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The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role.We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia.During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant.Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.

Maternal smoking reduces the risk of pre-eclampsia, but has been reported to increase the risk of adverse outcomes related to the disease. We used data from the trial of Calcium for Pre-eclampsia Prevention (CPEP) to explore whether clinical manifestations of pre-eclampsia were altered by maternal smoking. CPEP was a randomised study of 4589 nulliparous women conducted in five US medical centres. Smoking history was obtained at study enrolment and women were monitored for the development of hypertension, proteinuria, and other medical complications. Among pre-eclamptic women (n=274), the risk of severe disease was not elevated in smokers (adjusted odds ratio 0.87 [95% confidence interval (CI) 0.30, 2.51]). Compared with non-smokers, gestational age (days, +/-SE) at onset of pre-eclampsia was not reduced in smokers (264.8 +/- 1.5, and 268.2 +/- 5.5, respectively, P=0.48). The smoking-attributable deficit in birthweight was not increased in pre-eclamptic women compared with normotensive women (97 g [95% CI -49, 244] and 185 g [95% CI 141, 229] respectively). In conclusion, among women who developed pre-eclampsia, smoking during pregnancy was not associated with disease severity. We found no evidence that pre-eclampsia and smoking act synergistically to restrict fetal growth.