This is from Dr. Sher at SIRM. I am not sure if this helps you but I thought I would give you the information anyway. SIRM is one of the first clinics to use the intralipid method for immunological disorders.
http://www.haveababy.com/?Immunologic_Treatment
Immunologic Implantation Failure: A Rational Basis for Treatment.
Currently,
with few exceptions, practitioners of Assisted Reproduction tend to
attribute “unexplained and/or repeated” IVF failure(s), almost
exclusively to poor embryo quality, advocating adjusted protocols for
ovarian stimulation and/or gamete and embryo preparation as a potential
remedy. The idea that having failed IVF, all that it takes to
ultimately succeed is to keep trying over and over using the same
recipe is over simplistic. There are numerous non-embryologic that can
be responsible for failed IVF. This presentation addresses immunologic
factors that cause implantation failure:
The implantation
process begins six or seven days after fertilization of the egg. At
this time, specialized embryonic cells (i.e., trophoblast), which later
becomes the placenta, begin growing into the uterine lining. When the
trophoblast and the uterine lining meet, they, along with Immune cells
in the lining, become involved in a "cross talk" through mutual
exchange of hormone-like substances called cytokines. Because of this
complex immunologic interplay, the uterus is able to foster the
embryo’s successful growth. Thus, from the earliest stage, the
trophoblast establishes the very foundation for the nutritional,
hormonal and respiratory interchange between mother and baby. In this
manner, the interactive process of implantation is not only central to
survival in early pregnancy but also to the quality of life after birth.
Considering
its importance, it is not surprising that failure of proper function of
this immunologic interaction during implantation has been implicated as
a cause of recurrent miscarriage, late pregnancy fetal loss, IVF
failure, and infertility. A partial list of immunologic factors that
may be involved in these situations includes anti-phospholipid
antibodies (APA), antithyroid antibodies (ATA), and, perhaps most
importantly, activated natural killer cells (NKa). Presently, these
immunologic markers can be adequately measured by only a few (less than
a half dozen) highly specialized reproductive immunology laboratories
in the United States, from patient blood samples.
1) Antiphospholipid Antibodies (APA)
A
significant body of literature suggests that patients who experience
repeat IVF failures often have increased levels of circulating APAs.
Compelling evidence has also demonstrated that up to 50% of women with
pelvic endometriosis and unexplained infertility harbor APAs in their
blood. Despite this information, the role of APAs in reproductive
outcome is still controversial. In 1995, we proposed that in cases of
non-male factor infertility, women who test positive for APAs be
treated with a mini-dose heparin and low-dose aspirin to improve IVF
implantation and thus birth rates. This approach was based upon
research that suggested that heparin repels APAs from the surface of
trophoblast cells, thus enhancing their development and aspirin, by
inhibiting platelets from adhering to the early trophoblast, might
prevent clot formation in the early uteroplacental vasculature. We
subsequently demonstrated that heparin/aspirin therapy improved IVF
outcome only for women whose APA testing was positive for antibodies
other than those directed against two specific phospholipids, i.e.,
phosphatidylethanolamine (PE) and phosphatidylserine (PS), and that
only women who had IgG/IgM-related anti-PE or anti-PS antibodies
experienced a significant improvement in IVF implantation and birth
rates when IVIg therapy, instead of heparin/aspirin, was initiated more
than 1 week prior to embryo transfer.
Our recent observations
suggest that the use of heparin alone is just as effective as combining
it with aspirin. Accordingly we no longer prescribe aspirin at all.
Notwithstanding the above, the following recent observations suggest
that APAs rather than being causally linked to implantation failure,
might serve to identify a population at inordinate risk of implantation
failure and that NKa, through the unregulated release of embryotoxins,
are in fact the real culprits.
The presence of APAs in male factor cases appears to bear no relationship to IVF outcome;
Only APA positive women who also test positive for abnormal NK activity
appear to benefit from selective immunotherapy with IVIg.
More than 75% of APA+ women who have increased NK cell activity also harbor a PE and/or a PS antibodies
2) Natural Killer (NK) Cells
After
ovulation and during early pregnancy, NK cells comprise more than 70%
of the white blood cell population seen in the uterine lining. NK cells
produce a variety of local hormones known as TH-1 cytokines.
Uncontrolled, excessive release of TH-1 cytokines is highly toxic to
the trophoblast and endometrial cells, leading to their programmed
death (apoptosis) and, subsequently to failed implantation. In the
following situations these NK cells can become abnormally activated,
and thereby produce these TH-1 cytokines:
When both male and
female share specific DNA (DQ-alpha) similarities. In such cases, the
presenting problem is usually recurrent pregnancy loss, rather than
“infertility”.
In female patients that have both pelvic disease and abnormal APA testing
In about half of the cases where the woman forms antibodies against her own thyroid gland (i.e., antithyroid antibodies.)
Activated
NK cells (NKa) can spill over from the uterine lining into the
peripheral blood where their toxicity can be measured. IVIg therapy,
initiated more than 1week prior to embryo transfer, can subdue
activated NK cells, thereby reducing the risk of implantation failure.
3) Cytotoxic Lymphocytes (CTLs).
CTLs release “toxins”(perforins and granzymes) and TH-1 cytokines that
counter the humoral, TH-2 cytokine response that is a necessary
prerequisite for B-cells to produce antibodies. The “toxins” and TH-I
cytokines damage or kill the cells that form the outer layers of the
embryo’s root system”(i.e.; the trophoblast). By pitting their TH-1
response against the counter-effect of humoral TH-2 cytokines, both
CTL’s and activated NK-cells (Nka) regulate and control the degree to
which the trophoblast ( placenta) invades the uterine wall as well as
the tolerance and acceptance by the uterus of the foreign fetal
“transplant” (allographt). Studies have shown that women who experience
recurrent pregnancy miscarriages have significantly raised levels of
CTL’s, Nka’s and TH-1 Cytokines (the so called “embryotoxic factor”) in
their uterine linings as well as in the peripheral blood.
4) Antithyroid Antibodies (ATA)
A
clear relationship has been established between ATA and reproductive
failure (especially recurrent miscarriage and infertility). We have
previously reported on the ability to double IVF birth rates through
the administration of intravenous gammaglobulin (IVIg) to ATA+
patients. IVIg therapy should be initiated prior to initiation of
treatment with fertility drugs, and should be administered one more
time after pregnancy is diagnosed. About 50% of women who harbor ATAs
also test Nka positive. The risk of implantation failure in ATA
positive women appears to be confined to cases where ATAs coexist with
Nka+.
5) Alloimmune Implantation Dysfunction: HLA compatibility; HLA-G and DQ-alpha.
A
pregnancy must be recognized as foreign to trigger the appropriate
immunologic mechanisms. HLA compatibility plays an important role in
this recognition (HLA-A, B, C, DR, DQ and DP). Overall, if the father’s
HLA complex too closely resembles the mother’s HLA complex, then this
recognition does not occur thus resulting in a spontaneous abortion or
implantation failure. HLA-G is a unique HLA that is expressed by
cytotrophoblast cells which compose the inner layer of the placenta.
The HLA-G isotypes is vital to the maternal tolerance of the fetus and
functions as immunosuppressive. In other words, HLA-G serves as a
defense mechanism to protect the placenta (embryo) from the maternal NK
cells. We recently reported that it is now possible to determine the
accurate pregnancy potential of each embryo before IVF implantation.
The presence of high levels of sHLA-G had a positive predictive value
greater than 70% in women under the age of 39, and over 50% in women
from 39 to 44 years old.
Embryonic paternal antigens regulate
trophoblastic HLA-G expression which maintains a balanced TH-1: TH-2
release by T-Cell (CD-4) Lymphocytes In the absence of this paternal
antigen-induced HLA-G, normal trophoblastic proliferation and embryo
implantation cannot occur. When the sperm provider and the embryo
recipient share several HLA antigens (e.g HLA, B, C, DR, DQ or DP),
there is a break down in HLA-G related cytokine signaling and an
imbalance occurs in the TH-1-TH-2 balance with TH-1 cytokines
predominating. This often causes progressive or sudden implantation
(trophoblastic) failure, most commonly manifesting as recurrent
miscarriages and sometimes as unexplained IVF failure.
THERAPEUTIC IMMUNOMODULATION
a) Corticosteroid Therapy (Prednisone, Prenisolone and Dexamethazone)
Steroid
therapy is routine in most IVF programs. Some advocates use daily oral
methyl prednisolone .We prescribe oral dexamethazone commencing about
ten days prior to initiating ovarian stimulation with gonadotropins,
and continuing until the diagnosis of pregnancy, whereupon, in the
event of a negative test (Beta HCG or ultrasound), the dosage is
tapered over a period of seven to ten days, and then discontinued.
Pregnant patients continue treatment through the first trimester.
Steroids are believed to act by inhibiting the cellular immune response
b) Heparin
There
is compelling evidence that the subcutaneous administration of heparin
(at a dosage of 5000 U twice daily to women undergoing IVF for female
causes of infertility who test positive for APAs, but negative for NK
activation), significantly improves IVF birth rates. Heparin
administration is withheld on the day of egg retrieval until
immediately following embryo transfer, whereupon it is recommenced and
continued until the 8th week of pregnancy. Heparin is thought to act by
repelling APAs from the surface of the trophoblast (early "root system"
of the embryo). Provided that platelet counts are normal, are checked
on a regular basis, and heparin is withheld on the day of egg
retrieval, its administration is virtually risk-free.
c) Intravenous Immunoglobulin (IVIg)
Intravenous
Immunoglobulin (IVIG) is a sterile protein preparation derived from
human blood. Every effort has been made to ensure that it is free of
bacterial and viral contamination. There are basically four ways in
which IVIG is believed to offset or counter the anti-implantation
effects associated with reproductive immunologic deficiencies. First,
it is a potent suppressor of activated (toxic) Natural Killer cells
(NKa). Second, IVIG reduces the activity of CTL’s ( activated T-cells),
which are major producers of TH1 cytokines ("toxins") that can damage
the early implanting conceptus. Third, IVIG is believed to suppress the
ability of B cells to produce damaging autoantibodies such as APAs and
antithyroid antibodies (ATA) and, Fourth, IVIG contains anti-idiotype
antibodies that directly counter many of the damaging effects of
autoantibodies (antibodies that attack the bodies own cells), such as
antiphospholipid antibodies (APAs), thereby protecting the early "root
system” of the embryo/conceptus from damage.
IVIG has had some
undeserved bad press. Since it is a blood derivative, the thought of
administering it in an era where HIV is rampant, is frightening to
most. However, consider the following: IVIG products available in the
United States and the United Kingdom are subject to the most stringent
controls and scrutiny. According to the manufacturers of IVIG, there
has not been a single case of HIV viral transmission in more than two
million administrations and there have only been a few isolated cases
of Hepatitis C. This is not surprising since IVIG is derived from the
very same blood pool used for transfusion purposes, and since millions
of units of blood have been administered in the United States over the
last 7 years without any reports of HIV transmission. The IVIG
available in the U.S is thoroughly tested .We hold, that if
administered properly by qualified medical personnel, and the
appropriate precautions are taken, IVIG, currently used in this
country, is virtually devoid of viral contamination.
We
recommend that IVIG in cases for specific clinical conditions where in
spite of having transferred numerous “good quality embryos”
implantation does not occur and there is associated activation of NK
cells when there is a known history or family history of Autoimmune
disease in association with the woman testing positive for NK cell
activation(Nka+). In cases of Alloimmune implantation failure (see
above) Isolated Nk cell activation, without one of these associated
clinical situations, is not in and of itself an absolute indication for
IVIG therapy since some Nka+ women do conceive and then continue with
healthy pregnancies… without IVIG therapy. IVIG treatment should be
initiated at least 7 days prior to embryo/bastocyst transfer.
The
selective use of immunotherapy has, on numerous occasions, enabled us
to achieve successful pregnancy in many patients who had previously
suffered repeated IVF failures (4 or more). Many such patients had
previously been advised, not to try again with their own eggs. We are
able to report IVF births occurring in numerous cases, where the woman
had previously experienced more than ten (10) IVF failures. One such
case involved a 42-year-old woman who was successful with us (using her
own eggs) following 22 consecutive prior IVF failures. We believe that
such results could not have been achieved without access to selective
immunomodulation.
d)Corticosteroid Therapy (Prednisone, Prenisilone andDexamethazone)
Steroid therapy is a mainstay of most IVF programs. Some programs
use daily oral methyl prednisilone while others prescribe oral
Dexamethazone commencing about ten days prior to initiating ovarian
Stimulation with gonadotropins, and continuing until the diagnosis of
pregnancy, whereupon, in the event of a negative test (Beta HCG or
ultrasound), the dosage is tapered over a period of seven to ten days,
and then discontinued. Pregnant patients continue treatment through the
first trimester. Steroids are believed to act by inhibiting the cellular
immune response.
Because
immunologic problems may lead to implantation failure, it is important
to properly evaluate women with risk factors such as:
• Unexplained or recurrent IVF failures
• Endometriosis,
• Unexplained infertility or
• A family history of autoimmune diseases (e.g. rheumatoid arthritis, lupus erythematosus & hypothyroidism).
Rather
than being causally linked to implantation failure, the detection of
APAs (in women whose infertility is not male factor-related), probably
function as markers that point to a population at risk. We have
demonstrated that in cases of female infertility, women who test APA
positive but Nka negative who are treated with heparin (oid),
experience significantly improved IVF outcomes, while APA/ATA positive
women who also test Nka positive experience similar benefit when IVIG
is given prior to egg retrieval.
“In the pursuit of optimizing
outcome with IVF, the clinician has a profound responsibility to make
every effort at enhancing the environment for implantation. By so
doing, he/she will not only maximize the chance of pregnancy, will also
promote the noble objective of enhancing the very quality of the life
produced.”