Main findings
The vast majority of women treated with Anti-D had unremarkable
pregnancy and delivery. More than 70% of all pregnant women delivered
healthy children. Interestingly, the efficacy of this treatment does not
appear to be dependent on age, thrombophilia, and prior treatment.
Nevertheless, by these data there could be a relation between those
parameters and outcome of a pregnancy, but
case numbers are too low for
significant statistical analysis. Treatment with Anti-D was safe with no
signs of significant hemolysis.
Worldwide, RPL represents a serious and unresolved
problem.1,2,6 Immune pathways play a key role in the
pathophysiology of RPL. Already at early stage, gestation induces a
major immune response which presumably involves all immune cells,
including lymphocytes, macrophages and decidual dendritic cells. Thus,
the question whether immunotherapy may help in management of RPL is
increasingly focused in new studies.18
Macrophages are presumably the main player in regulation of pregnancy,
including implantation, placentation, fetal development, parturition,
and most importantly vascular remodeling at the maternal-fetal
interface. Thus, some modulation of macrophages may prevent miscarriages
related to immune imbalance. On this, the question rised, whether a
subtle attraction of these cells by coating of autologous red blood
cells in such affected women may result in successful pregnancies. In
fact, the results obtained during observation were encouraging. The vast
majority of treated women had unremarkable pregnancy and delivery.
Interestingly, the efficacy of this treatment does not appear to be
dependent on age, thrombophilia, and prior treatment. Nevertheless, by
these data there could be a relation between those parameters and
outcome of a pregnancy, but case numbers are too low for significant
statistical analysis. Since all treated women received simultaneously
LMWH and/or aspirin, the question remains open whether the beneficial
effect was solely related to Anti-D or to a combined effect of both
drugs. This is supported by the finding that LWMH beyond its
anti-coagulating effect may induce immunomodulation.19Until now, a monotherapy with Anti-D has not been undertaken. However,
it has been shown that treatment with intravenous immunoglobulins (IvIg)
that somewhat resembles Anti-D, may improve the outcome in pregnant
women with miscarriages.
Similarly, there is evidence that polyclonal Anti-D has an
immunomodulatory effect, which could not fully be explained
yet.20,21 In our experience, this treatment is safe
when it is given subcutaneously or at least slowly by intravenous
route.22 In previous studies we have demonstrated that
the administration of LMWH and/or aspirin results in live births in most
women with RPL.7 In this retrospective study, we used
low Anti-D doses (2 to 3 times 300 µg) for treatment of RPL in Rh(D)
positive women who remained abortive despite treatment with LMWH and/or
aspirin.
At first glance, the question may arise whether this treatment could be
justified in Rhesus positive pregnant women. Based on the following
facts, this treatment is, we think, rational as long as no alternative
therapy is available for such affected patients. Anti-D is used in
treatment of adults and children since four decades with little or no
side effects, if the drug was carefully injected.22The injection of 300 µg is harmless compared to that dose given in ITP
(50 - 75 µg/kg body weight), and to that amount reaching Rh(D) positive
infants in Rh(D) negative pregnant women who receive at least two times
100 - 300 µg prophylaxis.
The positive influence of Anti-D on RPL is evident as reflected by the
significantly increased rates of successful pregnancies in the majority
of treated women in our practice. This effect does not appear to be
dependent on age, inherited haemophilias or blood group. The question
whether Anti-D per se or only in combination with LMWH is effective is a
matter of speculation. Since the mechanisms by which LMWH influences the
outcome in RPL is largely unknown, a synergic effect can not be
excluded. Ultimately, LMWH has been shown to induce in vitro andin vivo a proinflammatory profile on RPL. It has been suggested
that this effect could be valuable at the implantation
stage.7 Thus, it remains unclear whether Anti-D alone
could also be effective as well as the combination with LMWH.
The question why this treatment was ineffective in 26 % of the treated
pregnant women remains to be answered. A possible explanation could be
related to unknown predisposition factors that cannot be influenced by
immunological modulations. Similarly, the phenomenon that the treatment
may again result in miscarriage in some women who had been shown to be
responsive remains also obscure. Whether this ineffectivity could be
related to the giving dose or timing of Anti D admininistration remains
to be answered.
Though, the most possible explanation for the successful pregnancy
following treatment with Anti-D may be attributed to an immunomodulatory
effect, some other questions remain open. For example, when and by which
mechanisms Anti-D may induce the tolerance of the semiallogeneic fetus.
There is no doubt that pregnancy is surroundingly controlled by immune
reactions which simultaneously maintain immune response (defense) and
tolerance (semi-allogeneicity), respectively. 10,11,23
Changes during pregnancy include an increase in phagocytic cells and
their functional capacity to ingest IgG coated RBCs,24an increase of T and B regulatory cells, reduction of natural killer
cells, and polarization of decidual
macrophages.23,25-28 It has been demonstrated that RPL
is associated with an imbalance of pregnancy related immune
haemostasis,10,11,29 which could, at least in part, be
normalized by immunomodulation.18,30
Anti-D administration into Rh(D) positive pregnant women results in
coating of autologous RBCs with IgG antibodies. This happening
represents a dangerous signal, and attracts macrophages to recognize IgG
opsonized RBCs. Although the attracted macrophages do not appear to
ingest a significant amount of the IgG coated RBCs, they could be
influenced in the presence of IgG-coated RBCs.
In addition, polyclonal Anti-D may contain antibodies other than Anti-D
which may have influence on macrophages, independent of phagocytosis,
i.e. HLA and anti-idiotype antibodies. Thus, it would not be surprising
that the reactions to Anti-D may lead to polarization of decidual
macrophages. These cells exhibit wide plasticity and are sensitive to
small microenvironmental changes, including nutrition, smoking, toxins,
inflammation, and physiological stress.13-15
It seems that the M1 subtype predominates over the M2 subtype in RPL.
Coating of autologous RBCs with antibodies represents unphysiological
condition in vivo , which may lead to polarization of M1 to M2
phenotype. The latter cells seem to be responsible for immunotolerance,
which is a prequisite for successful implantation a fetal development.
This hypothesis can only be proved by phenotyping of decidual
macrophages prior to and following treatment. Alternatively, an extended
investigation of cytokines and changes of peripheral immune cells may
give an explanation of this phenomenon.8-11,26,28