The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature.

AIM: This study aims to determine, based on existing data, whether the mechanism resulting in liver dysfunction in HELLP syndrome resembles that in Sinusoidal Obstruction Syndrome (SOS). BACKGROUND: HELLP syndrome is a serious pregnancy disorder with high maternal and perinatal morbidity and mortality rates. Because of poor insight in its pathophysiology, particularly that of the liver involvement, clinical management is limited to symptomatic treatment, often followed by termination of pregnancy. SOS is a rare, potentially life-threatening complication of radio and/ or chemotherapy in the preparation of hematopoietic cell transplantation. The etiology of liver dysfunction in SOS is - unlike that in HELLP syndrome - better-understood and seems to be initiated by direct toxic damage and demise of endothelial cells, causing hepatic sinusoidal obstruction and ischemia. METHODS: We searched Pubmed, Embase and Cochrane for reports on the etiology of HELLP and SOS. This yielded 73 articles, with 14 additional reports from the references listed in these articles. RESULTS: The dysfunctional placenta in women developing HELLP initiates a cascade of events that eventually results in liver dysfunction. The placenta releases, besides anti-angiogenetic factors, also necrotic debris and cell-free DNA, a mixture that not only induces systemic endothelial dysfunction as in preeclampsia, but also a systemic inflammatory response. The latter aggravates the endothelio-toxic effects in the systemic cardiovascular bed, amplifying the already increased pro-thrombotic conditions. Particularly in microcirculations with extremely low shear forces, such as in the hepatic sinusoids, this will facilitate microthrombi formation and fibrin deposition eventually resulting in obstruction of the sinusoids similar as in SOS. The latter causes ischemic damage and progressive demise of hepatocytes. CONCLUSION: The available information supports the concept that the liver damage in HELLP and SOS results from sinusoidal ischemia, presumably resulting from partially overlapping pathophysiological mechanisms.

Early-Pregnancy Circulating Antioxidant Capacity and Hemodynamic Adaptation in Recurrent Placental Syndrome: An Exploratory Study.

BACKGROUND/AIMS: Placental syndromes (PS) refer to pregnancy complications that include gestational hypertension, (pre)eclampsia, HELLP syndrome, and/or placental insufficiency-induced fetal growth restriction. These disorders are characterized by increased oxidative stress. This study aims to test the hypothesis that the abnormal hemodynamic adaptation to pregnancy, typical for early PS pregnancy, is accompanied by abnormal maternal levels of antioxidants relative to those in normal pregnancy. METHODS: Before, and at 12, 16, and 20 weeks pregnancy, we measured trolox equivalent antioxidant capacity (TEAC), uric acid (UA), and TEACC (TEAC corrected for UA) in maternal serum of former PS patients, who either developed recurrent PS (rPS; n = 16) or had a normal next pregnancy (non-rPS; n = 23). Concomitantly, we also measured various hemodynamic variables. RESULTS: rPS differed from non-rPS by higher TEACC levels before pregnancy (178 vs. 152 µM; p = 0.02) and at 20 weeks pregnancy (180 vs. 160 µM; p = 0.04). Only non-rPS responded to pregnancy by significant rises in hemodynamic measures. CONCLUSION: These data indicate that rPS pregnancies are preceded by an increase in antioxidant capacity, presumably induced by subclinical vascular injury and low-grade chronic inflammation.

First trimester placental vascularization and angiogenetic factors are associated with adverse pregnancy outcome.

BACKGROUND: Hypertensive disorders, fetal growth restriction and preterm birth are major obstetrical complications and are related to impaired placentation. Early identification of impaired placentation can advance clinical care by preventing or postpone adverse pregnancy outcome. OBJECTIVES: Determine whether sonographic assessed placental vascular development and concomitant changes in inflammation- and/or angiogenesis-related serumproteins differ in the first trimester between uncomplicated pregnancies and pregnancies with adverse outcome. STUDY DESIGN: This prospective longitudinal study defines adverse pregnancy outcome as conditions associated with impaired placentation; fetal growth restriction, hypertensive disorder, preterm birth and placental abruption. The vascularization index, flow index, vascularization flow index and placental volume were determined at 8, 10 and 12 weeks pregnancy from 64 women using 3D power Doppler. Serum levels were analyzed for Angiopoetin-1 and -2, Leptin, VEGF-R, VEGF, and EGF. RESULTS: The vascularization index and vascular flow index increased in uneventful pregnancies with almost 50% between 8 and 12 weeks, resulting in a ∼50% higher vascularization index at 12 weeks compared to women with an adverse pregnancy outcome. Women with an adverse pregnancy outcome (n = 13) had significantly lower indices and placental volumes at all time points measured and these indices did not increase between 8 and 12 weeks. Reduced vascular development was associated with increased Angiopoietin-1 levels at 8 and 12 weeks and increased Leptin levels at 8 weeks. CONCLUSIONS: Pregnancies with an adverse outcome caused by conditions associated with impaired placentation differ from uneventful pregnancies in having reduced placental vascularization accompanied by elevated circulating levels of Angiopoietin-1 and Leptin already in the first trimester.

First-trimester placental vascular development in multiparous women differs from that in nulliparous women.

OBJECTIVE: Multiparas differ from nulliparas by delivering larger babies with larger placentas and by having a lower risk of developing placental syndromes. We postulate that these differences result from a different initial course of placental vascular development. STUDY DESIGN: We measured placental flow index (FI), vascularization index (VI) and placental volume by 3D power Doppler and obtained blood samples at 8, 10 and 12 weeks pregnancy in 34 healthy nulliparous and 16 multiparous women with an uneventful pregnancy. RESULTS: Between 8 and 12 weeks multiparas differed from nulliparas in a more rapid initial rise in FI, a higher angiopoietin-2 (ang2) level at eight weeks and no decline in the VEGF/sVEGF-R ratio. Nevertheless, at 12 weeks the FI and placental volume were indistinguishable between both study groups. CONCLUSIONS: These results combining serially measured placental vascularization, placental volume and circulating angiogenetic factors show initial differences in placental development, that howeve, did not maintain till the end of first trimester. The results support the concept that early placental vascular development differs between nulliparas and multiparas. Nevertheless, it is unclear whether these differences contribute to the development later on in pregnancy of intergroup differences in birthweight and incidence of placental syndromes.

Circulating Fibronectin and Plasminogen Activator Inhibitor-2 Levels as Possible Predictors of Recurrent Placental Syndrome: An Exploratory Study.

BACKGROUND/AIM: Placental syndromes (PS) are characterized by endothelial dysfunction complicating placental dysfunction. Possible markers for endothelial dysfunction and amount of trophoblast are fibronectin and plasminogen activator inhibitor-2 (PAI-2), respectively. We aimed (1) to determine whether in women with recurrent PS (rPS), this complication is preceded by deviating fibronectin- and PAI-2-levels, and (2) whether this is dependent on pre-pregnant plasma volume (PV). METHODS: In 36 former patients, we determined fibronectin- and PAI-2-levels in blood-samples collected preconceptionally and at 12-16 weeks in their next pregnancy. Differences were analyzed between pregnancies with rPS (n = 12) and without rPS (non-rPS, n = 24) using linear mixed models, with subanalyses based on pre-pregnant normal or subnormal PV. RESULTS: We observed higher fibronectin-levels at 12-16 weeks (p < 0.05 and p < 0.01, respectively) and lower PAI-2-levels at 16 weeks (p < 0.01) in the rPS subgroup, the intergroup differences being larger in women with subnormal PV. CONCLUSION: We showed that former PS patients who developed rPS have raised fibronectin- and reduced PAI-2-levels already in early/mid pregnancy. These deviations are even more prominent in women with subnormal pre-pregnant PV, supporting development of a 2-step screening program for former patients to identify the high-risk subgroup of women who may benefit from closer surveillance.

A1. Volume load and pressure load both relate to relative wall thickness in former PE.

AIMS: To study the relationship between volume and pressure load on the one hand and relative wall thickness (RWT) on the other hand in former preeclamptic women. METHODS: In 654 former PE women, blood pressure (BP) and PV (iodine 125 albumin indicator dilution technique) where measured. PV was indexed for body surface area (BSA). Echocardiography was performed to calculate RWT. The study population was divided in 4 subgroups consisting of women with either normal- or high-systolic BP (sysBP) (<140 versus ≥140mmHg, respectively) and normal- or low-PV index (>1373 versus ≤1373 ml/m2 respectively). Differences between the four subgroups where analyzed with ANOVA. Pearson's rho is calculated for the correlation between PV and sysBP on the one hand and RWT on the other hand. RESULTS: RWT was the lowest in the group with normal sysBP and normal PV and the highest in the subgroup with high sysBP and low PV subgroup (Table 1). Moreover, PVindex correlated negatively with RWT in the setting of both normal sysBP and high sysBP (Figure 1a and b) while systolic BP correlated positively with RWT in the setting of normal sysBP but not in the setting of high sysBP (Figure 1c and d). DISCUSSION: Raised RWT, as a measure for concentric remodelling, relates to both decreased volume load and increased pressure load.

Perihepatic adhesions: an unusual complication of hemolysis, elevated liver enzymes and low platelet syndrome.

We present a case of symptomatic perihepatic adhesions, which developed after a pregnancy complicated by hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome, in which a subcapsular liver hematoma occurred. Our patient presented with complaints of persistent, severe right-sided upper abdominal pain. The complaints developed gradually, one year after a pregnancy that had been complicated by HELLP syndrome with a subcapsular liver hematoma. The hematoma had resolved spontaneously. An upper-abdominal magnetic resonance imaging revealed a density between liver and diaphragm at the site of the former subcapsular hematoma, suspect of perihepatic adhesions. The presence of perihepatic adhesions was confirmed during a laparoscopy and treated by adhesiolysis in the same session. The adhesions may have developed in response to the degradation process of the subcapsular liver hematoma during conservative treatment. This case of perihepatic adhesions may therefor be the first presentation of a long term sequel of subcapsular liver hematoma in HELLP syndrome.

Care-as-usual provided to formerly preeclamptic women in the Netherlands in the next pregnancy: health care consumption, costs and maternal and child outcome.

OBJECTIVE: To explore hospital costs by pregnant women with a history of early-onset preeclampsia or HELLP syndrome, managed according to customary, but non-standardized prenatal care, by relating maternal and child outcome to maternal health care expenditure. STUDY DESIGN: This was a cohort study, in women of 18 years or older who suffered from early-onset preeclampsia or HELLP syndrome in their previous pregnancy (n=104). We retrieved data retrospectively from hospital information systems and medical records of patients who had received customary, non-standardized prenatal care between 1996 and 2012. Our analyses focused on the costs generated between the first antenatal visit at the outpatient clinic and postpartum hospital discharge. Outcome measures were hospital resource use, costs, maternal and child outcome (recurrence of preeclampsia or HELLP syndrome, incidence of eclampsia, gestational age at delivery, intrauterine fetal demise, small-for-gestational-age birth and low 5min Apgar score). We used linear regression analyses to evaluate whether maternal and child outcome and baseline characteristics correlated with hospital costs. RESULTS: Maternal hospital costs per patient averaged € 8047. The main cost drivers were maternal admissions and outpatient visits, together accounting for 80% of total costs. Primary cost drivers were preterm birth and recurrent preeclampsia or HELLP syndrome. CONCLUSION: Hospital costs in the next pregnancy of formerly preeclamptic women varied widely with over 70% being medically unexplainable. The results of this study support the view that care standardization in these women can be expected to improve costs and efficacy of care without compromising outcome.

Long-Term Risk to Develop Hypertension in Women With Former Preeclampsia: A Longitudinal Pilot Study.

INTRODUCTION: Women with former preeclampsia (exPE) develop chronic hypertension 4 times more often than healthy parous controls. Women, destined to develop remote chronic hypertension, had increased left ventricular mass index (LVMI) and diastolic blood pressure (BP) prior to the onset of hypertension as compared to those remaining normotensive. However, longitudinal data on the progress of this increased LVMI in women destined to develop hypertension are lacking. METHODS: We included 20 women with exPE and 8 parous controls. At both 1- and 14-year postpartum (pp), we performed cardiac ultrasound and determined circulating levels of the metabolic syndrome variables. Of 14-year pp, 7 (35%) former patients had developed chronic hypertension. We compared these 7 former patients with both the 13 former patients who remained normotensive and the 8 parous controls using the Mann-Whitney U test and Kruskal-Wallis analysis. RESULTS: Women with hypertensive exPE differed from their normotensive counterparts by a higher incidence of early-onset preeclampsia (PE) in their index pregnancy and a higher rate of recurrence in next pregnancies. At 1-year pp, they also had high/normal BP and higher fasting insulin levels. At 14 years pp, the relative left ventricular wall thickness was higher, and the E/A ratio was lower, in the hypertensive group relative to those remaining normotensive. CONCLUSION: Women with exPE are at increased risk of developing chronic hypertension, when (1) the PE in the index pregnancy had an early-onset and/or recurred in next pregnancies and (2) the 1-year pp. Blood pressure was high normal. We also noticed that at 14 years pp, the hypertensive group showed signs of concentric left ventricular remodeling along with a decreased E/A ratio.

C-reactive protein and fibrinogen levels as determinants of recurrent preeclampsia: a prospective cohort study.

OBJECTIVE: Women with a history of early-onset preeclampsia have an increased risk of recurrent preeclampsia and are more prone to develop future cardiovascular disease. At present, risk factors underlying this association are not well characterized. We investigated whether the risk of recurrent preeclampsia is associated with pre-pregnancy levels of common cardiovascular and inflammatory markers. METHODS: Reproductive follow-up and cardiovascular parameters were obtained for 150 primiparae with a history of early-onset preeclampsia 6-12 months after their first delivery. Simultaneously, fasting plasma samples were collected and tested for lipids, glucose, C-reactive protein and fibrinogen. The relative contribution of each marker to the recurrence risk of preeclampsia and preterm delivery was estimated by Cox proportional hazard models. RESULTS: Forty-two women (28%) developed preeclampsia in a next pregnancy. Recurrent preeclampsia was related to elevated pre-pregnancy levels of C-reactive protein and fibrinogen when compared to women who did not develop recurrent disease. We found no associations between recurrent preeclampsia and maternal age, pre-pregnancy BMI, smoking or fasting levels of total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides and glucose. CONCLUSION: These observations support a role for inflammation in recurrent hypertensive disorders of pregnancy similar to its contribution to later-life atherosclerosis and risk of cardiovascular disease.

Hypertension after preeclampsia is preceded by changes in cardiac structure and function.

Preeclampsia is associated with a 4-fold higher risk for developing remote chronic hypertension. Preeclampsia is accompanied by left ventricular hypertrophy and decreased diastolic function, which may or may not resolve postpartum. We tested the hypothesis that increased measures of cardiac geometry and decreased cardiac function persisting for ≥ 6 months postpartum in normotensive women with a history of preeclampsia precede the development of later chronic hypertension. Formerly preeclamptic women (n=652) underwent echocardiography at 9 months (range, 6-19) postpartum. We excluded women with preexisting hypertension (n=42), hypertension at the postpartum screening (n=133), and those that did not return any checklist (n=128). Eventually, 349 women were included. Remote health was evaluated by a biennially checklist. We used Cox regression for analysis. Twenty-seven (8%) normotensive women had developed chronic hypertension during a medium follow-up period of 6 years. At screening they differed from their counterparts who remained normotensive by hazard ratio for left ventricular mass index (1.11; 95% confidence interval [CI], 1.03-1.18), diastolic blood pressure (1.13; 95% CI, 1.06-1.20), systolic blood pressure (1.07; 95% CI, 1.02-1.11), mean arterial pressure (1.11; 95% CI, 1.05-1.18), heart rate (1.05; 95% CI, 1.01-1.10), and E/A ratio (0.22; 95% CI, 0.06-0.85). Backward stepwise analysis showed independent hazard ratio for left ventricular mass index and diastolic blood pressure 1.08 (95% CI, 1.01-1.16) and 1.13 (95% CI, 1.06-1.21), respectively. In conclusion, the development of later chronic hypertension in initially normotensive formerly preeclamptic women is preceded by increased left ventricular mass index and diastolic blood pressure at postpartum screening.

IVF culture medium affects human intrauterine growth as early as the second trimester of pregnancy.

STUDY QUESTION: When does a difference in human intrauterine growth of singletons conceived after IVF and embryo culture in two different culture media appear? SUMMARY ANSWER: Differences in fetal development after culture of embryos in one of two IVF media were apparent as early as the second trimester of pregnancy. WHAT IS KNOWN ALREADY: Abnormal fetal growth patterns are a major risk factor for the development of chronic diseases in adult life. Previously, we have shown that the medium used for culturing embryos during the first few days after fertilization significantly affects the birthweight of the resulting human singletons. The exact onset of this growth difference was unknown. STUDY DESIGN, SIZE AND DURATION: In this retrospective cohort study, all 294 singleton live births after fresh embryo transfer in the period July 2003 to December 2006 were included. These embryos originated from IVF treatments that were part of a previously described clinical trial. Embryos were allocated to culture in either Vitrolife or Cook commercially available sequential culture media. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed ultrasound examinations at 8 (n = 290), 12 (n = 83) and 20 weeks' (n = 206) gestation and used first-trimester serum markers [pregnancy-associated plasma protein-A (PAPP-A) and free ß-hCG]. Differences between study groups were tested by the Student's t-test, χ(2) test or Fisher's exact test, and linear multivariable regression analysis to adjust for possible confounders (for example, parity, gestational age at the time of ultrasound and fetal gender). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 294 singleton pregnancies (Vitrolife group nVL = 168, Cook group: nC = 126) from 294 couples were included. At 8 weeks' gestation, there was no difference between crown-rump length-based and ovum retrieval-based gestational age (ΔGA) (nVL = 163, nC = 122, adjusted mean difference, -0.04 days, P = 0.84). A total of 83 women underwent first-trimester screening at 12 weeks' gestation (nVL = 45, nC = 38). ΔGA, nuchal translucency (multiples of median, MoM) and PAPP-A (MoM) did not differ between the study groups. Free ß-hCG (MoM) ± SEM differed significantly (1.55 ± 0.19 in Vitrolife versus 1.06 ± 0.10 in Cook; P = 0.031, Student's t-test). At 20 weeks' gestation, a more advanced GA, reflecting an increased fetal growth, was seen at ultrasound examination in the Vitrolife group (n = 115) when compared with the Cook group (n = 91). After adjustment for confounding factors, both the difference between GA based on three biparietal diameter dating formulas minus the actual (ovum retrieval based) GA (adjusted mean difference + 1.14 days (P = 0.04), +1.14 days (P = 0.04) and +1.36 days (P = 0.048)), as well as head circumference (HC) and trans-cerebellar diameter (TCD) were significantly higher in the Vitrolife group (HCvl 177.3 mm, HCc 175.9 mm, adjusted mean difference 1.8, P = 0.03; TCDvl 20.5 mm, TCDc 20.2 mm, adjusted mean difference 0.4, P = 0.008). LIMITATIONS, REASONS FOR CAUTION: A first trimester (12 weeks) fetal screening was not yet offered routinely during the study period, therefore only 28% of women in our study participated in this elective screening programme. Although all sonographers were experienced and specially trained to perform these ultrasound examinations and were unaware of the randomization procedure, we cannot totally rule out possible intra- and inter-observer variability. Despite being indispensable in daily practice, sonographic weight formulas have a limited accuracy. WIDER IMPLICATIONS OF THE FINDINGS: According to the fetal origins hypothesis, many adult diseases originate in utero owing to adaptations made by the fetus to the environment it encounters. This study indicates that the embryonic environment is already important for fetal development. Therefore, our study emphasizes the need to investigate fetal growth patterns after assisted reproduction technologies and long-term health outcomes of IVF children, especially in relation to the culture medium used during the first few days of preimplantation development. TRIAL REGISTRATION NUMBER: Not applicable.

Anxiety and depression following preeclampsia or hemolysis, elevated liver enzymes, and low platelets syndrome. A systematic review.

Women who suffered from pregnancy complications are at increased risk for anxiety and depression. The aim of this study was to evaluate whether having suffered from preeclampsia (PE) or HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is associated with anxiety and depression, and whether PE/HELLP is an independent risk factor for developing anxiety and depression. Systematic search on PubMed and PsycInfo with no time limit. Studies presenting original data, including women with a history of PE/HELLP and at least one comparison group of women without PE/HELLP, reporting the results for each group separately or in a multivariate regression analysis with PE/HELLP as an independent variable. Study characteristics and outcomes were extracted using a prespecified form. If necessary, additional calculations were performed. The search yielded 267 articles, with only six being suitable for inclusion in this review. Studies on depression (six studies) showed generally positive associations between PE/HELLP and the prevalence of depression or severity of depressive symptoms. However, the results of three studies were not statistically significant. Studies addressing anxiety (two studies) did not show significant associations between PE/HELLP and anxiety scores. Associations between post-traumatic stress and PE/HELLP, investigated in four studies, were often nonsignificant. Due to heterogeneity of study methods, a meta-analysis of the results was not possible. In most studies, confounder control was poor. Evidence is mixed but generally points to positive associations between various forms of psychopathology and previous PE/HELLP. Causality of the associations can, however, not be judged adequately.

Characteristics of heart, arteries, and veins in low and high cardiac output preeclampsia.

OBJECTIVE: To assess the feasibility of non-invasive measurements of maternal cardiac output in relation to birth weight percentile and cardiovascular physiology in preeclampsia. STUDY DESIGN: In a cohort of 62 women with preeclampsia, impedance cardiography was used to measure cardiac output and to evaluate heart and arteries. Venous characteristics were assessed by combined electrocardiogram-Doppler ultrasonography. Statistical differences were evaluated by Mann-Whitney U-tests. RESULTS: Cardiac output correlated with birth weight percentile (P=.002), with more small for gestational age newborns in low cardiac output preeclampsia (<7.5L/min) than in high cardiac output preeclampsia (≥8.9L/min) (12/29 vs. 2/16, P=.044). This was associated with lower aortic flow indices and shorter venous pulse transit times in low than in high cardiac output preeclampsia. CONCLUSION: Non-invasive impedance cardiography measurements of maternal cardiac output correlate with birth weight percentile and are associated with different functionality of heart, arteries, and veins in low and high cardiac output preeclampsia.

Physiological implications of arteriovenous anastomoses and venous hemodynamic dysfunction in early gestational uterine circulation: a review.

This review summarizes current information on anatomical and physiological properties of the early gestational uteroplacental circulation, and implications of normal or abnormal functioning of the venous compartment. It is illustrated that these properties serve intra-uterine redistribution of blood flow, which is a crucial activity during different stages of trophoblastic remodelling of spiral arteries. Maintaining conditions of pressure and flow constant in the developing intervillous space is important towards normal functioning of the placenta in advanced pregnancy. Failure of this process predisposes to damage of trophoblastic villi, which is commonly seen in preeclampsia and/or fetal growth restriction. Basic principles of vascular physiology allow linking venous hemodynamic dysfunction to increased intervillous pressure. From this, it is concluded that current methods to explore the uteroplacental circulation in normal pregnancy and preeclampsia should be expanded with integrative methods focussing on each site of the microvascular network, the arterial ànd the venous compartment.

PP035. Genome-wide expression profile of first and second trimester human uterine natural killer cells.

INTRODUCTION: Uterine Natural Killer (uNK) cells are key regulators of the placental bed during early placental development and account for 40% of decidual cells. uNK cells have been suggested to play a role in pregnancy complications including maternal placental syndromes, such as preeclampsia. Furthermore uNK cells are involved in angiogenesis, immunomodulation, trophoblast invasion and spiral artery remodeling. These temporal processes are essential for normal placentation and may suggest a time dependent role for uNK cells. OBJECTIVE: To determine uNK cell phenotypic changes during early human placental development. METHODS: uNK cells were isolated from first (7-8 wks, n=6) and second trimester decidual tissue (13-14wks, n=6) by enzymatic digestion and flow sorting, based on uNK cell specific surface marker expression (CD56(high)CD16-CD3-). Total RNA was isolated and subjected to genome-wide gene expression profiling. Expression patterns were validated by quantitative rt-PCR. RESULTS: Using purified uNK cells we identified 140 transcripts that are differentially expressed between the first and second trimester of pregnancy. Many of these transcripts cluster into promising novel and established NK cell functional characteristics. CONCLUSION: The uNK cell phenotype changes over the course of early pregnancy. We propose that these phenotypic changes of NK cells may be dictated by the "uterine niche" to promote the orderly and precisely timed process of placentation.

PP056. Cardiac adaptation in the preclinical phase of recurrent preeclampsia in women with a history of early preeclampsia.

INTRODUCTION: Preeclampsia is thought to be preceded by first trimester circulatory maladaptation. Early and late onset PE may exhibit two different cardiac and hemodynamic states. Moreover, early PE relates to postpartum impaired cardiac function. Incomplete resolved or impaired cardiac function may influence the pattern of cardiac adaptation in the next pregnancy and may relate to recurrent disease. We postulate that in women with a history of early PE, the pattern of early cardiac adaptation differs between those that do and those that do not develop recurrent disease. OBJECTIVES: We hypothesize that after early onset PE, in the subsequent gestation, the pattern of cardiac adaptation differs between those that do and those that do not develop recurrent disease. METHODS: In this cohort study, we included 84 women with a history of early-onset PE. Former PE patients who concomitantly experienced HELLP-syndrome, fetal growth restriction and/or fetal demise, were excluded. The remaining 51 women underwent serial cardiac ultrasound and automated blood pressure and heart rate recordings, once before, and again at gestational age 12, 16 and 20 weeks. Post hoc, women were subdivided into those who did (RECUR) or did not develop recurrent PE (CONTR). We analyzed data using repeated measures analysis of variance. RESULTS: 14/51 (27%) women developed recurrent PE. Pre-pregnant heart rate was higher (71 vs 64 bpm, p<0.05) and stroke volume lower (68 vs 77mL, p<0.05) in RECUR as compared to CONTR. Even though LVM index was consistently lower in the RECUR group, the two subgroups responded to the next pregnancy with a comparable pattern of cardiac adaptation. CONCLUSION: Despite consistently lower LVM and SV and higher HR, after early onset PE, the pattern of subsequent early pregnancy cardiac adaptation is comparable in those that do and do not develop recurrent disease.

PP078. The influence of maternal position on gestational hemodynamics.

INTRODUCTION: Cardiovascular profiling is useful for gestational hemodynamic studies. Conflicting results of cardiac output evolution from third trimester pregnancy to term are frequently reported. OBJECTIVES: To stress the effect of maternal position in the assessment of maternal cardiac and arterial parameters during normal pregnancy. METHODS: Impedance cardiography measurements were executed during 16 normal pregnancies using a standard protocol with known reproducibility. Gestational evolution of stroke volume, cardiac output, cardiac cycle time intervals, aortic flow parameters and total peripheral vascular resistance was measured in supine, standing and sitting positions. SAS procedure MIXED for linear mixed models was used for each parameter separately. RESULTS: Evolution of stroke volume and cardiac output in supine position differed from standing (p<0.01) and sitting positions (p<0.05). Next to this, pre-ejection period, left ventricular ejection time index, systolic time ratio and total peripheral vascular resistance also showed a different evolution between supine and standing positions (p<0.05); no differences were observed between standing and sitting positions (p⩾0.19). CONCLUSION: Next to the frequently reported cardiac output, gestational evolutions of other pre-load dependent parameters are influenced by maternal position. This study shows the importance of a standardized protocol for the measurement of cardiovascular parameters in pregnancy.

PP087. Multicenter external validation and recalibration of a model for preconceptional prediction of recurrent early-onset preeclampsia.

INTRODUCTION: In an earlier paper we reported on the development of a model aimed at the prediction of preeclampsia recurrence, based on variables obtained before the next pregnancy (fasting glucose, BMI, previous birth of a small-for-gestational-age infant, duration of the previous pregnancy, and the presence of hypertension). OBJECTIVE: To externally validate and recalibrate the prediction model for the risk of recurrence of early-onset preeclampsia. METHODS: We collected data about course and outcome of the next ongoing pregnancy in 229 women with a history of early-onset preeclampsia. Recurrence was defined as preeclampsia requiring delivery before 34 weeks. We computed risk of recurrence and assessed model performance. In addition, we constructed a table comparing sensitivity, specificity, and predictive values for different suggested risk-thresholds. RESULTS: Early-onset preeclampsia recurred in 6.6% of women. The model systematically underestimated recurrence risk. The model's discriminative ability was modest, the area under the receiver operating characteristic curve was 58.9% (95% CI: 45.1 - 72.7). Using relevant risk-thresholds, the model created groups that were only moderately different in terms of their average risk of recurrent preeclampsia (Table 1). CONCLUSION: Compared to an AUC of 65% in the development cohort, the discriminate ability of the model was diminished. It had inadequate performance to classify women into clinically relevant risk groups.

Index event bias-a numerical example.

Studies of determinants of recurrent disease often give unexpected results. In particular, well-established risk factors may seem not to have much influence on the recurrence risk. Recently, it has been argued that such paradoxical findings may be because of the bias caused by the selection of patients based on the occurrence of an earlier episode of the disease. This bias was referred to as index event bias. Here, we give a theoretical quantitative example of index event bias, showing that, as a result of selection of patients on the basis of previous disease: (1) risk factors become inversely associated when they are not in the unselected population, and (2) the crude association between the risk factor of interest and disease becomes biased toward the null.