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| William Matzner, MD, Simi Valley, California |
Excerpt: High Fecundity Rates Following In-Vitro Fertilization
and Embryo Transfer in Antiphospholipid Antibody Seropositive Women Treated with
Heparin and Aspirin
This is an excerpt of an article
originally published in Human Reproduction and was
co-authored by Dr. William Matzner. The full article is available here.
INTRODUCTION
One of
the great endeavours facing reproductive medicine is to improve pregnancy rates
following in-vitro fertilization (IVF) and embryo transfer. Patients undergo
IVF and embryo transfer for infertility secondary to organic pelvic disease,
ovarian dysfunction, male factor, and immunological and unexplained
aetiologies. It has been well documented that fertilization rates by assisted
reproductive technologies are high (Lopata et al., 1982), yet the North
American national IVF/embryo
transfer birth rate for the year ending December 1991 was only 15.2% per egg
retrieval (Society for Assisted Reproductive Technology, 1993). Autoantibodies
have been detected in humans and other animals who have failed to conceive
despite repeated attempts at IVF/embryo transfer. One such study has implicated
antibodies to negatively charged phospholipids in unsuccessful IVF/embryo
transfer cycles (Fisch et al., 199l). An increased prevalence of
antiphospholipid antibodies (APA) has also been demonstrated in patients
diagnosed with pelvic endometriosis (Gleicher et al., 1987). This has led to
speculation that autoimmune processes similar to those known to be associated
with recurrent pregnancy wastage may compromise embryo implantation following IVF/embryo
transfer.
Several
mechanisms have been proposed to explain how APA contribute to pregnancy
wastage: platelet membrane and/ or endothelial cell wall damage may initiate
the clotting cascade, and inhibition of prostacyclin and inability to activate
protein C (an endogenous anticoagulant) may contribute to a hypercoagulable
state (Harris et al., 1985). More recent work has demonstrated that several
negatively charged APA, notably antiphosphoserine and antiphosphoethanolamine,
interfere with the formation of syncytiotrophoblasts from cytotrophoblasts
(Rote et al., 1992). This latter mechanism may also play a significant role in
IVF/embryo transfer, as it emphasizes the function of phospholipids as adhesion
molecules modulating the process of implantation. Interference with these
adhesive properties may preclude implantation altogether or result in
spontaneous abortions.
A
study was undertaken to evaluate the effect of APA on women undergoing
IVF/embryo transfer so as to determine (i) the prevalence of APA seropositivity
in women with organic pelvic disease (i.e. post-surgical adhesions,
endometriosis and/or pelvic inflammatory disease), compared to women whose
infertility was not associated with tissuedamaging conditions (e.g. male factor
and/or unexplained infertility), (ii) whether APA seropositivity adversely
affects implantation and pregnancy rates with IVF/embryo transfer, and (iii)
whether combined treatment with heparin and aspirin (H/A) improves ongoing
clinical pregnancy rates in seropositive women who undergo IVF/embryo transfer.
MATERIALS
AND METHODS
Patient
population
We
evaluated 429 women <40 years of age who underwent IVF/ embryo transfer at
the Pacific Fertility Medical Centers in California, during the 30 month period
commencing January 1, 1992 through June 30, 1994 in order to assess the
relationship between APA seropositivity and the cause of infertility. The
assessment of outcome following IVF/embryo transfer was confined to those
cycles of treatment which immediately followed the diagnosis of APA status.
Patients were divided into two groups: group 1 comprised 365 women with organic
pelvic disease. Male factor infertility was absent in all cases. This group was
further subdivided according to diagnosis as follows: group 1A comprised 79 women
with endometriosis and of these, 52 (66%) women were APA seropositive; group 1B
comprised 187 women who underwent IVF/embryo transfer for infertility due to
pelvic inflammatory disease, and of these 85 (45%) women were APA seropositive;
group 1C comprised 99 women who underwent IVF/embryo transfer for infertility
due to abdominal/pelvic adhesions unassociated with prior pelvic inflammatory
disease or endometriosis and 57 (58%) of these women were APA seropositive.
Group
2 comprised 64 women whose infertility was not associated with female pelvic
pathology. The cause of infertility in this group was an ‘isolated male factor’
in 49 of these women and was ‘unexplained’ in 15 cases. Nine (14%) women in
group 2 were APA seropositive.
The
diagnosis of ‘isolated male factor infertility’ required the detection of <
10 x 106/ml motile spermatozoa on semen analysis in the absence of any
identifiable female cause for infertility. Organic pelvic pathology was
diagnosed or excluded by any combination of hysterosalpingography, laparoscopy
and/or laparotomy. All women in the study had normal uterine cavities as
observed at hysteroscopy. Women with thyroid dysfunction or hyperprolactinaemia
were treated appropriately prior to commencing IVF/embryo transfer cycles.
Laboratory
evaluation
All
women were required to undergo serum follicle stimulating hormone (FSH) and
oestradiol measurements (by radioimmunoassay) on the second or third day of a
preceding menstrual cycle and were only included in this study if the FSH and
oestradiol concentrations were < 15 mIU/ml and 40 pg/ml respectively. These
women also underwent concomitant APA testing using an enzyme-linked
immunosorbent assay for antibodies to six phospholipid epitopes (cardiolipin,
phosphoserine, phosphoglycerol, phosphoethanolamine, phosphatidic acid and
phosphoinositol), as previously described (Matzner et al, 1994). Cervical swabs
and cultures were obtained tor Ureaplasma urealyticum as well as DNA probes for
Chlamydia and Gonococcus. Male partners underwent semen evaluations which
included sperm counts, motility, morphology and culture for pathogenic
organisms. In addition, both women and men had sperm antibody serologies
performed using the indirect immunobead test.
Treatment
Since
women of a similar age with organic pelvic disease in the absence of male
factor are expected to have comparable clinical pregnancy rates following
IVF/embryo transfer attempts, evaluation of treatment with H/A was limited to
patients in group 1. Antiphospholipid antibody seropositivity was defined by
the detection of any concentration of APA in the IgG, IgM and/or IgA
immunoglobulin fraction. There were 194 IVF/embryo transfer cycles performed on
APA seropositive women. Of these, a total of 169 women received heparin
sulphate [Lyphomed, Deerfield, Illinois, 60015; (5000 units s.c.)] twice daily,
along with aspirin [Bayer, Division of Sterling Winthrop Inc, New York, NY
10016; (81mg)] orally once a day and there were 25 APA seropositive women who
did not receive H/A. Treatment with H/A commenced with the initiation of
ovarian stimulation on cycle day 2 to be continued through the 34th week of
pregnancy. A luteal phase pituitary gland ‘down-regulation’ protocol using a
gonadotrophin-releasing hormone agonist in conjunction with gonadotrophins was
employed to achieve optimal ovarian stimulation as previously described
(Feinman et al., 1993). Heparin was temporarily withheld after the morning
administration on the day prior to oocyte retrieval and aspirin was withheld 2
days prior to this procedure (i.e. from the day of human chorionic
gonadotrophin administration). Both heparin and aspirin therapy were
reinitiated immediately following transvaginal ultrasound-guided oocyte
retrieval. All patients undergoing H/ A therapy had normal activated partial
prothrombin times, serum glutamic-oxalacetic transaminase and serum
glutamic-pyruvic transaminase concentrations and normal red blood cell and
platelet counts prior to initiating treatment. These tests were repeated at 2
week intervals for 2 months and thereafter at monthly intervals until
termination of the medication regimen.
Endpoint
The
endpoint was defined as either a viable pregnancy or delivery. The diagnosis of
a viable pregnancy was based on sonographic confirmation of fetal cardiac
activity.
Statistical
methods
Comparisons
of individual proportions in any two treatment groups were carried out using
Fisher’s exact test. A collective test for treatment over several subgroups,
such as groups 1A, 1B, and 1C in Table II, was made using the logarithmic
regression model proposed by Cox (1972). The estimates and confidence limits
obtained by this technique are computed from the complete data, and not simply
from the marginal totals.
RESULTS
Table
I illustrates that there was no evidence of systematic differences in the mean
ages, ovarian stimulation protocols employed and the number of embryos
transferred per IVF attempt among the group of women with organic pelvic
pathology, male factor and unexplained infertility. There was, however,
evidence that women in group l had a higher prevalence (P < 0.001) of APA
seropositivity (53%) than women in group 2 (14%).
To
determine whether APA seropositivity adversely affected IVF/ embryo transfer
outcome, the pregnancy rates of untreated APA seropositive women were compared
with those for APA seronegative women, following one IVF/embryo transfer cycle
performed on group 1 patients, in the cycle that followed the diagnosis of the
women’s APA status (see Table II). However, there was no firm statistical
evidence of differential pregnancy rates. The ratio of pregnancy rates (APA-
/APA+) was estimated as 1.66 with 95% confidence limits of 0.58 and 4.72, which
embraced the ‘null hypothesis’ value of 1.0. The small number of untreated APA
+ women no doubt contributed to this failure to find evidence of an effect.
There
was statistical evidence that the pregnancy rate in H/ A-treated APA
seropositive women (49%) was significantly higher (P < 0.05) than for
untreated APA seropositive women (16%). The logarithmic regression estimated
the ratio of pregnancy rates (treated/untreated) as 3.02, with 95% confidence
limits of 1.09 and 8.40); limits which do not embrace the ‘null hypothesis’
value of 1.0. The viable pregnancy rates per IVF/embryo transfer cycle,
stratified by subgroups of organic pelvic pathology, are presented in Table II.
The
pregnancy rate of the APA seropositive treatment group treated with heparin and
aspirin (49%) was also significantly higher (P < 0.001) than that obtained
from the APA seronegative group (27%). The ratio of pregnancy rates (APA +
/APA-) was estimated as 1.79, with 95% confidence limits of 1.24 and 2.59,
providing convincing evidence of the effect.
Rest of the article can be found at the link provided above.
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-matzner William 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.
