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124. Immune-driven polyunsaturated fatty acid (PUFA) metabolism in preeclampsia
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Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 13 (2018) S16–S49
124. Immune-driven polyunsaturated fatty acid (PUFA) metabolism in preeclampsia Florian Herse, Martin Gauster, Olivia Nonn, Nadine Haase, Michaela Golic, Kristin Kräker, Anna Birukov, Stefan Verlohren, Ulrich Pecks, Jan Stener Jorgensen, Louise Bjorkholt Anderse, Henrik Christesen, Anne Cathrine Staff, Dominik N. Müller, Ralf Dechend (Max-Delbrück Center for Molecular Medicine, Berlin, Germany) Introduction: Placental macrophages regulate villous trophoblast differentiation and activity. Disturbance of this well-balanced immune-regulation and a pro-inflammatory cytokine milieu can lead to dysfunctional placentas and preeclampsia. Cluster of differentiation 74 (CD74) downregulation in placental macrophages leads to altered macrophage-trophoblast interaction, a pro-inflammatory status and is involved in preeclampsia. Oxylipins, metabolites derived from polyunsaturated fatty acids (PUFAs), are implicated in the development of preeclampsia. Hypothesis: Disturbed pro-inflammatory cytokine milieu activates a dysregulated PUFA metabolism enzyme expression pattern leading to disturbed oxylipin levels that can be detected in circulation of preeclamptic mothers. Methods: A trophoblast-derived cell line (SGHPL-4) and first trimester villous explants were stimulated by the pro-inflammatory cytokines TNFa, CCL5 and MCP-1. Furthermore, we analyzed placental expression pattern of cytochrome P450 epoxygenases, cyclooxygenases and lipoxygenases by microarray and qRT-PCR from human cohorts and analyzed serum from preeclamptic and uneventful pregnancies by mass spectrometry. Results: Microarray studies of preeclamptic placentas revealed a distinguished expression pattern of PUFA metabolism enzymes. Results could be confirmed on two different cohorts (qRT-PCR). Stimulation of SGHPL-4 and villous explants by the proinflammatory cytokines TNFa, CCL5 and MCP-1 resulted in similar expression pattern. Oxylipins were dysregulated in the circulation of preeclamptic women compared to uneventful pregnancies atgestational week 28 and week 9–12. Composition of oxylipins at week 9–12 in women that later develop preeclampsia showed a good ROC predictive performance with an AUC = 0.8. Conclusion: The pro-inflammatory cytokine milieu induced by the disturbed macrophage-trophoblast interaction induces a distinguished PUFA metabolism leading to dysregulated oxylipins that can predict preeclampsia before onset of clinical symptoms. doi:10.1016/j.preghy.2018.08.072
125. Peripheral maternal haemodynamic adaptation across gestation in hypertensive disorders of pregnancy Petra Verburg a, Claire Roberts b, Emma Mcbean b, Mylene Mulder b, Shalem Leemaqz b, Jan Jaap Erwich c, Gus Dekker b (a Robinson Research Institute — UMCG, Adelaide & Groningen, Australia, b Robinson Research Institute, Adelaide, Australia, c University Medical Center Groningen, Groningen, The Netherlands) Introduction: Preeclampsia is characterized by haemodynamic maladaptation but the timing of its onset is controversial. Objective: To evaluate maternal haemodynamics across pregnancy in hypertensive disorders of pregnancy (HDP) compared to uncomplicated pregnancies. Study design: Prospective cohort study from 2015–2018 of healthy, nulliparous, singleton-bearing women. Maternal haemodynamic adaptation between 11 and 32 weeks’ gestation in pregnancies complicated by HDP: preeclampsia with severe (sPE) and without severe features (nsPE), gestational hypertension (GH) and
occasionally hypertensive (OH) were compared uncomplicated pregnancies using mixed-effects linear modelling. Main outcome measures: Maternal haemodynamics assessed by Uscom BP+ [peripheral and central blood pressure (BP), augmentation index (AIx)] in uncomplicated pregnancies and those complicated by HDP. Results: Maternal haemodynamics at 11 weeks’ were different in all hypertensive groups compared to uncomplicated pregnancies (n = 286). When corrected for initial measurement, women who developed sPE (n = 12) and nsPE (n = 49) had a relative haemodynamic maladaptation by 34 weeks’. Compared to those with uncomplicated pregnancies, preeclamptics showed an additional increase in peripheral systolic BP [SBP; 14.33 mmHg, 8.61–20.05 (sPE)], peripheral diastolic BP [DBP; 7.70 mmHg, 3.31–12.09 (sPE); 2.58 mmHg, 3.31–12.09 (nsPE)], peripheral mean arterial pressure [MAP; 10.60 mmHg, 5.75–15.45 (sPE); 3.39 mmHg, 0.83–5.96 (nsPE)], peripheral pulse pressure [PP; 6.63 mmHg, 2.13–11.13 (sPE)], central SBP [15.83 mmHg, 10.43–21.22 (sPE); 2.94 mmHg, 0.08–5.80 (nsPE)], central DBP [8.26 mmHg, 3.89–12.64 (sPE); 2.46 mmHg, 0.15–4.78 (nsPE), central MAP [10.79 mmHg, 6.39–15.19 (sPE); 2.62 mmHg, 0.29–4.95 (nsPE)], central PP [7.57 mmHg, 3.85– 11.28 (sPE)] and AIx decreased less (15.48% 6.32–24.65 (sPE); 9.00% (4.15–13.56 (nsPE)]. Haemodynamic adaptation in women who developed GH (n = 25) and OH (n = 33) was similar to those with uncomplicated pregnancies. Conclusion: Haemodynamic adaptation in women who develop preeclampsia was altered, while those who develop GH or OH had comparable haemodynamic changes, to those with uncomplicated pregnancies. These data indicate that women with preeclampsia fail to undergo proper cardiovascular adaptation to pregnancy. This occurs as early as the first trimester. doi:10.1016/j.preghy.2018.08.073
126. Sex and growth specific characteristics of small for gestational age neonates: A prospective cohort study Eva van der Vlugt a, Petra Verburg b, Shalem Leemaqz b, Lesley Mccowan c, Lucilla Poston d, Louise Kenny e, Jenny Myers f, James Walker g, Gustaaf Dekker b, Claire Roberts b (a Robinson Research Institute — VU University, Adelaide & Amsterdam, Australia, b Robinson Research Institute, Adelaide, Australia, c University of Auckland, Auckland, New Zealand, d Women’s Health Academic Center, London, United Kingdom, e INFANT, Cork, Ireland, f Maternal and Fetal Health Research Centre, Manchester, United Kingdom, g Section of Obstetrics and Gynaecology, Leeds, United Kingdom) Introduction: Male bearing pregnancies and asymmetric fetal growth are associated with preeclampsia (PE). However, this has not been studied in small for gestational age (SGA) neonates, a group that is also associated with PE. Objective: To provide insight regarding risk factors and differences in neonatal outcome for SGA neonates based on sex and growth symmetry. Methods: Data from the Screening for Pregnancy Endpoints (SCOPE) study were used with 5628 nulliparous participants, of which 633 pregnancies were complicated with SGA and 3376 women had uncomplicated pregnancies. SGA pregnancies were grouped based on fetal sex (male/female) and growth symmetry [ponderal index below (asymmetric) and above (symmetric) the 10th percentile for gestation]. Association between risk factors for SGA, SGA subgroups and uncomplicated pregnancies were assessed with multinominal analyses. Results: Of all asymmetric neonates, 24.2% were SGA, while 7.4% of all symmetric neonates were SGA. Of all SGA neonates, 45.8%
Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 13 (2018) S16–S49
124. Immune-driven polyunsaturated fatty acid (PUFA) metabolism in preeclampsia Florian Herse, Martin Gauster, Olivia Nonn, Nadine Haase, Michaela Golic, Kristin Kräker, Anna Birukov, Stefan Verlohren, Ulrich Pecks, Jan Stener Jorgensen, Louise Bjorkholt Anderse, Henrik Christesen, Anne Cathrine Staff, Dominik N. Müller, Ralf Dechend (Max-Delbrück Center for Molecular Medicine, Berlin, Germany) Introduction: Placental macrophages regulate villous trophoblast differentiation and activity. Disturbance of this well-balanced immune-regulation and a pro-inflammatory cytokine milieu can lead to dysfunctional placentas and preeclampsia. Cluster of differentiation 74 (CD74) downregulation in placental macrophages leads to altered macrophage-trophoblast interaction, a pro-inflammatory status and is involved in preeclampsia. Oxylipins, metabolites derived from polyunsaturated fatty acids (PUFAs), are implicated in the development of preeclampsia. Hypothesis: Disturbed pro-inflammatory cytokine milieu activates a dysregulated PUFA metabolism enzyme expression pattern leading to disturbed oxylipin levels that can be detected in circulation of preeclamptic mothers. Methods: A trophoblast-derived cell line (SGHPL-4) and first trimester villous explants were stimulated by the pro-inflammatory cytokines TNFa, CCL5 and MCP-1. Furthermore, we analyzed placental expression pattern of cytochrome P450 epoxygenases, cyclooxygenases and lipoxygenases by microarray and qRT-PCR from human cohorts and analyzed serum from preeclamptic and uneventful pregnancies by mass spectrometry. Results: Microarray studies of preeclamptic placentas revealed a distinguished expression pattern of PUFA metabolism enzymes. Results could be confirmed on two different cohorts (qRT-PCR). Stimulation of SGHPL-4 and villous explants by the proinflammatory cytokines TNFa, CCL5 and MCP-1 resulted in similar expression pattern. Oxylipins were dysregulated in the circulation of preeclamptic women compared to uneventful pregnancies atgestational week 28 and week 9–12. Composition of oxylipins at week 9–12 in women that later develop preeclampsia showed a good ROC predictive performance with an AUC = 0.8. Conclusion: The pro-inflammatory cytokine milieu induced by the disturbed macrophage-trophoblast interaction induces a distinguished PUFA metabolism leading to dysregulated oxylipins that can predict preeclampsia before onset of clinical symptoms. doi:10.1016/j.preghy.2018.08.072
125. Peripheral maternal haemodynamic adaptation across gestation in hypertensive disorders of pregnancy Petra Verburg a, Claire Roberts b, Emma Mcbean b, Mylene Mulder b, Shalem Leemaqz b, Jan Jaap Erwich c, Gus Dekker b (a Robinson Research Institute — UMCG, Adelaide & Groningen, Australia, b Robinson Research Institute, Adelaide, Australia, c University Medical Center Groningen, Groningen, The Netherlands) Introduction: Preeclampsia is characterized by haemodynamic maladaptation but the timing of its onset is controversial. Objective: To evaluate maternal haemodynamics across pregnancy in hypertensive disorders of pregnancy (HDP) compared to uncomplicated pregnancies. Study design: Prospective cohort study from 2015–2018 of healthy, nulliparous, singleton-bearing women. Maternal haemodynamic adaptation between 11 and 32 weeks’ gestation in pregnancies complicated by HDP: preeclampsia with severe (sPE) and without severe features (nsPE), gestational hypertension (GH) and
occasionally hypertensive (OH) were compared uncomplicated pregnancies using mixed-effects linear modelling. Main outcome measures: Maternal haemodynamics assessed by Uscom BP+ [peripheral and central blood pressure (BP), augmentation index (AIx)] in uncomplicated pregnancies and those complicated by HDP. Results: Maternal haemodynamics at 11 weeks’ were different in all hypertensive groups compared to uncomplicated pregnancies (n = 286). When corrected for initial measurement, women who developed sPE (n = 12) and nsPE (n = 49) had a relative haemodynamic maladaptation by 34 weeks’. Compared to those with uncomplicated pregnancies, preeclamptics showed an additional increase in peripheral systolic BP [SBP; 14.33 mmHg, 8.61–20.05 (sPE)], peripheral diastolic BP [DBP; 7.70 mmHg, 3.31–12.09 (sPE); 2.58 mmHg, 3.31–12.09 (nsPE)], peripheral mean arterial pressure [MAP; 10.60 mmHg, 5.75–15.45 (sPE); 3.39 mmHg, 0.83–5.96 (nsPE)], peripheral pulse pressure [PP; 6.63 mmHg, 2.13–11.13 (sPE)], central SBP [15.83 mmHg, 10.43–21.22 (sPE); 2.94 mmHg, 0.08–5.80 (nsPE)], central DBP [8.26 mmHg, 3.89–12.64 (sPE); 2.46 mmHg, 0.15–4.78 (nsPE), central MAP [10.79 mmHg, 6.39–15.19 (sPE); 2.62 mmHg, 0.29–4.95 (nsPE)], central PP [7.57 mmHg, 3.85– 11.28 (sPE)] and AIx decreased less (15.48% 6.32–24.65 (sPE); 9.00% (4.15–13.56 (nsPE)]. Haemodynamic adaptation in women who developed GH (n = 25) and OH (n = 33) was similar to those with uncomplicated pregnancies. Conclusion: Haemodynamic adaptation in women who develop preeclampsia was altered, while those who develop GH or OH had comparable haemodynamic changes, to those with uncomplicated pregnancies. These data indicate that women with preeclampsia fail to undergo proper cardiovascular adaptation to pregnancy. This occurs as early as the first trimester. doi:10.1016/j.preghy.2018.08.073
126. Sex and growth specific characteristics of small for gestational age neonates: A prospective cohort study Eva van der Vlugt a, Petra Verburg b, Shalem Leemaqz b, Lesley Mccowan c, Lucilla Poston d, Louise Kenny e, Jenny Myers f, James Walker g, Gustaaf Dekker b, Claire Roberts b (a Robinson Research Institute — VU University, Adelaide & Amsterdam, Australia, b Robinson Research Institute, Adelaide, Australia, c University of Auckland, Auckland, New Zealand, d Women’s Health Academic Center, London, United Kingdom, e INFANT, Cork, Ireland, f Maternal and Fetal Health Research Centre, Manchester, United Kingdom, g Section of Obstetrics and Gynaecology, Leeds, United Kingdom) Introduction: Male bearing pregnancies and asymmetric fetal growth are associated with preeclampsia (PE). However, this has not been studied in small for gestational age (SGA) neonates, a group that is also associated with PE. Objective: To provide insight regarding risk factors and differences in neonatal outcome for SGA neonates based on sex and growth symmetry. Methods: Data from the Screening for Pregnancy Endpoints (SCOPE) study were used with 5628 nulliparous participants, of which 633 pregnancies were complicated with SGA and 3376 women had uncomplicated pregnancies. SGA pregnancies were grouped based on fetal sex (male/female) and growth symmetry [ponderal index below (asymmetric) and above (symmetric) the 10th percentile for gestation]. Association between risk factors for SGA, SGA subgroups and uncomplicated pregnancies were assessed with multinominal analyses. Results: Of all asymmetric neonates, 24.2% were SGA, while 7.4% of all symmetric neonates were SGA. Of all SGA neonates, 45.8%