Immunotherapy Drugs Can Prevent Multiple Miscarriages

It is important that patients who have experienced immune-mediated reproductive failure follow any medication recommendations made, unless they have had an allergic reaction, serious side effect or medical problem that precludes the use of the drugs.

Some patients are uncomfortable about taking any medication during pregnancy. Rest assured that all medication and doses have been thoughtfully selected to minimize any drug related side effects.

As your pregnancy progresses your blood test results may change, justifying a modification in your medication regime. If changes are indicated, they will be communicated to you and initiated immediately.

Aspirin

Aspirin is an anti-inflammatory and antiplatelet agent. Should you require low dose aspirin, the recommendation is 81 mg per day, which is equivalent to a baby aspirin.

Aspirin, like all medication, can cause allergic reactions. Manifestations of aspirin allergy may include dermatitis, rhinitis, bronchospasm and even anaphylaxis. People who have a history of asthma and nasal polyps are at increased risk for allergic reactions.

Side effects of low dose aspirin are infrequent but can include nausea, reflux esophagitis, abdominal discomfort, anorexia and gastrointestinal and urinary tract bleeding. Use of high dose aspirin during pregnancy may affect maternal and neonatal blood clotting mechanisms, leading to an increased risk of bleed. High dose aspirin may also impair maternal kidney function and has been causally related to increased perinatal mortality, intrauterine growth retardation and congenital defects. Aspirin at low doses has not been associated with these risks.

Aspirin is excreted into breast milk in low concentration ranging from 1.1 to 10 mcg/ml. Adverse effects of platelet function in the nursing infants have not been reported, but are a potential risk. If you choose to breast feed your baby you should not take aspirin at that time.

Routine laboratory testing while on aspirin should include complete blood count, chemistries, APTT and antiphospholipid antibody panel.

Heparin

Heparin, an anticoagulant, is a purified preparation derived from animal tissue. It is delivered as a subcutaneous (sq) injection and a typical dose would be 5000 IU twice a day. Low molecular weight heparins like Lovenox and Fragmin are more purified forms of heparin. The typical dose for Lovenox is 40 mg sq once a day. The dosing for Fragmin is 5000 IU sq once a day. Their advantage is that they only have to be administered once a day. Also, fewer side effects have been reported. Low molecular weight heparin preparations are the medication of choice for patients who suffer Inherited Thrombophilias. Both drugs are significantly more expensive than standard heparin. When heparin is recommended, it should be started 14 days before IVF transfer or 5 days before a natural cycle.

Duration of treatment depends upon the clinical history. Patients with miscarriage use medication through week 34. Those who only have failed IVF and + APA should continue at least through week 12. Patients suffering from hereditary thrombophilia continue with medication six weeks post partum.

Allergic reactions may include chills, fever, dermatitis, asthma and anaphylactic shock. Before a therapeutic dose is administered, a trial of 1000 IU would be prudent. Fortunately, allergy to heparin is rare.

Because of heparin's blood "thinning" property the user is more susceptible to bleeding (skin, nose, gastrointestinal tract, bladder, etc.). Almost all patients experience some bruising at the site where heparin is injected.

Long term heparin therapy has been associated with osteoporosis and spontaneous fractures in patients who have received in excess of 15,000 units per day for more than six months. One study of 117 patients on long term heparin (up to 15 years) report no spontaneous fracture when subjects received less that 10,000 units per day. Although our protocol utilizes low dose heparinization, supplementation (dietary) with calcium is recommended. Exercise and sun tanning may also prevent osteoporosis.

Please note that the study group consisted of women who had severe maternal disease necessitating high dose anticoagulant therapy. Although heparin is the preferred anticoagulant during pregnancy it is not risk free.

Heparin is not excreted in breast milk.

Relative contraindications to the use of heparin are active bleeding, hemophilia, thrombocytopenia or other blood dyscrasia, endocarditis or tuberculosis. Caution should be exercised when there is underlying hypertension and liver kidney disease.

Routine platelet, hematocrit, APTT and antiphospholipid antibody panel monitoring during heparinization is recommended.

Heparin Treatment

See Instructions for Heparin Injections

Prednisone

Prednisone is a corticosteroid. If indicated, prednisone should be started prior to conception; 30 days before an IVF cycle or 5 days before ovation in a natural cycle. Drug dosage may be adjusted depending upon follow-up blood tests. Duration of treatment may continue well into the second trimester.

Allergy to prednisone is rare, as the human body manufactures a similar compound. In fact prednisone is used to treat moderate to life threatening allergies.

Possible adverse reaction(s) to moderate and high doses of prednisone include fluid and electrolyte imbalance; metabolic disturbances e.g. hyperglycemia or gestational diabetes and osteoporosis; susceptibility to infection; peptic ulcer; behavioral changes e.g. nervousness, insomnia, irritability and mood swings; myopathy; and cataracts.

Prednisone should be used with caution in people with hypertension, congestive heart failure, diabetes mellitus, osteoporosis, ulcerative colitis, ocular herpes and others (please consult with doctor if you have any chronic illness). Osteoporosis can be retarded with calcium supplementation and exercise.

Prednisone should be discontinued if pregnancy is not achieved, but should be resumed five days prior to ovation of the next cycle. Rapid withdrawal of prednisone may cause fatigue, myalgias, arthralgias, dizziness, hypotension, hypoglycemia and dyspnea.If you experience these symptoms, please contact your doctor.

There are a number of studies that review the use of prednisone during pregnancy and effects on the fetus. The fetus appears to be protected by at least three mechanisms: 1) enzymes in the placenta degrade the drug to an inactive form, 2) prednisone in maternal circulation is bound to a large protein making it harder to cross the placenta and 3) fetal liver is not able to activate prednisone until the end of the second trimester.

Trace amounts of prednisone have been measured in breast milk. Although these quantities are of doubtful clinical significance, your baby's pediatrician should be notified.

Laboratory studies to monitor while on prednisone include complete blood count, chemistries, electrolytes and antinuclear antibody panel.

Immunoglobulin G Infusion (IVIg)

Immunoglobulin G is a preparation of human derived antibodies. In some patients, conventional immunotherapy with aspirin, heparin and paternal white cell immunization may have to be supplemented with this medication. Patients at risk for developing intruauterine growth retardation, oligohydramnios, toxemia, or severe side effects of steroids, or have preexisting maternal disease are prime candidates.

Immunoglobulin G is contradindicated in patients who are known to have had anaphylactic or severe systemic reaction to human immune globulin. Patients with IgA deficiency should not receive this product.

Side effects to immunoglobulin G include fever, chills, headache, nausea, malaise and back pain. Mild erythema following infiltration at the site of infusion has been reported.

Laboratory tests that need to be followed while on this treatment are quantitative immunoglobulins, immunophenotype, natural killer cells (NK) activation studies and intrecellular tumor necrosis factor alpha (TNFa) assay and blocking antibody levels.

Enbrel

Enbrel (etanercept) is an inhibitor of tumor necrosis factor (TNF) and works by binding directly to it. TNF alpha is a chemical (cytokine) that is secreted by NK and some other cells. This cytokine can lead to destruction of the placenta. Enbrel is administered as a subcutaneous injection, 25 mg twice per week. It is usually started one month prior to the cycle of planned conception and stopped when there is ultrasonic evidence of a fetal heartbeat.

Some of the more common side effects are injection site reactions (swelling and itching), headache, nausea, dizziness, infections and rash. Toxicity studies performed in pregnant rats and rabbits have revealed no evidence of harm to the fetus, even at dose equivalent to 60 times the normal human dose. No controlled studies have yet been performed in pregnant women.

Paternal Leukocyte Immunization

Paternal leukocyte immunization (PLI), a purified preparation of husband's white blood cell, is administered intradermally. Because this is a blood product, the recipient (wife) risks acquiring infectious diseases that donor (husband) may harbor. Rh sensitization is also possible; however, extensive steps are taken to prevent this.

Most women will experience redness and itching at the site of immunization. Please notify your doctor if you have any unexpected or serious reaction.

Maternal antipaternal leukocyte antibodies (blocking antibodies), by flow cytometry, should be followed to monitor efficacy of treatment.

This therapy is currently not available in the United States.

Written by: William L. Matzner, PhD