Discussion
Although PlGF is a well-recognized first trimester PE screening tool and the sFLT-1/PlGF ratio is gradually gaining ground as a marker to identify PE and its complications later in pregnancy, the role of PlGF alone in the second trimester and beyond, for the prediction of adverse pregnancy outcome is still under evaluation. In the present study by serial evaluation of its levels at three time intervals in the second half of pregnancy, the cut-offs and the best timing of test for the PE prediction was determined. PE occurred in one out of every six high risk women included in the study, it was early onset in one out of fourteen of them. PlGF proved to be a reliable prognostic and diagnostic marker in the study cohort. Early onset PE could be predicted in 9 out of 10 cases by testing at 28-30 weeks and in all cases of preterm PE by PlGF estimation at 34-36 weeks of gestation.
In the present study, nearly 30% of the high risk women had PlGF below cut-off, in the study by Mclaughlin et al on the similar cohort PlGF was below cut -off of 100pg/ml in 29.5% cases 10 . Other previous studies have also taken 100 pg/ml as PlGF cut-off and estimated it only once any time between 20- 36 weeks 10,11, however, in the present study it was done successively thrice and the gestation specific cut-offs were derived (224pg/ml, 211pg/ml and 176 pg/ml at 20-22, 28-30 and 34-36 weeks respectively). In the study by Omsher et al  a low PlGF (<12 pg/ml) was associated with a shorter test-birth interval and universally (100% PPV)12 , in our study women with values less than 12pg/ml constituted only 1.4% (4/287) cases and already had severe clinical features. As the PlGF levels differ with gestation using the different cut-offs deemed more appropriate and is a subject for further research.
PlGF was effective in the prediction of severe maternal and fetal complications. Its values were below cut off at all time points in significantly high number of women who delivered preterm, with the highest odds at 28-30 weeks. All women with hypertension and its complications such as preeclampsia, early onset preeclampsia or severe preeclampsia had significantly low PlGF in second as well as third trimester. In the study done by Mc Laughlin et al, low PlGF was similarly found to significantly increase the risk of preterm delivery and early-onset preeclampsia (adjusted odds ratio, 58.2 [95% CI, 32.1–105.4] 10. In the multi-centric randomized controlled trial by Duhig et al (PARROT study), PlGF estimation in the intervention group resulted in substantially fast clinical confirmation of preeclampsia, and a lower incidence of maternal adverse outcome11. A meta-analysis by Lim et al, demonstrated that PlGF had moderate sensitivity and specificity for predicting adverse maternal or perinatal outcomes (sensitivity ranged from 46–87%, specificity from 78–90% and area under the receiver operating characteristic curve ranged from 0.63–0.96) 13, 14, 15, 16.. But in most of the earlier studies, the cohort consisted of suspected cases of PE, in our study we included women who were clinically at high risk of PE , which is more commonly observed and poses a management dilemma with respect to the degree of surveillance needed 12, 13, 14. In the present study, a significant number of early onset FGR cases and those who had more than one week nursery stay had significantly low PlGF but there was no marked difference in its levels between late onset FGR and normal outcome. Sharp et al , reported that revealing the PlGF values in women with suspected PE was associated with lower perinatal mortality but lead to earlier delivery with more neonatal respiratory morbidity15. Hence, there is need for more robust data for better clinical management of cases at high risk of PE.
In our study, the performance of PlGF was similar or slightly better than sFlt-1/PlGF ratio in predicting adverse outcome, and performed better in women with severe PE and early onset preeclampsia compared to those with late onset PE. Doing sFLT-1/PlGF ratio doubles the cost of the test; hence use of PlGF alone as a marker of preeclampsia in the second half of pregnancy is certainly more cost effective. The inclusion of PlGF levels in routine biochemical testing would enable individualized treatment of patients, hence avoiding severe morbidity and ensuring timely delivery. There is also a double benefit of appropriately reassuring women who do not need intensive investigation and minimizing excessive health service use by avoiding unnecessary admission and follow up17. In a commentary by Stephan et al, it was proposed that the American College of Obstetricians and Gynecologists definition of preeclampsia should may also include new-onset of altered angiogenic factors (sFlt-1/PlGF ratio or PlGF alone) 18.
The strength of the study was that serial evaluation of PlGF and determination of the gestational age specific cut-off in clinically high risk women was done, and the time to delivery interval for guidance in management could be provided. The weakness could be that early pregnancy assessment was not done, and only high risk women were included.
Conclusion :
The PlGF is a good marker to be done at 28-30 weeks for prediction of PE especially early onset and its adverse outcome; it can also be done at 34-36 weeks for prediction of preterm PE. The new cut-offs derived in the study need further validation and research.