1 Department of Obstetrics and Gynaecology, 2 Department of Immunology, University of Liverpool, L69 3BX, 3 Liverpool Womens Hospital, Crown Street, Liverpool L8 7SS and 4 Medical School and School of Biological Sciences, University of Manchester, Research Floor, St Marys Hospital, Manchester M13 OJH, UK
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Abstract |
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Key words: abnormal pregnancies/embryonic period of gestation/endometrial receptivity/recurrent miscarriage/recurrent pregnancy loss
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Introduction |
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The current definition of RM is three consecutive pregnancy losses before week 24 of pregnancy. This definition was derived from the following epidemiological data. The sporadic miscarriage rate in the general population is 15% (Warburton and Frazer, 1964; Poland et al., 1977
; Stray-Pederson and Stray-Pederson, 1984
) so that, by probability alone, the RM rate in fertile couples would be 0.153 = 0.30.4%. The actual prevalence of RM in all fertile couples of reproductive age is 0.51.0% (Tho et al., 1979
; Alberman, 1988
). Thus, it has been assumed that some couples are more prone to miscarriage than others. This hypothesis is supported by studies showing a positive correlation between the number of previous miscarriages and the miscarriage rate in the next pregnancy in women who have had at least three miscarriages (Parazzini et al., 1988
; Regan et al., 1989
; Quenby and Farquharson, 1993
).
Epidemiologically, advanced maternal age is a strong risk factor for both spontaneous miscarriage and RM, implying that pregnancy abnormality is a significant contributory factor to miscarriage (Quenby and Farquharson, 1993; Nybo Andersen et al., 2000
).
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The contribution of abnormal pregnancies to recurrent pregnancy loss |
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Recently, preimplantation genetic diagnosis (PGD) has been used to investigate women with RM, revealing that they produce more aneuploid embryos than normal women (Simón et al., 1998; Vidal et al., 1998
; Pellicer et al., 1999
; Gianaroli et al., 2000
). When PGD is used to discard karyotypically abnormal embryos (known as aneuploidy screening), the miscarriage rate after IVF decreases (Munné et al., 1999
). The majority of these aneuploid embryos are a result of maternal oocyte abnormalities (Cobo et al., 2001
; Robinson et al., 2001
). Ovarian hyperstimulation increases the rate of oocyte abnormality (London et al., 2000
). Recent publications have also suggested an association between sperm chromosomal anomalies (and sperm DNA damage) and RM (Giorlandino et al., 1998
; Rubio et al., 1999
; Egozcue et al., 2000
). Thus there may well be a paternal contribution to recurrent embryonic abnormality. Therefore, artificial reproductive technology has highlighted the importance of embryo quality in miscarriage. However, the question remains as to why couples who recurrently produce abnormal embryos do not present with infertility because of recurrent subclinical pregnancy loss.
Karyotyping does not detect pregnancies complicated by structural abnormalities in the presence of morphologically normal chromosomes, or many other types of abnormality. Newly introduced medical therapeutic abortion methodology has allowed detailed examination of undamaged first trimester pregnancies (Blanch et al., 1998). Severe structural abnormalities likely to be incompatible with survival into the second trimester were found in 34% of specimens examined (Blanch et al., 1998
). Had these pregnancies continued they would have represented sporadic miscarriages. The structural abnormalities in our data (Blanch et al., 1998
) and the karyotype abnormalities discussed above represent slightly different groups, but together they indicate that embryo abnormality is a prominent feature of miscarriage.
Screening for known causes of RM includes tests for antiphospholipid syndrome, endocrine abnormalities, parental chromosome abnormalities, uterine structural abnormalities, thyroid function, diabetes and thrombophilias (Li, 1998).
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The endometrium in recurrent miscarriage |
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Expression of the endometrial protein, MUC1, was found to be lower in the endometrium of women suffering from RM than controls (Aplin et al., 1996), suggesting that epithelial function may be compromised in some cases of RM. MUC1 is an anti-adhesion molecule that is thought to contribute to the barrier function of the endometrial surface, which resists implantation except during a specific time window in the mid-secretory phase (Bergh and Navot, 1992
; Aplin, 2000
). In-vitro implantation experiments have demonstrated that MUC1 is selectively removed from the human maternal epithelial cell surface in the immediate vicinity of an attaching embryo (Aplin et al., 2001
; Meseguer et al., 2001
). This appears to depend on an embryo to maternal signalling mechanism, the details of which have not been elucidated. However, any process that is initiated by a signal emanating from the embryo can be put to use in selection. It is stated that epithelial abnormality with impairment of barrier function could lead to a situation in which poor quality embryos that are otherwise destined to fail, implant and present later as miscarriages (Aplin et al., 1996
).
The most abundant leukocyte in the maternal decidua is the uterine natural killer cell, also known as the uterine large granular lymphocyte (LGL). This uterine-specific cell type is more abundant in decidua than in non-pregnant endometrium (Bulmer, 1996). Lachapelle and colleagues demonstrated that the endometrium of (non-pregnant) women with RM contains an increased proportion of CD16+ CD56dim LGL compared with normal fertile women in whom CD16- CD56bright LGL predominate (Lachapelle et al., 1996
). Using immunohistochemistry, increased numbers of CD56+ LGL were found in the preimplantation endometrium of RM patients compared with controls (Clifford et al., 1999
; Quenby et al., 1999
). Furthermore, there were more CD56+ leukocytes in the endometrium of patients who subsequently miscarried than in those who had live births (Quenby et al., 1999
). There is no general agreement as to the function of uterine CD56+ LGL in relation to pregnancy, but these observations suggest that they might facilitate the implantation of blastocysts, including those with abnormal karyotypes, leading to the clinical presentation of RM. The latter interpretation is supported by data showing that CD56+ LGL are more numerous in the decidua from chromosomally abnormal miscarriages than in chromosomally normal miscarriages (Yamamoto et al., 1999
). However, until the phenotype of these cells is further defined, the possibility that RM is associated with an altered LGL phenotype cannot be refuted.
T helper and other immune cells can differentiate into subsets with distinctive patterns of cytokine release, and it has been proposed that type 1 responses [characterized by the production of interleukin (IL)-2 and interferon-] are systemically suppressed in murine pregnancy and that local expression of type 2 cytokines (e.g. IL-4, IL-6, IL-10) in placental tissue might be beneficial for fetal survival (Wegmann et al., 1993
). During human pregnancy, systemic maternal immune responses may be biased in favour of a type 2 profile (Wegmann et al., 1993
; Marzi et al., 1996
) and it has been suggested that RM is an abnormal type 1 response (Makhseed et al., 1999
; Raghupathy et al., 1999
, 2000
). Peri-implantation endometrium was found to have a predominance of type 2 cytokines (Krasnow et al., 1996
; Lim et al., 1996
, 1998
), and in pregnancy a 10-fold increase in decidual type 2 cytokine secretion occurred (Krasnow et al., 1996
). We prospectively studied the early pregnancy cytokine profile of women suffering RM. This study was designed to elucidate whether a failure of the cytokine shift predated miscarriage and was therefore likely to be an aetiological factor in RM. Contrary to our hypothesis, the cytokine shift, which appears to characterize normal pregnancy, was accentuated rather than diminished in RM pregnant women (Bates et al., 2002
). Therefore, the failure of type 1/type 2 shift seen by other authors (Raghupathy et al., 2000
) may be a consequence rather than a cause of miscarriage. In our RM population, women appear immunologically more receptive to abnormal pregnancies.
There were more activated leukocytes in the decidua from the miscarriages of women with unexplained RM and a normal fetal karyotype than in decidua from women with RM and a trisomy 16 fetus (Quack et al., 2001). This suggests different cellular immunity associated with the miscarriage of karyotypically normal and abnormal pregnancies, and indeed a possible maternal immunological aetiology for the failure of chromosomally normal conceptuses. Our view is that T lymphocytes, LGL and other immune cells may be capable of expressing either a progestational or contragestational phenotype and, crucially, may be able to switch rapidly from the former to the latter in response to an abnormal gestation. Testing this proposal requires a better grasp of the functions of each category of cells so that specific phenotypic markers can be measured in healthy and RM tissue.
At present, we argue that the immunological data do not support a case for the endometrium being either hostile or defective in RM. They are equally consistent with a higher rate of abnormal embryos in RM women being further compounded by reduced endometrial selectivity, and thus presenting clinically as RM rather than infertility. Further evidence needs to be gathered to test this hypothesis in the future.
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Ultrasound perspective |
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Improvements in the resolution of ultrasonography should enable many of the structural and karyotypic abnormalities seen macroscopically to be diagnosed in utero. Anembryonic pregnancies, seen as empty sacs on ultrasound, are clearly abnormal. Cystic hygromas, anencephaly, body stalk defects and even lethal dwarfism can also all be recognized prior to miscarriage with modern ultrasonography (Jurkovic and Jauniaux, 1995).
Clinical observation points to the causes of miscarriage being fetal rather than placental, as the ultrasound identification of embryo/fetal death often occurs many weeks prior to clinical signs of pregnancy failure due to placental malfunction. Pregnancies with placental mosaicism (containing both karyotypically normal and abnormal trophoblast cells) and a normal fetal karyotype are associated with intrauterine growth restriction rather than miscarriage (Wilkins-Haug et al., 1995). However, the proliferative and invasive characteristics of chromosomally abnormal trophoblast are unknown.
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The selection failure hypothesis |
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Miscarriage of an abnormal pregnancy in the first trimester incurs significant cost to maternal resources and often requires time for physical and mental recovery during which the individual is reproductively inactive. Therefore, in the context of a high rate of abnormal embryos seen in humans, active selection by the female tract in the early stages of pregnancy, that is at fertilization, gamete transport, implantation and corpus luteal rescue, is the best way for the biological system to maximize reproductive success.
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Clinical implications |
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At present, karyotyping the products of conception following miscarriage may be viewed in some hospitals as an unnecessary luxury. However, in the absence of karyotyping, it is assumed that women who repeatedly miscarry are losing normal pregnancies. Data detailed above have shown this unlikely to be the case. Women with RM are given expensive, intensive treatment (for example, heparin or i.v. immunoglobulin) to prevent miscarriage. Such treatment is not appropriate if the losses are due to karyotypic or structural abnormalities. Therefore, obtaining a karyotype after several pregnancy losses is of extreme importance.
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Implications for treatment trials |
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Implications for future research |
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Conclusions |
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Acknowledgements |
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Notes |
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References |
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