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| Dr. William Matzner, Simi Valley, CA |
Excerpt: The Selective Use of Heparin/Aspirin Therapy, Alone or in Combination with Intravenous Immunoglobulin G in The Management of Antiphospholipid Antibody Positive Women Undergoing In Vitro Fertilization
This is an excerpt of an article
originally published in American Journal of Reproductive Immunology and was
co-authored by Dr. William Matzner. The full article is available here.
INTRODUCTION
Despite
the introduction of enhanced protocols for ovarian stimulation, improved embryo
culturing techniques, assisted hatching and intracytoplasmic sperm injection,
the national average birthrate per completed cycle of In Vitro Fertilization
(IVF) and Embryo Transfer (ET) has minimally improved over the last few years
and is still not much above 20% per egg retrieval (1). The successful implantation of a
morphologically normal embryo transferred to the uterus remains the bottleneck
in every IVF program.
For
several years, researchers have shown a link between abnormalities relative to
the woman’s immune system and recurrent pregnancy loss (2-5). More recent data suggests that the
immunologic pathophysiology associated with recurrent pregnancy loss and early
implantation failure may be similar.
Clearly, implantation failure at a preclinical stage is often
misdiagnosed as “infertility”. Perhaps
the term Failed Pregnancy Recognition (FPR) would be more appropriate in such
cases. It is likely that immunologic
deficiency plays a significant role in a variety of implantation related
problems, including but not limited to; FPR, biochemical pregnancy, blighted
ovum and first trimester miscarriage (4-9).
Bustillo,
et al. reported a five fold increase in the prevalence of APA seropositivity in
84 women who failed to conceive following the transfer of twelve or more
embryos over a number of IVF/ET cycles (10).
Sher, et al. described a high prevalence of antiphospholipid antibodies
(APA) in women with pelvic organic disease who underwent in vitro fertilization
(IVF) and embryo transfer (ET), and demonstrated a three fold improvement in
clinical PR with the first IVF cycle when H/A was administered to APA+ women
under the age of 40 years
(7), suggesting that autoimmune mechanisms associated with early implantation
failure are potentially treatable.
It has
been demonstrated that APA+ patients undergoing IVF benefit from H/A therapy
(7), therefore, we tested all IVF candidates prior to commencing their first
IVF attempt. Over the years, we noted a trend from the results in our clinic
suggesting that women who possessed IgG or IgM antibodies to phosphoserine (PS)
or phosphoethanolamine (PE), had lower pregnancy rates than women with any
other APA. With this observation, and Coulam, et. al. reported success using
intravenous immune globulin (IVIg) on unselected patients who had failed
several IVF attempts (11), we attempted to establish specific criteria for
which patients might benefit from H/A along with IVIg. IVIg was felt to be an
appropriate immune modulator because it has been proven useful in a variety of
autoimmune disorders such as Kawasaki’s disease, idiopathic thrombocytopenic
purpura and Wiskott-Aldrich syndrome.
Although the mechanism of action is unclear, it is believed that the
anti-idiotype antibodies in the IVIg play an immune modulating function
(12). The specific objectives of this
analysis are: 1) To determine whether the effect of H/A therapy was influenced
by the phospholipid (PL) epitope against which the APA were directed as well as
the gammaglobulin isotype involved; and 2) To ascertain whether H/A treated,
APA+ women who failed to conceive following two consecutive IVF cycles of
treatment, would experience improved birthrates following the combined administration
of H/A and IVIg during the third consecutive IVF attempt, and to establish if
any particular APA type predicts which women may benefit from IVIg therapy.
MATERIALS
AND METHODS
A
study was undertaken, involving 687 APA+ women (age range 29-40 years, mean age
36.25 years) who underwent IVF/ET at Pacific Fertility Medical Center during a
four year period commencing January 1992.
Cases of male infertility, ovum donation and gestational surrogacy were
excluded. The data analysis was
conducted in three phases.
Phase
I
Six
hundred eighty seven (687) women who tested APA+ to one or more PL epitope each
underwent < 2 IVF cycles for a total of 1050 completed treatment
cycles. All women were offered treatment
with heparin and aspirin. Those who
accepted were put into Group A and those that declined were placed in Group
B. Six hundred three (603) of these
women (Group A) underwent a total of 923 IVF cycles of treatment where H/A
alone was administered, while the remaining 84 women (Group B) underwent 127
IVF cycles where H/A was not administered.
Phase
II
We
evaluated whether IVF outcome following two consecutive cycles of H/A therapy
was influenced by the APA profile (i.e. the specific PL epitope to which APA
were directed and the associated gammaglobulin isotype). Since the number of
individual APA sub-profiles was quite large, the sub-groups were too small to
permit statistical comparison in patients who had APA directed against multiple
phospholipids. In addition, it would be difficult to ascertain if one specific
PL influenced outcome in the presence of other PLs. Accordingly, Group C represents those 322
women from Group A who each tested
positive to only one APA.
Phase
III
Group
D represents one hundred twenty one (121) women from Group C who did not achieve viable pregnancies in
Phase II (i.e. following two consecutive IVF attempts), where immunotherapy was
confined to H/A alone. These women
received IVIg in combination with H/A during their third consecutive IVF cycle.
LABORATORY
EVALUATION
All
women underwent serum follicle stimulating hormone (FSH) and estradiol (E2)
measurements (by radioimmunoassay or enzyme assay) on day two or three of a
prior menstrual cycle. Only those women
who had a serum FSH concentration of < 10mIU/ml and a plasma E2 of <
70pg/ ml on cycle day three, were included in the study. All women underwent APA testing using an
enzyme-linked immunosorbent assay for antibodies to the following six
phospholipid epitopes: cardiolipin (CL), phosphoserine (PS), phosphoglycerol (PG),
phosphoethanolamine (PE), phosphatidic acid (PA), and phosphoinositol (PI), as
previously described in detail (13).
Antiphospholipid antibody seropositivity (APA+) was defined by the
detection of APA measuring > two (2) standard deviations from the mean to
IgA, IgM and/or IgG isotypes. Borderline
values were defined as >2 SD above the mean, and positive values were
defined as >3 SD above the mean of normal controls. The control group for
the APA assay consisted of non-infertility patients who had no history of
clinical or subclinical autoimmune disease, or recurrent pregnancy loss.
Each
time the ELISA assay was performed, both known negative and positive controls
were run simultaneously for each epitope and isotype. This was important to assess the performance
of the antigen coated on each plate, the antibody conjugates, the pipetting
technique, washing method, incubation times, incubation temperature and
substrate.
Cervical
or semen specimens were cultured for Ureaplasma, Chlamydia and Gonococcus, in
all cases. Male partners all underwent
semen analyses to exclude male factor infertility.
DETERMINANTS
OF OUTCOME
The
number of babies born per transferred embryo, was determined in order to
provide a measure of the viable implantation rate. Multiple births and miscarriages were
documented. A successful IVF outcome was
defined as a live birth.
TREATMENT
All
patients underwent controlled ovarian hyperstimulation (COH) with menotropins,
preceded by pituitary down regulation with gonadotrophin releasing hormone
agonist (GnRHa) by a previously described protocol (14).
All
patients included in this study were APA+ and received aspirin 81 mg po qd and
heparin 5000 U sq bid, starting on day two of Controlled Ovarian
Hyperstimulation. Heparin was withheld
on the morning of egg retrieval, and reinstated that same evening while aspirin
was withheld from the ninth day of menotropin stimulation and was reinstated on
the evening following egg retrieval. H/A
was discontinued if pregnancy did not occur as evidenced by rising quantitative
human chorionic gonatotropin (HCG) blood levels measured respectively on the
8th and 10th day postET. Patients with a positive HCG blood test continued with
H/A treatment through the diagnosis of a clinical pregnancy, 3-4 weeks post ET. H/A was continued until, at least the 10th
gestational week. H/A treatment was
monitored as previously described (7).
STATISTICAL
METHODS
Data
was placed into two-by-two tables; and analyses between and within groups were
performed using the Chi Squared test for significance. P values below 0.05 were considered to
indicate statistical significance.
Analysis was performed using the CHITEST and CHIINV functions of
Microsoft Excel 97 for Windows.
About William L.
Matzner, M.D., PhD, FACP
Dr.
William Matzner works in the area of healthcare economics consulting at
Healthcare Analytics, LLC, in California. He graduated Phi Beta Kappa from
Stanford University. He received his M.D. with Honors from Baylor College of
Medicine. In 1988, he was the Solomon Scholar for Resident Research at Cedar
Sinai Medical Center. Dr. Matzner subsequently was awarded a PhD in Neuro
Economics from Claremont Graduate University. He is board certified in Internal
Medicine and Palliative Medicine. He has researched and published extensively
on the issue of reproduction and immunology in medical literature. He has been
in private practice since 1989, specializing in Reproductive Immunology and
Internal medicine.
Website: https://drwilliammatzner.com
Consulting Website: https://healthcareanalytics.biz
News: https://medicogazette.com/dr-william-matznerWilliam Matzner, MD (Simi Valley, California), has been practicing medicine since 1989, Internal Medicine and Reproductive Immunology. M.D. with Honors from Baylor College of Medicine.
