Cardiovascular origins of Preeclampsia

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Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 7 (2017) 56–64

pled with receptor-specific antagonists [3]. Blood from 10 of the women from 5 to 8 years postpartum was also analyzed for AT1AA. Non-parametric statistics were used and P < 0.05 was considered statistically significant. Results: Preeclamptic women had a significantly higher incidence of AT1-AA than controls (57% vs 22%, P = 0.03). Acute atherosis did not correlate with AT1-AA. At 5–8 years postpartum, 2 of 10 women had circulating AT1-AA. Both these had previously a diagnosis of preeclampsia, without acute atherosis. Conclusions: Preeclamptic women have high rates of AT1-AA, but AT1-AA have no general correlation to acute atherosis. AT1-AA may persist after preeclampsia, and their association with future cardiovascular risk is unknown. References [1] P. Alnaes-Katjavivi, F. Lyall, B. Roald, C.W. Redman, A.C. Staff, Acute atherosis in vacuum suction biopsies of decidua basalis: An evidence based research definition, Placenta (2016) 37 (2016) 26–33. [2] N.K. Harsem, A.C. Staff, L. He, B. Roald, The decidual suction method: a new way of collecting decidual tissue for functional and morphological studies, Acta Obstet. Gynecol. Scand. (2004) 83 (8) (2004) 724–730. [3] F. Herse, R. Dechend, N.K. Harsem, G. Wallukat, J. Janke, F. Qadri, et al, Hypertension (2007) 49 (3) (2007) 604–611. doi:10.1016/j.preghy.2016.10.019

Validation of predictive models for pre-eclampsia Federico Prefumo (Department of Obstetrics and Gynaecology, University of Brescia, Italy) Prediction model are frequently proposed for use in obstetrics. It is recommended that they undergo internal and external validation. The latter involves determining external validity or generalizability of the prognostic model, ideally by independent investigators in a hospital or population different from those where the model was initially established. Moreover, when the performance of a model is reported, not only its discrimination power (e.g. sensitivity, specificity, receiver-operating characteristics curves) should be assessed, but also its calibration i.e. the agreement between predicted and observed outcomes. In a recent systematic review [1], it was found that only 20% of published predictive models for pre-eclampsia were internally validated, and even less (7%) underwent external validation. Calibration was only assessed for 12% of the models. Another systematic review assessed models predicting the risk of preeclampsia in the first trimester, including uterine artery Doppler among independent variables [2]. In 22% of the models, the number of events per variable was fewer than the commonly recommended value of 10 events per predictor; this proportion increased to 94% in models for early pre-eclampsia. Treatment and handling of missing data were not reported in 97% of the models. Only 8% of the models reported validation. In conclusion, predictive models for preeclampsia have variable methodological quality and frequently lack validations studies. Therefore, they should be introduced with caution into clinical practice. References [1] C.E. Kleinrouweler, F.M. Cheong-See, G.S. Collins, A. Kwee, S. Thangaratinam, K. S. Khan, B.W. Mol, E. Pajkrt, K.G. Moons, E. Schuit, Prognostic models in obstetrics: available, but far from applicable, Am. J. Obstet. Gynecol. (2016) 214 (2016) 79–90.e36. [2] V.B. Brunelli, F. Prefumo, Quality of first trimester risk prediction models for pre-eclampsia: a systematic review, BJOG (2015) 122 (2015) 904–914. doi:10.1016/j.preghy.2016.10.020

Fetal monitoring in pre-eclampsia Nicola Fratelli (Department of Obstetrics and Gynaecology, University of Brescia, Italy) Early onset preeclampsia is often associated with fetal growth restriction. Management with immediate delivery leads to high neonatal mortality and morbidity rates and prolonged hospitalization in the neonatal intensive care unit because of the association of growth restriction and prematurity. The intervals to delivery, perinatal death and severe morbidity are related to the presence and severity of maternal hypertensive conditions [1]. In selected women with early onset preeclampsia below 32 0/7 weeks of gestation, in absence of severe maternal conditions requiring immediate delivery, expectant management monitoring fetal wellbeing including ductus venosus flow pattern evaluation and safety-net delivery indication of very low short term fetal heart rate variation and/or recurrent decelerations, increases infant survival without neurological impairment at two years [2]. In non severe hypertensive disorders at 34+0/7–37+0/7 weeks of gestation, immediate delivery significantly increases the risk of neonatal respiratory distress syndrome, without a significan decrease in the already small risk of adverse maternal outcomes. Therefore, routine immediate delivery does not seem justified in these cases and a strategy of expectant monitoring until the clinical situation deteriorates can be considered [3]. References [1] C. Lees, N. Marlow, B. Arabin, C.M. Bilardo, et al, Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE), Ultrasound Obstet. Gynecol. (2013) 42 (2013) 400–408. [2] C.C. Lees, N. Marlow, A. van Wassenaer-Leemhuis, et al, 2 year neurodevelopmental and intermediate perinatal outcomes in infantswith very preterm fetal growth restriction (TRUFFLE): a randomised trial, Lancet (2015) 385 (2015) 2162–2172. [3] K. Broekhuijsen, G.J. van Baaren, M.G. van Pampus, et al, Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label,randomised controlled trial, Lancet (2015) 385 (2015) 2492–2501. doi:10.1016/j.preghy.2016.10.021

Cardiovascular origins of Preeclampsia Basky Thilaganathan (Feto-Maternal Medicine, University Hospital NHS Foundation Trust, UK)

St

Georges

Preeclampsia is the leading cause of maternal mortality in industrialized countries, accounting for 42% of maternal deaths and 25% of overall neonatal morbidity. The definition of the disease is seemingly straightforward: the new onset of hypertension and proteinuria after 20 weeks of gestation. However, it is well known that the simplicity of this arbitrary definition does not reflect the complexity of the multisystem disorder. It has been shown recently that angiogenic and antiangiogenic factors have the highest accuracy in predicting pregnancy complications associated with preeclampsia in singletons and twins presenting with signs and symptoms for preeclampsia in the second and third trimester. Despite these advances, the pathophysiology of preeclampsia is still largely unresolved, being labelled a ‘‘disease of theories”. According to the two-stage theory of preeclampsia, the maternal syndrome, hypertension and proteinuria, constitutes the end-stage of a pathogenetic cascade beginning in the first trimester. The initial pathognomonic lesion, a failure in trophoblast invasion, is localized in the placenta. It has been proposed that placental dysfunction disorders such as early onset PE comprise a disease entity, which is more or less distinct from late onset PE.26 The latter has been attributed as ‘‘maternal” preeclampsia, while the

Abstracts / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 7 (2017) 56–64

first has been dubbed as ‘‘fetal” preeclampsia. We propose that this dichotomy is rather simplistic. It has been shown previously that women with a history of preeclampsia have an increased for cardiovascular diseases in later life. The prevalence of hypertension in women with previous preeclampsia is approximately 50% at an average of 14 years after pregnancy, which is 3–4 times the risk found in women without preeclampsia. Large epidemiologic studies have shown that the onset of the disease constitutes an important factor of cardiovascular mortality in later life. From public health perspective, cardiovascular disease due to preeclampsia constitutes a major burden. Recent studies focussing on the role of maternal cardiovascular adaptation to pregnancy might potentially change our perception of the maternal cardiovascular changes in normal pregnancy. Triggered by the known fact that women with a history of preeclampsia have a higher incidence of cardiovascular morbidity and mortality in later life, prospective studies have been initiated to further elucidate the role of cardiac function in hypertensive pregnancy diseases. The results of these studies have shed a light on firstly the extent of cardiovascular dysfunction in pregnancy and secondly the impact on longterm cardiovascular morbidity in later life. But most of all, thirdly, these new data haven given insights in the cardiovascular adaptations to pregnancy and thus the etiology of preeclampsia. In this talk, the recent understandings of maternal cardiovascular adaptation to pregnancy and its failure in preeclampsia are to be reviewed. The recent findings of our group on cardiac function in preeclampsia have confirmed and improved existing literature on cardiovascular adaptation of the maternal organism to pregnancy. With the introduction of up to date methods such as Tissue Doppler as well as the normalization of indices according to cardiological standards, we were able to clarify the central role of cardiac dysfunction for the pathogenesis of preeclampsia. doi:10.1016/j.preghy.2016.10.022

Role of the first trimester combined screening test in the prediction of early onset preeclampsia Tullio Ghi, Andrea Dalla’sta, Alice Suprani, Letizia Galli, Tiziana Frusca (Obstetrics and Gynecology Unit, University of Parma, Parma, Italy) Although first trimester combined screening test (CST) has been originally implemented for the screening of chromosomal anomalies, more recent evidences have shown its role in the estimation of the risk of preeclampsia (PET). Pathophysiological basis of PET are related to impaired trophoblastic invasion of the maternal spiral arteries occurring during the process of placentation as early as 9 weeks of gestation, which in normal conditions leads to the conversion of uterine vessels into low resistance reservoirs allowing feto/maternal blood exchange. Uterine artery pulsatility index (PI) is inversely related to the extent of trophoblastic invasion of the spiral arteries. Impaired placentation is featured by an abnormal functional and biochemical environment which consists in increase in uterine artery PI, increase in antiangiogenetic and proinflammatory factors – i.e. sEng, sFLT1, AFP, Inhibin-A, AFP – and reduction in angiogenetic and mitogenic factors - i.e. PlGF, PAPP-A, PP13. These biomarkers are responsible for a subclinical syncitiotrophoblastic injury in the first trimester and PET arising before 34 weeks of gestation. Combined assessment of maternal history and characteristics together with the above mentioned biomarkers and uterine artery Doppler in the first trimester has shown high specificity in the detection of women at risk to develop early onset PET.

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Even though the administration of Cardio Aspirin (ASA) seems efficient in decreasing the PET rate in high risk patients, it is uncertain whether the same prophylaxis is effective in ‘‘low risk” patients identified at ‘‘high risk” of early onset PET at first trimester CST. ASPRE (ASpirin for evidence-based PREeclampsia prevention – ASPRE – study) is the acronym of an ongoing Randomized Controlled Trial investigating the effectiveness of low-dose Aspirin in the prevention of early onset PET in high risk patients identified at first trimester CST. Results from this study are warranted in order to provide further insights in prevention strategies for PET. doi:10.1016/j.preghy.2016.10.023

Of mice and women: Statins as a potential treatment to prevent preeclampsia in antiphospholipid syndrome. Guillermina Girardi (King’s College London, United Kingdom) Pregnancy complications in antiphospholipid syndrome APS have been associated with placental insufficiency. While in vitro and ex vivo studies suggest that the placenta is the main target organ in obstetric APS, in vivo data was missing. Using 111In labelled antiphospholipid antibodies (aPL) and single photon emission computed tomography we identified the placenta as the main organ target in a new mouse model of obstetric APS that closely resembles the clinical scenario. The cause of placental insufficiency in APS was attributed to the procoagulant effects of aPL antibodies. However, we demonstrated that APS is a proinflammatory syndrome. Based on our previous findings on the crucial role of complement activation in placental mal perfusion in APS, we developed an MRI-based method in which anti-complement C3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles were used for the noninvasive detection of complement activation in placenta in utero. C3 deposition was detected in the placenta using this novel method, confirming the role of inflammation in obstetric APS. Management of obstetric APS is based on attenuating the procoagulant state. In many cases, however, there is no evidence of decidual thrombosis and instead inflammatory signs are present. Current treatment fails in a significant number of pregnancies- raising the need to explore other therapies to improve obstetrical outcome. Based on our preclinical studies in which pravastatin prevented adverse pregnancy outcomes in mouse models of preeclampsia and APS we performed translational studies in women. Our aim was to investigate the clinical use of pravastatin in APS women refractory to classical treatment LDA+LMWH that developed PE and/or severe IUGR. Eleven pregnant women with APS that developed PE or severe IUGR despite conventional antithrombotic therapy were treated with pravastatin (20mg/day) when signs of placental insufficiency (PE, IUGR) were observed. After pravastatin addition, placental blood flow and maternal symptoms of PE improved significantly leading to live birth in 100% of the patients. The beneficial effects of pravastatin were observed as early as 10 days, with a mean response time of 14.08 ± 3.25. Pregnancies survived 14 weeks [IQR 12–15] in patients cotreated with pravastatin. In this group. all babies were born close to term and alive and are now healthy while the neonates in the group that did not receive pravastatin experienced still births, preterm birth, were admitted at NICU and some of tem showed developmental abnormalities. Our study indicates that the addition of pravastatin at the time of onset of PE or severe IUGR to conventional treatment is worthy of further assessment in the management of women with APS and preeclampsia. RCT should be organized to confirm these observations. doi:10.1016/j.preghy.2016.10.024