Immune Treatment Information
A guide to the most common reproductive immunology treatments
Information gathered from Reproductive Immunology Support Group discussions**
**Disclaimer. Information in this document has been put together by patients and to be used as a general guide only. This document not to be taken as medical advice.
I. What is IVIG? (Intravenous immunoglobulin)?
II. What is LIT (Lymphocyte Immune Therapy)?
III. What is Humira?
IV. What is Heparin (Lovenox or Clexane)?
V. What is Prednisone (and Dexamethasone)?
VI. What is Intralipid?
VII. What is G-CSF (Neupogen)?
I. What is IVIG?
(Taken from Dr Alan Beer’s old website document http://repro-med.net/guides/ivig.html)
IVIg (Intravenous Immunoglobulin G) is a preparation of human-derived antibodies, made from pooled donor blood that is washed and processed. IVIg works by modulating abnormal responses of the immune system. in particular by decreasing the toxic activities of Natural Killer (NK) cells. Elevated NK cells can damage the early cells of the baby that will create the placenta, and can cause implantation failure, miscarriage or intrauterine fetal growth retardation.
According to Dr. Alan Beer, IVIg was introduced in 1981, shortly after the widespread utilization of another gammaglobulin called Rh immunoglobulin ( RHOGam) had been proven save for use in pregnancy. IVIg has been used since 1981 for immune disorders of pregnancy. Dr Beer always utilized the preparation that is prepared from virus negative donors and then prepared and processed exactly like RhoGam which is certified for use during pregnancy by the FDA. This preparation, utilized since 1968, has had no viral transmission history.
IVIg as originally prepared did not inactivate all viruses, especially hepatitis C. This was true in 1978 (clinical studies) when the first case of hepatitis B was seen following IVIg administration. In 1986. there were 12 cases of hepatitis C reported. The next year there were reports of hepatitis C in 4 additional patients additional patients ans in 1988, 16 patients with hepatitis C were identified. This was not seen in modern preparations, because they have been through an extra step of solvent/detergent viral inactivation.
What is clear, and what the consumer needs to know, is that IVIg preparations that do not include a viral inactivation step can transmit hepatitis C, and possibly other viruses. In addition to this, all plasma donors who donate plasma for IVIg preparation are hepatitis C antibody and antigen negative. “Solvent/detergent treatment has effectively eliminated the transmission of all viruses including Hepatitis viruses of all types known and unknown.” In addition to this, the IVIg is DNA fingerprinted in search for viruses (viruses, viral peptides. viral DNA), known or unknown. IVIg also contains antibodies against hepatitis A. B. and C. This is similar to the gamma globulin shots given to a person who has been exposed to decrease the risk.
In summary, solvent detergent treatment is l00 % effective in eliminating viruses including HIV-1,HTLV-1,HBV,HCV and HIV-2.
Why is IVIG used?
IVIG is used to treat:
Elevated CD 56+ cells (Natural Killer cells) producing too much tumor necrosis factor alpha.
These problems often reflected with:
1. Elevated NK Assay cytotoxicity (50:1 over 15%)
2. Elevated NK Assay numbers (CD56 over 12%)
3. Elevated 19+5+ cells (CD19+5+ over 10%)
4. Low blocking antibodies (LAD IgG T cells or IgG B cells less than 30%) however LIT is the preferred treatment for this.
5. High titer ANA
6. High titer antiphospholid antibodies
7. Intrauterine growth retardation of the baby (IUGR)
8. Oligohydroamnios of immune cause (low amniotic fluid volume)
9. Subchorionic Hematomoma with autoimmune abnormality ( blood hemorrhage by gestational sac seen on ultrasound)
10. Low preconception T regulatory cell numbers (<0.7%)
Approximate Cost: $2,200 for one 25g dose + $300 infusion fee.
2 to 10 infusions often needed per pregnancy.
For more information about IVIG:
IVIG for recurrent miscarriage
Comparing IVIG brands
More about comparing IVIG brands
General IVIG information
How IVIG works
II. What is LIT (Lymphocyte Immune Therapy)?
(Taken from Dr Beer’s old LIT document http://repro-med.net/tests/litdoc.html)
Lymphocytes (white blood cells) of two classes are isolated from the male spouse. The two classes isolated from whole blood are the T cells (CD-3) and the B cells (CD-19). The Consumer’s Guide to the Reproductive Immunophenotype further defines how these white blood cells differ from others. Forty million lymphocytes are washed three times and then concentrated into an immunization that is less than 0.6 cc. This concentrate of lymphocytes is then injected in the skin of the woman (intradermally) just like an allergy skin test. It usually requires 4 injections, two on each forearm. The injected areas then become red, slightly swollen and itch just like a positive skin test. One month later the process and the injections are repeated. The second injection sites usually become less red, swollen and itch less than the first ones. One month later blood is drawn from the woman (serum) and blood is drawn from the man (lymphocytes). A test called the lymphocyte antibody detection assay (or Crossmatch) is done to determine if the immunizations have worked and the woman has made blocking antibody to her spouse’s T and B cells.
This test has two parts, 1) a microcytotoxicity assay and 2) a flow cytometry assay. The first test (microcytotoxicity) becomes positive in only 30% of women. If it does not become positive, this is not a bad result. Women who remain negative in this assay become mothers with the same frequency as women who become positive in this microcytotoxicity assay. The proper response is for the woman to become positive in the flow cytometry test. If the second part of the test does not become positive, then booster immunizations are given or donor lymphocytes are mixed with the husband’s lymphocytes and the immunizations are done again with donor plus paternal. It should be noted here that there are two types of donors, and both types are screened. Type I uses blood that has been frozen for a minimum of six months. Type II uses fresh blood from the donor. Testing for the leukocyte antibody detection assay (Crossmatch) is done one month later.
Why is LIT used?
LIT is used to treat:
Inadequate maternal immune response to paternal antigen. More specifically:
1. Low crossmatch test result (LAD test IgG T cells or IgG B cells are below 30%)
2. Elevated NK cytotoxicity (NK Assay 50:1 is above 15%)
3. Often used in combination with IVIG in patients who show poor suppression on the NK Assay with IVIG in the test tube (50:1 over 15% at 6.25mg/ml or 12.5 mg/ml)
4. Low preconception T regulatory cell numbers (<0.7)
Approximate cost: $600 per LIT done in Nogales, Mexico.
420 UK pounds for LIT done with Dr. Armstrong in London +120 UK pounds for the initial consult cost.
Often 2 LIT doses are needed one month apart before conception.
For more information about LIT see:
Reproductive Immunology Associates description of LIT (“PLI”)
III. What is Humira?
Humira (adalimumab) is a recombinant human lgGl monoclonal antibody given as a subcutaneous injection given once or twice every two weeks Humira works in a similar manner to Enbrel and Remicade, by blocking TNF alpha (tumor necrosis factor alpha) that causes inflammation in the body’s tissues. By binding specifically to TNF-alpha, Humira reduces the symptoms of Rheumatoid Arthritis and possibly reduces the incidence of miscarriage and IVF failure.
Why is Humira used?
Humira is used to treat:
1. Elevated uterine resident CD57 cells in the endometrial tissue (4 or more NK cells seen in 400X microscope field)
2. Elevated TH1 TH2 TNFa/IL-10 ratios (over 30).
3. Poor suppression with IVIG in the test tube (NK Assay 50:1 over 15% at 6.25mg/ml and/or 12.5 mg/ml)
4. Patients who have failed with IVIG and LIT
5. Repeat implantation failures or IVF failures
6. Patients with endometriosis
7. Patients who have failed or developed a bad reaction to other anti-TNF medications
Approximate cost: $1,300 (800 UK pounds) for two 40mg Humira subcutaneous injections (about one month’s supply).
Humira is taken preconception and discontinued before pregnancy.
IV. What is Heparin (and Lovenox or Clexane)?
There are three injectable anticoagulants that are often used for reproductive immunology patients. These medications are unfractionated heparin, Lovenox® (Clexane®) and Arixtra® and they are given by subcutaneous injections once or twice a day. These drugs do not cross the placenta so there is no fetal exposure. Numerous studies do not demonstrate an increase in birth defects.
i. Regular heparin
Unfractionated heparin (heparin sodium) is used infrequently for long term therapy in patients who have antiphospholipid antibodies or immunological infertility. It has been replaced by the fractionated low molecular weight heparins, Lovenox® or the synthetic product Arixtra®. These two drugs are safer and more convenient than heparin.
ii. Lovenox®/Clexane® (enoxaparin sodium)
Lovenox ®(or Clexane®) is a low molecular weight heparin that has less binding to blood proteins and thus has a more predictable dose response than unfractionated heparin. For this reason blood tests to monitor for the proper dose of the medication are not required.
iii. Arixtra® (Fondaparinaux sodium)
Arixtra® is a synthetic anticoagulant that works by inhibiting Factor Xa. Other anticoagulants inhibit multiple factors in the coagulation process. Therefore Arixtra® is not a heparin and the risks of thrombocytopenia is less than with Lovenox® or heparin. It has a longer half life than Lovenox® and is given as a once a day injection. Studies done with our patients reveal equal successful results with Lovenox ®or Arixtra®.
Why is heparin used?
It is used to treat:
1. Elevated antiphospholipid antibodies (even at borderline levels)
2. Inherited Thrombophila (heterozygous or homozygous) for the Factor V Leiden mutation, Prothrombin mutation, MTHFR mutations (C677T and/or A1298C), Factor XIII mutation, B-fibrinogen G455A mutation and PAI-1 gene polymorphism. See: Thrombophilia, recurrent miscarriage and infertility
Approximate cost for Lovenox©: $1,670 a month for two 30mg subcutaneous injections/day.
Injections are started CD 6 the cycle of conception and continued throughout pregnancy and often 6 weeks postpartum.
For more information about heparin, see:
About low molecular weight heparin
Regular heparin information
Heparin injection tips
More heparin tips
V. What is Prednisone (and Dexamethasone)?
Dexamethasone and prednisone are oral synthetic corticosteroids that suppress the immune system and inflammation. These drugs mimic the action of cortisol which is a natural occurring corticosteroid produced in the body by the adrenal glands. Corticosteroids may be prescribed if you test positive for ANA (antinuclear antibodies), antibodies to DNA or histones or other autoantibodies. In reproductive immunology, low dosages for short periods of time are used. This tends to minimize the side effects and risks of corticosteroid medication.
Dexamethasone – 1 mg per day starting on cycle day 6 in the menstrual cycle you are attempting to conceive. If no pregnancy results, stop the medication with onset of menses until cycle day 6 of the next attempted cycle. If pregnant, continue the dexamethasone until you are 11 weeks and then taper off the medication.
Prednisone- 10 mg per day starting cycle day 6 in the menstrual cycle you are attempting to conceive. If no pregnancy, stop the medication with the onset of menstrual flow until cycle day 6 of the next attempted cycle. If pregnant, increase the dose to 20mg (10mg in the morning and 10 mg in the evening). At 11 weeks, taper off the prednisone.
With prolonged therapy and with high doses, corticosteroids can suppress the adrenal glands so they will not produce cortisol. For this reason, you must taper off (lower gradually) the medication to allow the adrenal glands to recover. There is no need to taper off the steroids if you are on them less than a month.
The schedule for tapering off are as follows:
Dexamethasone- At 11 weeks, take one half of a tablet (0.5mg) for 1 week, then one half of a tablet every other day for a week then stop.
Prednisone- At 11 weeks, decrease from 20 mg to 10 mg for 1 week then use 5 mg/day for one week then 5 mg every other day for 1 week and then stop.
What are prednisone and dexamethasone used to treat?
1. Antinuclear antibodies (ANA)
2. Elevated Natural Killer cell levels (mild cases)
Approximate cost (prednisone): One hundred 5mg tablets (about one month’s supply) $20
Two 5 mg prednisone tablets taken once a day preconception. Dose increased to 10 mg twice daily after a positive pregnancy test and discontinued at about 10 weeks pregnant.
Note: 7 mg prednisone is approximately equivalent to 1 mg dexamethasone.
Also, for dose conversion help, see: corticosteroid converter
VI. What is Intralipid?
Intralipids are a fat emulsion solution used as a nutritional supplement in patients with nutritional deficiencies. It is a synthetic product that has 10% soybean oil, egg yolk phospholipids, glycerin and water. It also contains a small amount of aluminum (25mcg/L). It is administered intravenously (injected in the vein).
Some recent studies have shown it may decrease the killing activity (cytotoxicity) of natural killer cells (NK cells). NK cells are part of the immune system that helps control infection and cancer growth. In infertility patients this may improve implantation and successful pregnancy outcome rates. The conventional treatment for increased cytotoxicity is an infusion of intravenous gamma globulin (IVIG).
An IV is started in the hand or forearm and an infusion is given over 1-2 hrs.
Side effects (SE) are rare but include an irritation or infection in the vein at the site of infusion. Other SE’s that occur in less than 1% of patients are: fever, chills, sweating, nausea, vomiting, dizziness, headaches, back pain, chest pain, shortness of breath and increased blood clotting. A deposition of pigment in lymph nodes, spleen and liver called “intravenous fat pigment” has been detected in experimental animals and patients after multiple intralipid infusions. The cause and significance of this finding is unknown. The safety of intralipids in pregnancy has not been established therefore it is not recommended for use in pregnancy. The FDA has rated intralipids as a category C drug although animal studies have not yet been done.
Intralipids should not be given to patients who have severe liver disease, recent heart attack or stroke or have any disease of fat metabolism. Patients with renal disease should not use intralipids because of possible aluminum toxicity. Women with allergies or sensitivities to soy products, egg yolks or egg whites may have a reaction to intralipids and should not use the medication.
The advantages of intralipids versus IVIG are its lower cost and that it is not a blood product.
The disadvantages of intralipid therapy is that there are limited patient studies available on the efficacy and safety of the product in infertility patients. It also has not been studied in patients with other immune conditions such as low Treg cells or elevated Th1:Th2 cytokines. It has not been studied in combination with other medicines such as Humira® or Lovenox®.
$100 a dose (2006 price)
$400 for the infusion for the first hour, $160/hr after that.
Intralipids in IVF:
Start Intralipids as follows:
· 100ml Intralipid dissolved in 500cc of normal saline between day 6-10 of conception cycle, depending on the response to the ovulation inducing drugs.
· 100ml Intralipid dissolved in 500cc of normal saline within two days of embryo transfer or ovulation.
An NK assay and a TH1:TH2 Cytokine test should be done 7-10 days after completion of each Intralipid infusion.
For more information, see:
Dr Braverman’s page on Intralipids
VII. What G-CSF (Neupogen)?
NEUPOGEN® is a synthetic form of granulocyte colony-stimulating factor (G-CSF. It stimulates the growth of neutrophils, a type of white blood cell important in the body’s fight against infection.
How is G-CSF used in Reproductive Immunology?
1. G-CSF increases development and proliferation of the trophoblast into the uterine lining.
2. G-CSF increases the “tolerogenic” dendritic cells which is a critical step in the formation of T regulator cells
3. G-CSF has also been shown to increase the thickness of the uterine lining.
Who may be eligible for G-CSF?
1. Recurrent Miscarriages that have failed IVIG, LIT and demonstrate immunological elevations
2. Unexplained repeat failed IVF failure
3. Poor egg quality under age 38 years
4. Poor uterine lining
(G-CSF protocol Information gathered from Reproductive Immunology Support Group discussions)
G-CSF protocol based on Italian Study:
Treatment is given at the dose of subcutaneous 100 mg/day started at 6th day after the ovulation then patients are assessed by ultrasound and treatment is continued through the 35th day after ovulation (for a total of about 30 consecutive days).
Another G-CSF Protocol: (as of 4/26/05)
Protocol consists of 10-13 injections starting at the beginning of a natural conception cycle or the day after transfer of an IVF cycle. (about £1,000 UK)
Third Protocol option (some patients have used)
100 mg/day starting from 3 days before ovulation.
One IVF protocol option (4/8/11)
“In an IVF cycle, the earliest you can start 48 hours before the trigger shot. Starting 48 hours before the trigger shot helps with final maturation of follicles and helps with ovulation by increasing the follicle fluid, it also helps with increasing the lining thickness. 1mcg/kg/day is the dose which was used”
Note: Additional protocols are still being developed and may be used
For more information on G-CSF, see:
Dr Braverman’s page on G-CSF treatments
Clinical trial of G-CSF for infertility and pregnancy loss
Neupogen patient information