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45 On the origin and disappearance of sFlt-1 and PlGF in preeclampsia
Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 6 (2016) 178–252
Methods: In this ongoing observational study, the sFlt-1/PlGF ratio was determined (Elecsys assay, Roche Diagnostics) at P2 time points in women with (suspected) PE based on the presence of P1 of the following symptoms: new onset or aggravation of hypertension or proteinuria; renal insufficiency (serum creatinine >100 lmol/l); neurological complications (severe headache, hyperreflexia, persistent visual scotoma, blindness, stroke, seizures); severe edema or HELLP symptoms (right upper quadrant/epigastric abdominal pain; elevated transaminases; thrombocytopenia; hemolysis). Results: We included 49 women (singleton pregnancies), aged 1847 years and with a median pregnancy duration of 35 weeks (range 20-41 weeks). In those with a ratio 638 (median 8 (range 2-37); n=30) at baseline, the ratio remained constant for up to 70 (range 26-107) days despite the fact that their protein-to-creatinine ratio and blood pressure often rose. In contrast, in those with a ratio >38 (97 (range 42–991); n = 19) at inclusion, the ratio rapidly increased further, often doubling every week. Conclusions: A sFlt-1/PlGF ratio at inclusion 638, does not result in a further rise, while a steep rise occurs in those with an inclusion ratio >38. doi:10.1016/j.preghy.2016.08.126
Clinical science 45 On the origin and disappearance of sFlt-1 and PlGF in preeclampsia Angiogenic factors Langeza Saleh, Jan A.H. Danser, Jeanine E. Roeters van Lennep, Anton H. van den Meiracker, Willy Visser (Erasmus Medical Center, Rotterdam Netherlands) Background: The pro-angiogenic placental growth factor (PlGF) and the anti-angiogenic, PlGF-sequestering soluble receptor (sFlt-1) are both released from the placenta into the maternal circulation during pregnancy. In preeclampsia (PE), the balance shifts towards sFlt-1, resulting in an elevated sFlt-1/PlGF ratio. It is currently unknown how fast these proteins disappear after delivery, and to what degree extraplacental sources contribute to their levels. Objective: To investigate the changes in sFlt-1 and PlGF levels in PE women after delivery. Methods: Serum sFlt-1 and PlGF levels were measured in 23 women aged 20–41 years with a median duration of labor of 27 weeks (range 24–32 weeks) using the automated Elecsys system. The women were randomly chosen from a big PE cohort, and samples were taken both before and after delivery. Concentrations after delivery were expressed as a percentage of the concentration in the last sample that was taken during pregnancy. Results: Median sFlt-1 and PlGF concentrations at the final stage of pregnancy were 11007 (3593–85000) and 26 (6–237) pg/mL, respectively, and the ratio was 544 (83–1034). SFlt-1 decreased with a half-life of 1.2 0.4 days, and then stabilized at levels corresponding with 0.3 0.2% of the level during pregnancy. PlGF decreased with a half-life of 4.8 1.6 and then stabilized at levels corresponding with 14.7 4.1% of the level during pregnancy. Changes in the ratio paralleled those in sFlt-1. Conclusions: sFlt-1, but not PlGF, almost exclusively (>99%) originates in the placenta, and disappears more rapidly after delivery, thus allowing a quick normalization of the sFlt-1/PlGF ratio. Future studies should address the kinetics of these parameters in women
199
with an uncomplicated pregnancy, and investigate whether sFlt-1 levels, despite a massive reduction, remain elevated in PE women vs. healthy pregnant women after delivery. doi:10.1016/j.preghy.2016.08.127
Basic science 46 MTHFR gene polymorphism A1298C and development of preeclampsia Biomarkers, prediction of preeclampsia Sarah Cristina Sato Vaz Tanaka, Andrezza Cristina Cancian Hortolani, Cristina Wide Pissetti, Marina Carvalho Paschoini, Marly Aparecida Spadoto Balarin (Universidade Federal do Triangulo Mineiro, Uberaba MG Brazil) Introduction: Pre-eclampsia (PE) is a pregnancy-specific disease diagnosed by hypertension and proteinuria after 20th week of pregnancy. The methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme for folate and homocysteine metabolism. The A1298C (rs1801131) is a common polymorphism of MTHFR gene and has also been suspected as a contributor of altered serum homocysteine levels. Hyperhomocysteinemia has been associated with pregnancy complications such as pre-eclampsia. Objective: Determine wheter MTHFR A1298C polymorphism is associated with PE susceptibility. Methods: In this case-control study, a total of 53 preeclamptic pregnant women were recruited from Departament of Obstetrics and Gynecology of Clinical Hospital, of Triangulo Mineiro Federal University, Uberaba, Brazil. PE was defined according clinical findings, including increased blood pressure (P140 mmHg systolic or P90 mmHg diastolic on 2 or more measurements at least 6 h apart) and proteinuria P0.3 g/24 h or P +1 on a urine dipstick after 20 weeks of gestation. The control group included 179 normal pregnant women. None of PE patients and healthy controls had hypertension history. Genomic DNA was extracted from EDTA-treated whole blood by standard procedure of phenol–chloroform. Polymerase chain reaction–restriction fragment length polymorphism (PCR– RFLP) was performed for MTHFR A1298C (rs1801131) genotyping and subsequent digestion of PCR products with MboII restriction enzyme. Differences in the distribution of genotypes and alleles between groups and deviations from the Hardy-Weinberg equilibrium were tested using the chi-square test. Results: No deviation from the Hardy–Weinberg equilibrium was observed for MTHFR A1298C polymorphism either in PE patients or in healthy controls (p = 0.81 and p = 0.21 respectively). The frequency of 1298C allele in PE patients and controls was 28% and 20% and was not statistically different. The frequency of AA genotype was 54.2% and 62.3%, AC genotype was 36.3 and 33.9% and CC genotype was 9.5 and 3.8% in PE patients and controls, respectively, which was not significantly different (p = 0.337). Conclusion: The MTHFR A1298C (rs1801131) polymorphism is not associated with risk of developing pre-eclampsia. Conflict of interest: The authors declare that they have no conflicts of interest. doi:10.1016/j.preghy.2016.08.128
Methods: In this ongoing observational study, the sFlt-1/PlGF ratio was determined (Elecsys assay, Roche Diagnostics) at P2 time points in women with (suspected) PE based on the presence of P1 of the following symptoms: new onset or aggravation of hypertension or proteinuria; renal insufficiency (serum creatinine >100 lmol/l); neurological complications (severe headache, hyperreflexia, persistent visual scotoma, blindness, stroke, seizures); severe edema or HELLP symptoms (right upper quadrant/epigastric abdominal pain; elevated transaminases; thrombocytopenia; hemolysis). Results: We included 49 women (singleton pregnancies), aged 1847 years and with a median pregnancy duration of 35 weeks (range 20-41 weeks). In those with a ratio 638 (median 8 (range 2-37); n=30) at baseline, the ratio remained constant for up to 70 (range 26-107) days despite the fact that their protein-to-creatinine ratio and blood pressure often rose. In contrast, in those with a ratio >38 (97 (range 42–991); n = 19) at inclusion, the ratio rapidly increased further, often doubling every week. Conclusions: A sFlt-1/PlGF ratio at inclusion 638, does not result in a further rise, while a steep rise occurs in those with an inclusion ratio >38. doi:10.1016/j.preghy.2016.08.126
Clinical science 45 On the origin and disappearance of sFlt-1 and PlGF in preeclampsia Angiogenic factors Langeza Saleh, Jan A.H. Danser, Jeanine E. Roeters van Lennep, Anton H. van den Meiracker, Willy Visser (Erasmus Medical Center, Rotterdam Netherlands) Background: The pro-angiogenic placental growth factor (PlGF) and the anti-angiogenic, PlGF-sequestering soluble receptor (sFlt-1) are both released from the placenta into the maternal circulation during pregnancy. In preeclampsia (PE), the balance shifts towards sFlt-1, resulting in an elevated sFlt-1/PlGF ratio. It is currently unknown how fast these proteins disappear after delivery, and to what degree extraplacental sources contribute to their levels. Objective: To investigate the changes in sFlt-1 and PlGF levels in PE women after delivery. Methods: Serum sFlt-1 and PlGF levels were measured in 23 women aged 20–41 years with a median duration of labor of 27 weeks (range 24–32 weeks) using the automated Elecsys system. The women were randomly chosen from a big PE cohort, and samples were taken both before and after delivery. Concentrations after delivery were expressed as a percentage of the concentration in the last sample that was taken during pregnancy. Results: Median sFlt-1 and PlGF concentrations at the final stage of pregnancy were 11007 (3593–85000) and 26 (6–237) pg/mL, respectively, and the ratio was 544 (83–1034). SFlt-1 decreased with a half-life of 1.2 0.4 days, and then stabilized at levels corresponding with 0.3 0.2% of the level during pregnancy. PlGF decreased with a half-life of 4.8 1.6 and then stabilized at levels corresponding with 14.7 4.1% of the level during pregnancy. Changes in the ratio paralleled those in sFlt-1. Conclusions: sFlt-1, but not PlGF, almost exclusively (>99%) originates in the placenta, and disappears more rapidly after delivery, thus allowing a quick normalization of the sFlt-1/PlGF ratio. Future studies should address the kinetics of these parameters in women
199
with an uncomplicated pregnancy, and investigate whether sFlt-1 levels, despite a massive reduction, remain elevated in PE women vs. healthy pregnant women after delivery. doi:10.1016/j.preghy.2016.08.127
Basic science 46 MTHFR gene polymorphism A1298C and development of preeclampsia Biomarkers, prediction of preeclampsia Sarah Cristina Sato Vaz Tanaka, Andrezza Cristina Cancian Hortolani, Cristina Wide Pissetti, Marina Carvalho Paschoini, Marly Aparecida Spadoto Balarin (Universidade Federal do Triangulo Mineiro, Uberaba MG Brazil) Introduction: Pre-eclampsia (PE) is a pregnancy-specific disease diagnosed by hypertension and proteinuria after 20th week of pregnancy. The methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme for folate and homocysteine metabolism. The A1298C (rs1801131) is a common polymorphism of MTHFR gene and has also been suspected as a contributor of altered serum homocysteine levels. Hyperhomocysteinemia has been associated with pregnancy complications such as pre-eclampsia. Objective: Determine wheter MTHFR A1298C polymorphism is associated with PE susceptibility. Methods: In this case-control study, a total of 53 preeclamptic pregnant women were recruited from Departament of Obstetrics and Gynecology of Clinical Hospital, of Triangulo Mineiro Federal University, Uberaba, Brazil. PE was defined according clinical findings, including increased blood pressure (P140 mmHg systolic or P90 mmHg diastolic on 2 or more measurements at least 6 h apart) and proteinuria P0.3 g/24 h or P +1 on a urine dipstick after 20 weeks of gestation. The control group included 179 normal pregnant women. None of PE patients and healthy controls had hypertension history. Genomic DNA was extracted from EDTA-treated whole blood by standard procedure of phenol–chloroform. Polymerase chain reaction–restriction fragment length polymorphism (PCR– RFLP) was performed for MTHFR A1298C (rs1801131) genotyping and subsequent digestion of PCR products with MboII restriction enzyme. Differences in the distribution of genotypes and alleles between groups and deviations from the Hardy-Weinberg equilibrium were tested using the chi-square test. Results: No deviation from the Hardy–Weinberg equilibrium was observed for MTHFR A1298C polymorphism either in PE patients or in healthy controls (p = 0.81 and p = 0.21 respectively). The frequency of 1298C allele in PE patients and controls was 28% and 20% and was not statistically different. The frequency of AA genotype was 54.2% and 62.3%, AC genotype was 36.3 and 33.9% and CC genotype was 9.5 and 3.8% in PE patients and controls, respectively, which was not significantly different (p = 0.337). Conclusion: The MTHFR A1298C (rs1801131) polymorphism is not associated with risk of developing pre-eclampsia. Conflict of interest: The authors declare that they have no conflicts of interest. doi:10.1016/j.preghy.2016.08.128