Severe Preeclampsia Predicted by 2nd Trimester Serum Markers

SAN FRANCISCO – Levels of serum markers measured early in the second trimester of pregnancy may help identify women who are likely to develop severe preeclampsia, the results of a nested case-control study indicated.

In the study, there was no association between the level of vitamin D and levels of two angiogenic factors that have been previously implicated in the development of preeclampsia, soluble FMS-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF).

But both the level of vitamin D and the ratio of sFlt-1 to PlGF predicted the development of severe preeclampsia after other risk factors were taken into account. And in ROC (receiver operating characteristic) curve analysis, the combination outperformed either measure individually.

"These results suggest that 25-hydroxyvitamin D and angiogenic factors play independent roles in the pathogenesis of preeclampsia," lead investigator Dr. Padmashree Chaudhury Woodham told attendees at the annual meeting of the Society for Maternal-Fetal Medicine.

"Our findings suggest that the combination of 25-hydroxyvitamin D level and sFlt-1:PlGF ratio is a better predictor of preeclampsia in midgestation than either marker alone," she added.

A low 25-hydroxyvitamin D level has previously been shown to be a risk factor for severe preeclampsia, according to Dr. Woodham, who is a fellow in ob.gyn. at the University of North Carolina at Chapel Hill. But its association with angiogenic factors is unclear.

"In vitro and animal studies have found that its active form regulates [vascular endothelial growth factor] production through vitamin D response elements in the VEGF promoter," she explained. "The clinical significance of these findings remains to be determined."

The investigators drew their study patients from a large cohort of pregnant women who gave blood for routine prenatal screening early in the second trimester (gestational age, 15-20 weeks). They restricted analyses to women with a singleton pregnancy who did not have chronic medical illnesses and whose fetuses did not have congenital abnormalities.

Each woman who developed severe preeclampsia (n = 41) was matched by race/ethnicity with three control women who had uncomplicated births at term (n = 123).

Banked frozen serum samples were assayed to determine levels of vitamin D (total 25-hydroxyvitamin D) and the angiogenic markers sFlt-1, PlGF, and VEGF.

The severe preeclampsia and control groups were similar in terms of age, parity, and body mass index, Dr. Woodham reported. Overall, 39% were black, 29% were white, 27% were Hispanic, and 5% were Asian.

The season and the median gestational age at the time blood was drawn were also similar. But the median gestational age at delivery was younger in the preeclampsia group (32.6 vs. 39.6 weeks; P less than .001).

Relative to their control counterparts, the women who developed preeclampsia had lower levels of vitamin D (P less than .001), VEGF (P less than .001), and PlGF (P = .03), and a higher ratio of sFlt-1 to PlGF (P = .02).

Levels of vitamin D were not correlated with levels of any of the angiogenic factors or with the sFlt-1:PlGF ratio, contrary to the findings of in vitro and animal studies, according to Dr. Woodham.

However, in a multivariate model, each 1-nmol/L increase in total vitamin D level was associated with a 5% reduction in the odds of preeclampsia, whereas each 1-unit increase in the sFlt-1:PlGF ratio was associated with an 11% increase in the odds.

ROC curve analysis showed that for predicting preeclampsia, the area under the curve was 0.745 for vitamin D alone and 0.669 for the sFlt-1:PlGF ratio alone. But it was higher with their combination (0.834).

There was also a small further improvement when VEGF level was added to the mix, with an area under the curve of 0.851.

"Clinical trials targeting risk factors such as we have identified in this study will be needed to establish whether these associations are causal," she concluded.

Dr. Woodham did not report any relevant conflicts of interest.

SAN FRANCISCO – Levels of serum markers measured early in the second trimester of pregnancy may help identify women who are likely to develop severe preeclampsia, the results of a nested case-control study indicated.

In the study, there was no association between the level of vitamin D and levels of two angiogenic factors that have been previously implicated in the development of preeclampsia, soluble FMS-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF).

But both the level of vitamin D and the ratio of sFlt-1 to PlGF predicted the development of severe preeclampsia after other risk factors were taken into account. And in ROC (receiver operating characteristic) curve analysis, the combination outperformed either measure individually.

"These results suggest that 25-hydroxyvitamin D and angiogenic factors play independent roles in the pathogenesis of preeclampsia," lead investigator Dr. Padmashree Chaudhury Woodham told attendees at the annual meeting of the Society for Maternal-Fetal Medicine.

"Our findings suggest that the combination of 25-hydroxyvitamin D level and sFlt-1:PlGF ratio is a better predictor of preeclampsia in midgestation than either marker alone," she added.

A low 25-hydroxyvitamin D level has previously been shown to be a risk factor for severe preeclampsia, according to Dr. Woodham, who is a fellow in ob.gyn. at the University of North Carolina at Chapel Hill. But its association with angiogenic factors is unclear.

"In vitro and animal studies have found that its active form regulates [vascular endothelial growth factor] production through vitamin D response elements in the VEGF promoter," she explained. "The clinical significance of these findings remains to be determined."

The investigators drew their study patients from a large cohort of pregnant women who gave blood for routine prenatal screening early in the second trimester (gestational age, 15-20 weeks). They restricted analyses to women with a singleton pregnancy who did not have chronic medical illnesses and whose fetuses did not have congenital abnormalities.

Each woman who developed severe preeclampsia (n = 41) was matched by race/ethnicity with three control women who had uncomplicated births at term (n = 123).

Banked frozen serum samples were assayed to determine levels of vitamin D (total 25-hydroxyvitamin D) and the angiogenic markers sFlt-1, PlGF, and VEGF.

The severe preeclampsia and control groups were similar in terms of age, parity, and body mass index, Dr. Woodham reported. Overall, 39% were black, 29% were white, 27% were Hispanic, and 5% were Asian.

The season and the median gestational age at the time blood was drawn were also similar. But the median gestational age at delivery was younger in the preeclampsia group (32.6 vs. 39.6 weeks; P less than .001).

Relative to their control counterparts, the women who developed preeclampsia had lower levels of vitamin D (P less than .001), VEGF (P less than .001), and PlGF (P = .03), and a higher ratio of sFlt-1 to PlGF (P = .02).

Levels of vitamin D were not correlated with levels of any of the angiogenic factors or with the sFlt-1:PlGF ratio, contrary to the findings of in vitro and animal studies, according to Dr. Woodham.

However, in a multivariate model, each 1-nmol/L increase in total vitamin D level was associated with a 5% reduction in the odds of preeclampsia, whereas each 1-unit increase in the sFlt-1:PlGF ratio was associated with an 11% increase in the odds.

ROC curve analysis showed that for predicting preeclampsia, the area under the curve was 0.745 for vitamin D alone and 0.669 for the sFlt-1:PlGF ratio alone. But it was higher with their combination (0.834).

There was also a small further improvement when VEGF level was added to the mix, with an area under the curve of 0.851.

"Clinical trials targeting risk factors such as we have identified in this study will be needed to establish whether these associations are causal," she concluded.

Dr. Woodham did not report any relevant conflicts of interest.

SAN FRANCISCO – Levels of serum markers measured early in the second trimester of pregnancy may help identify women who are likely to develop severe preeclampsia, the results of a nested case-control study indicated.

In the study, there was no association between the level of vitamin D and levels of two angiogenic factors that have been previously implicated in the development of preeclampsia, soluble FMS-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF).

But both the level of vitamin D and the ratio of sFlt-1 to PlGF predicted the development of severe preeclampsia after other risk factors were taken into account. And in ROC (receiver operating characteristic) curve analysis, the combination outperformed either measure individually.

"These results suggest that 25-hydroxyvitamin D and angiogenic factors play independent roles in the pathogenesis of preeclampsia," lead investigator Dr. Padmashree Chaudhury Woodham told attendees at the annual meeting of the Society for Maternal-Fetal Medicine.

"Our findings suggest that the combination of 25-hydroxyvitamin D level and sFlt-1:PlGF ratio is a better predictor of preeclampsia in midgestation than either marker alone," she added.

A low 25-hydroxyvitamin D level has previously been shown to be a risk factor for severe preeclampsia, according to Dr. Woodham, who is a fellow in ob.gyn. at the University of North Carolina at Chapel Hill. But its association with angiogenic factors is unclear.

"In vitro and animal studies have found that its active form regulates [vascular endothelial growth factor] production through vitamin D response elements in the VEGF promoter," she explained. "The clinical significance of these findings remains to be determined."

The investigators drew their study patients from a large cohort of pregnant women who gave blood for routine prenatal screening early in the second trimester (gestational age, 15-20 weeks). They restricted analyses to women with a singleton pregnancy who did not have chronic medical illnesses and whose fetuses did not have congenital abnormalities.

Each woman who developed severe preeclampsia (n = 41) was matched by race/ethnicity with three control women who had uncomplicated births at term (n = 123).

Banked frozen serum samples were assayed to determine levels of vitamin D (total 25-hydroxyvitamin D) and the angiogenic markers sFlt-1, PlGF, and VEGF.

The severe preeclampsia and control groups were similar in terms of age, parity, and body mass index, Dr. Woodham reported. Overall, 39% were black, 29% were white, 27% were Hispanic, and 5% were Asian.

The season and the median gestational age at the time blood was drawn were also similar. But the median gestational age at delivery was younger in the preeclampsia group (32.6 vs. 39.6 weeks; P less than .001).

Relative to their control counterparts, the women who developed preeclampsia had lower levels of vitamin D (P less than .001), VEGF (P less than .001), and PlGF (P = .03), and a higher ratio of sFlt-1 to PlGF (P = .02).

Levels of vitamin D were not correlated with levels of any of the angiogenic factors or with the sFlt-1:PlGF ratio, contrary to the findings of in vitro and animal studies, according to Dr. Woodham.

However, in a multivariate model, each 1-nmol/L increase in total vitamin D level was associated with a 5% reduction in the odds of preeclampsia, whereas each 1-unit increase in the sFlt-1:PlGF ratio was associated with an 11% increase in the odds.

ROC curve analysis showed that for predicting preeclampsia, the area under the curve was 0.745 for vitamin D alone and 0.669 for the sFlt-1:PlGF ratio alone. But it was higher with their combination (0.834).

There was also a small further improvement when VEGF level was added to the mix, with an area under the curve of 0.851.

"Clinical trials targeting risk factors such as we have identified in this study will be needed to establish whether these associations are causal," she concluded.

Dr. Woodham did not report any relevant conflicts of interest.