Maternal, gestational and neonatal characteristics and maternal angiogenic factors in normotensive pregnancies.

OBJECTIVE: Alterations in maternal circulating angiogenic factors are proposed to result in hypertension and proteinuria and development of preeclampsia. The aim of this study was to explore whether preeclampsia risk factors are associated with maternal angiogenic profile in normotensive pregnancies. STUDY DESIGN: Associations of pregnancy characteristics and maternal serum concentrations at delivery of proangiogenic placental growth factor (PlGF), antiangiogenic soluble fms-like tyrosine kinase receptor (sFlt1) and soluble endoglin (sEng), as well as the antiangiogenic ratios sFlt1/PlGF and (sFlt1+sEng)/PlGF were analyzed in 43 normotensive and 44 preeclamptic pregnancies. RESULTS: In normotensive pregnancies, increasing maternal age was associated with a more antiangiogenic profile, including lower PlGF concentrations and a higher (sFlt1+sEng)/PlGF ratio (P<0.05). In preeclampsia, shorter length of gestation and lower birth weight percentile were associated with a more antiangiogenic profile. CONCLUSION: A greater antiangiogenic profile with older maternal age may suggest a biological mechanism which mediates this preeclampsia risk factor. In preeclampsia, the antiangiogenic state was more pronounced with clinical characteristics indicative of greater disease severity.

Blood pressure augmentation and maternal circulating concentrations of angiogenic factors at delivery in preeclamptic and uncomplicated pregnancies.

OBJECTIVE: The objective of the study was to determine whether blood pressure increases are associated with maternal angiogenic factors in uncomplicated and preeclamptic pregnancies. STUDY DESIGN: Associations of blood pressure increases from mid- to late pregnancy with maternal serum concentrations of soluble fms-like tyrosine kinase receptor (sFlt1), soluble endoglin (sEng), and placental growth factor (PlGF) at delivery were analyzed in 43 uncomplicated and 44 preeclamptic pregnancies. RESULTS: In uncomplicated pregnancies, increases in diastolic and mean arterial pressure were inversely associated with PlGF at delivery and positively associated with sEng and sFlt1/PlGF ratio. There were no significant associations between blood pressure increases and angiogenic factor concentrations in preeclampsia. CONCLUSION: These data suggest that angiogenic factors are involved in blood pressure modulation in normotensive pregnancy and are consistent with the hypothesis that angiogenic balance plays a role in maternal breast cancer risk reduction associated with mid- to late blood pressure increases in uncomplicated pregnancies.

Circulating concentrations of soluble endoglin (CD105) in fetal and maternal serum and in amniotic fluid in preeclampsia.

OBJECTIVE: We explored whether concentrations of soluble endoglin in fetal serum and amniotic fluid and in maternal serum were elevated in preeclampsia. STUDY DESIGN: Umbilical vein serum, amniotic fluid, and maternal serum from 42 preeclamptic and 43 uncomplicated pregnancies that were delivered by cesarean section were analyzed by enzyme-linked immunosorbent assay for soluble endoglin. RESULTS: Median maternal serum and amniotic fluid soluble endoglin concentrations were elevated in preeclampsia, compared with control pregnancies (66.9 ng/mL vs 15.1 ng/mL; P < .001, and 1.9 ng/mL vs 0.6 ng/mL; P < .001). Low concentrations of soluble endoglin were found in fetal circulation, which did not differ between preeclampsia and control pregnancies (5.0 ng/mL vs 4.7 ng/mL; P = .2). Maternal serum soluble endoglin levels correlated with circulating soluble fms-like tyrosine kinase 1 concentrations. CONCLUSION: We confirmed elevated soluble endoglin in maternal circulation in preeclampsia, which correlated with soluble fms-like tyrosine kinase 1 concentrations and soluble fms-like tyrosine kinase 1/placental growth factor ratio. The fetus appears not to contribute to elevated circulating maternal soluble endoglin concentrations in preeclampsia.

Homocysteine, cysteine, and related metabolites in maternal and fetal plasma in preeclampsia.

Homocysteine is associated with endothelial dysfunction and cardiovascular disease, and elevated concentrations of homocysteine have been found in preeclampsia. The purpose of this study was to investigate maternal and fetal concentrations of total homocysteine and related metabolites (including cysteine, choline, and betaine), and possible associations with infant birth weight. Women with preeclampsia (n=47) and controls (n=51), who underwent cesarean section, were included. Maternal plasma, umbilical vein, and artery plasma were analyzed. Median concentrations of homocysteine, cysteine, choline, and betaine were significantly higher in women with preeclampsia than controls, both in maternal and fetal plasma. There were no differences in folate and vitamin B12 concentrations between the groups, neither for maternal nor fetal samples. Maternal homocysteine concentration was a negative predictor for birth weight only in the preeclampsia group. Elevated homocysteine and cysteine concentration in maternal circulation in preeclampsia is reflected in the fetal circulation. The clinical significance of elevated homocysteine and cysteine concentrations in maternal and fetal compartments in preeclampsia remain to be explored, both regarding fetal growth and development of disease later in life.

Regulation of ADRP expression by long-chain polyunsaturated fatty acids in BeWo cells, a human placental choriocarcinoma cell line.

Transplacental transfer of maternal fatty acids is critical for fetal growth and development. In the placenta, a preferential uptake of fatty acids toward long-chain polyunsaturated fatty acids (LCPUFAs) has been demonstrated. Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that has been ascribed a role in cellular fatty acid uptake and storage. However, its role in placenta is not known. We demonstrate that ADRP mRNA and protein are regulated by fatty acids in a human placental choriocarcinoma cell line (BeWo) and in primary human trophoblasts. LCPUFAs of the n-3 and n-6 series [arachidonic acid (20:4n-6), docosahexaenoic acid (22:6n-3), and eicosapentaenoic acid (20:5n-3)] were more efficient than shorter fatty acids at stimulating ADRP mRNA expression. The fatty acid-mediated increase in ADRP mRNA expression was not related to the differentiation state of the cells. Synthetic peroxisome proliferator-activated receptor and retinoic X receptor agonists increased ADRP mRNA level but had no effect on ADRP protein level in undifferentiated BeWo cells. Furthermore, we show that incubation of BeWo cells with LCPUFAs, but not synthetic agonists, increased the cellular content of radiolabeled oleic acid, coinciding with the increase in ADRP mRNA and protein level. These studies provide new information on the regulation of ADRP in placental trophoblasts and suggest that LCPUFA-dependent regulation of ADRP could be involved in the metabolism of lipids in the placenta.

Calprotectin, a marker of inflammation, is elevated in the maternal but not in the fetal circulation in preeclampsia.

OBJECTIVE: Preeclampsia is associated with excessive inflammatory response compared with normal pregnancy. Calprotectin is an inflammation marker not previously explored in preeclampsia. STUDY DESIGN: Calprotectin in maternal and fetal plasma and amniotic fluid was investigated at cesarean delivery in normal pregnancies and preeclampsia. C-reactive protein (CRP) and plasminogen activator inhibitor type1 (PAI-1) were also analyzed. RESULTS: Maternal median calprotectin, CRP, and PAI-1 concentrations were elevated in preeclampsia (1081 microg/L, 4.8 mg/L, and 51.0 U/mL) compared with control levels (552 microg/L, 3.8 mg/L, and 36.5 U/mL). In the umbilical vein, there were no differences between preeclampsia and controls regarding calprotectin and CRP levels. Maternal calprotectin concentrations correlate with CRP and PAI-1 values for the total study group, but a statistical significant correlation was not found in the preeclamptic group. CONCLUSION: Calprotectin is elevated in the maternal circulation in preeclamptic pregnancies. We found no evidence of inflammatory response in the fetal circulation in preeclampsia.

Circulating concentrations of sFlt1 (soluble fms-like tyrosine kinase 1) in fetal and maternal serum during pre-eclampsia.

OBJECTIVE: We hypothesized that umbilical vein serum soluble fms-like tyrosine kinase 1 (sFlt1) concentration was augmented in pre-eclampsia. We also explored a possible association between fetal and maternal concentrations of sFlt1. STUDY DESIGN: At cesarean delivery, maternal serum samples from pre-eclamptic (n=38) and uncomplicated (n=32) pregnancies were obtained, as well as umbilical vein serum and amniotic fluid samples. ELISA for human sFlt1, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were performed. RESULTS: Median sFlt1 concentrations were elevated in pre-eclampsia compared to uncomplicated pregnancy, in umbilical venous serum (246 and 163 pg/mL, P=0.04), in maternal serum (9932 and 3417 pg/mL, P<0.001), as well as in amniotic fluid (51,040 and 33,490 pg/mL, P=0.03). A positive association between the fetal and maternal serum levels of sFlt1 was found in the pre-eclampsia group. Median PlGF concentration in the maternal serum was significantly lower in the pre-eclampsia group compared to the control group (82 pg/mL and 169 pg/mL, P<0.001). CONCLUSIONS: sFlt1 concentration is elevated in the fetal circulation in pre-eclampsia, but at a much lower level than in the maternal circulation. The results of our study do not support a substantial fetal contribution to the elevated circulating maternal sFlt1 protein concentration in pre-eclampsia.

The decidual suction method: a new way of collecting decidual tissue for functional and morphological studies.

BACKGROUND: Studies of extravillous trophoblasts and placental bed spiral arteries are essential for a better understanding of pathological pregnancies such as preeclampsia, intrauterine growth restriction and diabetes mellitus. A major challenge is to obtain representative and sufficient tissue for morphological and functional investigations. Currently, tissue material is mostly harvested by placental bed biopsy (PBB). We describe a new suction method to obtain a larger volume of decidual tissue from the placental bed. METHODS: Tissue was harvested in 51 cesarean sections by vacuum suction of the placental bed. Sections from formalin-fixed, paraffin-embedded tissue were routinely stained with hematoxylin and eosin (H&E), immunostained with a panel of antibodies and morphologically examined for the presence of trophoblasts and spiral arteries. The results were compared with those from archive material from PBBs and placental basal plate sections (BPSs). Short-term adverse events were registered for the study patients. Long-term complications were registered from medical charts of 151 women having undergone the decidual suction method (DSM), with a follow-up of 38-60 months. RESULTS: In 86% (n = 44), one random section from the decidual suction material demonstrated at least one spiral artery. In 37% (n = 19), six or more spiral arteries were present. All sections revealed extravillous trophoblasts. No short- or long-term morbidity was recorded. CONCLUSIONS: The decidual suction method represents an important improvement in the work to obtain sufficient decidual tissue for morphological and functional studies of extravillous trophoblast function and spiral artery adaptation. The method is safe, as no short- or long-term complications were registered.