Fetal Adverse Outcomes in Pregnant Women With Hypertension
Fetal Adverse Outcomes in Pregnant Women With Hypertension
This study aimed to assess the performance of the Alere Triage® PlGF test, a rapid test for measuring PlGF levels in the maternal peripheral blood. Our study population consisted of women with chronic hypertension, gestational hypertension, HELLP syndrome, preeclampsia and superimposed preeclampsia. We earlier evaluated the diagnostic accuracy of this test in the study groups and healthy pregnant control subjects and found that using a gestational age-dependent threshold of 5% of a normal population, a positive PlGF test predicted delivery before 37 weeks in over 90% of hypertensive women. In this study we compared the diagnostic value of PlGF measured before 35 weeks using two absolute thresholds with the last Doppler ultrasonography before delivery in identifying preterm birth and IUGR neonates.
We found that PlGF concentration below 100 pg/ml identified all women with hypertensive disorders of pregnancy who required urgent delivery following an abnormal fetal flow result, and predicted all IUGR neonates, and 56/61 women who had a preterm delivery. Nearly 60% of women with normal fetal flow results had a preterm delivery. Our protocol for delivery dictated birth by Cesarean section, as clinically required, for women at any gestational age with evidence of fetal compromise including abnormal fetal flow, pathological CTG and severe oligohydramnios. The Triage PlGF test identified the majority of women with normal fetal flow who needed to be delivered preterm due to pathological CTG or oligohydramnios. Considering both test results together, no woman with a normal fetal flow and normal PlGF had an IUGR infant, and only 5 had a preterm delivery, 2 of whom were due to premature rupture of membranes.
In a small study Benton et al. found that Triage PlGF differentiated placental IUGR from constitutionally small fetuses with a sensitivity of 100% and a specificity of 86%. Consistently, all of our SGA neonates were asymmetrically small with no fetal structural abnormalities or genetic diseases suggesting placental IUGR and had low or very low PlGF. In 2007 Schlembach et al. correlated levels of angiogenic growth factors, including PlGF, with Doppler ultrasound parameters in women with preeclampsia and intrauterine growth restriction (suspected by ultrasound measurements and confirmed by birth weight). Maternal levels of PlGF were inversely correlated with PI values in both the umbilical and uterine arteries. PlGF levels in the umbilical vein were below the detection limit in nearly all samples of IUGR fetuses and lower than in those with preeclampsia (p<0.001). In our study, we observed low or very low PlGF even in hypertensive women with normal fetal flow and an IUGR neonate.
Taylor et al. reported in 2003 that maternal circulating PlGF levels in preeclampsia are lower if accompanied by IUGR. Furthermore they showed that in normotensive subjects with IUGR, PlGF concentrations are also decreased compared to controls. Our knowledge about IUGR in chronic and gestational hypertension in this regard is deficient. We found a positive PlGF test in all women with an abnormal fetal flow, all women with an IUGR neonate, the majority of women with pathological CTG or oligohydramnios, as well as in a high proportion of women carrying normal-size fetuses, many of whom had preterm delivery. Thus, the sensitivity of the PlGF test for fetal risk (IUGR, abnormal fetal flow, pathological CTG, oligohydramnios, preterm delivery) in the hypertension group with and without proteinuria was excellent.
The potential clinical impact of these findings is that PlGF may provide useful information before 35 gestational week to identify fetuses requiring urgent delivery, and those at risk of later adverse outcomes not identified by fetal flow Doppler ultrasonography. Similarly, for all women with hypertensive disorders of pregnancy, a combination of a normal fetal flow and normal PlGF test may identify women at lower risk of adverse outcomes.
However, the weakness of our study is its retrospective observational design following normal clinical practice and the low case number. Additionally, we did not measure circulating levels of anti-angiogenic factors (sFlt-1, soluble endoglin). In this retrospective observational study of a specific target population we are unable to calculate the specificity of either test with respect to preterm delivery or IUGR infant, or to calculate negative or positive predictive values. There is a need for prospective studies to prove the safety and efficiency of the test in the clinical management of hypertension in pregnancy.
Discussion
This study aimed to assess the performance of the Alere Triage® PlGF test, a rapid test for measuring PlGF levels in the maternal peripheral blood. Our study population consisted of women with chronic hypertension, gestational hypertension, HELLP syndrome, preeclampsia and superimposed preeclampsia. We earlier evaluated the diagnostic accuracy of this test in the study groups and healthy pregnant control subjects and found that using a gestational age-dependent threshold of 5% of a normal population, a positive PlGF test predicted delivery before 37 weeks in over 90% of hypertensive women. In this study we compared the diagnostic value of PlGF measured before 35 weeks using two absolute thresholds with the last Doppler ultrasonography before delivery in identifying preterm birth and IUGR neonates.
We found that PlGF concentration below 100 pg/ml identified all women with hypertensive disorders of pregnancy who required urgent delivery following an abnormal fetal flow result, and predicted all IUGR neonates, and 56/61 women who had a preterm delivery. Nearly 60% of women with normal fetal flow results had a preterm delivery. Our protocol for delivery dictated birth by Cesarean section, as clinically required, for women at any gestational age with evidence of fetal compromise including abnormal fetal flow, pathological CTG and severe oligohydramnios. The Triage PlGF test identified the majority of women with normal fetal flow who needed to be delivered preterm due to pathological CTG or oligohydramnios. Considering both test results together, no woman with a normal fetal flow and normal PlGF had an IUGR infant, and only 5 had a preterm delivery, 2 of whom were due to premature rupture of membranes.
In a small study Benton et al. found that Triage PlGF differentiated placental IUGR from constitutionally small fetuses with a sensitivity of 100% and a specificity of 86%. Consistently, all of our SGA neonates were asymmetrically small with no fetal structural abnormalities or genetic diseases suggesting placental IUGR and had low or very low PlGF. In 2007 Schlembach et al. correlated levels of angiogenic growth factors, including PlGF, with Doppler ultrasound parameters in women with preeclampsia and intrauterine growth restriction (suspected by ultrasound measurements and confirmed by birth weight). Maternal levels of PlGF were inversely correlated with PI values in both the umbilical and uterine arteries. PlGF levels in the umbilical vein were below the detection limit in nearly all samples of IUGR fetuses and lower than in those with preeclampsia (p<0.001). In our study, we observed low or very low PlGF even in hypertensive women with normal fetal flow and an IUGR neonate.
Taylor et al. reported in 2003 that maternal circulating PlGF levels in preeclampsia are lower if accompanied by IUGR. Furthermore they showed that in normotensive subjects with IUGR, PlGF concentrations are also decreased compared to controls. Our knowledge about IUGR in chronic and gestational hypertension in this regard is deficient. We found a positive PlGF test in all women with an abnormal fetal flow, all women with an IUGR neonate, the majority of women with pathological CTG or oligohydramnios, as well as in a high proportion of women carrying normal-size fetuses, many of whom had preterm delivery. Thus, the sensitivity of the PlGF test for fetal risk (IUGR, abnormal fetal flow, pathological CTG, oligohydramnios, preterm delivery) in the hypertension group with and without proteinuria was excellent.
The potential clinical impact of these findings is that PlGF may provide useful information before 35 gestational week to identify fetuses requiring urgent delivery, and those at risk of later adverse outcomes not identified by fetal flow Doppler ultrasonography. Similarly, for all women with hypertensive disorders of pregnancy, a combination of a normal fetal flow and normal PlGF test may identify women at lower risk of adverse outcomes.
However, the weakness of our study is its retrospective observational design following normal clinical practice and the low case number. Additionally, we did not measure circulating levels of anti-angiogenic factors (sFlt-1, soluble endoglin). In this retrospective observational study of a specific target population we are unable to calculate the specificity of either test with respect to preterm delivery or IUGR infant, or to calculate negative or positive predictive values. There is a need for prospective studies to prove the safety and efficiency of the test in the clinical management of hypertension in pregnancy.