Apheresis as emerging treatment option in severe early onset preeclampsia

Abstract

Based on an early suggestion by Winkler et al. 2003 and a subsequent successful study by Wang et al. 2006 using lipid apheresis (LA) in 9 patients with preeclampsia to prolong pregnancies, the use of apheresis as therapeutic option in severe early onset preeclampsia has received increasing attention. Further studies using different LA systems also prolonged pregnancy and have been published in the last few years. Albeit using different LA systems and relying on different working hypothesis, all studies demonstrated a promising stabilisation against the disease's progression. Overall time from hospitalisation to the need for mandatory delivery was longer for those patients receiving apheresis compared to historical or matched control patients not receiving apheresis. These data will be reviewed and different hypotheses about the beneficial mechanism of action of apheresis will be discussed. Since up to now there is no curative treatment for preeclampsia other than observation and delivery, future work shall be encouraged.

Introduction

Preeclampsia is a life-threatening condition and one of the most important causes for maternal and perinatal morbidity and mortality worldwide. In Europe, it affects 2–3% of pregnancies [1]. 0.5% present early before 34 weeks of gestation and in consequence need mandatory preterm delivery to prevent mother and baby from serious complications [2,3]. Despite high standards in perinatal intensive care, gestation duration remains a crucial factor determining perinatal mortality (stillbirth or neonatal death within 7 days post-partum). Below 32 weeks of gestation perinatal death is as high as 17.8% (33% before 28 weeks) [4] and serious neonatal diseases occur in up to 84% of survivors depending on the age of gestation at delivery [5] Before 28 weeks of gestation, each gained day of pregnancy may result in a 2–3% lower mortality risk for the unborn [6].

According to the International Society for the Study of Hypertension in Pregnancy (ISSHP), preeclampsia can be defined as new onset of hypertension >140/90 mm Hg occurring after the 20th week of gestation paralleled by proteinuria >300 mg/24 h [7].

Management of preeclampsia is restricted to control maternal blood pressure and to prevent maternal complications like stroke, brain haemorrhage, pulmonary edema and seizures (eclampsia). To date no causative therapy exists, except delivery and removal of the placenta [8,9]. The management and the final decision for delivery has to weigh both the risk of immanent delivery for the baby and the risk of continuation of the pregnancy for the mother [10]. As gestational age is the main determinant of neonatal outcome [3], prolongation of pregnancy would be beneficial if not vital in the situation of very preterm babies.

Though this common definition of preeclampsia characterises the clinical manifestation of maternal symptoms, the underlying pathology is now regarded as a complex mixture of maternal and placental malfunction and maladaptation to the requirements of pregnancy. Considering the heterogeneous nature of the disease, preeclampsia can be divided into an early-onset and a late-onset type according to clinical and pathophysiological features [7].

The concept has been broadened by differentiation into placental and maternal preeclampsia [11]. Placental preeclampsia is associated with placental malfunction and resulting fetal growth restriction (FGR) (mostly early-onset cases i.e. before 34 weeks of gestation). Maternal over-susceptibility to endothelial and placental stimuli without specific placental malfunction and FGR occurs mostly late-onset i.e. after 34 weeks of gestation [11]. Between these extremes exist hybrid forms, where placental malfunction congregates with maternal over-susceptibility, yet this being often the most severe early-onset forms of the disorder [12].

As generally accepted, early-onset preeclampsia with placental malfunction and imbalances in placental development has its initial incident early in pregnancy during placentation [13]. According to a three stage model, preeclampsia starts with incomplete maternal tolerance to the allogeneic trophoblast (stage 1). This leads to a poor placentation with dysfunctional utero-placental perfusion, which causes placental oxidative and inflammatory stress (stage 2). Resulting abnormal placental-maternal interplay leads to disturbances of the maternal metabolism and finally becomes apparent as clinically overt preeclampsia symptoms with severe endothelial dysfunction (stage 3) [14].

Accordingly, differences in serum levels between normotensive and preeclamptic pregnancies have been shown for immunologic factors [15], (pro/anti)-angiogenic molecules [16], inflammatory mediators [17,18], as well as lipoproteins and lipids [[19], [20], [21], [22]].

Hence, several biosystems are involved in the pathophysiology with angiogenesis and the lipid metabolism being of greater interest. The use of lipid apheresis (LA) in preeclampsia is based upon two different hypotheses, involving angiogenic imbalance and lipoprotein metabolism.

Lipid metabolism during pregnancy is characterised by tremendous changes [23] to meet the needs of the placental unit and the growing fetus. Triglycerides and cholesterol increase in all lipoprotein fractions from very-low-density lipoproteins (VLDL) to low-density lipoproteins (LDL) and high density lipoproteins (HDL) during advancing normotensive pregnancy [[23], [24], [25], [26]], serum cholesterol almost doubles, while serum TG increases up to 500%.

TG levels and postprandial response are increased in several pathologies like type 2 diabetes mellitus and metabolic syndrome [27,28], and closely related to cardiovascular diseases (CVD) [29,30]. Significantly elevated TG levels are a key feature of preeclampsia [19,22,[32], [33]]. Highest triglyceride levels are associated with a four-fold increased risk for preeclampsia [19] and levels of triglyceride-rich lipoproteins are higher as compared to normotensive pregnancies [22]. Diastolic blood pressure correlates positively with triglyceride-content in intermediate-density lipoproteins (IDL) [22]. Accumulation of remnant lipoproteins and accelerated lipoprotein turnover has been proposed as a possible pathological feature in preeclampsia [22,33].

Over the last decades, a piece of the puzzle in preeclampsia pathophysiology has been discovered: angiogenic and anti-angiogenic factors. It was the group of Prof. Karumanchi that demonstrated for the first time an upregulation in placental soluble fms-like tyrosine kinase (sFlt-1) in PE. As an antagonist of pro-angiogenic vascular endothelial (VEGF) and placental growth factors (PLGF), sFlt-1 has anti-angiogenic properties probably by clearance of the two binding partners from the circulation [34]. A year later, the same group provided evidence for the predictive value of sFlt-1 and PlGF in the maternal circulation for the development of preeclampsia [35]. In uncomplicated pregnancy, sFlt-1 levels in maternal plasma increase until delivery, whereas PlGF rises until mid-gestation and decreases thereafter until delivery (bell shaped curve) [36]. In preeclampisa, sFlt-1 in maternal serum is even more increased and PlGF is further decreased. Thus the ratio sFlt-1/PlGF is therefore augmented and the elevation of sFlt-1 precedes the onset of preeclampsia by approximately 5 weeks [35]. The angiogenic imbalance in preeclampsia has drawn more and more attention in recent years, and the factors sFlt-1 and PLGF have nowadays been introduced into obstetric management for diagnostic purposes and risk stratification [37].

Based on the observation of significantly elevated triglyceride rich lipoproteins in preeclampsia, LA has already been proposed as a possible therapeutic approach [22] years ago and subsequently a first pilot study by Wang et al. [38] showed promising results for the use of LA in preeclampsia. In the meantime, several studies have been conducted with LA techniques with different approaches and hypotheses about the mechanism of action [[39], [40], [41]]. While Wang et al. and the study of Winkler et al. [38,41] focussed on the lipid-lowering and pleiotropic actions of HELP-apheresis, other groups focussed on LA by the dextrane sulfate adsorption-apheresis because of their effect to remove circulating sFlt-1 [39,42], while the lipid lowering aspect was widely neglected [40].

In the following, we review the different therapeutic approaches of apheresis in preeclampsia and will discuss the different hypotheses and clinical impacts concerning the mechanism of action.