Key Words

Preeclampsia, Fibrinogen, Fibrin degradation product

Introduction

Preeclampsia is a systemic disease characterised by hypertension, oedema and proteinuria. Haematological, genetic and immunological factors play role in aetiopathogenesis of preeclampsia. Preeclampsia is a major cause of maternal morbidity and mortality in the world. It develops in 3.9% of all pregnancies.[1]. Fibrin deposit in vascular and endothelial area of many organs and placenta is the well – known feature of this disease[2] Normal pregnancy is associated with impressive changes in the haemostatic mechanism and is a hypercoagulable state associated with increase in many coagulation factors. Coagulation and fibrinolytic systems undergo major alteration associated with reduced fibrinolytic activity and increased levels of fibrinogen and FDP in normal pregnancy which has been reported in many studies[3,4] Endothelial cell dysfunction and inflammation are considered to have a role in the pathophysiology of preeclampsia[5] Mediators of an inflammatory response like plasma fibrinogen are altered in preeclamptic women. A systemic inflammatory response involves both the immune system and clotting and fibrinolytic system [6]. An excess of FDP with diminished or normal systemic fibrinolytic activity suggests that local intravascular fibrin deposition and fibrinolysis occur in preeclampsia. The high level of FDP is associated with the pathogenesis of defective hemostasis in preeclampsia [7] Increased fibrinolytic activity in preeclampsia patients has been reported earlier, resulting in increased levels of FDP [8,9] So this study was done with an aim to test the hypothesis that the plasma fibrinogen and fibrin degradation product levels are increased in women with preeclampsia as compared to normotensive pregnant women in their third trimester

Materials & Methods

This cross sectional study was conducted in the Department of Obstetrics and Gynaecology at SMS Medical college and associated hospital, Jaipur, Rajasthan. A total of 50 primigravida with 18-30 years of age, in their third trimester who were non-smoker and non-alcoholic were recruited for the study. Out of 50 subjects 25 were preeclamptics and 25 were healthy normotensive pregnant women. Pregnancy with known medical disorders such as chronic hypertension, endocrine disorders, epilepsy, hemorrhagic disorders, thrombhophilia, hepatic or renal disorders, women using any kind of oral contraceptives, anticoagulant drugs were excluded from the study. Demographic characteristics such as age, residence, socio-economic status, religion were noted. Fetomaternal outcome such as mode of delivery, birth weight of newborn, Apgar score at 1 and 5 min, NICU admission, neonatal mortality etc noted. Blood pressure was measured by auscultatory method using mercury sphygmomanometer in a sitting position after making patient comfortable and at least 10 minutes of rest. Systolic blood pressure was recorded at the appearance of and diastolic blood pressure was recorded at the disappearance of fifth phase korotkoff. Preeclampsia was diagnosed according to American College of Obstetrics and Gynaecology (ACOG) criteria: BP higher than 140/90 mm Hg and proteinuria more than 300 mg/24 hrs were observed on at least 2 occasions more than 6 hours apart after 20th week of pregnancy. Preeclampsia was classified as severe if diastolic blood pressure increased to at least 110 mm Hg, proteinuria >5000 mg/day and the presence of headache, visual disturbances, elevated liver function tests, elevated renal function tests and thrombocytopenia. The cases were further divided into 3 subgroups- mild preeclampsia (n=18), severe preeclampsia (n=4) and eclampsia (n=3). All patients were subjected to routine antenatal investigations such as CBC, ABO/Rh, LFT, RFT, VDRL, HbsAg, HIV and urine complete etc. Urine examination was done by dipstick method and readings were noted. Blood samples for plasma fibrinogen and FDP were collected into test tubes containing 1 ml of 3.8% sodium-citrate. Centrifugation of these samples was done for ten minutes at room temperature and at 2500xg. Plasma fibrinogen was estimated by Clauss method using Start analyser – a compact 4 channel coagulation instrument. The levels of FDP were investigated using latex immunoterbidimetric method based on the principle of ELISA. The results were expressed as mean±SD. Statistical analysis was performed with the SPSS, trial version 20. Data were compared by using Chi square test and student’s t test. P value <0.05 was considered statistically significant.

Results

  • The mean age of the study population was 22.24±1.954 years. The majority of the cases were in age < 25 years (96%). This reflects an increase prevalence of preeclampsia in young nulliparous women.
  • The majority of the study subjects came from urban population (58%). Middle class patients constituted the major part of the study population (56%) and the maximum numbers of subjects were Hindus (78%).
  • Maximum no. of the study population was able to read and write in one language (76%). Of all women studied only 56% received adequate antenatal care.
  • Women with gestational age between 36- 40 weeks comprise 86% of the study population. It was found that there was low gestational age in cases as compared to controls. The majority of the cases had urine albumin 1+ on dipstick.
  • The mean platelet counts in the case and control group were 1.494±0.654 and 2.200±0.596 respectively showing that mean platelet count was significantly decreased in women with preeclampsia (p=0.047).
  • 3 patients in Group A (cases) went into acute renal failure.
  • The mean plasma fibrinogen level in case and control group was (528.96±93.25) and (365.48±109.85) mg/dl respectively. The difference was statistically significant reflecting that the mean plasma fibrinogen level was increased in women with preeclampsia (p=0.001).
  • The mean values of plasma fibrinogen in cases with mild preeclampsia, severe preeclampsia and eclampsia were respectively 518.94±102.08, 534.0±74.18 and 582.33±48.01mg/dl showing a definitive rise in the values of plasma fibrinogen with the severity of preeclampsia increased. These findings were however statistically not significant (p=0.231).
  • The mean values of plasma FDP in the cases and controls were (8.52±12.50 ) and ( 5.72±1.96) µg/dl . When the value of mean plasma FDP is compared between case and control group, a significant increase in mean plasma FDP level was observed. The result was highly significant (p= 0.000). The mean values of FDP in cases with mild preeclampsia, severe preeclampsia and eclampsia were respectively 7.71±2.13, 8.99±0.51 and 12.40±2.49 µg/dl showing a definitive rise in the values of plasma FDP with the severity of preeclampsia increased (p=0.01).
  • There was significant association observed between plasma fibrinogen and FDP level and NICU admission, neonatal mortality, Apgar score. The plasma fibrinogen level was significantly higher in women whose neonates admitted in NICU, neonate had died and where neonate had low Apgar score at 1 min.
  • Approximately 40% of the study population had delivered by LSCS and 60% by vaginal route. LSCS was more done in cases while ND was more in controls (p= 0.000). The mean birth weight of Group A (cases) and Group B (control) were respectively 2.37±0.63 kg and 2.71±0.41 kg (p=0.319)
  • Significant difference was observed for Apgar score at 1 minute (p=0.041) but no significant difference was found for Apgar score at 5 minute in both cases and control(p=0.077).
  • The neonates of preeclamptic women were admitted more in NICU as compared to neonates of normotensive women. This was significant statistically (p=0.041).
  • In our study total 3 neonate were died, 2 were died due to severe IUGR and one died in utero probably due to severe oligohydramnios while no neonate died in the control group (p value=0.234).
  • In women with preeclampsia preterm termination of pregnancy was more done as compared to control group indicating a significant increase in number of preterm delivery (p value=0.041).

Table 1: INTERGROUP COMPARISION OF DEMOGRAPHIC PARAMETERS

Demographic Parameters Cases Controls p value* Statistical Significance
Mean Age (mean±SD) (years) 22.28±2.25 22.20±1..66 0.777 Not Significant
Residence Rural 11 (44%) 10 (40%) 1 Non-Significant
Urban 14(56%) 15 (60%)
Religion Hindu 22 (88%) 17 (68%) 0.172 Not Significant
Muslim 3 (12%) 8 (32%)
Others 0.00 (100.0%) 0.00 (100.0%)
Literacy Status Literate 18 (72%) 20 (80%) 0.741 Not Significant
Illiterate 7 (28%) 5 (20%)
Socio-economic Status Lower 11(44%) 8 (32%) 0.502 Not Significant
Middle 12(48%) 16 (64%)
Upper 2(8%) 1 (4%)

Table 2: Distribution of study population according to plasma fibrinogen

Plasma fibrinogen (mg/dl) Group A (cases) Group B (control) Total
No. % No. % No. %
200-300 0 0 8 32 8 16
301-400 0 0 8 32 8 16
401-500 9 36 4 16 13 26
501-600 11 44 4 16 15 30
>600 5 20 1 4 6 12
Total 25 100 25 100 50 100
Mean ± SD 528.96±93.25 365.48±109.85 447.22±130.34

X 2 = 23.856 df = 4 p value = 0.001 significant

Table 3: Association of plasma fibrinogen level with severity of preeclampsia

Plasma fibrinogen(mg/dl) Mild preeclampsia Severe preeclampsia Eclampsia
200-300 0 0 0
301-400 0 0 0
401-500 9 0 0
501-600 6 3 2
>600 3 1 1
Total 18 4 3
Mean±SD 518.94±102.08 534.0±74.18 582.33±48.01

Chi square = 5.606 df = 4 p value = 0.231 NS

Table 4: Distribution of study population according to plasma FDP level

Plasma FDP (µg/ml) Group A (cases) Group B (control)
No. % No. %
≤6 5 20 20 80
6.1-10 14 56 3 12
10.1-14 5 20 2 8
14.1 -18 1 4 0 0
Total 25 100 25 100
Mean±SD 8.52 ± 2.50 5.72 ± 1.96

X2 = 18.403 df = 3 p value = 0.000

Table 5: Association of plasma FDP level with severity of preeclampsia

Plasma FDP (µg/ml) Mild preeclampsia Severe preeclampsia Eclampsia
≤ 6 5 0 0
6.1-10 10 4 0
10.1-14 3 0 2
14.1-18 0 0 1
Total 18 4 3
Mean±SD 7.71±2.13 8.99±0.51 12.40±2.49

Chi square = 16.508 df = 6 p value = 0.01 S

Table 6: Distribution of study population according to Apgar score of new born at 1 min

Apgar score at 1 min Group A(cases) Group B (control) Total
No. % No. % No. %
≤ 5 9 36 2 8 11 22
>5 16 64 23 92 39 78
Total 25 100 25 100 50 100

X 2 = 4.196 df = 1 p value = 0.041 S

Table 7: Distribution of study population according to NICU Admission

NICU Admission Group A(cases) Group B (control) Total
No. % No. % No. %
Admitted 9 36 2 8 11 22
Not admitted 16 64 23 92 39 78
Total 25 100 25 100 50 100

X 2 = 4.196 df = 1 p value= 0.041 S

Table 8: distribution of study population according to neonatal mortality

Neonatal mortality Group A(cases) Group B (control) Total
No. % No. % No. %
No 22 88 25 100 47 94
Yes 3 12 0 0 3 6
Total 25 100 25 100 50 100

X2 = 1.418 df = 1 p value = 0.234

Discussion

In our study, the plasma fibrinogen and FDP (fibrin degradation product) were increased in preeclampsia. The severity of preeclampsia is increased as the level of plasma fibrinogen and FDP is increased. Enhanced coagulationfibrinolysis and coagulopathy are well known features of preeclampsia [10] . The results of our study showed that in preeclampsia the level of plasma fibrinogen was higher as compared to normal pregnancy and reconfirms the results from earlier studies [11,12] The increase in fibrinogen in normal pregnancy is also due to the inflammatory responses which explain that fibrinogen is the acute phase reactantmarker of inflammation, in both normal pregnancy and preeclamptic pregnancy. The increase in fibrinogen in normal pregnancy may also be due to utilisation in uteroplacental circulation, enhanced synthesis and also due to hormonal changes like oestrogen synthesis [13] . Fibrin degradation products (FDP) are components of the blood produced by clot degeneration. These are produced by the action of plasmin on deposited fibrin. Excess FDP can cause severe hemostatic defects [14]. High plasma FDP levels in preeclamptic patients in our study are similar with the finding of others [15,16]

Conclusion

So finally we can conclude that plasma fibrinogen and FDP measurement can be considered as an early, economical and rapid procedure for assessment of severity of preeclampsia along with other investigations. Clinically, plasma fibrinogen and FDP measurement can be a useful screening test for early identification of preeclampsia and eclampsia. Detection of these changes in early period can stop the progression towards eclampsia and will be useful to start the appropriate treatment. However, a larger study is required to substantiate the above fact.