Alfredo Palacio y un Discurso Conciliador

Only 30% of embryos survive to birth, of the 70% that do not survive 15% end in

recognisable miscarriage and 55% are lost in the early stages (Lindley, 1979). 91.7% of

the early stage losses are without the mothers knowledge (Edmonds et al., 1982).

Although a high number of these early pregnancy losses are attributable to chromosomal abnormality (30-60%), the remaining 40-70% of embryo mortality is not due to grossly

abnormal karyotype (Flamigni et al., 1991). There have been a number of theories put

forward to explain this wastage.

1.4.1 Endometrial, oocyte and hormonal factors

It has been proposed that implantation is the crucial event which differentiates fertile and

non-fertile cycles, (Navot et al., 1989) and that endometrial receptivity is the most

important factor differentiating between successful and unsuccessful implantation

(Flamigni et al., 1991). Data from in vitro fertilisation (IVF) supports this view; a 70-

90% fertilisation rate results in only a 15-25% pregnancy rate (Navo et al., 1986) despite

the replacement of multiple embryos. On average only 3-5% of embryos transferred

after IVF successfully complete implantation (Flamigni et al, 1991), the rates of

spontaneous miscarriage for IVF patients are higher than average and this reduces the live birth rate to below 10%. The timing of embryo replacement could be critical, as the

endometrium may be hostile to out of phase embryos (Edwards et al., 1981). This is an

important consideration in IVF, since embryos that are fertilised outside the body,

cultured in vitro, and replaced develop more slowly than in the normal in vivo situation

and therefore no longer match the dating of the endometrium into which they are replaced.

The drop in fecundity with age has been attributed by some to uterine ageing, and others to oocyte ageing. With advances in assisted reproductive technology these theories have been tested in oocyte donation programmes. The results are ambiguous with some

studies demonstrating uterine age as a parameter in successful pregnancy (Flamigni et al, 1993; Meldrum, 1993). Other studies report a restoration of fertility in older women

when donor eggs are used, independent of the age of the recipients (Abdalla et al., 1993;

Navot et al, 1994). Both factors are likely to play a role and the balance may vary between different women.

Hormonal imbalance and endometrial retardation (histological dating behind LH dating

by 2 or more days) are major factors in the aetiology of recurrent miscarriage (Horta et

al, 1977). Recurrent miscarriage is defined as three or more consecutive fetal losses before the gestational age of 20 weeks and 15% of all pregnancies are lost through miscarriage spontaneously therefore 3-4 out of every 1000 women will have 3 or more consecutive losses by chance alone. Even in these patients the chance of success in the next pregnancy is 40-70%. This makes it very hard to assess the efficacy of any treatment. Hormonal therapy can improve the pregnancy outcome in these patients but

emotional support and counselling can be equally as effective (Stray-Pederson & Stray-

Pederson, 1988). A combination of the two can restore the probability of successful

pregnancy to that of the normal population i.e. 85%, in the majority of patients (T.C. Li,

personal communication).

1.4.2 Blocking factors

An absence of blocking antibodies has been observed in recurrent miscarriage (Rocklin et

al., 1976). But the lack of antibodies may be the result of the pregnancy failure not the cause. Immunotherapy has been carried out as a treatment for recurrent miscarriage based on the theory that blocking antibodies must be induced to block a matemal-anti- fetal immune response. This treatment involves the immunisation of the patient with

paternal (Beer et al., 1985) or third-party (Taylor & Faulk, 1981) leukocytes. A

variation is immunisation with trophoblast vesicles (Johnson et al., 1988). Although

success rates of up to 78% have been reported, the placebo effect of entering a trial and

having careful monitoring and medical attention must not be underestimated (Stray-

secondary recurrent miscarriage patients, based on the assumption that these were the most likely group to be suffering from a reaction to their partners antigens rather than their secondary recurrent miscarriage being due to another cause. While this is a logical step to take in the design of such a trial it further complicates analysis of the efficiency of the treatment and comparisons with the general population of recurrent miscarriers may imply that the treatment is more successful than it actually is. Until the results from a number of controlled trials currently being carried out are known the role of blocking factors remains controversial.

1.4.3 Immunological imbalance

There may be an immunological imbalance in recurrent miscarriage patients, either the leukocytes of the decidua are over-activated and prevent implantation or initiate rejection

of the fetus or the natural immunosuppressive factors may be absent (Hill, 1990).

In spontaneous miscarriage the decidua shows large areas of necrosis and the fetal tissue

is infiltrated by cytotoxic T lymphocytes (Cray et al, 1982), the cells which are activated

by IL-2. These cells may have been activated due to a rise of cytokines in response to

immunological imbalance, clinical or sub-clinical infection such as Listeria or because of

recognition of the paternal antigens expressed by the fetus. In humans the presence of raised levels of TNF or IL-2 at the time of implantation has detrimental effects on the

embryo (Hill et al., 1987; Tezabwala et al, 1989) and can cause miscarriage. In mice

these cytokines can totally block pregnancy. However it is difficult to demonstrate that the cytotoxic cells are the cause of the fetal demise, their presence may only be a consequence of another mechanism already in process. In humans inevitably the evidence is only available after both cause and effect have already taken place.

The concept of immunologically mediated miscarriage is still controversial. However the evidence points to a system of immunological balance between activated leukocytes and immunosuppressive mechanisms during successful pregnancy. The breakdown of this system is likely to account for fertility problems in some women.