Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia.

OBJECTIVE: Soluble fms-like tyrosine kinase (sFlt-1) is an important mediator in the pathogenesis of preeclampsia. We sought to determine whether platelet-monocyte aggregates (PMAs) produced sFlt-1 and whether PMAs contributed to sFlt-1 production in preeclampsia. STUDY DESIGN: This was a case-control study of sFlt-1 release from PMAs using blood samples from women with preeclampsia matched by gestational age to pregnant controls. A third group of nonpregnant, reproductive-age women comprised an additional control group. Experiments were also performed using blood from nonpregnant women to elucidate whether inducing PMAs could stimulate sFlt-1 production and, if so, to determine the necessary receptors and pathways. RESULTS: Women with preeclampsia had increased total Flt-1 concentrations in platelets and monocytes at baseline compared with pregnant controls (25 vs 10 pg/mL, P = .0003). sFlt-1 production was elicited from monocytes incubated with thrombin-activated platelets from nonpregnant women. sFlt-1 production was regulated at the transcriptional level by p38 and nuclear factor-κB-dependent pathways. CONCLUSION: Activated platelets in preeclampsia bind monocytes to generate sFlt-1. PMAs are a previously unrecognized source of sFlt-1 that may contribute to endothelial dysfunction and systemic inflammation commonly observed in preeclampsia.

Progesterone receptor genotype, family history, and spontaneous preterm birth.

OBJECTIVE: To examine whether women with a personal or family history of preterm birth are more likely to have genetic variation in the human progesterone receptor (hPR). METHODS: Women with a singleton preterm birth at less than 37 weeks of gestation between 2002 and 2006 were identified from a prospectively collected clinical and biologic obstetric database (cases). Women in the control group were those with only term deliveries at or above 38 weeks of gestation. The Utah Population Database was queried for family history (first- or second-degree relative) of preterm birth. DNA was extracted from stored buffy coats and genotyped for six single nucleotide polymorphisms in the hPR. RESULTS: One hundred fifty-four patients (92 women in the preterm case group, 62 women in the term control group) were included. All were white or Hispanic. There were no statistical differences between white and Hispanic allele frequencies. Women in the preterm case group were more likely to carry the minor allele, G (minor allele frequency 0.29 compared with 0.18, P=.035) for rs471767, and were more likely to carry the GT haplotype across rs471767 and rs578029 compared with women in the term control group. Similar haplotype block variation was seen among women with preterm birth plus a family history of preterm birth. CONCLUSION: Allele and haplotype frequencies in the hPR are significantly different among women with preterm birth and women with preterm birth plus a family history of preterm birth. This suggests the hPR gene may be a candidate for association with preterm birth or familial preterm birth. LEVEL OF EVIDENCE: III.