In this study we observed two distinct patterns of maternal plasma PGF across pregnancy. One PGF pattern resembled that observed among uncomplicated normotensive pregnant women, while the other maternal plasma PGF pattern was consistently below the lower 95%CI of plasma PGF observed among uncomplicated pregnant women after 15 weeks gestation to delivery. This low pattern of maternal PGF was present in nearly half (46%, 23/50) of the women who developed preeclampsia in this study. It is obvious that subjects with this low PGF pattern prior to clinically evident preeclampsia account for the statistically significant differences in PGF observed among the entire longitudinal cohort of women who develop preeclampsia. Finally, we observed that preeclamptic subjects with the consistent low PGF pattern across pregnancy exhibited differences in clinical outcome data compared to preeclamptic subjects with the high PGF pattern including: significantly elevated blood pressure before 20 weeks gestation, significantly earlier gestational age at delivery, more preterm births, and more SGA infants. Low PGF alone was not sufficient to account for these findings in the absence of other components of preeclampsia pathophysiology since these clinical differences were not present in the 5% of normotensive control women with similarly low PGF concentrations across pregnancy (although blood pressure was slightly higher at delivery in this group). However, these data support the heterogenous nature of preeclampsia, and suggest that these strikingly different patterns of maternal PGF across pregnancy among women who later develop preeclampsia may identify important subsets of preeclamptic patients.
In addition, we have confirmed that women with preeclampsia have significantly lower plasma PGF and higher sFLT1 concentrations compared to women with uncomplicated pregnancies, and that these differences are greatest among women with preterm preeclampsia. We also observed that overall maternal plasma PGF concentrations were significantly lower by mid-pregnancy (15 to 25 weeks gestation) and remained lower among women who later developed preeclampsia, and that maternal sFLT1 concentrations were significantly elevated later in pregnancy (25 to 33 weeks gestation) and remained elevated among women who developed preeclampsia compared to women with uncomplicated pregnancies. These differences in PGF and sFLT1 preceded the clinical onset of preeclampsia by 7 to 11 weeks and 1 to 7 weeks respectively. These data are consistent with other published studies that have suggested these analytes, alone or in combination, as potential predictive markers of preeclampsia. 10, 12, 14, 15
However, the heterogeneity of PGF and sFLT1 concentrations among women who develop preeclampsia limits their practical use as predictive markers of the syndrome as evidenced by the poor ROC curves obtained using PGF, sFLT1 and the PGF/sFLT1 ratio values from samples obtained between 15 and 23 weeks gestation before the clinical onset of the syndrome.
The variability of PGF and sFLT1 among pregnant women and women who develop preeclampsia is evident in many studies. 8, 16–18
PGF is a member of the vascular endothelial growth factor subfamily, it is expressed by trophoblast cells, and has both vasculogenetic and angiogenetic functions. PGF’s angiogenic abilities have been speculated to play a role in normal pregnancy, and changes in the concentrations of PGF and sFLT1 have been proposed in the pathophysiology of preeclampsia. 7, 9, 19
However, given the heterogeneous nature of PGF and sFLT1 among women who develop preeclampsia it seems unlikely that a single pattern or mechanism can explain all cases of preeclampsia. Additionally, these data indicate that these angiogenic markers are not necessarily causative for the incomplete or failed uterine spiral artery remodeling reported in preeclampsia, since their concentrations are similar to those observed among uncomplicated pregnant women in early pregnancy when these placental abnormalities begin to develop. 20
Several studies have reported that the circulating concentration of maternal PGF is significantly lower in early pregnancy among women who later develop preeclampsia compared to women with uncomplicated pregnancies, and that low maternal PGF concentrations are more pronounced among women who develop early onset preeclampsia and/or deliver SGA infants. 12, 18, 21–25
As shown in this study, the observation of low PGF in early pregnancy among all women who later develop preeclampsia was driven by an identifiable subset of women who exhibited consistently low PGF across pregnancy, below the 95% CI of uncomplicated pregnant women. Importantly, the subset of preeclamptic women who exhibited consistently low PGF across pregnancy accounted for almost half of the preeclampsia cases in this longitudinal investigation. In addition, these subjects were more likely to deliver preterm and have SGA babies compared to preeclamptic women with PGF concentrations similar to normotensive controls. These women also exhibited elevated blood pressures in early pregnancy compared to women who developed preeclampsia and had PGF concentrations similar to uncomplicated controls.
The observation of low and high maternal PGF concentrations across pregnancy among women who later develop preeclampsia may be an important observation in relation to the pathophysiology and study of preeclampsia. First, the presence of these different patterns of maternal PGF across pregnancy may indicate that at least two different pathophysiological processes underlie this heterogeneous syndrome. Perhaps these different patterns of maternal PGF indicate that half of the cases of preeclampsia are the result of insufficient angiogenic signaling (low PGF) and half of the cases of preeclampsia are the result of insensitivity to angiogenic signaling (high PGF) or are determined by a different pathogenic factor. Based on these two different patterns of maternal PGF we speculate that this may represent a relevant division of preeclampsia, low vs. high PGF or type 1 vs. type 2 preeclampsia. This finding may be similar to that of diabetes with its well-defined and understood type 1 (low insulin) vs. type 2 (high insulin) classification. In addition, the presence of low and high patterns of maternal PGF in preeclampsia explains previous published data regarding the poor predictive nature of PGF and sFLT1 for preeclampsia. If low PGF in preeclampsia is present in only half of all cases, then it is obvious that many cases of preeclampsia would be missed if only using this marker. Conversely, these longitudinal data suggest women with persistent PGF concentrations below the lowest 5% of concentrations observed in uncomplicated pregnant women after 15 weeks gestation have a 30% chance of developing preeclampsia, and this group of women appears to represent half of the cases of preeclampsia. It is important for this observation to be duplicated in another independent longitudinal study.
Despite the large number of normotensive control subjects investigated in the longitudinal portion of this study, this group is limited in that none of these subjects had preterm birth and relatively few had SGA infants (3%). Therefore differences in preterm birth and SGA infants between controls and the preeclampsia subjects are more pronounced and are likely elevated compared to more heterogeneous control populations. However, because of this limitation, this study focused its attention primarily on differences between the low vs. high PGF preeclampsia groups, as well as comparisons between the low PGF normotensive control group and the low PGF preeclampsia group indicating that the low maternal PGF pattern is not just a consequence of SGA.