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.