Immune system infertility info- (TONS of info)

Here are a couple vids/ webinars on immunological issues regarding implantation dysfunction and infertility/RPL

(VERY LONG)

This is a VERY LONG read, but VERY worth it, if you feel like you may be dealing with or suspect any kind of immune issues playing apart in recurrent losses and the failure of prefectly good IVF embies etc...I got this info from the immune system infertility forum on fertility friend's forums. You have to be a VIP member to access that group, but it is worth it! For those who do not have fertility friend at all, I coped some of the best info on there in the FAQ thread they keep bumped...Enjoy! You brain is about to become MUSH with info overload!

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Do I have immune system problems? It is hard to know whether one has immune system problems. Sometimes there are obvious signs like repeated miscarriages or failed transfers of good embryos on IVFs. Lot of times it is just the intuition that there is something wrong in that area. Things to consider are family history of autoimmune problems, miscarriages that happen earlier and earlier or few miscarriages followed by no implantation at all as well as having no positive pregnancy tests at any point. Any of those can be due to immune system issues. The immune system issues can either prevent implantation altogether or cause repeated pregnancy loss. Immune system issues can also cause ectopics as the embryos have an easier time implanting in the tubes where the inflammation and/or high NK cell activity are not present. 

There are two types of immune system issues: autoimmune and alloimmune issues. Autoimmune issues are common when either the woman or her family has other autoimmune issues. Other autoimmune illnesses are for example - endometriosis, - adenomyosis, - thyroid problems, - celiac disease, - eczemas - allergies, - asthma, - autism etc. (see a list here). Alloimmune problems mean that there is a close match with the partner and body rejects the embryo for this reason. 

Here is a break down of reasons for repeated pregnancy losses: 

• Infection 1% 
• Anatomy abnormal 5-10% 
• Progesterone level low 20% 
• Chromosome abnormal - Primary miscarrier (no live births) 7% - Secondary miscarrier (one or more live births) 50% 
• Immune mechanisms 50% 
• Unknown 15% 

Which tests do I need? To test immune system issues, a good set to start with is most importantly the NK cell assay which shows how active the NK cells are in destroying the trophoblast (early placenta) and preventing implantation/causing miscarriages as well as underlying inflammation markers such as Th1/Th2 and Tnf-alpha along with some other inflammation markers of the list (below under tests). The inflammation markers are important because inflammation either causes NK cells to become activated, or NK cell activity causes an increase in inflammation. Therefore, even if the NK cell assay is normal, if there is underlying inflammation, implantation can be prevented when in the presence of an embryo, the immune system flairs up. 

For the alloimmune issues, one needs to tests a full HLA-panel as well as DQ-alpha matches. 

An additional issue is blood clotting problems. These are tested for under the RPL (repeated loss panel). RPL issues usually only come into play with 2nd trimester losses. So if someone does not get pregnant at all or has early losses, most likely auto- or alloimmune problems are to blame. 

How are immune system issues treated? Typical treatment consists of intralipid infusions for the elevated NK cells, prednisone and lovenox for the inflammation and NK cells (as well as for better egg quality, inflammation can cause poor egg quality) and Neupogen (with Dr. Braverman and Kwak-Kim at least) for the alloimmune matches. 

The RPL problems are treated with heparin and baby aspirin typically. 

Other things one can do at home are to start an anti-inflammatory diet, i.e. stop eating gluten, dairy and sugar which cause the immune system to flair up. Start anti-inflammatory supplements such as high doses of fish oil (6 capsules per day). Dr. Braverman recommends Maxi-Flavone. Limit exercise during treatment cycles (exercise causes and inflammatory state in the body). Though exercise outside of treatment cycles as over long term, exercise reduces inflammation. Use any relaxation methods. Eat/take antioxidants which reduce radical oxygen species (ROS). ROS are created by inflammation and cause destruction in the body. 

INFORMATION SOURCES 

• This is a very good article that explains the various immune issues in a way that is easily understandable with pictures also to go with explanations: http://www.naturalgynae.com/downloads/nav6_fact25.pdf 
• Here is a very good overview by Dr. Sher that explains the mechanisms by which both auto- and alloimmune infertility cause problems and how they can be treated: Part 1: http://www.ivfauthority.com/2011/05/understanding-immunologic-implantation.html Part 2: http://www.ivfauthority.com/2011/05/understanding-immunologic-implantation_16.html 
  
  
• Excellent article by Caroline Coulam and Nancy Hemenway:http://www.inciid.org/article.php?cat=immunology&id=374 
  
  
• Very good and clear short intro: http://www.rialab.com/miscarriages_prevented.php 
  
  
• Dr. Sher: www.ivfauthority.com 
  
  
• Dr. Braveman http://www.preventmiscarriage.com/Reproductive-Immunology/Non-Immune-Causes/Previous-IVF-Stimulation-Protocols.aspx 
  
  
• Dr Coulam's forum at Inciid: http://www.inciid.org/forum/forumdisplay.php?f=175 
  
  
• FF UK immune system group 
  
  
• Here is very easy and short introduction to how the immune system functions. http://www.precisionnutrition.com/rr-green-tea-hazards 
  
  
• Inciid http://www.inciid.org/index.php?page=immunology 
  
  
• immunologysupport in a common search engine that starts with Y 
  
  
• http://www.deepdyve.com has a special cheap "rental" system for articles on IVF, etc. that we can't usually get for less than 30$/reprint! 

CLINICS: US - Braverman: http://www.preventmiscarriage.com/ - Kwak-Kim: - Coulam: http://www.reproductivemedicineinstitute.com/pages/physicians - SIRM: http://haveababy.com/ 

UK - ARGC: http://www.argc.co.uk/ - Lister: http://www.ivf.org.uk/ 

France - Bluets, Natalie Ledee: http://www.bluets.org/ 

Australia - Gavin Sacks: http://www.ivf.com.au/specialists/specialists.aspx?specialistid=22

IMMUNE SYSTEM INFERTILITY ISSUES 

• NK cells
  • Natural Killer cells are large lymphocytes (a type of white blood cell ) that play a vital role in regulating the impanation of the embryo's root system (trophoblast).They produce a variety of local growth factors known as cytokines, of which there are two varieties: TH-1 and TH-2 cytokines. - In situations where NK cells become "activated" (i.e. NKa) there occurs an over-production of TH-1 cytokines. - This compromises the trophoblast cells, leading to dysfunctional implantation with the result being either total failure of the embryo to implant, miscarriage, or poor subsequent development of a surviving pregnancy. http://haveababy.com/infertility-education/causes-of-infertility/immune-factors/163.html 
    
    
  • There is a special class of NK cells (CD3-, CD16-, CD56+) in the placenta that promotes cell growth, secretes growth molecules for the placenta and down regulates the mother's immune response locally at the maternal/placenta interface. Opposing is another group of NK cells (CD3-, CD16+, CD56+), when activated by the cytokine IL-2, are cytotoxic to placental trophoblast. The same cells secrete tumor necrosis factor (TNF) which can destroy the placenta. Women with CD16+, CD56+ NK cells in excess of 20% are at risk for miscarriage despite optimal immune treatment (paternal leukocyte immunization, prednisone, aspirin and heparin). In a subset of women who have had multiple failed IVFs, it is believed that TNF is secreted in amounts that inhibit implantation and early formation of the placenta resulting in an IVF cycle which does not produce a clinical pregnancy. http://www.rialab.com/miscarriages_prevented.php 
    
    
  • The implantation process of the embryo in the uterus begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., the trophoblast), which later becomes the placenta, begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with Immune cells in the lining, become involved in a "cross talk" through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus is able to foster the embryo�s successful growth. 
    
    
    After ovulation and during early pregnancy, NK cells comprise more than 70% of the immune cell population of the uterine lining. NK cells produce a variety of local hormones known as TH-1 cytokines. Uncontrolled, excessive release of TH-1 cytokines is highly toxic to the trophoblast and endometrial cells, leading to their programmed death (apoptosis) and, subsequently to failed implantation. In the following situations, NK cells become activated and start to produce an excess of TH-1 cytokines: 1) Aloimmune implantation dysfunction where the male and female partners share specific genetic (DQ-alpha and/or HLA) similarities and 2) in Autoimmune conditions such as Rheumatoid arthritis, hypothyroidism endometriosis and Lupus Erythematosis. http://www.ivfauthority.com/2009/09/uterine-receptivity-its-role-in-embryo.html 
  - Treatment with IVIg or Intralipids, doesn't respond to heparin, aspirin or prednisone. 
  
  
• Alloimmune (Please see also a separate thread titled "Alloimmune Issues - The Role of DQ Alpha and Beta" for more information) 
  
  
  When DQ alpha and/or HLA sharing exists between a female and male it will usually require repeated embryo exposures for the host�s uterine natural killer cells to become sufficiently activated to cause damage to the embryo�s root system (trophoblast). Once natural killer cells become activated, they begin to over-produce substances known as TH-1 cytokines which attack the trophoblast and so damage it that the embryo is promptly rejected. 
  
  
  What does all this mean when it comes influencing IVF outcome? ��.Well, if we are dealing with a 50% chance of embryo DQa �matching� (see above), and we can successfully down-regulate NKa+ through the administration of Intralipid (IL) or immunoglobulin-G (IVIG) in combination with corticosteroids (e.g. prednisone or dexamethasone), then the transfer of a non-�matching� embryo would theoretically provide the same chance of a successful IVF outcome as in the absence of any DQa �matching� between the partners. On the other hand, when the chance of embryo DQa �matching� is 100% (see above) the ability to down-regulate NKa+ with IL or IVIG is diminished as is the likelihood of a successful pregnancy http://www.ivfauthority.com/2009/10/dq-alphahla-sharing-does-it-always-lead.html http://www.ivfauthority.com/2010/01/dq-alpha-matching-in-ivf-controversy.html http://www.ivfauthority.com/2011/05/understanding-immunologic-implantation.html http://www.ivfauthority.com/2011/05/understanding-immunologic-implantation_16.html 
  
  
• APAs Women who experience repeated IVF failures often have increased levels of circulating APAs-proteins that occur as small negatively charged structures on the outer surfaces of cells. Up to 50% of women with pelvic endometriosis and unexplained infertility have APAs in their blood. http://haveababy.com/infertility-education/causes-of-infertility/immune-factors/163.html - Causes blood clotting/poor blood flow - Treated usually with heparin/lovenox 
  
  
• ANAs The disease that we typically associate with antinuclear antibodies is Systemic Lupus Erythematosus (SLE). The miscarriage rate in SLE patients is much higher than that of the general population. Although most women who suffer recurrent miscarriages do not have clinical signs of SLE, many exhibit autoimmune phenomena which is similar to that seen in SLE patients. The placentas in these women are inflamed and weakened. http://www.rialab.com/miscarriages_prevented.php - Treated with prednisone - SIRM (Dr. Saleh) treats with baby aspirin only. If also have elevated APAs, then need aspiring + heparin. Braverman on Lupus: http://www.preventmiscarriage.com/Blog/2012/June/LUPUS-AND-PREGNANCY.aspx 
  
  
• ATAs Anti-thyroid antibodies are only a problem when they are associated with high NK cell activity. ATAs can lead to high NK cell activity, but don't necessarily. If you have high ATAs, Hashmiotos or Graves, it is a good idea to also test your NK cell activation. Sher: We have reported on the fact (1998, American Journal of Reproductive Immunology) that approximately 50% of women with TAI (regardless of the absence or presence of clinical hypothyroidism) have increased activated Natural Killer cell activity (NKa+) in their blood and that they are the ones that most commonly have reproductive failure. Since 50% of women with TAI do not have reproductive failure, it is probably not the presence of antithyroid antibodies themselves that causes reproductive failure. Rather, it is more likely a coexisting presence of NKa+ that causes the problem by damaging the early �root system� of the implanting embryo. We also showed that in such cases, aside from the need (in those with hypothyroidism) to adequately supplement with thyroid hormone replacement, the administration of intravenous gamma globulin (IVIG) or intralipid (IL) therapy in combination with steroids such as dexamethasone or prednisone (starting at least 4-7 days prior to ovulation or egg retrieval) markedly improves IVF birth rates. Women with TAI who do NOT have NKa+ do not manifest with reproductive failure and as such do not require or benefit from IVIG or IL +steroid therapy. http://www.ivfauthority.com/2009/08/hypothyroidism-and-infertility-ivf.html 

TESTS Here is a list of tests for immune system problems: From "Is Your Body Baby-Friendly" by Alan Beer, pg. 127-133 

Tissue Analysis: Miscarriage: the book discusses saving a sample of tissue for pathology inspection. If miscarriage occurs at home, place tissue sample in a sterile container in the refrigerator and take to the doctor's office as soon as possible. 

Blood tests: The most commonly ordered tests are marked with a * For interpretation see: http://www.repro-med.net/repro-med-site2/index.php?option=com_content&view=article&id=6:immunophenotype&catid=2:pages-ett&Itemid=25 or the immune system FAQ of Fertilityfriend UK 

1. Natural Killer Assay* The most important test First NK cells (effector) from blood are mixed with k562 cells (target). The sample is incubated for two hours and then it will be measured what percentage of the K562 cells will have been killed. This is done at three different dilutions 50:1, 25:1 and 12.5:1, where the first number is effector and second number is the target and the ratio is called effector-to-target ratio. The cut off values are: SIRM : 10% (According to Braverman, the lab SIRM-LV uses might be different and to compare these results with other labs, one should add 5%. This is the reason SIRM-LV has the lowest cut of point. Dr. Tortoriello uses the Rosalind Franklin lab with 15% cut-off.) Beer : 15% Braverman : 20% In the second part of the test it will be checked whether IVIg and/or intralipids will suppress the NK cell activity. According to Sher this is a meaningless test as it only tells what happens in test tube and our bodies are more complex. 

http://reprosource.com/reprosource_test/natural-killer-cell-activation-with-ivigintralipid-suppression/ 

If you use another lab, the Natural Killer cell test you need is called the K-562 target cell test - other labs may also call it something different, but it needs to be explained using this description, because this is the one test where it's very important to get the RIGHT test done. Also, what many of us have learned - it's totally unnecessary to get results on how well IVIG or intralipids work to lower NK cell activity (NKa), because what happens in a lab doesn't even come close to what happens within our bodies. Dr. Sher seems frustrated that this part of the test even exists, as it can end up worrying patients unnecessarily if it looks like these treatments don't work or don't work well enough. He said that part of the test means absolutely NOTHING. All that matters is getting the result of NKa in it's native state. Dr.Braverman says that at least one can see whether Intralipids or IVIg work at all even if the actual values can't be relied on. 2. HLA-DQ Alpha Testing* These test the number of genetic matches between you and your husband. According to Braverman, more than 5 is a problem and can cause the immune system become over-activated. 3. The Reproductive Immunophenotype* (panel of tests for white blood cells) 

• CD3 (Pan T cells) T cells make up the majority of lymphocytes found in the blood. These cells are the most important in our immune system. They may be low when the immune system is weak (suppressed) and normal when the immune system is healthy. Experience has shown that women with high values may be found in infertile patients and patients with recurrent pregnancy losses. 
• CD4 (T-helper cells)* These cells are a type of CD-3 T lymphocytes. They are the directors of the immune response. They cannot function without the road map provided by the CD-4 T Helper cells. Some T-helper cells help mount a response against foreign agents such as viruses that inhabit the infected cell. These are the Th1 type lymphocyte. When active, they are capable of secreting hormone-like substances known as cytokines that turn on the immune response removing infected cells. Identification of these helper T cells requires another test, the intracellular cytokine assay.Other T-helper cells are adapted to releasing cytokines that help in eliminating foreign organisms outside of cells. These are the Th2 type lymphocyte. They are also identified in the intracellular cytokine assay. 
• CD8 (T-Cytotoxic Suppressors)* CD8 T cells are the effectors of many of the immune responses. They efficiently eliminate infected and abnormal cells. They are infrequently abnormal in women with reproductive issues. 
• CD19 (B Cells)* These lymphocytes mature into plasma cells that produce antibody. In our experience B cells are frequently high normal or elevated in women with an immune cause for their infertility or recurrent pregnancy losses. We often see values greater than 12% elevation. 
• CD56+/CD16+ Natural Killer Cells* 
• CD 56+ Natural Killer Cells* Display of the CD56 protein on the cell surface identifies cells of the natural killer family. Natural killer cells are named such because, unlike T cells, they have an inherent capacity to identify foreign or abnormal self-self and effect their elimination. When their number reaches a certain level, in our experience, they are likely to be associated with reproductive failure. Interestingly, numbers that have been associated with failure may still remain within the range of healthy, non-pregnant women. To confirm suspicion that natural killer cells may be functioning too aggressively, a test, known as the NK Assay, is performed. In assay cells are actually tested for their ability to kill other cells. Natural killer cells are present both in the blood and in the uterine tissues of pregnancy. In the latter site, natural killer cells take on special functions unlike their brethren in the blood. There they assist in transforming the uterine blood vessels into vessels capable of the task of supporting the fetus and placenta over the nine months of pregnancy. Under normal, healthy circumstances, these NK cells serve a role that is unlike that of their blood borne brothers. That is until there is an infection. At that time natural killer cells assume their more recognized role in killing targeted cells. Often this response results in loss of the pregnancy. While these cells differ from those found in the blood, it is fortuitous that we can measure the natural killer activity of the cells in the blood and learn much about the activity of those within the uterus. 
• CD3/IL-2R+ Cells 
• CD19+/5+(B-1 Cells) B cells may be of two subtypes known as B-1 and B-2 cells. When we examine a second surface-displayed marker on CD19 expressing cells known as CD5, the cells are classified at B-1 B cells. They represent a class of B cells that is involved in autoimmune disorders (conditions where the body mounts an immune response against a body tissue). Women with elevations of these cells may be at risk for thyroiditis and the premature menopause. We pay close attention to the numbers of these cells when attempting to identify patients with immune-related conditions.

4. Antinuclear Antibody Test (ANA)* 5. Anti-DNA/Histone Antibodies 6. Anti-phospholipid Antibodies (APA)* 7. Lupus Anticoagulant Antibodies (LAC) 8. Antisperm Antibodies 9. Methylene-Tetra-Hydro-Folate-Reductase (MTHFR)* 10. Th1: Th2 Cytokine Assay* http://reprosource.com/reprosource_test/th1th2-cytokine-ratio/ Sher: Some reproductive immunologists might also test blood Treg cell concentration and/or recommend an endometrial biopsy to histolochemically evaluate uterine NK cells or assess the local TH-1/TH-2 balance. The performance of blood TH-1 and TH-2 cytokines to assess for TH-1 dominance is controversial and is of unproven value.http://www.ivfauthority.com/2011/05/understanding-immunologic-implantation_16.html Dr. Braverman measures Th1/Th2 ratio as well as TNF-alpha/IL10 ratio. These are inflammation markers, and can show an underlying inflammation even if NK cell activation is ok (from NK cell assay). Too many active NK cells cause inflammation and some type of inflammation also causes too many active NK cells. Hence, it's important for the inflammation to be "cooled" as well. 11. TNF-a:IL10 (CD3+CD4+)* Normal Range = 13.2 -30.6 12. IFN-g:IL10 (CD3+CD4+)* Normal Range = 5.8 -20.5 13: Other tests: fasting free-insulin, immunoglobin, anti-IgA, antithyroid antibody, thrombophilia (including factor V Leiden and prothrombin genetic mutations) 14. Beta 3 integrin Not sure if this is useful, SIRM doctors don't believe it is. http://repro-med.net/repro-med-site2/index.php?option=com_content&view=article&id=6:immunophenotype&catid=2:pages-ett&Itemid=25 15. Leukocyte Antibody Detection (LAD) Braverman: The purpose of the LAD test is to see if you have made anti HLA antibodies. The assumption is then made(erroneously) that if they are made then you also made the protective or anti idiotypic antibodies. Anti HLA antibodies are only made in the third trimester of a pregnancy , so if you have never been that far you will get no information from an LAD. The only benefit of an LAD is if you have secondary recurrent pregnancy loss i.e. one full term pregnancy then losses, it may suggest that your problem is too many anti HLA(or anti embryo ) antibodies. The more matches you have in the HLA the less likely you will make anti HLA antibodies and the less likely the LAD will be positive. so to answer your question , if you have primary recurrent pregnancy loss i.e never had a Full term pregnancy it is useful , if not , then it is not useful. For those that may have had the test anyway and had a positive result but never made it to end or even middle of a pregnancy this might signify other antibodies such as APA , Lupus, infection and should be worked up. The biggest mistake I see are people with primary RPL who get LIT because of a negative LAD , it should be negative if there was no Full Term Pregnancy. http://www.preventmiscarriage.com/Discussion-Forum/Questions-for-Dr-Braverman/LAD-.aspx 

Video of how NK cells are counted. http://www.jove.com/video/2540/expansion-purification-and-functional-assessment-of-human-peripheral-blood-nk-cells 

Reprosource arranges everything for the tests that can only be performed at a specialty lab - they will help figure out if your insurance will cover the tests for you or not, and if not, they will offer you a low cash pay price, that you can be billed for. your dr. would send a requisition to Reprosource, and they will call you to make all the arrangements. They will then send you the collection kit with instructions and all the tubes and everything needed for your tests. They also set up an appt time for a traveling phlebotomist to come to you to draw your (and your DH's) blood - and they pack it all up and drop it off at FedEx for you. 

All of the other tests you can have done at any hospital or local lab, and whatever tests they can't run themselves, can be sent out to another lab that does. It's best to use a local lab for this *regular* stuff, especially if you have insurance that covers it, in case you need to use an in-network facility. Those tests are: 

RPL (repeated pregnancy loss) panel: (Be careful, when you request immune system testing from your RE, many order this RPL panel rather than the immune system panel above. These RPL problems are associated more often with 2nd trimester miscarriages, so if you rather experience no bfp's at all or chemicals/early miscarriages, then the tests above are more appropriate (although these have some value as well). Many REs don't believe that immune system issues are important, but they are willing to test for RPL.) Lupus Anticoagulant: (result: negative/positive) Lupus PTT-LAC screen = (range is <40) Lupus DRVVT screen = l (range is <42) Homocysteine = (range <10.4) Protein C (activity and antigen) Protein S (activity, antigen free, antigen total) Antithrombin = (range 80-120) MTHFR APC resistence/protein C ratio = (range is >2.1) PT = (range is 9.6-11.3) INR = (range is 0.9-1.1) Anti-Thyroid Antibodies/peroxidase: normal (range is <35%) ANA - Anti-Nuclear Antibodies: (negative/positive) Thyroglobulin Antibody: (range is <20IU/mL) APA - Anti-phospholipid Antibodies - 9 part panel: ---> Cardiolipin AB - IGG: (range is <10 GPL U/mL - negative) Cardiolipin AB - IGM: (range is <10 MPL U/mL - negative) Cardiolipin AB - AGA: (range is <10 APL U/mL - negative) Phosphatidylserine AB IGM: (range is <25 U/mL - negative) Phosphatidylserine AB IGA: (range is <20 U/mL - negative) Phosphatidylserine AB IGG: (range is <10 U/mL - negative) B2 Glycoprotein I [IGA] AB: (range is <10 U/mL - negative) B2 Glycoprotein I [IGG] AB: (range is <20 U/mL - negative) B2 Glycoprotein I [IGM] AB: (range is <10 U/mL - negative) 

Additional tests that can be very helpful as part of a standard fertility work up: Prolactin Testosterone, free and total DHEA-S = (range is 40-325) DHEA = (range is 102-1185) Vitamin D = (level should be 50+, ideally 82+, under 50 is linked to infertility) Ferritin = (should be 70-90, anything below 50 can cause or contribute to infertlity) B12 TSH (should be near a level of "1" when dealing with IF/RPL) T4, free and total T3, free and total Inhibin B CBC (Complete blood Count) CMP (Complete Metabolic Panel) 

If you're paying out of pocket, it might be best to do a thrombophilia panel at a lab like ReproSource, which will include several of the tests I listed above, because it's probably cheaper that way: http://reprosource.com/reprosource_test/thrombophilia-panel/ Just be careful that you don't duplicate certain tests if you're having them done at separate places if you are paying out of pocket, so you don't end up paying more than necessary! 

Here is another one that could be helpful for those with RPL (recurrent pregnancy loss) issues: http://reprosource.com/reprosource_test/chromosome-karyotyping/ 

Ordering the testing yourself. It seems to be possible at least through Millenova labs. www.millenova.com. Download the order form and choose the NK cell assay at least. http://forums.haveababy.com/index.php?s=84f988b7c0100eb7ab1afc60039191ea&showtopic=49128 I think it is possible to also do this through Reprosource, but not sure. 

3D ultrasound Computes a vascularisation index. If high, it's a sign of high NK cell activity. NK cells are responsible for making small blood vessels (angiogenesis) in uterus, so the more blood vessels, the higher vascularisation index, and the higher chance of high NK cell activation. If it is low, there's a chance that there is not enough inflammation which is necessary for pregnancy to happen. http://onlinelibrary.wiley.com/doi/10.1002/uog.2659/pdf http://www.ncbi.nlm.nih.gov/pubmed/21334074

TREATMENTS

• Intralipids Reduce NK cell activation - calm down overactive immune system/inflammation. http://www.ncbi.nlm.nih.gov/pubmed/18782287 As effective as IVIg http://www.ncbi.nlm.nih.gov/pubmed/17362387 Intralipids are safer than IVIg as they do not contain any blood products. ILs are also around 10x cheaper than IVIg. More information: Intralipid (IL), is a synthetic product composed of 10% soybean oil, 1,2% egg yolk phospholipids, 2.25% glycerin and water. Based on research performed at SIRM and elsewhere, infusion of IL lowers Natural Killer cell activation (Nka) as effectively as does, intravenous gammaglobulin (IVIG.) When indicated IL (as with IVIG) is infused 7-10 days prior to ET and one more time again after a positive pregnancy in women whose Nka is due to an autoimmune causes (antiphospholipid antibodies and/or antithyroid antibodies). In cases of alloimmune implantation dysfunction (DQa and/ HLA matching between the embryo recipient and the male partner) the same applies but in this situation the infusion is repeated at 2-4 week intervals until the 24th week of pregnancy. We have supplanted IVIG with IL therapy in a significant number of women undergoing IVF , and who had immunologic embryo implantation dysfunction. The results thus far have been excellent, way beyond our initial expectations. At last we now have a safe and inexpensive alternative to IVIG therapy...Intralipid! What is more, IL costs about 10 times less than IVIG, is not a blood product and is without significant side effects. http://haveababy.com/sirm-innovations/immunologic-treatment.html 
  
  
• Neupogen, G-CSF G-CSF levels tend to be higher in the follicular fluid in cases of successful IVFs. http://www.ncbi.nlm.nih.gov/pubmed/20594599 http://www.ncbi.nlm.nih.gov/pubmed/15890733 According to Dr. Braveman this is the only treatment that works for complete alloimmune matches (why?) 
  
  
  Here is a study of Neupogen's effect on recurrent pregnancy loss: humrep.oxfordjournals.org/content/24/11/2703.full.pdf 
  
  
  Here's a good study which shows high success rates with G-CSF after failed implantation:http://humrep.oxfordjournals.org/content/25/8/2151.long 
  
  
  Here is about importance of G-CSF in uterus: http://www.ncbi.nlm.nih.gov/pubmed/20974989 
  
  
  Here is a very promising study which shows that with Neupogen flush women were able to regain their lining. Previously they had only <7mm, with Neupogen (G-CSF) flush they got it to over 7mm and all 4 patients got pregnant: http://www.ncbi.nlm.nih.gov/pubmed/21324451 
  
  
  In this study they measure both serum and follicular fluid levels of G-CSF. The higher the higher pregnancy rates and women with endometriosis tend to have lower levels: http://www.ncbi.nlm.nih.gov/pubmed/15890733 
  
  
  Here are some articles by Dr. Ledee. She has many on G-CSF levels in follicular fluid and how higher levels improve IVF success rates: http://www.ncbi.nlm.nih.gov/pubmed?term="Ledee N"[Author] 
  
  
• Vitamin E - As an fairly powerful antioxidant it reduces the damage by radical oxygen species (ROS), which are created as a result of inflammation and destroy surrounding tissue. - Reduces inflammation (Type 2 prostaglandin levels) - Improves blood flow 
  
  
• Progesterone - More non-inflammatory cytokines - Less inflammatory cytokines - Less TNF-alpha - Inhibits cytotoxity of NK cells - More Th2 (than Th1) - Inhibits release of arachidonic acid http://www.ncbi.nlm.nih.gov/pubmed/16198558 http://www.ncbi.nlm.nih.gov/pubmed/20367622 http://www.ncbi.nlm.nih.gov/pubmed/16129958 Beer center: Many women with infertility, implantation failures and/or miscarriages produce low levels of progesterone as seen in the bottom line of the graph. These women require progesterone supplementation to bring them into the safe levels (see thick line, which indicates mean values, on graph and limits of two standard deviations of the mean). Based on our experience in treating autoimmune women, this supplementation must continue until the 16th week is completed. 
  
  
  Progesterone-like steroid medication has a variety of effects on the immune system. This type of medication - Blocks inflammation that can lead to scarring and damage to the placenta - Blocks the T cells and the B cells (lymphocytes) that can cause rejection of the placenta- Blocks the natural killer cells from releasing factors such as tumor necrosis factor (TNF) that can damage the placenta and the lining of the uterus - Prevents lymphocytes from wandering into the placenta, sticking there and doing damage - Causes an increase in HCG production by the placenta, and HCG and progesterone block the killing power of NK cells - Prevents prostaglandin production by the uterus and stops contractions from occurring - Causes the cervix to produce a cervical plug that is rich in antibodies, which prevent germs and viruses from gaining access to the baby and the placenta 
  
  
  When progesterone supplementation is given to a mother, its half life in the blood is very short. In four minutes it begins to be excreted rapidly into the urine. The most efficient route to take the progesterone to insure the best blood levels and the longest survival of the progesterone in the blood is to use vaginal suppositories. The next best route of administration is to take injections of progesterone. The least effective is to take the progesterone by mouth. http://repro-med.net/repro-med-site2/index.php?option=com_content&view=article&id=25&Itemid=12 
  
  
  Braverman: In the same light the use of vaginal progesterone , although perfect for initiating luteal changes in the endometrium almost 100% of the times, does not raise serum(blood) levels of progesterone and there are clearly functions of serum(in the blood) progesterone in recruiting "friendly" immune cells from the blood stream to the uterine lining and helping to prevent differentiation of "friendly" immune cells that are found in the blood stream to the "toxic' forms. Again this is clearly not an issue with routine IVF(as we have great success with vaginal progesterone(crinone, endometrin) but in patients with immune issues it is becoming our practice to only use IM progesterone on our most difficult cases as this is the only one of the therapies that we use that will raise blood progesterone levels. http://www.preventmiscarriage.com/Discussion-Forum/Thread.aspx?Thread=168 
  
  
• hCG injections in LP hCG is required in the uterus to make the dendritic cells and macrophages (immune system) to tolerate the embryo. But sometimes hCG fails to develop in adequate amounts in the body of is somehow defective in shape. In that case hCG boosters in LP can help. http://m.preventmiscarriage.com/Reproductive-Immunology/Immunologic-Causes/Dendritic-Cells-Macrophages.aspx The first known human embryo-derived signal is chorionic gonadotropin (hCG) by which the embryo profoundly influences immunological tolerance and angiogenesis at the maternal-fetal interface. hCG levels coincide with the development of trophoblast tolerance. Indeed, it increases the number of uterine natural killer cells that play a key role in the establishment of pregnancy. hCG also intervenes in the development of local immune tolerance through the cellular system of apoptosis via Fas/Fas-Ligand. It modulates the Th1/Th2 balance and acts on complement C3 and C4A/B factors modulating decidual immunity. http://www.scopus.com/record/display.url?eid=2-s2.0-77952099311&origin=inward&txGid=H3Toxlj5K6b_v70EG-8_t9V%3a2 
  
  
• Estrogen Significantly reduces inflammation/NK cell activity. Strong enough support in LP of an IVF cycle is required for those with elevated NK cell activation. Those with not enough NK cell activity should only do minimal stims to avoid too high estrogen levels and hence, depletion of proinflammatory cytokines. http://www.ncbi.nlm.nih.gov/pubmed/21334074 
  
  
• Humira Shuts down Th1. Dr. Beer recommends Humira when: - Poor NK suppression with IVIg on the NK cell assay (over 15% 50:1 NK killing power at 12.5 mg/ml or 6.25 mg/ml added IVIg) - Failed past cycles with LIT and IVIg - Elevated numbers of CD57 cells in the endometrium - A history of endometriosis - Elevated TH1:TH2 ratios on the cytokine assay (TNF-alpha:IL-10 ratios over 30, INF-gamma:IL-10 ratios over 15) 
  
  
• Endometrial scratching For lack of inflammation (too low Nk cell activity). Should be done in the mid-luteal phase of the cycle prior to IVF. Those with high NK cell activity, should avoid scratching the endometrium in the previous cycle as well as during IVF transfer. A statistically significantly higher amount of macrophages/dendritic cells (HLA-DR+ CD11c+ cells) and elevated proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), growth-regulated oncogene-alpha (GRO-alpha), interleukin-15 (IL-15), and macrophage inflammatory protein 1B (MIP-1B), were detected in day-21 endometrial samples of the experimental group. A direct stimulatory effect of TNF-alpha on MIP-1B, GRO-alpha, and IL-15 messenger RNA (mRNA) expression was demonstrated. A positive correlation was found between the levels of macrophages/dendritic cells, MIP-1B expression, and TNF-alpha expression and the pregnancy outcome. http://www.ncbi.nlm.nih.gov/pubmed/20338560 http://www.ncbi.nlm.nih.gov/pubmed/21334074 
  
  
• Heparin/lovenox For elevated APAs Contrary to what is often assumed, the dose of heparin used is not enough to thin the blood and cause bleeding problems. Instead, the heparin repels APAs from the surface of trophoblast cells, thus enhancing their development. http://haveababy.com/infertility-education/causes-of-infertility/immune-factors/163.html 
  
  
• Aspirin SIRM: More recent analysis has shown that the use of heparin alone is just as effective as combining it with aspirin. Accordingly, we no longer prescribe aspirin. http://haveababy.com/infertility-education/causes-of-infertility/immune-factors/163.html http://www.ivfauthority.com/2009/06/unexplained-infertility-and-ivf-failure.html Often people are told to stop aspirin prior to ER because it increases a risk of bleeding which can lead to complications and more inflammation. However, just stopping the aspirin leads to a huge surge in inflammation: http://www.ncbi.nlm.nih.gov/pubmed/11022121 There are some studies that show that even baby aspirin (as a NSAID) increases m/c risk by 400%. http://www.bmj.com/content/327/7411/368.full So if there is a blood clotting problem, it's better to take just heparin/lovenox. For inflammation, fish oil, vitamin E and prednisone work better. 
  
  
• Prednisone 1. Prednisone lowers TH1 (inflammatory cytokine) production, while having no effect on the production of the TH2 (anti inflammatory) cytokines. This helps to lower the overall TH1/TH2 cytokine ratio and assist in the generation of immune tolerance. 2. Prednisone also binds to receptors on the same cells that TNFalpha and other inflammatory cytokines bind to, and the prednisone counteracts the normal immune stimulatory effect on these immune cells. In essence the prednisone is dampening the effect of the inflammatory cytokines so they can�t carry out their function of immune activation. 3. During the implantation process , many of the actions of anti phospholipid antibodies is through the over activation of the complement system in the implantation site that leads to inflammation and destruction of the vessels necessary to supply the embryo, prednisone helps to combat this process as well. 4. Prednisone decreases the production of antibodies that can interfere with embryo implantation. Such as ANA, APA, ACA and idiotypic antibodies that are produced by B cells and programmed to attack the embryo directly. 
  
  
  Note: With long term use, corticosteroids can have a bone thinning effect, which is why it is important to take them with a calcium supplement of 500 mg twice a day plus a good quality multivitamin containing vitamin D to help the body absorb the calcium. 
  
  
  A study which shows prednisolone to be effective at reducing NK cells killing power: http://www.ncbi.nlm.nih.gov/pubmed/18275519 
  
  
  Steroids help also with egg quality: Dexamethasone is a substrate for the enzyme type 1 (Best et al., 1997) 11-beta-hydroxysteroid dehydrogenase (11-beta;HSD). This isoform has been detected in luteinized human granulosa cells (Smith et al., 1997) and oocytes (Smith et al., 2000) suggesting that dexamethasone may directly influence follicular development. The developmental regulation of human beta;HSD isoform expression favours a high preovulatory follicular fluid cortisol concentration (Tetsuka et al., 1997) and other species require glucocorticoids for final oocyte maturation (Greeley et al., 1986). http://humrep.oxfordjournals.org/content/16/9/1861.full 
  
  
  To calculate how much dexamethasone is equivalent to x amount of prednisone, use this calculator: http://www.medcalc.com/steroid.html The standard dose of Prednisone is at least 20mg from cd1 until bfn or 10 weeks of pregnancy. After that wean to 10mg at 10 weeks, and 5mg at 11 weeks. Then stop completely at 12 weeks. Taking prednisone is safe in first trimester but can cause minor birth defects if taken later in pregnancy. 
  
  
• Pentoxifylline Is a phosphodiesterase inhibitor, is the first immune-modulator agent investigated for the treatment of endometriosis. Pentoxifylline inhibits phagocytosis and generation of toxic oxygen species and proteolytic enzymes by macrophages and granulocytes in vitro and in vivo [122]. Moreover, pentoxifylline inhibits both TNF-a production by macrophages [123], and the proinflammatory action of TNF-a and IL-1 on granulocytes in vitro [124]. In 1991, Steinleitner et al used pentoxifylline in a murine model of peritoneal inflammation. They showed that the transfer of activated peritoneal macrophages, but not basal state macrophages, into the peritoneal cavity of normal mice significantly inhibited fertilization. This was reversed by periovulatory pentoxifylline treatment [125]. Soon after their first report, they showed that the inhibition of fertilization by surgically induced endometriosis is also reversed by periovulatory pentoxifylline treatment [126]. Pentoxifylline was later found to inhibit endometriotic implant growth in an animal model without affecting circulating estradiol and progesterone levels [127]. In 1997 Balasch et al reported the first randomized clinical trial of pentoxifylline in the treatment of infertility associated with asymptomatic minimal or mild endometriosis [128]. Thirty women in each group were treated with 800 mg oral pentoxifylline for 12 months. The overall pregnancy rates were 31% and 18.5% in the pentoxifylline and placebo groups, respectively. However, the difference was not statistically significant because of the small study population. From book: Endometriosis: advances and controversies 
  
  
  Great for improving endometrial thickness when taken together with vitamin E: http://humrep.oxfordjournals.org/content/17/5/1249.full 
  
  
• Metformin Metformin improves insulin resistance which is one of the bigger culprits for inflammation. A low-dose (500 mg/day for 8-12 wks) metformin helps nonPCOS women that have failed IVF previously. http://www.docguide.com/low-dose-metformin-improves-pregnancy-rates-ivf-repeaters-presented-asrm http://www.hormones.gr/556/article/article.html 
  
  
  
  
• CCRM's anti-inflammatory/anti-allergy cocktail Starting two days before transfer: 10 mg prednisone once a day 10 mg Claritin once a day 20 mg Pepcid in morning and at night One month before transfer through post transfer no chocolate or caffeine. Here is one article about how anti-histamines can reduce TH1 and increase TH2, thereby returning the balance for someone with too overactive immune system: http://www.sciencedirect.com/science/article/pii/S1567576902002357 The protocol is known as "Rob's Cocktail" after one of the doctors at CCRM who had a patient who was dealing with repeat loss issues. Right before she hit the twelve week mark, she got flushed/itchy and threw up, and then miscarried thereafter. Then next time she got pregnant, the same thing happened, but this time at 8 weeks. Then she got pregnant again and same symptoms happened at 6 weeks. So it was progressively getting worse. 
  
  
  The doctor determined this was obviously a reaction going on, so he came up with the Claritin and Pepcid to deal with both TH1 and TH2 issues, and the Prednisone as overall drug to calm the immune system. 
  
  
  Shortly thereafter, she got pregnant and went to term. 
  
  
  Now of course, we don't know for sure if the protocol was what made her finally go to term, but since it worked, they've since used it for other patients. There are no clinical trials or anything "official" to back it up. 
  
  
  Braverman's view is that histamine is crucially important in the implantation process and it should therefore first be established whether there is over-production of histamines. Otherwise, the treatments may be harmful. http://www.preventmiscarriage.com/Blog/2012/May/ANTIHISTAMINES-CLARITIN-TO-PREVENT-IVF-FAILURE.aspx 
  
  
• Protocol by Dr. Ledee - Vitamin E 1000mg - start asap - Folic acid - Antagonist protocol (125IU FSH). Better for inflammation, as lupron would increase NK cell activity. - Prednisone 20mg from cd1 to pregnancy test at least - Ciprofloxacin (strong antibiotic) from day of trigger for 7 days to avoid infections after ER which increase inflammation/NK cell activity. - Very high dose progesterone (1200mg/day) and estrogen in LP (both lower NK cell activity) - No sex after transfer - at least w/o condom. The seminal fluid might carrry bacteria and cause more inflammation. 

Online pharmacy for prednisone, prometrium etc. without prescription: http://www.inhousedrugstore.biz 

Two online pharmacies for much cheaper meds: ivfmeds.com ivfpharmacy.com

OTC REMEDIES: For lowering inflammation. Obviously these would make things worst for someone with not enough inflammation. 

• Fish oil Animal studies showed that dietary flaxseed oil [rich in the n-3 polyunsaturated fatty acid alpha-linolenic acid (ALA)], evening primrose oil [rich in the n-6 polyunsaturated fatty acid gamma-linolenic acid (GLA)], and fish oil [rich in the long-chain n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] can decrease natural killer (NK) cell activity. There have been no studies of the effect on NK cell activity of adding these oils to the diet of humans. 
  
  
  NK cell activity was not significantly affected by the placebo, ALA, GLA, AA, or DHA treatment. Fish oil caused a significant reduction (mean decline: 48%) in NK cell activity that was fully reversed by 4 wk after supplementation had ceased. http://www.ajcn.org/content/73/3/539.short 
  
  
  There is a GPR120 receptor in pro-inflammatory macrophages of mature fat cells. When the receptor is turned off, the macrophage produces inflammatory effects. But when it is exposed to omega-3 fatty acids, specifically (DHA) and (EPA), the GPR120 receptor is activated and generates a strong anti-inflammatory effect. "It's just an incredibly potent effect," said Olefsky, a professor of medicine http://www.sciencedaily.com/releases/2010/09/100902121049.htm 
  
  
• Vitamin D Recommended by Dr. Braveman for treating immune system infertility: New research is showing the anti inflammatory benefits of Vit D. It has been shown to decrease NK cell activity, as well as alter the TH1/TH2 cytokine ratio in favor of the anti inflammatory response by lowering TH1 and increasing TH2. Its effects are very similar to the TH2 cytokine called IL-10 one of the most important TH2 cytokines produced for the maintenance of pregnancy. It is the TH2 cytokine we measure with our TH1/TH2 ratio. We recommend patients that require this therapy take between 2000 and 4000 IU /day. We have started screening our patients for what is turning out to be a common vitamin deficiency in this country. http://readytoconceive.com/?page_id=71 http://www.drmyattswellnessclub.com/VitaminDSpecialReport.htm 
  
  
  Increased concentrations of serum TNF-alpha, an inflammatory marker, were found in women who had insufficient vitamin D levels. http://www.sciencedaily.com/releases/2009/04/090408140208.htm 
  
  
• Maxi Flavone: Tumor Necrosis Factor-alpha (TNF-a) is an inflammatory cytokine that stimulates free radical production by mitochondria. Don't let the term "tumor" alarm you; everyone has TNF-alpha; in their body. Excessive amounts of TNF-alpha; impair fertility. In women, high TNF-alpha; suppresses ovarian function, increases Natural Killer cells (NK cells) and is associated with infertility. High TNF-alpha; is also associated with recurrent spontaneous abortion. In men, high TNF-alpha; is associated with decreased sperm count and motility Maxi Flavone is a broad-spectrum herbal antioxidant formula that affords protection from multiple ROS species, lowers TNF-alpha and is anti-inflammatory. Flavonoid-containing herbs have a synergistic effect when used in combination. http://www.drmyattswellnessclub.com/Fertility/MaxiFlavone.htm 
  
  
  Here is another link to another supplement that is like Maxi Flavone, only the price is better and there is actually more research to back it up. Dr. Sears also has fish oil on this link and multiple other things. His whole focus is on the "Silent Inflammation" that occurs inside our bodies and effects our organs without us ever knowing until there is a sudden issue. He does mention fertility as being affected and this diet and vitamin regime have proven to help. He also focuses a lot on obesity and treating all of its effects on the human body. http://shop.zonediet.com/product/detail/504.aspx?product_number=504&CatAdReferrer=ppc 
  
  
• Wobenzym: Might lower inflammation and therefore lower risk of m/c: http://systemicenzymesupport.org/conditions/infertility.htm Braveman cautions against using around egg retrieval as the anti-inflammatory component may prevent ovulation. http://forum.preventmiscarriage.com/viewtopic.php?f=3&t=2245 
  
  
• N-acetyl cysteine (NAC): NAC is an amino acid and specifically helps the liver filter toxins. (For this reason it should not be used during treatment cycles as it can metabolise the medicines too quickly). It is a precursor to glutathione which is a powerful antioxidant in the body but doesn't absorb well in supplement form. Inflammation causes ROS (radical oxygen species), which wreck havoc in the body. Antioxidants help reduce this damage. Pregnancy could be associated with a state of oxidative stress that could initiate and propagate a cascade of changes that may lead to pregnancy wastage. This process of oxidative stress may be suppressed by the antioxidant effect of N-acetyl cysteine (NAC). The current study aimed to evaluate the effect of NAC therapy in patients diagnosed with unexplained recurrent pregnancy loss (RPL). The study was a prospective controlled study performed in the Women's Health Centre, Assiut University, Egypt. A group of 80 patients with history of recurrent unexplained pregnancy loss were treated with NAC 0.6 g + folic acid 500 microg/day and compared with an aged-matched group of 86 patients treated with folic acid 500 microg/day alone. NAC + folic acid compared with folic acid alone caused a significantly increased rate of continuation of a living pregnancy up to and beyond 20 weeks [P < 0.002, relative risk (RR) 2.9, 95% confidence interval (CI) 1.5-5.6]. NAC + folic acid was associated with a significant increase in the take-home baby rate as compared with folic acid alone (P < 0.047, RR 1.98, 95% CI 1.3-4.0). In conclusion, NAC is a well-tolerated drug that could be a potentially effective treatment in patients with unexplained RPL." http://www.ncbi.nlm.nih.gov/pubmed/18983759 

Supplements to avoid 

• Royal Jelly/Bee pollen - Might increase TH1, is estrogenic (estrogen helps with inflammation, but can stop you from ovulating when taken at wrong times - also makes endometriosis worst). 
  
  
• Anything estrogenic: Soy, EPO, Vitex (behaves like estrogen), red raspberry (including leaves), milk thistle, dang quai... 
  
  
• Myo-inositol: Increases NK cell activity 
  
  
• Omega-6: Increases NK cell activity 
  
  
• Probiotics: Some of the strains increase NK cell activity http://www.faqs.org/patents/app/20090208469 

Anti-inflammatory diet http://www.endo-resolved.com/diet.html http://www.drweil.com/drw/u/ART02012/anti-inflammatory-diet http://www.drweil.com/drw/u/ART02995/Dr-Weil-Anti-Inflammatory-Food-Pyramid.html http://coolinginflammation.blogspot.com/search/label/anti-inflammatory%20diet http://theconsciouslife.com/top-10-inflammatory-foods-to-avoid.htm http://bodyecology.com/articles/top_ten_foods_that_prevent_inflammation.php http://www.epicurious.com/articlesguides/healthy/news/diet_antiinflammatory And a GREAT book that is not diet-specific-- but it helps you retrain your mind with behavior modification techniques that will work with any eating plan (Atkins, Paleo, anti-inflam, etc etc) is called the Beck Diet Revolution. 

Braverman's view on gluten free diet: An article published in the Journal of Immunology has shown a connection between gluten in the diet and "maturation" of dendritic cells. We have spoken often on this site how the maturation of dendritic cells (the messenger cells of the immune system) needed to be avoided in order to allow the embryo to turn off the immune response of the mother, and allow for successful implantation. In fact, many of the newer therapies we are using, such as Neupogen (G-CSF), have as their mechanism of action the ability to PREVENT maturation of the dendritic cells at the uterine lining. When dendritic cells are mature they take information about the embryo to the lymph node and present it in such a manner that the mother's immune system mounts a response against the embryo. 

It is becoming quite clear that patients where we suspect immune involvement of pregnancy rejection, a gluten free diet seems to be imperative. http://www.preventmiscarriage.com/Blog/2012/March/Evidence-for-Involvement-of-Gluten-in-Immune-Rej.aspx 

Foods and herbs to avoid: 

• Gluten 
• Dairy 
• Sugar 
• Coffee - Increases inflammation - Is a phytoestrogen http://www.ncbi.nlm.nih.gov/pubmed/15447891 
• Chocolate (per CCRM) 
• Saturated fat 
• Licorice root - Is estrogenic - Increases inflammation - Causes uterine contractions http://drholly.typepad.com/licorice/ http://www.webmd.com/vitamins-supplements/ingredientmono-881-LICORICE.aspx?activeIngredientId=881&activeIngredientName=LICORICE 
• Astragalus - Increases inflammation 
• Beta-sitosterol 
• Ashwaganda 
• Panax ginseng 
• Mushrooms (Maitake, Reishi, Shiitake) 
• Chlorella 
• Milk Thistle Theoretically, because milk thistle plant extract might have estrogenic effects, women with hormone sensitive conditions should avoid milk thistle above ground parts. Some of these conditions include breast, uterine, and ovarian cancer, endometriosis, and uterine fibroids. http://www.mayoclinic.com/health/silymarin/NS_patient-milkthistle/DSECTION=safetySilybin, an extract from seeds of milk thistle (Silybum marianum), is known to have hepato-protective, anticarcinogenic, and estrogenic effects. http://www.ncbi.nlm.nih.gov/pubmed/20183284 http://www.ncbi.nlm.nih.gov/pubmed/19577454 

Anti-inflammatory foods and herbs: 

• Turmeric: http://www.sciencentral.com/video/2008/07/31/curry-for-diabetes/ http://en.wikipedia.org/wiki/Turmeric http://www.edenlabs.org/tumeric.htm 
  
  
• Green Tea the EGCG in green tea can turn on the body�s defense system against TNF-alpha � a group of proteins and molecules involved in systemic inflammation. TNF-alpha, which is produced by white blood cells, can reach out to target and kill cells. http://www.sciencedaily.com/releases/2007/04/070419140910.htm Increases TH2 Reduces folic acid absorption, so better to take at different time of the day to folic acid. 
  
  
• Spirulina One benefit of spirulina is that it contains a very high concentration of evercetin. This substance is a powerful antioxidant and also has anti-inflammatory properties. It may be beneficial in the treatment of asthma and sinusitis. The suggested dose of spirulina is 3mg to 5mg per day. http://www.livestrong.com/article/356865-spirulina-nutrition-content/#ixzz23dePmHDX 
  
  
• CoQ10 Dr Braverman recommends CoQ10 in "higher doses [than 100mg/day]" for reducing inflammation: http://www.preventmiscarriage.com/Discussion-Forum/Questions-for-Dr-Braverman/Mitochondrial-Enhancers.aspx 
  
  
• Blueberries: Are very potent anti-oxidant and increase anti-inflammatory cytokines, but increase NK cell counts also. http://www.ncbi.nlm.nih.gov/pubmed/22111516 
  
  
• Genistein 
• Quercetin http://www.precisionnutrition.com/rr-green-tea-hazards 

Unsure about these herbs and foods: 

• Reservatol Increases Nk cell activity: http://www.ncbi.nlm.nih.gov/pubmed/20082299 Is a phytoestrogen. Phytoestrogens cause endometriosis to grow and can inhibit ovulation. http://lpi.oregonstate.edu/infocenter/phytochemicals/resveratrol/ http://www.ncbi.nlm.nih.gov/pubmed/11014220 
  
  
• Grape seed extract and pycnogenol Grape seed extract and pycnogenol are aromatase inhibitors. Aromatase is an enzyme present in fat tissue and in ovaries that converts testosterone to estrogen. When it is inhibited, there will be more testosterone. Sometimes in short doses this is ok, as femara is works by being an aromatase inhibitor. But it is not good to take this for longer times as it can inhibit ovulation and lead to high testosterone levels which are toxic to our eggs.http://cancerres.aacrjournals.org/content/66/11/5960/F4.expansion http://www.ncbi.nlm.nih.gov/pubmed/16740737 

Exercise - Exercise increases Nk cell activation as well as inflammation. http://www.ncbi.nlm.nih.gov/pubmed/8897029 http://www.medizin.uni-tuebingen.de/transfusionsmedizin/institut/eir/content/2011/6/article.pdf "Regular physical activity is reported to decrease markers of inflammation although the correlation is imperfect and seems to reveal differing results contingent upon training intensity. For instance, while baseline measurements of circulating inflammatory markers do not seem to differ greatly between healthy trained and untrained adults, long-term chronic training may help reduce chronic low-grade inflammation. On the other hand, levels of inflammatory markers (IL-6) remained elevated longer into the recovery period following an acute bout of exercise in patients with inflammatory diseases, relative to the recovery of healthy controls. It may well be that low-intensity training can reduce resting pro-inflammatory markers (CRP, IL-6), while moderate-intensity training has milder and less-established anti-inflammatory benefits. There is a strong relationship between exhaustive exercise and chronic low-grade inflammation. Marathon running may enhance IL-6 levels as much as 100 times over normal and increases total leuckocyte count and neturophil mobilization. As such, individuals pursuing exercise as a means to treat the other factors behind chronic inflammation may wish to balance their exercise protocol with bouts of low-intensity training, while striving to avoid chronic over-exertion." http://en.wikipedia.org/wiki/Inflammation

f you're trying to reduce inflammation: Quercetin and bromelain, from http://www.wellnesstrader.com/evidence/Quercetin%20and%20Allergies: 

"Among the flavonoids, quercetin is possibly the most biologically active. Quercetin is the aglycone (noncarbohydrate portion) of rutin, quercetrin and other glycoside flavonoids. It is widely distributed in the plant kingdom including oak trees (Quercus spp.), onions (Allium cepa) and tea (Camellia sinensis). It has effects on many different enzymatic systems in the body, most of them via its interaction with the calcium-regulating enzyme calmodulin. Quercetin’s effect on allergies is unmatched by other natural substances. It inhibits phospholipase A (responsible for converting phospholipids into arachidonic acid), lipoxygenase (responsible for converting arachidonic acid into leukotrienes), platelet aggregation, and mast cell and basophil degranulation. Quercetin has been shown to bind to calcium/calmodulin complexes, preventing the influx of calcium into mast cells and basophils. This inhibition prevents the mast cells from destabilizing and degranulating, keeping histamine and other preformed mediators from being released. In fact, quercetin so consistently blocks calcium induced mast cells destabilization that researchers often use it in experiments as a control substance for such activity. The activity of quercetin has been well known for years, leading to the synthesis of similar compounds by pharmaceutical companies. One such compound, cromyln (the active ingredient in Intal), has been used as a mast cell stabilizer for years. The only problem is that cromyln cannot be absorbed orally and must me delivered as a powder through spinhalers or an aerosol inhaler. Even then, only 8% is absorbed in the respiratory tract leading to the need to take 2 metered dosages four times per day. Like most biologically active flavonoids, quercetin’s pharmacology is quite interesting. The absorption of quercetin is about 20-52% depending on the form. While this may seem quite low, the elimination of quercetin and its derivatives is very low, and high plasma levels are easily maintained with a regular supply of quercetin in the diet. Studies conducted in rats showed that more than 25% of the absorbed quercetin was localized in the lung tissue, an added benefit to combat allergy and associated asthma. While these radioactive studies have not been repeated in man, it is likely that similar results would be found. It has been known for some time that the concomitant administration of bromelain, an enzyme derived from the stem of the pineapple plant, can enhance the absorption of quercetin as well as other flavonoids such as rutin. An added benefit included with bromelain is its ability to block inflammatory pathways (fibrin and kinin) and decrease the viscosity of mucus in the lungs. 

Patients should begin to take quercetin upon the first signs of allergen exposure. Since quercetin is prophylactic (stabilizing mast cells rather than blocking histamine) and will stay in the blood stream, initial doses should be 400-600 mg, three times per day, for the first 5-7 days. Symptom relief may begin in the first several hours. Once plasma levels are up, 200-400 mg per day should be sufficient through the rest of the allergy season. Quercetin is extremely safe, and has so many other benefits (antioxidant, anti-inflammatory, capillary stability etc.) it should make it the foundation of any natural approach to allergic rhinitis therapy. 

While other botanical products have been used for allergic rhinitis over the years, most of these work as anti-allergic agents due to the high amount of quercetin in them. Among them, garlic, onion, and green tea are the most popular." 

Foods to Avoid 

An anti-inflammatory diet must avoid foods that stimulate inflammation, such as the preservative monosodium glutamate. Avoid advanced glycation end products, substances caused by cooking at high temperatures, as well. Research by scientists at the University of Toyama in Japan published in the "Journal of Autoimmunity" in 2008 found monosodium glutamate in mice leads to development of inflammation of the liver. Meat, chicken and potato products cooked at high temperatures produce compounds called advanced glycation end products that cause inflammation. Consume whole foods without preservatives that are raw, steamed or cooked at low temperatures if you have an inflammatory condition 

Read more: http://www.livestrong.com/article/417827-menu-ideas-for-an-anti-inflammatory-diet/#ixzz23dinYQXG 

Improving egg quality: 

L arginine- 16 mg daily from cd1 to trigger-- " the numbers of large follicles (>17 mm), the number of collected oocytes and transferred embryos were significantly higher in the l-arginine group. On day 8 and on day of HCG administration, oestradiol and GH plasma concentrations were significantly increased in the treated group. Plasma l-arginine, l-citrulline and NO2–/NO3– concentrations were also significantly higher in the arginine supplemented group. In these patients oestradiol and l-arginine plasma concentrations correlated with the number of developed follicles. The above data agree with previous data (Stone and Marrs, 1992) confirming that women with increased GH concentrations produce significantly more oocytes and high oestradiol concentrations at each stage of ovarian stimulation and suggest that l-arginine supplementation may minimize poor response." 

http://humrep.oxfordjournals.org/content/14/7/1690.full 

dexamethasone 1mg at night from start of FSH to night before ER-- "In cycles reaching oocyte retrieval no difference in oocyte number or total gonadotrophin dose was observed (Table III). Fertilization rates were similar and a trend towards a higher embryo implantation rate in the dexamethasone group was observed." 

Alloimmune Issues - The Role of DQ Alpha and Beta 

Information based on Dr. Beer's website and former discussion boards 

Disclaimer. This document to be used as a general guide only, not to be taken as medical advice. 

Contents: 

I. Introduction 

II. DQ alpha explanations 

III. The DQ alpha 4.1,4.1 issue 

IV. The DQ beta 201 issue 

V. DQ alpha matching problems 

VI. More examples of DQ alpha matches 

VII. When donor LIT is needed 

VIII. What DQ alpha numbers should a couple look for in a gestational carrier? 

I. Introduction 

When a pregnancy is conceived, it must be immunologically protected so the body does attack it as foreign tissue. This protection is achieved by the production of blocking antibodies. When there is too close of a DNA match between the father (similar HLA DQ alpha numbers) the mother's and baby's tissue resemble each other too closely, the immune system no longer sees the baby as "baby", not enough produce blocking antibodies are produced. The result: the pregnancy is left immunologically unguarded Natural Killer (NK) cells "attack" the pregnancy as if it were "altered self" like cancer tissue. Natural killer cells release TNFa cytokines, theatening the pregnancy. 

Treatments to prevent these events from occurring: 

1. LIT can boost the blocking antibodies allowing the baby to be recognized and immunologically protected again. 

2. IVIG can reduce the Natural Killer (NK) cell numbers and cytotoxicity. 

3. Humira and Enbrel can inactivate the TNFa released by the NK cells at the final level. 

Tests to identify whether these immune problem exist: 

1. DQ Alpha Female and Male testing (CPT 86816) $151 (11 days to run) (to see if there is a DQ alpha match within the couple) 

2. The Leukocyte Antibody Detection assay (LAD test or "Crossmatch") can determine if the blocking antibodies are at sufficient levels. 

(CPT 86805, 86021 x4. Cost $296) 

3. The NK assay will determine is the Natural Killer cells have become too aggressive. 

http://repro-med.net/tests/nkassay.php 

4. TH1 TH2 cytokine assay can determine if there was a pregnancy induced immune flare. 

http://repro-med.net/tests/th1th2.php 

II. DQ alpha explanations 

Taken from Dr Beer's website document 

http://repro-med.net/guides/consume.php 

There are two different tests for the DQ, the Alpha and the Beta test. Most patients are only tested for the Alpha. The mother-to-be and the father-to-be get back two numbers (1.1, 1.2, 1.3, 1.4, 2.1, 3.1 or 4.1, 4.2/4.3) one each from each of their respective parents (the baby-to-be's grandparents). Although there are breakdowns of the 2's, 3's and 4's, many people find that only the 1's are significant, so they break those down to one more decimal. If both the mother-to-be's and the father-to-be's DQ Alpha come back with a 4 DQ Alpha or the father-to-be's DQ Alpha comes back with a 2, a DQ Beta test is run. (Note: the 1.2 translates to 102, so any 2's could be 201's). 

89% of the people who test APA positive either have DQ alpha 4.1 or closely matched DQ alphas between partners. DQ Alpha compatibility is seen between mother and pregnancies that failed (through IVF failure or recurrent pregnancy loss). DQ incompatibility between mother and baby was far more common in women successfully delivering babies. 

Also, anytime you have two of the same numbers (in the same person or in a couple), that reduces the numbers of different possible embryo combinations. This can also cause an immune problem. The worst numbers are the 4's, such that you will have one liveborn baby with two 4's, and often times no others without immune treatment. The next [worst] group of numbers are the 1.1's and 1.2's. Any number is bad if the mother continues to gestate embryos that carry the same numbers that she has. Secondary aborting women are hardest to get the blocking antibody back, but it is possible it just takes a little longer. 

III. The DQ alpha 4.1,4.1 issue 

Answers based on Dr. Beer's responses from his former discussion boards and website 

Why is Sharing DQ 4.1 the worst Category 1 problem? 

Sharing DQ 4.1 the worst Category 1 problem because 4.1 protein most resembles " cancer" to the immune system, aggravating Natural Killer cells to attack the pregnancy as if it were foreign tissue. When there is a DQ alpha 4.1 match, women have the greatest difficulties in pregnancy with immune flares, miscarriages, subchorionic hemorrhages, abruption of the placenta, placental immune changes, early deliveries, and IUGR. 

DQ 4.1,4.1: If the mother-to-be and father-to-be share a DQ 4.1 number, they often produce a DQ 4.1,4.1 baby. Unfortunately, this first 4.1,4.1 baby born into the family activates the mother's killer cells and lowers her blocking antibodies. This process often prevents her from having a second child without immune treatment. Often couples with one live birth then subsequent repeat miscarriages find their first live born is indeed 4.1,4.1 baby or find a close DQ alpha match between husband and wife. Surviving DQ alpha 4.1,4.1 babies are at higher risk of developing autoimmune problems later in life due to their own bodies fighting their own tissue. However, it should be noted, there are many, many happy healthy DQ alpha 4.1,4.1 children out there today. 4.1,4.1 is not a dooming sentence. Treatments exist for these problems. 

IV. The DQ beta 201 issue 

DQ beta 201: If the father-to-be has a 2 in his DQ Alpha number, 2% of the time a DQ Beta will show that he also has a DQ 201. If a man is DQ alpha 201 and DQ beta 201, these sperm will produce only a placenta when they fertilize the egg. There will be an empty sac or "blighted ovum" and no baby. 

Men can only have one set of DQ beta 201. The worst it can do is affect 50% of the sperm. (If they had two DQ beta 201 numbers they would be a blighted ovums themselves). When the DQ beta 201 comes from the mother, the child lives, when the DQ beta 201 comes from the father, the baby is a blighted ovum. Please know that this blighted ovum problem will account for no more than 50% of the pregnancy losses of a mother as only half the man's sperm are affected. The treatment for this problem is to put back more embryos to see if the couple can produce an embryo that is not DQ beta 201. 

V. DQ matching problems 

DQ alpha numbers run in families. Each person has two DQ alpha numbers, one from mother and one from the father . Examples are as follows. 

Mother DQ alpha 3.1, 1.1 

Father DQ alpha 4.1, 1.1 

Possible combinations of children will be : 

25% DQ Alpha 3.1, 4.1 

25% DQ Alpha 4.1,1.1 

25% DQ Alpha 3.1,1.1 

25% DQ Alpha 1.1,1.1 

Each child will share one DQ Alpha number from each parent. DQ alpha matches can exist regardless of ethnic or racial background. 

Examples: 

Case 1) DH 1.1, 1.1 and DW 1.1, 1.1. Bad combination, not only is the male homozygous for DQ, but then every unlucky embryo will have placenta DQ proteins that are identical to the mother's AND the baby itself will be a 1.1, 1.1. The mother won't make blocking antibodies and her immune system will interpret the baby as a cancer and reject it. 

Case 2) DH 2.1, 2.1 and DW 3.1, 4.1. Bad again, the male is homozygous ( two of the same numbers), the placenta will have 2.1, 2.1 on the surface and the mother won't make blocking antibodies. However, the baby itself will be either 2.1, 3.1 or 2.1, 4.1 (gets one number from the mother and one from the father) so the baby itself will be different from the mother (who is 3.1, 4.1), good news. Bad if father tests DQ beta 201 

Case 3) DH 1.1, 4.1 and DW 1.2, 4.1. The father is not homozygous, that's good, but he shares a 4.1 with the mother. The placenta will have 1.1, 4.1 on the surface. But that 4.1 shared with the mother can lead to trouble. The baby itself will be either a 1.1, 1.2, a 1.1, 4.1, a 1.2, 4.1, or a 4.1, 4.1. So there is a 3.1 out of 4.1 chance the embryo will share a 4.1 with the mother, which can cause problems. The 4.1, 4.1 embryo is especially troublesome and can cause severe immunological problems in the mother during pregnancy ( as explained above). 

VI. More examples of DQ alpha matches explained in detail 

Example #1 

Mother 3.1, 4.1 Father 2.1, 4.1 

Children 

2.1, 3.1 This embryo contains a 201. If the DQ beta number in the baby is also 201 (the father needs to be tested) then these embryos will be blighted ovums. Multiples are strived for in this instance as only half the man's sperm can be DQ beta 201, half the embryos will still be normal. 

2.1, 4.1 This pregnancy contains a DQ alpha 4.1 which resembles "cancer" to the immune system. This 4.1 number is most likely to activate the mother's Natural Killer cells. This pregnancy also contains a DQ alpha 201 increases the risk of DQ beta 201 and blighted ovums. 

3.1, 4.1 This pregnancy is an identical match to the mother. This identaical match has the baby appear too much like the mother's tissue "altered self:" or "cancer:" High risk of NK cell attack if not treated . 

4.1, 4.1 The 4.1, 4.1 embryo is especially troublesome because it most resembles cancer to the immune system. The 4.1, 4.1 baby is most likely to cause severe immunological problems in the mother during and after pregnancy, The mother may experience worsened autoimmune problems after the baby is born. Subsequent 4.1,4.1 baby pregnancies are miscarried unless immune treatment is given. Also, in this example, the embryo has no different DQ alpha numbers to the mother so could fail to create appropriate blocking antibodies making already bad situation even worse. . 4.1,4.1 is the worst match this couple could have. LIT + IVIG maybe Enbrel or Humira may be needed to sustain this pregnancy 

Example #2 

Mother: 1.2, 4.1 

Father: 1.1, 3.1 

1.1, 4.1 This is essentially an identical match with the mother (breakdowns of the 1 numbers are essentially the same) so this pregnancy will have difficulty recognizing the baby as " baby" so may have difficulty producing enough blocking antibodies. The 4.1 number also resembles cancer so also will aggravate NK cells. This pregnancy will likely need both LIT and IVIG. 

1.1, 1.2 As stated above, breakdowns of the 1 number are esssentially the same number. This pregnancy has all numbers resembling the mother's so may not produce enough blocking antibodies in pregnancy. LIT may be needed. 

1.2, 3.1 This is the best match for this couple. There is no 4.1 number and the 3.1 number is different from the mother, helping to boost blocking antibodies. 

3.1, 4.1 The 4.1 resembles cancer so will also aggravate the NK cells. Good news is there is a 3.1 number that is different to the mother's, so blocking antibodies have a better chance of forming if a baby with this number is conceived . 

Example match #3 

Mother 1.2, 4.1 

Father 1.2, 1.2 

Children 

50% 1.2, 1.2 This baby does not have any differing numbers to the mother. The mother will have difficulty recognizing the baby as " baby" and not enough blocking antibodies may be produced. 

50% 1.2, 4.1 This baby has completely identical DQ alpha numbers to the mother. As a result, the pregnancy may be attacked as "altered self" or " cancer" because it resembles the mother's tissue type too much. In addition, there is a 4.1 match that will aggrevate NK cells as well. 

VII. When donor LIT is needed: 

Occasionally the father's DQ alpha numbers resemble the mother's too closely and paternal LIT alone is not enough to stimulate the full blocking antibody response. 

There are essentially three situations where donor LIT is needed: 

1) When there is a complete DQ alpha match between the couple; 

2) When this is some difference between the match, but the husband has all the numbers as the wife (break downs of 1's 2's etc often count as the same number); 

3) And the 15% of the cases where LIT fails to boost blocking antibodies for no particular reason. Then the donor LIT is recommended, once again. 

In these cases, donor LIT is used. An unrelated donor with DQ alpha numbers different to the mother is used. 

VIII. What DQ alpha numbers should a couple look for in a gestational carrier? 

When looking for a good gestational carrier to carry a pregnancy, it is best to look for a carrier with numbers that are different from both the mother's and the father's. For example: If the Mother is 1.1, 1.2 and the father is 3.0, 4.2/4.3 we want a gestational carrier to have 2.1 or 1.3 or both.