Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Angiogenic Factors in Women Ten Years after Severe Very Early Onset Preeclampsia

Background: Women with a history of mainly severe and early onset preeclampsia have an increased risk of future cardiovascular disease. During these complicated pregnancies increased levels of anti-angiogenic factors can be found. We hypothesize that women with a history of severe very early onset preeclampsia still have increased levels of these biomarkers years after this pregnancy, resulting in increased risk for cardiovascular disease. Methods: Twenty women with severe early onset preeclampsia before 24 weeks' gestation, who delivered between 1993-2003 in a tertiary referral centre and twenty matched controls with uncomplicated pregnancies and healthy term infants, were addressed for participation in the study. Venous plasma samples were analyzed for basic fibroblast growth factor (bFGF), placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF), E- and P-selectin, soluble intercellular adhesion molecule-3 (sICAM-3) and thrombomodulin by ELISA. Results: Sixteen case subjects and 18 control subjects consented participation. The median time interval index pregnancy to study was 9.4 and 9.7 years for cases and controls, respectively. Median levels for cases-controls (p-value) were not different; bFGF: 17.43-11.11 pg/mL (0.33), sFlt-1: 102.98-101.92 pg/ml (0.84), PLGF: 3.57-4.20 pg/mL (0.38), VEGF: 64.05-45.72 pg/mL (0.73), E-selectin: 5.11-4.68 ng/mL (0.20), P-selectin: 85.35-71.69 ng/mL (0.69), sICAM-3: 0.42-0.63 ng/mL (0.41) and Thrombomodulin: 0.92-0.93 ng/mL (0.59). Conclusion: There were no differences in angiogenic biomarkers between women with a history of severe early onset preeclampsia versus uncomplicated pregnancy almost 10 years later, suggesting that these angiogenic factors will not contribute to the early detection of women at risk for future cardiovascular disease

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Maternal psychosocial outcome after early onset preeclampsia and preterm birth.

Objective.To evaluate the impact of severe, early onset preeclampsia on long-term maternal psychosocial outcome after preterm birth. Methods.Women with severe, early onset preeclampsia before 32 weeks' gestation (cases) admitted in a tertiary university referral center between 1993 and 2004, and women with preterm delivery without preeclampsia (controls), matched for age, parity, gestational age at delivery, ethnicity, and year of delivery. Women who consented to participation received three questionnaires in 2008 concerning depression (Zung Depression Scale: score range 020; 20 items with 2-point frequency scale: no=0 and yes=1), posttraumatic stress symptoms (Impact of Event Scale: score range 075; 15 items with 4-point frequency scale: not at all=0, rarely=1, sometimes=3 and often=5. Scores>19 are regarded as high symptom levels), and social aspects (Social Readjustment Rating Scale: selection of six items concerning relational aspects with husband/partner, employer, or future family planning). Results.Included in the study were 104 cases and 78 controls (response rate 79% and 58%, respectively). There was no difference in depression scores between cases (5.4 ± 4.0) and controls (5.4 ± 4.3). Patients with severe, early onset preeclampsia had significantly higher scores of posttraumatic stress symptoms (28.7 ± 8.6 vs. 25.7 ± 7.9). The majority of women among both cases and controls had high-posttraumatic stress symptom levels (88% vs. 79%). No differences could be found in relational aspects. Conclusion.Women with preterm birth due to severe, early onset preeclampsia experience more often posttraumatic stress symptoms on average 7 years after the pregnancy compared to women with preterm birth without preeclampsia. © 2012 Informa Uk,Ltd

Mode of delivery in severe preeclampsia before 28 weeks' gestation: A systematic review

Importance Preeclampsia with an onset before 28 weeks' gestation poses dilemmas for the obstetrician with regard to the mode of delivery. Objective The aim of this study was to analyze the success rate of attempted vaginal delivery and the maternal and neonatal outcome according to the mode of delivery in women with preeclampsia and an indicated delivery before 28 weeks' gestation. Evidence Acquisition A comprehensive search was performed in the bibliographic databases PubMed, Embase.com, and Wiley Cochrane Library. The main outcome was success rate of attempted vaginal delivery. Secondary outcomes were maternal and neonatal outcomes. Results Eight studies describing a total of 800 women were included. Success rates of vaginal delivery varied from 1.8% to 80%, and rates for cesarean delivery after induction of labor varied from 13% to 51%. The rates for planned cesarean delivery varied from 0% to 73%. Two studies (n = 53) described no statistical significant differences in maternal outcomes. Two other studies (n = 107) report no statistical difference in neonatal outcome. Conclusions Studies that report the success rate of attempted vaginal delivery are limited in size. However, giving the available evidence in the reported studies a trial of labor is a considerable option in counseling women with a pregnancy complicated by preeclampsia before 28 weeks' gestation due to the similar maternal and neonatal outcome. No differences in maternal or neonatal outcome were attributed to the mode of delivery, however, numbers are small. Target Audience Obstetricians and gynecologists, family physicians. Learning Objectives After completing this activity, the learner should be better able to counsel women with early-onset preeclampsia on mode of delivery; critically appraise articles on mode of delivery in women with preeclampsia with an onset before 28 weeks' gestation; and avoid performing randomized controlled trials on mode of delivery in women with preeclampsia before 28 weeks' gestation, due to limited feasibility

Mifepristone followed by misoprostol compared with placebo followed by misoprostol as medical treatment for early pregnancy loss (the Triple M trial): A double-blind placebo-controlled randomised trial

Contains fulltext : 232470.pdf (Publisher’s version ) (Open Access)BACKGROUND: Worldwide, millions of women seek treatment for early pregnancy loss (EPL) annually. Medical management with misoprostol is widely used, but only effective 60% of the time. Pre-treatment with mifepristone prior to misoprostol might improve the success rate of medical management. METHODS: This was a multi-centre, double-blind, placebo-controlled randomised trial in 17 Dutch hospitals. Women with a non-viable pregnancy between 6 and 14 weeks of gestation were eligible for inclusion after at least one week of expectant management. Participants were randomised (1:1) between oral mifepristone 600 mg or an oral placebo tablet. Participants took 400 μg misoprostol orally, repeated after four hours on day two and, if necessary, day three. Primary outcome was expulsion of gestational sac and endometrial thickness <15 mm after 6-8 weeks. Analyses were done according to intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT03212352. FINDINGS: Between June 28th 2018 and January 8th 2020, 175 women were randomised to mifepristone and 176 to placebo, including 344 in the intention-to-treat analysis. In the mifepristone group 136 (79•1%) of 172 participants reached complete evacuation compared to 101 (58•7%) of 172 participants in the placebo group (p<0•0001, RR 1•35, 95% CI 1•16-1•56). Incidence of serious adverse events was significantly lower in the mifepristone group with 24 (14%) patients affected versus 55 (32%) in the placebo group (p = 0•0005) (Table 3). INTERPRETATION: Pre-treatment with mifepristone prior to misoprostol was more effective than misoprostol alone in managing EPL. FUNDING: Healthcare Insurers Innovation Foundation, Radboud University Medical Centre, Canisius Wilhelmina Hospital