1 Departments of Histopathology and 2 Obstetrics and Gynaecology, Imperial College School of Medicine, St Mary's Hospital, Paddington, London, W2 1PG and 3 Department of Reproductive Pathology, St Mary's Hospital, Manchester, UK
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Abstract |
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Key words: antiphospholipid antibodies/antiphospholipid antibody syndrome/endovascular trophoblast/pregnancy loss/recurrent miscarriage
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Introduction |
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Materials and methods |
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Results |
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Implantation site fragments were present in 80% (16/20) of the cases from terminations of pregnancy and normal endovascular trophoblast invasion with `plugging' of decidual vessels was identified in 75% (12/16). Implantation site fragments were identified in 56% (28/50) of the PAPS cases and endovascular trophoblast invasion of decidual vessels was identified in 61% (17/28). Implantation site fragments were present in 55% (17/31) of the PAPS+ cases and endovascular trophoblast invasion of decidual vessels was identified in only 24% (4/17; Figure 1). Normal endovascular trophoblast invasion was identified significantly less frequently in the PAPS+ cases compared with PAPS cases and terminations of pregnancy (Z = 2.4, P = 0.02 and Z = 3.0, P < 0.01 respectively). There was no significant difference in the frequency of endovascular trophoblast invasion identified between terminations of pregnancy and PAPS POC [Z = 0.96, P = not significant (0.34)]. Implantation site fragments were present in 17 of the 34 (50%) aneuploid cases and endovascular trophoblast invasion was present in nine of the 17 (53%). This was not significantly different from the chromosomally normal PAPS group [Z = 0.51, P = not significant (0.61); Table I
]. In all cases in which decidual implantation site fragments were present, there was apparently normal interstitial extravillous trophoblast invasion, the difference between the PAPS+ and other groups being specifically in endovascular extravillous trophoblast invasion. In all pregnancies in which implantation site fragments were present and endovascular trophoblast `plugging' was identified, there were additional intradecidual vessels present which appeared uninvolved by endovascular trophoblast invasion.
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Discussion |
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Our findings suggest that the commonly stated assumption that intraplacental `thrombosis' is the main cause of pregnancy failure in women with PAPS is unlikely to be true in first trimester pregnancy loss, and further, that abnormalities of early trophoblast invasion may be the primary pathological mechanism in such cases. In normal early pregnancy, extravillous trophoblast invasion of the decidual stroma is associated with a subpopulation of trophoblast which invades the decidual vessels. This endovascular trophoblast initially forms aggregates or `plugs' within the vessels, which subsequently dissociate, and the endovascular trophoblasts spread and convert the branches of the uterine arteries to low resistance uteroplacental vessels (Pijnenborg et al., 1980, 1981
, 1983
). Defective trophoblast invasion of the uteroplacental arteries is now well described in association with the development of later pregnancy complications such as intrauterine growth restriction and pre-eclampsia (Brosens, 1977
; Brosens et al., 1977
; Pijnenborg et al., 1991
; Meekins et al., 1994
; Starzyk et al., 1997
), and it has been previously postulated that defective trophoblast invasion may be associated with some cases of early pregnancy loss (Michel et al., 1990
). Ultrasonographic studies have demonstrated that a continuous intervillous circulation is not present until the late first trimester (Jurkovic et al., 1991
; Jauniaux et al., 1997
). In early pregnancy, trophoblast `plugging' of the maternal circulation may play an important role in limiting the extent of intervillous blood flow with the result that both pressure-related and oxidative damage to the developing placenta are limited (Jauniaux et al., 1997
). Hence, defective endovascular trophoblast invasion may explain both the occurrence of early pregnancy loss and later pregnancy complications in women affected by PAPS. Severely abnormal endovascular trophoblast invasion may lead to excessive blood flow into the early intervillous space resulting in early pregnancy loss, whereas lesser degrees of abnormal trophoblast invasion may allow the pregnancy to proceed into the second or third trimester, but complications related to uteroplacental vasculopathy subsequently supervene. This hypothesis may also explain the excess of late pregnancy complications in women with PAPS and a history of early pregnancy loss treated with aspirin and heparin (Backos et al., 1999
). This treatment appears to reduce the severity of the defective endovascular trophoblast invasion, effectively converting potential early pregnancy losses into continuing pregnancies. However, later pregnancy complications secondary to the underlying uteroplacental vasculopathy remain a significant consideration.
Normal trophoblast invasion is a dynamic process which is tightly controlled via a complex series of interactions between trophoblast and decidual products (Bischof et al., 2000). The differentiation of trophoblast into an invasive phenotype is related to specific spatial and temporal alterations in the expression of cell surface adhesion and signalling molecules (Burrows et al., 1994
; Damsky et al., 1994
; Aboagye-Mathiesen et al., 1996
; Aplin et al., 2000
; Castellucci et al., 2000
). Both extravascular interstitial and endovascular trophoblast invasion is required in normal pregnancy since interstitial trophoblast-mediated modification of the vessel walls precedes replacement of the endothelial cells by endovascular trophoblast (McMaster et al., 1994
; Kam et al., 1999
). There are three main possibilities to explain the mechanism by which the presence of aPLs may affect this process of trophoblastic invasion. Firstly, aPLs may bind to components on the cell surface of invading trophoblast, either inhibiting the function of other cell surface molecules or causing trophoblast damage by way of complement activation or other similar mechanisms. There is in-vitro evidence that aPLs can bind to receptors on trophoblast and may lead to alterations of cellular behaviour (Rote et al., 1998
). Secondly, circulating aPLs may bind to the endothelium of maternal vessels, including those within the decidua, and either prevent the correct endothelialtrophoblast interaction via cell surface molecule modification, or lead to direct endothelial damage, thus preventing normal trophoblast invasion. Thirdly, aPLs may directly bind to the endovascular trophoblast population, leading to dissolution or abnormal formation of the endovascular trophoblast plugs.
Fetal aneuploidy is reported as the commonest `cause' of early pregnancy loss, with subclassifications into various types of defect (Jauniaux et al., 1997), but the mechanism for fetal death in such cases remains undetermined. Throughout pregnancy, specific fetal chromosomal defects have different rates of intrauterine lethality (Snijders et al., 1995
), with sex chromosome defects having a relatively low chance of intrauterine death and trisomies 18, 13 and triploidy having extremely high rates, whilst some chromosomal defects found in first trimester pregnancy loss specimens are never seen in later pregnancy (Jauniaux et al., 1997
). The results of the present study suggest that trophoblastic invasion is not significantly altered in the presence of fetal chromosomal defects and this is also in accordance with the lack of specific or characteristic placental villous features in cases of fetal trisomy (Fox, 1997
). In the majority of our cases, the karyotypic abnormality was a fetal trisomy, the vast majority of which are maternal in origin. Early placental development appears to be predominantly controlled by paternal genes, whereas early fetal development is primarily controlled by maternally derived genes (Fisher, 1997
), which may explain the lack of defective placental development or trophoblast invasion seen in many of our cases. Nevertheless, it is possible that this mechanism may depend upon the individual chromosomal defect. In the present study, although the numbers remain too small for meaningful statistical subgroup analysis, both cases with fetal trisomy 21 and all four cases with fetal trisomy 16 had apparently normal endovascular trophoblast plugging. In contrast, the cases with fetal trisomy 7, 9, 20 and 22, all of which are recognized as lethal at an early gestation, showed no endovascular trophoblast plugging.
POC obtained from evacuation of the uterus by curettage may contain fragments of chorionic villi, gestation sac, decidua and implantation site. An implantation site is present in all pregnancies, but implantation site fragments cannot be identified in specimens of POC in all cases examined. This is related to factors associated with surgical uterine evacuation and sampling at the tissue processing stages. Furthermore, even in the specimens obtained from terminations of pregnancy, the presence of endovascular trophoblast invasion may be identified only focally within the decidual fragments examined. In this study, since specimen retrieval, handling and processing were the same in all groups, the different proportions in implantation site fragments between the groups is unlikely to be a significant factor.
This study has demonstrated that histopathological examination of POC may provide evidence for the mechanism of early pregnancy failure in women with recurrent pregnancy loss. Abnormal endovascular trophoblast invasion does not appear to be a major factor in early pregnancy loss in cases of fetal chromosomal abnormality whereas, in woman with PAPS, there may be defective early endovascular trophoblast invasion. In these cases it is possible that imaging techniques, such as colour Doppler examination of early uteroplacental blood flow, may identify abnormal intervillous flow patterns prior to pregnancy failure and hence provide useful prognostic and therapeutic information.
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Notes |
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References |
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Submitted on July 30, 2001; accepted on November 8, 2001.