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| William Matzner, MD, Simi Valley, California
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This is an excerpt of an article originally published
in The Female Patient and was co-authored by Dr.
William Matzner. The full article is available here.
Immunology
of Recurrent Spontaneous Abortion
Introduction
The immunology of reproduction is a dynamic field, with
data forthcoming exponentially. Immune mechanisms are operative in infertility,
endometriosis, eclampsia/preeclampsia, miscarriage, and other aspects of
reproduction. This paper focuses on the immunology of recurrent spontaneous
abortion (RSA). Classically, a patient is considered to have RSA if she has had
three or more consecutive miscarriages, but many clinicians are now evaluating
couples after two consecutive losses.
The causes of RSA have been classified as infection (1%),
anatomic abnormalities (5% to 10%), lutealphase defect (5% to 20%), chromosomal
abnormalities (7% to 50%), immune mechanisms (50%), and unknown (15%). Some
women have multiple reasons for RSA. A workup comprising ultrasonography,
hysterosalpingography, laparoscopy, endometrial biopsy, parental and fetal
chromosome analysis, cervical culture, and progesterone testing would explain
only about 50% of the pregnancy losses. There is strong evidence that the
remainder of miscarriages are mediated by immune mechanisms.
The uterus is an enigma. Despite a full complement of
immunocompetent cells, it allows the fetal allograft to thrive for 40 weeks.
During pregnancy, the fetoplacental unit orchestrates immune mechanisms via T
and B Iymphocytes, natural killer cells (NK), a variety of soluble
immunoregulatory factors (cytokines), and antibodies. To a significant degree,
the interaction between maternal and fetoplacental tissue and the immune system
will determine whether a pregnancy succeeds. Three antibodies are critically
important to pregnancy maintenance: maternal antipaternal leukocyte antibodies
(APLA) (ie, blocking antibodies), antiphospholipid antibodies (APA), and
antinuclear antibodies (ANA).
When the immune system is the cause of miscarriage, the
mother has a 30% chance of having a successful pregnancy without intervention
after 3 miscarriages, a 25% chance after 4 miscarriages, and a 5% chance after
5 miscarriages. With proper treatment, the overall success rate has been reported
at 70% to 85% in parity and agematched
controls.
Antipaternal Leukocyte Antibodies
APLA are antibodies that mask paternal human leukocyte
antigens (HLA) found on the fetus from maternal immune effector cells. Genes
that code for HLA or tissue type are located on chromosome 6. HLA consist of
class I and class II antigens. Class I antigens, which include the A, B, and C
loci, are found on all nucleated cells and platelets and are the only HLA
expressed on nonactivated T Iymphocytes. More recently, another class I HLA,
designated G, has been identified on cytotrophoblasts versus
syncytiotrophoblasts, which do not express any HLA. However, studies using the
polymerase chain reaction have shown that the placental barrier is not
impervious to tissue, so that maternal cells have been found in the fetal
circulation and fetal cells in maternal circulation.
In the RSA couple, APLA levels should be ascertained prior
to conception using cell-flow cytometry. The husband’s Iymphocytes are combined
with the wife’s serum (which would contain APLA if present), and incubated with
fluorescent markers. The entire mixture is placed into the cytometer, which
utilizes laminar flow fluidics and argon lasers. Under laser illumination,
cells that have APLA attached will fluoresce. The emission will be captured by
photomultiplier tubes and transferred to a computer that digitizes the signal.
Treatment involves immunizing the mother with concentrates
of paternal Iymphocytes so that the signal is amplified approximately 10,000
times the level normally seen in early pregnancy. Paternal leukocyte
immunization (PLI) treatments are usually administered 4 weeks apart. Four
weeks after the second immunization, the APLA level is remeasured.
Antiphospholipid Antibodies
Phospholipid molecules are normal components of all cell
membranes. Antibodies to phospholipids have been implicated in numerous disease
states, generating much academic interest. APA are capable of vascular
compromise via damage to vascular endothelium and platelet membrane by
inhibiting prostacyclin (vasodilator) and interfering with the activation of
protein C. The result is increased platelet adhesion and a relative rise in
thromboxane (vasoconstrictor), resulting in a milieu conducive to thrombotic
events. In the uteroplacental circulation these insults translate into fetal
demise or intrauterine growth retardation.
With each pregnancy loss, there is a 10% chance that the
mother will develop an antibody to a phospholipid molecule, and the effect is
cumulative. Most women with APA are asymptomatic, but some have underlying
autoimmune tendencies and should be evaluated appropriately. Although there is
a high incidence of APA in patients with systemic lupus erythematosus (SLE),
there is a significant population who have APA but no other disease. The
diagnosis assigned to patients with thrombotic events in the presence of APA is
primary antiphospholipid antibody syndrome.
Treatment of APA involves the use of low-dose (baby)
aspirin and prophylactic heparin, which is a large molecule that cannot cross
the placenta. Heparin activates the formation of antithrombin III, which
interferes with the coagulation cascade. Although aspirin can traverse the
placenta, the dose is small and usually does not affect the fetus. Aspirin
inhibits cyclooxygenase and the formation of thromboxanes, allowing
prostacyclin to act unopposed. Treatment is more effective when medication, if
indicated, is started prior to conception and continued throughout pregnancy.
Antinuclear
Antibodies
There is an increased prevalence of RSA patients who
demonstrate ANA compared with parity- and age-matched nonaborters. What causes
these antibodies to be synthesized is currently under investigation, but there
appears to be a genetic susceptibility dictated by the HLA tissue type. This is
compounded by the production of autoantibodies like ANA with fetal demise. The
disease typically associated with ANA is SLE, which confers a much higher
miscarriage rate than that of the general population— approaching 50% in
patients with active disease. Although most women with RSA do not fulfill the
American College of Rheumatology criteria for SLE, many exhibit lupus-like
tendencies. Polyclonal B cell activation appears to be more common in these
patients. Although the exact mechanisms whereby ANA contribute to miscarriage
is unknown, placental pathology studies reveal inflammatory changes in the
uterine and placental tissue (villitis) and vasculitis.
When ANA are present in the context of RSA, prednisone is
recommended to suppress the inflammatory process and stabilize cell membranes.
Prednisone does not cross the placenta easily because it is highly bound to
albumin, which is a large protein molecule. In addition, the placenta contains
Beta2-dehydrogenase, which metabolizes this steroid. Suppression of the fetal
adrenal axis has not been reported. When indicated, prednisone is instituted
prior to conception. With treatment, there is an 80% to 85% chance of
successful term pregnancy. As the body is dynamic, antibody levels may change
over time. Patients who develop new autoantibodies during pregnancy have a more
guarded prognosis.
Conclusion
Failure of maternal response to the fetal allograft, as
well as the production of autoantibodies, can result in repetitive pregnancy
loss. Contrary to popular belief, miscarriage is not a benign process, as the
patient may develop autoantibodies. Fortunately, these problems are easily
identified and amenable to treatment. Miscarriage due to immune dysfunction is
largely preventable today, and couples desiring parenthood should be given
appropriate consideration and evaluation.
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
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.
