A Study on Sensitivity of Angiogenic Factors as Predictors of Preeclampsia and Role of Aspirin in Preventing Preterm Preeclampsia

Introduction

Preeclampsia (PE) is a complex multisystem disorder affecting pregnant women, causing maternal and perinatal mortality and morbidity. Global burden of preeclampsia and eclampsia is 5-10%.¹ Prevalence of preeclampsia complicating pregnancy in In 7.8%. It is associated with maternal complications like eclampsia, HELLP (H: Hemolysis; E: Elevated liver enzymes; LP: Low platelet count), abruptio placenta and fetal complications like fetal (intrauterine) growth restriction (FGR), prematurity, small for gestational age (SGA) and neonatal intensive care unit (NICU) admission. Maternal deaths each year around the world are >70,000 due to pre-eclampsia.² Occurrence of preeclampsia in early gestation before 37 weeks results in severe complications. Long-term risk of developing cardiovascular disease and cerebrovascular disease in the future is 2-7 times more in mothers who had preeclampsia during pregnancy when compared to mothers who did not have preeclampsia.^3-4 One of the complications of preeclampsia is preterm delivery, and sometimes it is associated with fetal growth restriction. Prematurity often leads to lifelong consequences for the child, including higher risk of cerebral palsy and neurodevelopmental delay, respiratory disorders, hypertension, renal dysfunction, insulin resistance, obesity, cardiovascular disease, and impaired work capacity.⁵

The aetiopathogenesis of pre-eclampsia is still an enigma. Some studies consider this to be the consequence of impaired trophoblastic invasion of the maternal spiral arteries. Maternal endothelial dysfunction is the cause for hypertensive disorders of pregnancy.^6,7 Many studies have shown that preeclamptic syndrome is a consequence of reduced angiogenic factors like vascular endothelial growth factor (VEGF) and placenta growth factor (PLGF).^8,9 These factors are inhibited by soluble fms-like tyrosine kinase (sFlt-1) which is produced by hypoxic placenta. Serum concentrations of free PLGF, Pregnancy-associated plasma protein A (PAPP-A) and VEGF are found to be low in women with pre-eclampsia, while soluble fms-like tyrosine kinase (sFlt-1) is found in high concentrations.⁹ Studies have shown that these angiogenic factors, biophysical parameters like mean arterial pressure and uterine artery doppler can predict preeclampsia in early pregnancy.¹⁰ These screening tests have a very good sensitivity of 76.6% in detecting preterm preeclampsia, 38.3% for term preeclampsia and a false positivity rate of 10%.^6-8

Multicentric studies have demonstrated the role of low dose aspirin in preventing pre-eclampsia. It has been hypothesized that aspirin supresses COX1 and COX2 enzymes, thereby inhibiting release of prostaglandins and thromboxane which leads to inhibition of platelet aggregation and has antithrombotic effect. This effect is beneficial in preventing preeclampsia.⁷ Studies have shown that use of aspirin before 16 weeks of gestation is more beneficial in preventing adverse effects of preterm preeclampsia as it corresponds to period of placentation. The use of aspirin at a dose of more than 100 mg in preventing preterm preeclampsia has been studied in ASpirin for evidence-based PREeclampsia prevention (ASPRE) trial. Aspirin has not been associated with any fetal or maternal complications and is very economical.

The intent of our study was to identify women at risk of developing PE using screening tests in early trimester and start prophylactic aspirin. In our study, we compared the benefits of 150 mg of aspirin with 75 mg in preventing preterm pre-eclampsia and feto-maternal complications.

Materials and Methods

Design and study setting

The study group included women attending antenatal clinic at Rajarajeswari Medical College and Hospital. The study was conducted for two years from January 2019 to January 2021.

Data for the study was collected from women attending antenatal clinic at 11 weeks 0 days to 13 weeks 6 days after obtaining informed consent. The study was approved by the institutional ethics committee of Rajarajeswari Medical College & Hospital.

Detailed maternal demographic details and obstetric history were collected. Body mass index (BMI) and mean arterial pressure (MAP) were recorded, transabdominal scan was used to see the uterine artery doppler and uterine artery pulsatality index (PI) and to measure the crown rump length for calculating gestational age. Samples were collected for PAPP-A and PLGF.

Women screened as high risk for preeclampsia were divided into Group A and Group B. Women in Group A were given 75 mg of aspirin and women in Group B were given 150 mg of aspirin from 11 to 16 weeks of gestation until 36 weeks of gestation. Maternal and fetal outcomes with respect to preeclampsia and its complications were analyzed. The study included pregnant women above 18 years of age and singleton pregnancies. Exclusion criteria were women having anomalous fetus, women on regular treatment with aspirin and women with bleeding disorders such as Von Willebrand’s disease, peptic ulcer, hypersensitivity to aspirin.

Sample collection and quantification of PAPP-A and placental growth factor

Two mL of blood was collected in SST BD Vacutainers from pregnant women. The blood samples were centrifuged at 3000 rpm for 15 minutes. Serum obtained was separated and stored at -80°C for estimation of PAPP-A and placental growth factor. Quantification of PAPP-A and placental growth factor from the serum was done by using COBAS 411 (Roche– Hitachi; USA) auto analyzer based on the principle of electrochemiluminescence.

Screen positive definition

Women with maternal factors like high BMI, increased MAP, uterine artery PI more than 2, PAPP-A, PLGF ratio more than 35 were considered as high risk for developing PE.

Statistical analysis

Data were analyzed as mean standard deviation (SD), frequency and percentage whenever appropriate. Comparison of different variables between the study groups was done using t test (for independent samples in case of continuous data) and χ2-test. For smaller values, Fisher’s exact test was used.

Results

In the present study, 500 women who fulfilled the inclusion criterion were subjected to PE screening, among which 48 women screened positive for pre-eclampsia (9.6%). These women were further randomized to Group A who received 75 mg of aspirin and Group B who received 150 mg of aspirin (Figure 1). These women were further analyzed for maternal and fetal outcomes.

There were no significant differences between the 75 mg aspirin group and 150 mg aspirin group in terms of demographic characteristics (Table 1). Most women in the study group were in the age group of 25 to 30 years with a mean age of 28.2 years. In our study, 66.3% of women taking 150 mg aspirin were multigravida. Most women in the study group had BMI of 18-24 kg/m² , with a mean value of 22 kg/m² .

Pre-eclampsia occurred in 6 of 22 participants (27.2%) in the 75 mg aspirin group compared to 1 of 24 (4.1%) in the 150 mg aspirin group. Significant difference was observed in the incidence of PE (p=0.0293), its severity and period of gestation at delivery in the two groups (Table 2). No significant difference was observed in other complications like Gestational Diabetes Mellitus (GDM) and Preterm premature rupture of membranes (PPROM) in both the groups (p = 0.492 and 1, respectively).

Fetal complications and outcomes were checked in both groups, and no statistically significant difference was observed between them (Table 3).

Discussion

Preeclampsia affects about 2–8% of pregnancies. The prevalence of preeclampsia-complicating pregnancy in India is 7.8%. In this study, 500 pregnant women were screened, among which 48 women (9.6%) were found positive. In our study, we used maternal biophysical parameters like BMI, MAP, biochemical tests PAPP-A, PLGF ratio, and uterine artery PI to screen pregnant women for preeclampsia in the first trimester (11 weeks to 13.6 weeks). Positive predictive value of this screening method was 12.7% and the negative predictive value was 91.6%. Studies by Poon et al. (2010), Odibo et al. (2011), Akolekar et al. (2013) showed positive predictive values of 4.2%, 11.3%, 6.8%, respectively, and a negative predictive value of 99.6%, 99.8% and 99.8%, respectively.8,11 Studies have shown that the addition of biochemical tests to predict preeclampsia has a detection rate of 77%.

Screened-positive women were further randomized to Group A & B, and were given prophylactic aspirin of 75 mg and 150 mg, respectively. Maternal and fetal outcomes were monitored. Pre-eclampsia occurred in 6 of 22 participants (27.2%) in the 75 mg aspirin group, while it occurred in 1 of 24 (4.1%) in the 150 mg aspirin group. There was a significant difference in the incidence of PE (p=0.0293). In our study, two women in Group A (75 mg aspirin) developed early onset pre-eclampsia (<34 weeks of gestation) and were associated with Intrauterine Growth Restriction (IUGR). One patient in Group B (150 mg) developed pre-eclampsia. Similar results were observed in the study conducted by Kumar et al., with the occurrence of PE in 17.5% of women taking 75 mg aspirin in comparison to 6.5% in women taking 150 mg of aspirin. ASPRE trial also showed beneficial effects of 150 mg of aspirin. In the present study, 40.9% of women taking 75 mg aspirin developed fetal growth restriction in comparison to 16.6% of women taking 150 mg aspirin. Studies by Bujold E¹² and Roberge S¹⁶ reported similar results.

Our study indicates prescription of 150 mg of aspirin for women from early gestational age (12 to 14 weeks) up to 36 weeks of gestation is beneficial in preventing pre-eclampsia, and its severity, and helps in reducing maternal and fetal morbidity. Studies have shown that the use of aspirin at bedtime reduces ambulatory blood pressure. Hence it is recommended to be given at night. In our study, use of aspirin showed no adverse effects on the mother and fetus.

Conclusion

Hypertension and pre-eclampsia are global health issues. Maternal and fetal morbidity and mortality due to hypertensive disorders in pregnancy is more due to factors like low socio-economic status, lack of education, poor knowledge about antenatal care, lack of expertise in diagnosing and managing hypertensive disorders in pregnancy. Our study demonstrated that screening tests are beneficial in identifying high-risk cases; however, the sample size included was very less. Early screening and use of prophylactic aspirin reduces the risk of development of preterm pre-eclampsia. Aspirin is safe, economical, and easily available. Prophylactic use of aspirin at a higher dose of 150 mg in women at high risk for preeclampsia from early trimester is beneficial in reducing the occurrence of preeclampsia and also the severity of complications.

Conflict of Interest

None