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.

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.

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.

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.

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.

Age-related alterations in cardiac geometry in formerly preeclamptic women and healthy parous controls: an explorative study.

INTRODUCTION: Preeclamptic pregnancies induce concentric left ventricular hypertrophy instead of eccentric left ventricular hypertrophy as seen in healthy pregnancies. Although these differences persist for at least several months postpartum, the long-term fate of these changes is unknown. OBJECTIVE: To explore the age-related changes in cardiovascular structure and function in formerly preeclamptic women relative to parous controls. METHODS: A total of 20 formerly preeclamptic women and 8 parous controls underwent 2 echocardiograms at 1 and 14 years of postpartum. With the nonparametric Mann-Whitney U test and the Wilcoxon Signed Ranks test, we analyzed the between-group differences in cardiac structure and function at both time points and the time-related changes in these indices. RESULTS: Left ventricular geometry and dimensions and systolic function were comparable in the 2 study groups at both time points. The age-related decline in E/A ratio and increase in intraventricular septum thickness were noted in both groups over time, without appreciable differences between groups. CONCLUSION: A history of preeclampsia does not affect the age-related cardiac remodeling over a period of 14 years.

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.

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.

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.

Metabolic syndrome as a risk factor for hypertension after preeclampsia.

OBJECTIVE: To identify metabolic and obstetric risk factors associated with hypertension after preeclampsia. METHODS: We analyzed demographic and clinical data from a postpartum screening (blood pressure, microalbuminuria and fasting plasma levels of glucose, insulin, and lipid profile) from 683 primiparous women with a history of preeclampsia. We excluded women with pre-existing hypertension, kidney disease, or diabetes mellitus. In the group of women who were normotensive at postpartum screening, we evaluated the risk of developing chronic hypertension in the years after screening using questionnaires. RESULTS: Hypertension at postpartum screening (n=107, 17% of all cases) was related to obesity (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.2), elevated fasting levels of insulin (OR 1.7, 95% CI 1.0-2.9), low-density lipoprotein (OR 1.6, 95% CI 1.1-2.6), microalbuminuria (OR 2.3, 95%-CI 1.3-4.0), family history of hypertension (OR 1.8, 95% CI 1.1-2.8), and delivery before 34 weeks of gestation (OR 2.5, 95% CI 1.6-4.0). We identified 27 cases of hypertension within 2,095 person-years during a median 6-year follow-up in the group of women normotensive at postpartum screening. The hazard rate for the development of hypertension was 2.9 (95% CI 1.2-7.5) and 8.1 (95% CI 2.8-22.9), respectively, when two and three or more components of the metabolic syndrome were present; 3.7 (95% CI 1.4-10.0) for family history of hypertension; and 4.3 (95% CI 1.6-11.5) for recurrence of a hypertensive disorder in pregnancy. CONCLUSION: Several metabolic and obstetric risk factors related to hypertension postpartum in the short term and predisposed to the subsequent development of chronic hypertension after preeclampsia in initially normotensive women. LEVEL OF EVIDENCE: III.

Renal function after preeclampsia: a longitudinal pilot study.

BACKGROUND: Women with a history of preeclampsia are at increased risk to develop end-stage renal disease. In this longitudinal study, we evaluated renal function in women with a history of severe preeclampsia and parous controls over a period of 14 years. METHODS: Renal function was measured 1 and then 14 years postpartum by para-aminohippurate and inulin clearances in 20 women with a history of severe preeclampsia and 8 parous controls. RESULTS: The difference in glomerular filtration rate 1 year postpartum between women with a history of preeclampsia and parous controls (112 ± 10 and 125 ± 8 ml/min/1.73 m(2), p < 0.01) had disappeared 14 years postpartum (104 ± 10 and 109 ± 13 ml/min/1.73 m(2), p = 0.37). There was a consistent trend for a lower effective renal plasma flow both 1 and 14 years postpartum (477 ± 90 and 543 ± 92, p = 0.09 and 473 ± 85 and 543 ± 98 ml/min/1.73 m(2), p = 0.07). CONCLUSIONS: This explorative study suggests no accelerated renal function loss in the first decade after preeclampsia.

Electrocardiographic findings in women with a recent history of pre-eclampsia.

OBJECTIVE: To assess the prevalence of electrocardiographic (ECG) abnormalities after a pregnancy complicated by pre-eclampsia and/or syndrome of hemolysis, elevated liver enzymes and low platelets (PE) and to compare the ECG characteristics, at least six months after pregnancy, between primiparous early-onset PE women with and without recurrent PE. DESIGN: Longitudinal observational study. SETTING: Tertiary referral centre in The Netherlands from 1996 to 2008. SAMPLE: Six hundred and fifty-eight formerly pre-eclamptic women. For our second objective, we used a subgroup of 79 primiparae with a history of early-onset PE. METHODS: Data were obtained during a postpartum screening program for women with hypertensive disorders during pregnancy. MAIN OUTCOME MEASURES: Electrocardiographic abnormalities in PE women and characteristics of the ECG in women with recurrent PE after a first pregnancy complicated by early-onset PE. RESULTS: The ECG of 13 (2.0%), two (0.3%) and two (0.3%) former patients suggested ischemia, left ventricular hypertrophy and left atrial enlargement, respectively. Primiparae with recurrent PE in their second pregnancy differed from their counterparts with an uneventful second pregnancy by a leftward deviation of both the P- and the R-axes of 11° (p= 0.022) and 12° (p= 0.021), respectively, with a prolonged QT interval (p= 0.025). CONCLUSIONS: The prevalence of ECG abnormalities in women with a recent history of PE was low and did not differ appreciably from that in a large population of healthy women of comparable age. The ECGs in primiparae with a history of early-onset PE who developed recurrent PE in their second pregnancy differed slightly from women with an uneventful second pregnancy, probably related to potential confounders.

A model for preconceptional prediction of recurrent early-onset preeclampsia: derivation and internal validation.

OBJECTIVE: To develop a model to identify women at very low risk of recurrent early-onset preeclampsia. METHODS: We enrolled 407 women who had experienced early-onset preeclampsia in their first pregnancy, resulting in a delivery before 34 weeks' gestation. Preeclampsia was defined as hypertension (systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg) after 20 weeks' gestation with de novo proteinuria (≥300 mg urinary protein excretion/day). Based on the previous published evidence and expert opinion, 5 predictors (gestational age at previous birth, prior small-for-gestational-age newborn, fasting blood glucose, body mass index, and hypertension) were entered in a logistic regression model. Discrimination and calibration were evaluated after adjusting for overfitting by bootstrapping techniques. RESULTS: Early-onset disease recurred in 28 (6.9%) of 407 women. The area under the receiver operating characteristic (ROC) curve of the model was 0.65 (95% CI: 0.56-0.74). Calibration was good, indicated by a nonsignificant Hosmer-Lemeshow test (P = .11). Using a predicted absolute risk threshold of, for example, 4.6% (ie, women identified with an estimated risk either above or below 4.6%), the sensitivity was 100%, with a specificity of 26%. In such a strategy, no women who developed preeclampsia were missed, while 98 of the 407 women would be regarded as low risk of recurrent early-onset preeclampsia, not necessarily requiring intensified antenatal care. CONCLUSION: Our model may be helpful in the identification of women at very low risk of recurrent early-onset preeclampsia. Before widespread application, our model should be validated in other populations.

Platelet monitoring follow-up in a pregnant patient with HELLP syndrome.

Monitoring the course of platelet function in HELLP (haemolysis, elevated liver-enzymes and low platelets) syndrome is important for clinical decision-making. We present a primigravid woman developing HELLP syndrome at 29 weeks and 6 days. Platelet function was monitored by multiple electrode aggregometry (MEA), platelet function analyzer (PFA-100®), platelet count and mean platelet volume (MPV) over an 11-day period. MPV and PFA-100® seem better predictors for platelet function than platelet levels.

Pregnancy reduces the accuracy of the estimated glomerular filtration rate based on Cockroft-Gault and MDRD formulas.

OBJECTIVE: This study aims to determine the effect of pregnancy on the accuracy of 3 commonly used methods to estimate glomerular filtration rate ([GFR] creatinine clearance, the Cockroft-Gault, and modification of diet in renal disease [MDRD] formulas) using the inulin clearance as a reference. DESIGN: Longitudinal study design. SETTING: University hospital. POPULATION: A total of 44 parous nonsmoking Caucasian women. They had a history of uneventful pregnancy (n = 9), preeclampsia (n = 27), and intrauterine fetal demise (n = 8). METHODS: Measurements were performed both in pre-pregnancy and early pregnancy (8 weeks of gestation) and included inulin infusion, blood pressure, and 24-hour urinary and serum creatinine. Agreement between methods to estimate GFR was assessed by the Bland and Altman method. MAIN OUTCOME MEASURES: GFR estimated by inulin and creatinine clearances and the Cockroft-Gault and MDRD formulas. RESULTS: During early pregnancy, the GFR measured by inulin increased 32% compared with the pre-pregnant value (from 115 ± 18 to 150 ± 23 mL/min·1.73 m(-2)), whilst the GFR measured by the indirect methods only increased 20%. The observed bias and limits of agreements are larger in early pregnancy relative to the pre-pregnant state for all 3 methods. CONCLUSION: The renal hyperfiltration during pregnancy decreases further the accuracy of the creatinine clearance and the Cockroft-Gault and MDRD formulas to estimate GFR.

Cost-effectiveness of recurrence risk guided care versus care as usual in women who suffered from early-onset preeclampsia including HELLP syndrome in their previous pregnancy (the PreCare study).

BACKGROUND: Preeclampsia and HELLP syndrome may have serious consequences for both mother and fetus. Women who have suffered from preeclampsia or the HELLP syndrome, have an increased risk of developing preeclampsia in a subsequent pregnancy. However, most women will develop no or only minor complications. In this study, we intend to determine cost-effectiveness of recurrence risk guided care versus care as usual in pregnant women with a history of early-onset preeclampsia. METHODS/DESIGN: We developed a prediction model to estimate the individual risk of recurrence of early-onset preeclampsia and the HELLP syndrome. In a before-after study, pregnant women with preeclampsia or HELLP syndrome in their previous pregnancy receiving care as usual (before introduction of the prediction model) will be compared with women receiving recurrence risk guided care (after introduction of the prediction model). Eligible and pregnant women will be recruited at six university hospitals and seven large non-university tertiary referral hospitals in the Netherlands. The primary outcome measure is the recurrence of early-onset preeclampsia or HELLP syndrome in women allocated to the regular monitoring group. For the economic evaluation, a modelling approach will be used. Costs and effects of recurrence risk guided care with those of care as usual will be compared by means of a decision model. Two incremental cost-effectiveness ratios will be calculated: 1) cost per Quality Adjusted Life Year (mother unit of analysis) and 2) cost per live born child (child unit of analysis). DISCUSSION: This is, to our knowledge, the first study that evaluates prospectively the efficacy of a multivariable prediction rule for recurrent hypertensive disease in pregnancy. Results of this study could either be integrated into the current guideline on Hypertensive Disorders in Pregnancy, or be used to develop a new guideline.