated with Other pathological developments such as placental inflammatory decidual vasculopathy, placental diffuse  thrombosis, and/or abnormal invasive trphoblastic activity to the  endometrial lining [6-10 ].

The pathophysiological  pathways of  PET are not well settled  , although the chiefly accepted theoretical pathway  is that of  deficient  trophoblastic Invasive action of the placenta  to  deciduas causing endothelial cell insult,  reduced intravascular volume, chronic inflammatory process, and  affected vascular responsiveness [11-15].

The consecutive  maternal adaptive pathway to gestational abnormal immunologic response  to  pregnancy is an immunological  response against placental tissue and  paternal  derived antigens  causing fetal hypoxia and inflammatory mediators secretion that  have a negative impact on  endothelium .  A prominent inflammatory mediator secreted is the CA125 antigen. Clinically used in practice as a sensitive but nonspecific tumor marker in management protocols of ovarian malignancies  . The value  of CA125 in obstetric related diseases  is not fully clarified  as most  research trials performed  investigating its applicability are experimental in fashion[16-20]. In gestation, the fetal chorionic villi, amniotic fluid and decidua are possible biological sources and origin of CA125 antigen during the first trimester of gestation and during the period of  puerperium with serum  concentrations  of CA125 elevating during the first gestational trimester and  falling back to normal  non-gestational range of values  during the 2nd and 3rd gestational  trimesters . Damage in decidual lining of cells  due to  chorionic villi invasive action during  early gestation causes the CA125 originated from the decidual lining adittionally that occurs during placental separation at delivery. Consequently, considering decidual destruction and trophoblastic seperation from the decidual lining are cellular mechanisms for rise of CA125 in PET  gestations[21-23].

Previous performed research came to a conclusion that  the hypoalbuminemia occurring  in PET gestations  is considered  contributing  factor  in rising   serum CA125  concentration levels  since reduced  levels of albumin   is correlated   to clinical and subclinical edema and ascites in PET  gestations . Another research group additionally displayed a rise in binding activity of CA125 antigen on immune cells of pregnant females and gestations with PET. The current research study aimed to assess and investigate the serum levels of CA125 in patients with and without PET and values its clinical applicability in the diagnosis pathway and prognostic power in PET[24,25].

The current research study  is a prospective research study conducted at private hospital in Jeddah, KSA,United Doctors Hospital after ethical approval from hospital ethical committee , over 3 years from April 2014 to April 2017.  The research study was conducted on 200 singleton gestations having PET ( Research study groups involving mild PET ,severe PET ). Cases clinically diagnosed with PET after 32 gestational weeks have been enrolled for the research study group. While for the research control group(n=100), the gestations visiting the outpatient clinic the hospital for routine

antenatal care visit after 32  gestational weeks  were recruited. The 32nd gestational week was randomly used by the research group as an inclusive criterion. PET clinical diagnosis and classification as the bulletin of the ACOG. Hypertension was featured as an absolute blood pressure measrement [140/90 mmHg after 20 gestational weeks

by at least two blood pressure 4 hours apart measurements. Protein in urine have been featured as 0.3 g protein excretion in urine. Exclusive research criteria have been presence of  DM, chronic hypertensive disease, clear history of peripheral vascular disorder  and/or antihypertensive medication and a  BMI  <19> 30 kg/m2. Study Subjects were Divided  into 3 research  groups: control research group (n = 100), mild PET research group (n = 100) and severe PET research group (n = 100). The 3 research study groups were displayed and revealed as statistically Alike  as regards maternal age, gestational age and BMI. Maternal blood samples for CBC, serum creatinine, Serum uric acid and  serum CA-125 levels  have been obtained  by consistent phlebotomy withdrawal  procedure from all study subjects after  being recruited to the research study and control  categorical groups . Obtained blood samples for CA-125 have been collected into anticoagulant-free glass test tubes, centrifuged instantaneously at 6,420 g (4 degree celcius) and stored without delay at -70 degree Celcius.  Additionally ,24-hours  urine have been gathered from each study subject  to investigate  the quantity of protein excreted in urine  . Levels of CA 125 in serum have been measured  by electrochemoluminescence immunoassay , however  CBC  indices  have been obtained by an automated blood counter machine .Serum creat. and uric acid levels  were assayed by an automatic chemical analyzer machine, TBA 40FR . The intra- and inter-assay statistical  coefficients of variation (CVs) were reported to be 4 and 2%, consecutively for serum CA-125 assays obtained . The normal range was rated as 0–35 IU/m as regards  CA-125 serum levels. Patient age, parity, BMI, gestational age, SBP,DBP, treatment protocols, CBC indices and serum concentrations of uric acid, creatinine and CA-125, the expected  fetal weight, the occurence of intrauterine growth restriction and intrauterine fetal death  for all study subjects  were recorded.

The obtained data have been coded, tabulated, and statistically analyzed by using IBM SPSS statistics (Statistical Package for Social Sciences) software version 18.0, IBM Corp., Chicago, USA, 2009.Descriptive statistics were done for quantitative data as minimum& maximum of range in addition to mean±SD (standard deviation) for quantitative normally distributed data, whereas it was done for qualitative data as number and percentage.

Inferential analyses was  performed for   quantitative variables using independent t-test in cases of two independent groups ANOVA test with post hoc Tukey test for more than two independent groups. In qualitative data, inferential analyses for independent variables were done using Chi square test for differences between proportions with post hoc Bonferroni test. The level of significance was taken at P value < 0>

Table 1: Comparison between the studied groups

^ANOVA test with post hoc Tukey test, #Chi square test with post hoc Tukey test, *Significant, HG: Homogenous groups by post hoc test have the same letter (a,b,c)

Table (1) and figures (1) : reveal and display  that: No statistical  significant difference between the research study groups as regards  age, BMI, parity, smoking, GA and serum creatinine. However SBP, DBP, serum urea, serum CA125, urine protein, and NICU admission were statistically significantly lowest in control group followed by mild PET research group and significantly highest in severe PET research group. Fetal birth weight was statistically significantly highest in control research group followed by mild PET research group and statistically significantly lowest in severe PET in comparison to control group. Platelets count was statistically significantly lowest in severe PET research group with no statistically significant difference between control and mild groups. Expected fetal weight was  statistically significantly highest in control group with no statsistically significant difference between mild and severe PET research groups.

Figure 1: CA125 among the studied groups

Table 2: Correlation between CA125and other variables among study groups

Pearson correlation, *Significant

Table (3) and figures (2) show that: Only CA125 had significant negative correlation with platelets in severe group

Figure 2: Correlation between CA125and platelts among group

Table 3: Comparison between IUFD and lived fetuses regarding CA125 (IU/mL)

^Independent t-test

CA125 was significantly higher in cases with IUFD in mild and severe groups

Table 4: Diagnostic performance of  lab investigations in differentiation between research study groups

AUC; Area under curve, SE: Standard error, CI: Confidence interval, *Significant

Table (4) and figures (3,4) display that: Serum BUN, serum CA125 and urine protein had  statistically significant high diagnostic performance and characteristics in differentiating PET from normal (highest in urine protein).On the other hand Serum BUN had statistically significant moderate diagnostic performance and characteristics, whereas serum CA125 and urine protein had statistically significant high diagnostic performance  and characteristics in differentiating severe from mild PET (highest in urine protein).

Figure 3: ROC curve for serum creatinine, serum BUN, serum CA125 and urine protein in differenting PET from normal groups

Figure 4: ROC curve for serum creatinine, serum BUN, serum CA125 and urine protein in differenting severe from mild PET groups

Various priorly conducted research studies  have investigated  the correlation  between maternal CA 125  serum levels and PET, but these  researches are mainly experimental, widely unapproved  and the results are debatable showing great deal of conflict [1,3,5,7]. The current research study displayed that no statistical  significant difference existed between the research study groups  concerning  age, BMI, parity, smoking, GA and serum creatinine. On the other hand SBP, DBP, serum urea, serum CA125, urine protein, and NICU admission were statistically significantly lowest in control research group followed by mild PET research group and statistically significantly highest in severe PET research group. Fetal birth weight was statistically significantly highest in control research group followed by mild PET research group and statistically significantly lowest in severe PET research group. Interestingly it has been revealed in the current research findings that platelets count was statistically significantly lowest in severe PET research group with no statistically significant difference between control and mild groups. Expected fetal weight was statistically significantly highest in control research group with no statistically significant difference between mild and severe PET research groups. Additionally when statistically comparing and contrasting between IUFD and live birth in correlation to serum CA 125 levels have shown that CA125 was significantly higher in cases with IUFD in mild and severe groups. The current research study have evaluated in addition diagnostic performance of laboratory investigations performed between research study groups displayed the following  Serum BUN, serum CA125 and proteinuria had  statistically significant high diagnostic performance and features in discriminating  between PET from normal (highest in urine protein).On the other hand Serum BUN had statistically significant moderate diagnostic performance and features , whereas serum CA125 and urine protein had statistically significant high diagnostic performance  and features in discriminating severe from mild PET (highest in urine protein). In a similar research approach fashion Schröcksnadel et al research group investigated the correlation  between serum CA125 levels in cases with gestational hypertensive disorders ,normally healthy gestations  and normal non-gravid research control groups however did not find statistical significant difference between the three research categories [4-15 ]Another research group additionally mentioned  that although CA125 levels in maternal serum  are revealed to be greater  during the first and third gestational trimesters but did not show a correlation with PET but another research study, investigated serum CA125 levels in gestations with normal blood pressure and gestations that developed PET [17-24]. Revealing That serum CA125 levels did not vary as regards gestational outcome however they implied and observed a liability to elevation in serum CA125 levels for gestations  that  develop PET. Our current research, on the other hand, had findings in harmony with the Cebesoy et al. research group displaying a statistically significant greater levels  of serum CA125 in gestations that developed PET. On the other hand it was suggested that the rise in CA125 levels in PET is due to ascites present in PET gestations  due to hypoalbuminemia. The current research study displayed in a clear fashion that elevation of CA125 serum levels in PET gestations  in comparison to gestations with normal blood pressure levels and in addition statistically  significantly greater in cases suffering severe grade of  PET, these observations are similar and inharmony with observations obtained by Karaman et al. research group [12-25] .A priorly performed research study  studied 54 PET gestations/and 56 healthy gestations. The serum CRP and CA-125 serum levels.

were displayed  to be statistically  significantly greater  in gestations with PET in comparison to  healthy gestations . Additionally CRP and CA-125 serum levels in gestations with severe PET and eclampsia were statistically significantly greaterr than gestations with mild PET. Furthermore, statistical significant correlations have been revealed between CRP levels, serum albumin concentration, CA-125 serum levels and mean arterial blood pressure. The research group in that study concluded that CRP and CA-125 are potential biological markers in PET .This reveals the possible value of CA125 antigen as a biological marker or for uncovering of the prognosis of illness severity. Various priorly performed research studies reveal that sFlt-1, PIGF, and sFlt-1/PIGF ratio as biological markers are  not considered clinically  simple, and are not of  low-cost, due to financial and practical issues . While CA-125 is more readily available and considered less costly form of testing, therefore   it is considered a promising biological marker for screening PET. The current research study has various limitations such as the sample size is small and the research should consider racial and ethnic differences that could have an influence on the disease severity [4,9,12].

Our research group concluded that raised levels of maternal serum CA 125 is correlated with the development of PET and that it have a role in reflecting disease severity. Therefore, our research group recommends future research to be performed on wider scale to confirm the findings of the current research study performed .to reveal and uncover the clinical predictive value as a biological marker for PET in addition to determining a suitable cut-off level value particularly within cases having severe disease presentation. More prospective research is needed to reveal and clarify the precise pathological pathway of raised CA-125 serum levels in gestations with PET and to reveal the clinical value of CA-125 in PET.