Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies

Wolf, Myles; Shah, Anand; Lam, Chun; Martinez, Abelardo; Smirnakis, Karen; Epstein, Franklin H.; Taylor, Robert N.; Ecker, Jeffrey L.; Karumanchi, S. Ananth; Thadhani, Ravi

doi:10.1016/j.ajog.2005.03.016

Cited by 120 publications

(75 citation statements)

References 26 publications

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“…This observation agrees with the previous epidemiological evidence that nulliparity is a predominant independent risk factor for pre-eclampsia [21][22][23] and that (non-diabetic) women with a first pregnancy have a three-to fivefold increased risk compared with subsequent pregnancies [24]. There is evidence that serum sFlt1 levels are significantly increased in the first compared with second pregnancies, which may account in part for the increased risk of preeclampsia among nulliparous women [25]. Interestingly, our own results also indicated a consistent trend towards higher sFlt1 levels in the first than in subsequent pregnancies both in diabetic and non-diabetic groups (data not shown), but this did not reach statistical significance.…”

Section: Discussionsupporting

confidence: 91%

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Jenkins

Nankervis

et al. 2008

Diabetologia

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Aims/hypothesis Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFβ1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia. Methods Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial-derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term. Diabetologia (2009) Results Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n=26) vs those without hypertensive complications (diabetic normotensive, n=95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p<0.05) and the normal rise of PlGF during pregnancy was blunted (p<0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r 2 =42%, p<0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p<0.0001). Conclusions/interpretation Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

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Section: Discussionsupporting

confidence: 91%

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Jenkins

Nankervis

et al. 2008

Diabetologia

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“…The natural role of sFlt1 in pregnancy is not known; however, it may contribute to the pathogenesis of preeclampsia. Preeclampsia, like PM, is most frequent in first-time mothers, and sFlt1 levels are elevated in healthy first vs. second pregnancies (19). We speculate that exposure to malaria during human evolution influenced sFlt1 regulatory mechanisms, and this might continue to affect pregnancies outside of malaria endemic areas.…”

Section: Discussionmentioning

confidence: 99%

Natural selection of FLT1 alleles and their association with malaria resistance in utero

Muehlenbachs

Fried

Lachowitzer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Placental malaria (PM) caused by Plasmodium falciparum contributes significantly to infant mortality in sub-Saharan Africa and is associated with pregnancy loss. We hypothesized that fetal genes that modify PM would be associated with fetal fitness. During PM, placental trophoblasts produce soluble fms-like tyrosine kinase 1 (sFlt1), also known as soluble VEGF receptor 1, an angiogenesis inhibitor associated with preeclampsia. Here we present a study examining the genotype of the fms-related tyrosine kinase 1 (FLT1) 3 UTR in Tanzanian mother-infant pairs. First-time mothers suffer the most PM, and newborn FLT1 genotype distribution differed by birth order, with newborns of first-time mothers outside of HardyWeinberg equilibrium (HWE) during peak PM season. Among first-time but not other mothers, maternal FLT1 genotype was associated with a history of prior pregnancy loss. During PM, newborn FLT1 genotype was associated with low birth weight and placental inflammatory gene expression. FLT1 genotype was also associated with Flt1 levels among study subjects and in vitro. Thus, FLT1 variants confer fetal fitness in utero and are associated with the maternal immune response during PM. This indicates that FLT1 is under natural selection in a malaria endemic area and that human exposure to malaria can influence the evolutionary genetics of the maternal-fetal relationship.angiogenesis ͉ parasitology ͉ pregnancy ͉ placenta ͉ Plasmodium falciparum

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“…44 Serum sFlt-1 and PlGF levels are known to rise and decrease during the third trimester of pregnancy, respectively. 19,35 Cigarette smoking was previously shown to be associated with lower maternal sFlt-1 concentrations in uncomplicated pregnancy and pre-eclampsia.…”

Section: Discussionmentioning

confidence: 99%

Circulating angiogenic factors determined by electrochemiluminescence immunoassay in relation to the clinical features and laboratory parameters in women with pre-eclampsia

et al. 2010

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The purpose of this study was to determine whether increased serum soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased placental growth factor (PlGF) levels in pre-eclampsia are related to the clinical features and laboratory parameters of the patients, including markers of inflammation, endothelial activation and injury, oxidative stress and trophoblast debris. A total of 54 pre-eclamptic patients, 58 healthy pregnant and 52 healthy non-pregnant women were involved in this case-control study. Serum sFlt-1 and PlGF levels were measured by electrochemiluminescence immunoassay. Serum levels of sFlt-1 and PlGF were significantly higher in pre-eclamptic patients and healthy pregnant women than in healthy non-pregnant women. In addition, pre-eclamptic patients had significantly higher sFlt-1 levels and significantly lower PlGF concentrations compared with healthy pregnant women. According to the subgroup analyses, sFlt-1 levels were significantly higher in severely pre-eclamptic patients than in those with mild pre-eclampsia, whereas pre-eclamptic patients with fetal growth restriction or preterm onset of the disease had significantly lower PlGF concentrations compared with those without intrauterine growth restriction or with a disease onset at term. In the pre-eclamptic group, there were significant positive correlations between serum sFlt-1 levels and systolic and diastolic blood pressure, serum levels of blood urea nitrogen and creatinine, as well as plasma levels of von Willebrand factor antigen, fibronectin and cell-free fetal DNA. Furthermore, serum PlGF concentrations of pre-eclamptic patients showed significant positive correlations with gestational age at disease onset and delivery, as well as with fetal birth weight, and significant inverse correlations with levels of blood urea nitrogen, creatinine and fibronectin. In conclusion, increased serum sFlt-1 and decreased PlGF levels are associated with blood pressure, renal and endothelial dysfunction, trophoblast deportation, as well as with a shorter duration of pregnancy, fetal growth restriction, the severity and preterm onset of the disease in pre-eclampsia. These findings indicate the central role of an angiogenic imbalance in the pathogenesis of this pregnancy-specific disorder.

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Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies

Cited by 120 publications

References 26 publications

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Natural selection of FLT1 alleles and their association with malaria resistance in utero

Circulating angiogenic factors determined by electrochemiluminescence immunoassay in relation to the clinical features and laboratory parameters in women with pre-eclampsia

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