Excerpt: Immunology of Recurrent Spontaneous Abortion

William Matzner, MD, Simi Valley, California
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


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.


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.

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.

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