Antiphospholipid antibodies and the placenta: a systematic review of their in vitro effects and modulation by treatment.

BACKGROUND: Antiphospholipid antibodies (aPL) are a family of auto-antibodies that are associated with an increased risk of recurrent miscarriage, intrauterine growth restriction and preterm birth. The placenta is a major target of aPL and it is likely that these antibodies promote pregnancy morbidity by affecting trophoblast function. Numerous studies have investigated the effect of aPL on trophoblast function in vitro. However, different trophoblast models and a variety of culture conditions have been employed, resulting in a myriad of different reported findings. This review systematically summarized those published studies that have investigated the effect of aPL on trophoblast function in vitro. In addition, the reported effects of pharmacological treatment on trophoblast function in the presence of aPL were also systematically reviewed. METHODS: PubMed, Scopus, Embase and Web of Science databases were searched using the keywords 'placenta OR trophoblast' AND 'antiphospholipid antibody OR antiphospholipid syndrome' up to 25 April 2014. Studies were excluded based on the absence of appropriate controls. The effects of aPL on trophoblast proliferation, death, syncytialization, invasion, hormone production, cytokine production, coagulation and complement activation were recorded. The effects of different treatments on the function of trophoblasts in the presence of aPL were also recorded. RESULTS: A total of 1071 records were retrieved from the four databases. After removing duplicates, the titles and abstracts of 529 articles were reviewed. Of those, 48 articles were read and relevant experimental results were extracted from 47 articles. CONCLUSIONS: This systematic review provides an overview of all the studies performed to date on the effects of aPL on trophoblast function in vitro. There is considerable support for aPL decreasing trophoblast viability, syncytialization and invasion in vitro. Some work has also suggested that aPL may affect the production of hormones and signalling molecules by trophoblasts, and may stimulate coagulation and complement activation in vitro. Current reports of the in vitro effects of therapeutic treatments on trophoblast function in the presence of aPL are inconclusive. This systematic review has highlighted many gaps in our knowledge of how aPL work and may direct future research in this area.

Trophoblast debris extruded from preeclamptic placentae activates endothelial cells: a mechanism by which the placenta communicates with the maternal endothelium.

INTRODUCTION: Preeclampsia is characterized by maternal endothelial dysfunction. While the mechanisms leading to preeclampsia are unclear, a factor(s) from the placenta is responsible for triggering the disease. One placental factor implicated in triggering preeclampsia is trophoblast debris which may transmit pathogenic signals from the placenta to endothelial cells. In this study, we investigated whether trophoblast debris from preeclamptic placentae triggered endothelial cell activation. METHODS: Trophoblast debris from preeclamptic or normotensive placentae, or trophoblast debris from normal placental explants that had been cultured with preeclamptic (n = 14) or normotensive sera (n = 14) was exposed to endothelial cells. Activation of the endothelial cells was quantified by cell surface ICAM-1 and U937 adhesion to endothelial cells. The levels of IL-1ß, pro-caspase-1 and active caspase-1 in the trophoblast debris were measured. RESULTS: Compared to controls, the levels of ICAM-1 and U937 adhesion to endothelial cells were significantly increased following exposure of the endothelial cells to trophoblast debris from preeclamptic placentae or placentae treated with preeclamptic sera. The levels IL-1ß, pro-caspase-1 and active caspase-1 were significantly increased in both trophoblast debris from preeclamptic placentae and placentae treated with preeclamptic sera. DISCUSSION: These results provide the first direct evidence that trophoblast debris produced from preeclamptic placentae or placentae treated with preeclamptic sera can activate the endothelium. CONCLUSIONS: Trophoblast debris from preeclamptic but not normotensive placentae can induce endothelial cell activation. This may be one mechanism by which the preeclamptic placenta communicates with the maternal endothelium to induce activation of the endothelium.

Development of a simple, cost-effective, semi-correlative light and electron microscopy method to allow the immunoelectron localisation of non-uniformly distributed placental proteins.

Immunoelectron microscopy is wrought with technical limitations that complicate its use. However, advances in correlative light and electron microscopy have recently lead to improvements in this field. We report the development of a semi-correlative approach to investigate the ultrastructural location of an antiphospholipid antibody within the syncytiotrophoblast. This method offers several advantages over existing methodologies, since it preserves antigenicity, shows good immunolabel penetrability and does not require specialized equipment. The use of a pre-embedding screen has also allowed us to target individual placental villi and overcome sampling limitations of the electron microscope. This simple, cost-effective method is likely to find widespread application in placental research.

Review: where is the maternofetal interface?

Ask where the maternofetal interface is and placental biologists will tell you, the syncytiotrophoblast and extravillous cytotrophoblasts. While correct, this is not full extent of the maternofetal interface. Trophoblast debris that is extruded into the maternal blood in all pregnancies expands the maternofetal interface to sites remote from the uterus. Trophoblast debris ranges from multinucleated syncytial nuclear aggregates to subcellular micro- and nano-vesicles. The origins of trophoblast debris are not clear. Some propose trophoblast debris is the end of the life-cycle of the trophoblast and that it results from an apoptosis-like cell death, but this is not universally accepted. Knowing whether trophoblast debris results from an apoptosis-like cell death is important because the nature of cell death that produced trophoblast debris will influence the maternal responses to it. Trophoblast debris is challenging to isolate from maternal blood making it difficult to study. However, by culturing placental explants in Netwells™ we can readily harvest trophoblast debris from beneath the Netwells™ which is very similar to debris that has been isolated from pregnant women. We have found that trophoblast debris from normal placentae shows markers of apoptosis and is phagocytosed by macrophages or endothelial cells, producing a tolerant phenotype in the phagocyte. Whereas, when we culture normal placental explants with factors such as antiphospholipid antibodies (a strong maternal risk factor for preeclampsia), or IL-6 (which is found at increased levels in the sera of preeclamptic women), the death process in the syncytiotrophoblast changes, such that the trophoblast debris becomes more necrotic. Phagocytosis of this necrotic debris leads to activation of endothelial cells. Trophoblast debris greatly expands the maternofetal interface and the nature of that debris is likely to strongly influence the responses of the maternal vascular and immune systems to the debris.

Anti-phospholipid antibodies increase non-apoptotic trophoblast shedding: a contribution to the pathogenesis of pre-eclampsia in affected women?

Pre-eclampsia is associated with trophoblast shedding-deportation and endothelial cell dysfunction. Anti-phospholipid autoantibodies increase a women's risk factor of developing pre-eclampsia. In this study we examined the hypothesis that anti-phospholipid antibodies alter the number and nature of trophoblasts shed from the placenta, and that phagocytosis of these altered trophoblasts results in endothelial cell activation. To investigate this we used a placental explant model in which explants were treated with anti-phospholipid antibodies. This treatment resulted in a doubling of the amount of trophoblast shed from the explants. Furthermore, the trophoblasts shed from anti-phospholipid antibody-treated explants were more readily phagocytosed by endothelial cells and subsequently caused the activation of the endothelial cells, as indicated by increased expression of endothelial cell surface ICAM-1 determined by cell-based ELISA, and monocyte adhesion as determined by flow cytometry. Confocal microscopy analysis of trophoblasts shed from anti-phospholipid antibody-treated or control explants demonstrated that anti-phospholipid antibodies, but not control antibodies, were internalised within trophoblasts shed from the explants, and this was accompanied by a reduction in the activity of caspases 3 and 7 in the shed trophoblasts as indicated by FLICA. These results suggest that anti-phospholipid antibodies are selectively transported into trophoblasts where they affect the regulation of the cell cycle leading to excess and aberrant death (necrotic or aponecrotic) and shedding of trophoblasts. If reflected in vivo this might explain, at least in part, how anti-phospholipid antibodies contribute to the pathogenesis of pre-eclampsia.

High tech home care: surviving and prospering in a changing environment.

Managed care plans are expanding rapidly into new marketplaces. Reimbursement for home infusion therapy, including parenteral and enteral nutrition, is significantly affected under managed care, especially when capitated payment mechanisms are used. Home care companies have experienced downsizing, mergers, acquisitions, and fierce competition in the managed care environment. Clinicians who are entering the home care setting may find that, in addition to clinical expertise, their marketability depends on a set of new skills and abilities in order to prosper in this new environment.

Daily access of implanted venous ports. Implications for patient education.

The implanted venous access port was originally developed for occasional use in the oncology patient. Patients who were candidates for externally accessed, long-term silastic catheters are having ports implanted for daily use for therapies such as total parenteral nutrition. Implanted venous access ports require careful patient selection and education. The patient must be aware of the advantages and disadvantages of the port before it is implanted. This article discusses the implications of daily access of the implanted port and educational considerations when patient accessing is taught.

A double-blind clinical trial comparing the gastrointestinal side effects of two enteral feeding formulas.

Adequate enteral nutritional support is often limited by gastrointestinal (GI) side effects. In this pilot clinical trial we compared an enteral nutrition formula based on soy hydrolysate (study formula, SF) against a widely used intact casein formula (control formula, CF) for the incidence of GI side effects in a completely randomized double blind design. Twenty-three nonsurgical hospitalized patients requiring enteral nutritional support and free of GI symptoms were randomly assigned to receive either the CF or the SF for 6 days continuously. Both formulas were isotonic, low in residue, lactose free and isocaloric, but differed in the type and concentration of protein and the concentration of medium-chain triglycerides. After randomization both groups were comparable in demographic characteristics, and nutritional status, but there were more patients on antibiotics in the CF group. The amount of formula infused per day and the route of administration were equivalent. The number of bowel movements per day was 1.0 +/- 0.5 for the CF group and 0.6 +/- 0.3 for the SF group (p less than 0.05). The incidence of diarrhea was 10.8% days for the CF group and 6.2% for the SF group (p = NS). High gastric residuals occurred in 16.9% of days in the CF group and 3.3% in the SF group (p less than 0.05). Vomiting incidence was 10.8% in the CF group and 1.5% in the SF group (p less than 0.05). After adjustment for the use of antibiotics as a covariate, the differences in number of bowel movements, vomiting and incidence of high residuals became less significant (p less than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)