Immunology FAQ/Research

Good link-list from the Yahoo e-group on reproductive immunology– go here after reading the below information.  http://health.groups.yahoo.com/group/immunologysupport/links

Shamelessly copied from the FAQ on the Immune board at Fertility Friend.  Compiled mainly by Annukka, patient of Dr. Nathalie Ledee in France and currently 39 weeks 🙂  .  Info on IVF specifically for immune patients at the bottom.

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, thyroid problems, celiac disease, eczemas and 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

CLINICS:
US
– Braverman: http://www.preventmiscarriage.com/
– Kwak-Kim: http://www.rosalindfranklin.edu/faculty/KwakKim_Joanne.aspx
-Alan E Beer Center: https://www.repro-med.net/

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

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

Australia

Dr. Matthias– “Dexamethasone 1.5mg (or 25mg pred). He said which ever I wanted to take [2 weeks before transfer].  Lovenox is 40mg once per day [2 weeks before transfer].  Neuopogen not sure, all I know it will cost me $2,000 AUD!”  So Sounds like this doctor in Australia is immune-friendly.
– Gavin Sacks: http://www.ivf.com.au/specialists/specialists.aspx?specialistid=22

*** Note: current patients of Dr. Sacks’ do not recommend him as an immune-friendly doctor; they say he is very resistant to anything outside of clexane/lovenox and occasionally he will prescribe prednisone.  No IVIg or IL or neupogen.

A comment re Dr. Sacks in Australia:  Not Immune Friendly!

“The comment I would also like to make to you is that I noticed you have listed Dr Sacks as a RI here in Australia. I thought I should share with you my experience with him. After 6 miscarriages I went to an IVF clinic not to do IVF initially, but to investigate why was I having those m/c. I was sent to have the NK cell test and because my Dr was away when I got the result ( and I had a BFP on that same day ), I contacted Dr Sacks as he was from the same clinic as my FS that ordered the tests. He was the one who prescribed me the prednisolone. Unfortunately, I lost that pregnancy as well. Parallel to that I made an appointment to see the recurrent miscarriage clinic in the Randwick Women’s hospital and try to find out a bit more about my problem. When I got there to my appt, I was very surprised to find out Dr Sacks was in charge of the clinic. So when I told him who I was ( the patient who contacted him by e mail etc… ), he said he couldn’t help me and I should go back to my IVF clinic and schedule a PGD cycle. He affirmed that the only way I would carry to term was if I had a PGD cycle. I said to him that this made me think that he thought all my losses were due to chromosomal issues and he said yes. I found it unbelievable the fact that a Dr who claims to be an RI would ignore all the immune issues that were playing on my system, and explain 6 losses in a row as purely bad luck !!!! I was pretty upset to hear that I wouldn’t carry to term if I didn’t have a PGD cycle, because I knew I was falling pregnant so frequently, and I had immune issues that were playing up and making me loose the pregnancies. So what would be the point on purely getting me pregnant again if I would still miscarry ???

Besides that, I know a lot of women who have been to Dr Sacks and the only treatment he offers is prednisolone + clexane and ba. That’s it. He doesn’t believe in IL or Ivig. After a lot of search, I finally found the ONLY Dr in Sydney who does IL and Ivig for recurrent miscarriage, and he used to be a disciple from Dr Beer. I am not entirely happy with him, but I realize that is the best I can get on this country, where we face so many limitations in terms of tests and treatments for RI.”
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. 127-133Tissue 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/

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
  • IVIg insurance coverage info:
  • I just want to share this info as it may help one of you in the future. I
    > am a Dr. B patient. He ordered IVIG for me. I called my insurnce company
    > three weeks ago and they said it was covered 100 percent.
    > Shocked but OK.. Anyway ..
    >
    > Dr. B’s nurse gave me an infusion company to contact. They contacted my
    > insurance company and I was told by them this past Tuesday my insurance
    > denied the claim.
    > So I went on to the black market to find IVIG.
    > I had a woman who is a member on here tell me she would sell me IVIG and
    > then backed out due to fear. She literaly interviewed me for 30 minutes
    > asking what my issues were etc.
    >
    > Anyway — moving on .. There are many things I would like to say about
    > that but I wont. But I would love to say no one should have to go through
    > that. We are already stressed. But she did me a favor..
    >
    > My stress level was through the roof. I had neupogen and was thinking of
    > mixing one treatment of ivig with neupogen.
    >
    > Anyway I decided since the flake flaked out on selling the ivig. I will
    > pay for the ivig cost. Since I am paying for it. I want to shop around for
    > a price.
    > I asked Dr. B office for a list of other home infusion services.
    > I started calling.
    > I called a lovely lady who said call the insurance company and ask WHY
    > I said OK.. I called them they said it wasnt denied. The order was placed
    > through a pharmacy when it should be through speciality.
    > I AM 100 percent covered. I pay up front and I wil be reimbursed 100
    > percent..
    > I guess I should thank the flake.
    >
    > So Ladies please please follow up on all denials.
  • 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.pdfHere’s a good study which shows high success rates with G-CSF after failed implantation:
    http://humrep.oxfordjournals.org/content/25/8/2151.longHere is about importance of G-CSF in uterus:
    http://www.ncbi.nlm.nih.gov/pubmed/20974989Here 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/21324451In 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/15890733Here 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 placentaWhen 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=12Braverman: 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
  • 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.
  • I have been told that actually baby aspirin is the only thing that will prevent cord clots as the lovenox doesn’t cross the placenta.  Need to make more inquiries on that.
  • 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/18275519Steroids 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.fullTo 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 controversiesGreat 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.
OTC REMEDIES:
For lowering inflammation. Obviously these would make things worst for someone with not enough inflammation.

Unsure about these herbs and foods:

Lupron increases NK activity:

http://www.ncbi.nlm.nih.gov/pubmed/10394096
Annukka’s RI  Dr Ledee recommended antagonist protocol only in cases of inflammation or high NKa.
Another more recent one by Kwak-Kim:
http://www.ncbi.nlm.nih.gov/pubmed/20367626

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

 SOME INTERESTING GRAPHS
The earlier the stage of endo, the more inflammation (toxins) in peritoneal fluid (pelvis).

Higher estrogen levels are associated with lower NK cell activity:
Source: http://www.ivf.com/endoimm.htmlOTHER INTERESTING RESEARCH ON INFLAMMATION/IMMUNE SYSTEM:There is a link to autism from uterine inflammation during pregnancy:
http://www.nytimes.com/2012/08/26/opinion/sunday/immune-disorders-and-autism.html?_r=1&pagewanted=all
If 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 AvoidAn 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 conditionRead 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.fulldexamethasone 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.”http://humrep.oxfordjournals.org/content/16/9/1861.full

By JMcHenry:
Alloimmune Issues – The Role of DQ Alpha and Beta
Information based on Dr. Beer’s website and former discussion boardsDisclaimer. This document to be used as a general guide only, not to be taken as medical advice.
Contents:I. IntroductionII. DQ alpha explanationsIII. The DQ alpha 4.1,4.1 issueIV. The DQ beta 201 issueV. DQ alpha matching problemsVI. More examples of DQ alpha matchesVII. 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.

* * * * * *
Collaborating doctorsIt can be a daunting to find a doctor open to immune issues. A good place to start looking is this list of doctors who have collaborated with the Beer Center. If you know of any changes, please pm me.https://www.dropbox.com/s/bd83ctf2ye5av71/Collaborating%20doctor%20list%20June%2018%202012.docx
* * * * * *
Fish OilCheck the IFOS website http://www.ifosprogram.com/consumer-reports.aspxThis link lists all of the fish oil products that pass the international refined standards, meaning that they have less than the acceptable amount of metals and contaminates and the right ratio of EPA to DHA in the omega 3s. It is a very good link if you are unsure of fish oil.
* * * *
“Make sure your dh has a full work-up by a Reproductive Pathologist. My dh was having health issues along with bacteria in his ejaculate & prostate that were causing severe morphology issues. The only Repro Pathologist I know is Dr. Attila Toth in NY. You can email him at drtoth@fertilitysolution.com about your dh’s SA report directly & he will respond. Go to www.fertilitysolution.com for more info. He is an excellent doctor & resolved many pathology related issues that we were having. Hope this helps you…”
 * * * * *
IVF PROTOCOLS
Lupron may increase NK cell activity.
http://www.ncbi.nlm.nih.gov/pubmed/20367626
http://www.ncbi.nlm.nih.gov/pubmed/8692508
http://www.ncbi.nlm.nih.gov/pubmed/9170480
It could be because Lupron decreases estrogen levels and estrogen suppresses NKa.
Although this study doubts it:
Results indicate that the standard GnRH-a treatment for endometriosis and uterine leiomyoma might increase NK cell activity. The etiology of the increase of NK activity with GnRH-a treatment is likely related to factors other than E2 concentration.
http://www.ncbi.nlm.nih.gov/pubmed/10394096
Birth control pills
It is good to be on bcp’s prior to cycling as the estrogen and progesterone in the bcp’s reduce NKa and inflammation.  Bcp’s also help avoid lead follicles so that at the beginning of the cycle all the follicles start at same sizes and there will be more even growth of them and hence more of the eggs will be mature at trigger.  However, bcp’s do suppress quite a bit, so if there is DOR, and no overlap with Lupron (such as in an A/ACP protocol), then the bcp’s might oversuppress and stunt the response too much.
http://haveababy.com/fertility-information/ivf-authority/birth-control-pill-ivf-outcome/
Estrogen
It is good to be on bcp’s prior to cycling as the estrogen and progesterone in the bcp’s reduce NKa and inflammation. For this reason it is useful to also supplement with high doses of estrogen after ER.

A significant inverse relationship was observed between natural killer activity and serum estradiol levels, which resulted in moderate and severe disease (r = -0.4, p = 0.009) but not in stages I and II.
http://www.ncbi.nlm.nih.gov/pubmed/7502688Progesterone
It is important to be on very high doses of progesterone after ER, as progesterone reduces inflammation and NKa.
See the links under “Progesterone” on the TREATMENTS post.SIRM protocols
Details of SIRM protocols are listed here:
http://forums.haveababy.com/lofiversion/index.php?t36938.htmlDifferent protocols
A good link to read up on different protocols:
http://www.advancedfertility.com/ivfstim.htmGreat chat with Dr. Alan Beer (now deceased but one of the pioneers of reproductive immunology)– transcript covers numerous issues but is somewhat out of date given current research …http://repro-med.net/info/qabeer_08-04.pdf
And a great repost from the Yahoo immunological infertility group from Beer Center doctors discussing why placental clotting means early delivery for immune babies is so important:Hi Dee,
>
> First of all congratulations for making it to 26 weeks. This is a
> milestone in itself.
>
> You ask about the reasons for 38 week induction in immune patients.
> Good question. I am glad you brought this up because it is a very
> importnat topic to discuss withn the group. Basically Dr Beer has
> found that the placentas of immune patients (on average) age more
> quickly and are more prone to placental clotting than non immune
> patients. This aging and clotting can increase of placenta abruption,
> premature labor, premature abruption of the membranes etc etc.. and
> the list goes on. Because the baby is basically fully developed at 38
> weeks, Dr Beer feels the baby is often healthier “outside” than “in”
> so to speak, this is all based on Dr Beer’s statistics. Better safe
> than sorry is the thinking.
>
> Just for reference, I had one of my Beer babies induced at 38 weeks
> for all the reasons described above.. Even though my body was not
> ready to go into labor this early (my cervix was”unripe”) and my baby
> seemed healthy, I had suffered many NK flares in pregnancy so Dr Beer
> felt my placenta had probably suffered.. He was right.. I had my
> healthy baby’s placenta saved and sent to Dr Beer’s PSL lab. PSL
> found, even though my baby had been induced early and was basically
> healthy, the were already signs of immune attack in the placental
> tissue. The placenta was very small for its age, with areas of
> infarction ( tissue death) plus there had been some oxygen stress
> during delivery. I guess my point is: I was very glad I induced at 38
> weeks! I feel the placenta had really reached its maximum lifespan
> and was already deteriorating. Ofcourse this is just one case. But,
> nonetheless, my baby’s 38 week placental report was a real wake up
> call for me.
>
> Also ( contining on with this ) I have known Beer babies whose
> placentas abrupted and were brain damaged because they were born too
> late. I have known babies be born unexpectedly stillborn because
> their pregnancies were born too late. And these tragedies are totally
> precentable with early induction. Remember at 38 weeks babier are
> fully developed! Why wait?
>
> Also know that Dr Beer has experience with high risk immune
> pregnancies that few OBGYNs have. OBGYNs have not seen what Dr Beer
> has seen.
>
> Below I have added some Dr Beer quotes about this and some immune
> studies. Maybe you could print some of these out for your doctor.
>
> Best of luck and let us know how everything goes. Ofcourse every case
> is different. But I am glad you are doing your research, you really
> cannot be too careful, there is such precious cargo at stake!
>
> Jane
>
> ********
> Dr Beer posts:
>
> *********
> I have read other posts that indicate that 60% of your patients
> deliver via c-section due to fetal distress.
>
> THIS IS TRUE UNFORTUNATELY.
>
> Do you know what causes the fetal distress and if NK cells are
> supressed and all the numbers are looking normal (for ANA, APA, anti-
> DNA histones) is it more likely that the patient could have a normal
> delivery?
>
> THERE IS PERSISTING PATHOLOGY IN ALMOST ALL OF THE PLACENTAS OF THESE
> BABIES WHICH GIVES RISE TO THE STRESS DURING LABOR.
>
> Also I know that patients on Lovenox have to follow specific
> guidelines for stopping Lovenox before an epidural or spinal is
> administered.
>
> THIS IS TRUE.
>
> If an emergency c-section is necessary is it safe to just use a
> general anaesthetic or are there other safe options?
>
> THE LOVENOX NEW GUIDELINES ARE TO STOP IT 6 HOURS BEFORE THE C
> SECTION. I STILL RECOMMEND 24 HOURS. IF AN EMERGENCY C SECTION IS
> NEEDED YOU WILL BE PUT TO SLEEP.
>
> In all honesty I would love to avoid an epidural or spinal
> completely. I would love to have a natural childbirth, but I am
> uncertain how likely this will be if it is more common to need a c-
> section due to fetal stress. Also how is the fetal stress detected?
>
> BY MONITORING THE FETAL HEART AND THE UTERINE CONTRACTIONS DURING THE
> ENTIRETY OF LABOR.
>
> Is it detected by performing the non-stress test only? When in my
> pregnancy should I begin the non-stress tests and how often should
> they be done?
>
> TWICE WEEKLY DURING THE LAST MONTH.
>
> I suspect my local OB may not wish to do non-stress testing
> frequently as he has already said that monthly ultrasounds are
> unnecessary.
>
> HE DOES NOT UNDERSTAND THEN. HAVE HIM TALK TO ME.
>
> He feels he can monitor any problems that could be detected with an
> ultrasound by noting that my abdomen is properly growing at my
> regular visits.
>
> THIS IS NOT ENOUGH IN THE IMMUNE PATIENTS. TRUST ME.
>
> Is there a way to get an order from your office for the ultrasounds
> (if they are necessary) and the non-stress tests so that I can just
> go to a clinic or hospital and get them done?
>
> OF COURSE WE CAN DO THIS FOR YOU.
>
> I should only need 3 more ultrasounds at most.
> Thank you so much! I know that because my history is so full of loss,
> I have been slightly paranoid thru this pregnancy.
>
> ALL WOMEN ARE, THEY ARE AFRAID TO BOND WITH THEIR BEAUTIFUL CHILD
> BECAUSE OF THE FEAR OF ANOTHER LOSS.
>
> I have made it to my 27th week now and I am really looking forward to
> holding my baby and knowing he is okay.
>
> THIS WILL HAPPEN AND YOU WILL REJOICE IN A WAY NOT KNOW BEFORE
>
> ********
> I’m positive for ANA,APA and have been on Apsirin,Heparin,and IVIG
> for first 2 months. But have reduced my heparin. MY OBGYN said if we
> can get rid of my injectables before my due date, then I can deliver
> normally instead of C.Section.
>
> 40% DO AND 60% REQUIRE A C SECTION FOR FETAL DISTRESS DURING LABOR.
>
> Is this really possible Dr. Beer?
>
> YES OF COURSE BUT DO NOT PUSH IT TOO FAR.
>
> Or will it pose a risk, base on your experience. I personally prefer
> normal delivery but if I’m going to end up having a c-section in the
> end due to fetal distress then i’d rather go straight C.S.
>
> TALK TO YOUR DOCTOR ABOUT THE ABOVE STATS IN IMMUNE PATIENTS OF MINE.
>
> **********
>
> >I am in my 32nd week
> >of pregnancy and starting to
> >search out my birthing options.
> > I know that because
> >of my immune issues (Cat
> >1, 3, 5 +MTHFR hetero)
> >I am a special case
> >that needs special care.
> >I know that non-stress testing
> >during the entire labor is
> >necessary and I am prepared
> >to do this.
> ALL OF THIS IS TRUE. YOU WILL NEED TO BE MONITORED ALL THROUGH YOUR
> LABOR AND DELIVERY.
> I
> >have always dreamed of having
> >a natural childbirth. I
> >know that you have previously
> >said this is possible, but
> >I would like to mention
> >some of the things I
> >have considered that I would
> >prefer to do during my
> >labor and delivery.
> JUST REMEMBER 60% OF WOMEN WITH YOUR PROBLEM HAVE EMERGENCY C
> SECTIONS FOR FETAL DISTRESS. PREPARE YOURSELF FOR THIS.
> >
> >I would like to be able
> >to eat small snacks if
> >I am hungry when I
> >am in labor to help
> >keep my energy up.
> NO, I WOULD NOT ALLOW THIS. YOU MAY NEED A C SECTION AND TO DO THIS
> WITH A FULL STOMACH PUTS YOU AT RISK FOR ASPIRATION.
> >I feel this is especially
> >important since I am hypoglycemic.
> > I would like to
> >walk around the hospital to
> >let my labor progress, which
> >I know the hospital I
> >am going to has a
> >monitor that hangs around the
> >neck to check baby’s heart
> >and mom’s
> NO YOU NEED TO BE MONITORED IN A HIGH RISK ENVIRONMENT. I KNOW YOU
> WANT TO VIEW YOUR PREGNANCY AND DELIVERY AS NATURAL BUT YOU HAVE TO
> TRUST MY RECOMMENDATIONS.
>
> contractions. I
> >don’t want to be examined
> >vaginally often.
> BECCA, WE NEED TO TALK. YOU ARE TALING DANGEROUSLY AND I WILL NOT
> RESPOND FURTHER.
> I don’t
> >really want an IV, but
> >definitly want an IV –
> >heplock incase of emergency.
>
> I WOULD ASK YOU TO FIND ANOTHER DOCTOR IF YOU REQUESTED THIS OF ME.
> SORRY. I WOULD NOT OBLIGE YOU ON ANY OF THESE REQUESTS FOR SAFETY
> REASONS. SORRY. BABIES CAN DIE OR BE DAMAGED IN LABOR AND WE NEED TO
> KNOW IF YOURS WILL BE AT RISK.
> >I really want to deliver
> >naturally without medication, but I
> >am aware that if baby
> >is in distress a c-section
> >may be necessary.
> TRUE AND PREPARE FOR THIS.>
> >In your experience with immune patients,
> >are babies suppose to be
> >delivered at 1st sign of
> >distress?
> OF COURSE, WHY DO YOU ASK. DO YOU WANT YOUR BABY TO SUFFER UN
> NECESSARILY.
> What are the
> >signs of distress?
> YOUR DOCTORS AND NURSES KNOW ALL OF THIS.
> I
> >know that some doctors will
> >rupture the amniotic membranes or
> >administer pitocin at the 1st
> >sign of distress to move
> >the labor along faster.
>
> WE FOLLOW THE RIGHT PROTOCOLS.
>
> >Are immune babies in such
> >danger when in distress that
> >c-section is necessary pronto?
>
> YES, YES, YES AND I HAVE LEARNED THAT IF THIS IS NOT DONE BABIES ARE
> BORN WITH DAMAGED BRAINS.
>
> >I am just trying to
> >figure out how my local
> >OB and I will know
> >when the baby NEEDS to
> >come out if things happen
> >this way.
>
> YOU SHOULD BE MANAGED BY A HIGH RISK DOCTOR.
> YOUR E MAIL HAS GIVEN ME CHILLS AND GOOSE BUMPS. IT FRIGHTENS ME
>
> **************
>
> We are still
> >having the weekly NST’s.
> >We had one this morning
> >and he was reactive.
> I AM HAPPY.
> >We read in the archives
> >that you advised women who
> >have taken enbrel to start
> >twice weekly NST’s if they
> >go past 38 weeks.
> THIS IS TRUE. THE NEW DATA ON 183 WOMEN HAVE SHOWN THAT THEY DELIVER
> NATURALLY AT 38.4 WEEKS AND THAT THE BABIES ARE NORMALLY GROWN OR
> HEAVIER THAN EVEN CONTROLS. THE DATA SHOWS THAT 60% NEED C SECTIONS
> FOR FETAL DISTRESS AND I AM COMING TO AN OPINION THAT ALL OF YOU WITH
> ENBREL ARE HIGH RISK FOR FETAL DISTRESS AND SHOULD THINK ABOUT A
> CONTROLLED DELIVERY AFTER 37 WEEKS. MOST DOCTORS WILL ARGUE WITH YOU,
> BUT I CANNOT TOLERATE LOSSES, DEAD BABIES OR DAMAGED BABIES FROM
> DISTRESS WHEN I KNOW THE SET UP IS THERE TO DO IT.
> >Is this still the accepted
> >protocol?
> >SEE ABOVE.
> >Our perinatologist has us scheduled for
> >one last biophysical profile at
> >34 weeks (next week).
> MY PROTOCOL IS TWICE WEEKLY IN WOMEN WITH HIGH RISK PROBLEMS LIKE
> YOURS.
> >What do you think about
> >this? Should we continue
> >the biophysical profiles past this
> >point?
> OF COURSE, OF COURSE. I AM REALLY SURPRISED THAT YOU ASKED. I WORRY
> MORE NOW THAN I HAVE UP TO THIS POINT.
> >
> >We see the ob next week.
> > At that time he
> >will do a group b
> >strep culture and internal exam.
> > We will also be
> >discussing birth options (i.e., inducing,
> >c-section, continue to monitor and
> >wait and see how things
> >progress).
> SEE HOW THINGS PROGRESS AND ALWAYS LOOK FOR TROUBLE.
> Any suggestions for
> >other things we should be
> >discussing with him. As
> >you know, we are the
> >first Beer pregnancy that he
> >has ever co-managed.
> HE HAS DONE WELL BECAUSE HE HAS LISTENED TO YOU AND ALSO TO ME.
> >
> >We just want to make sure
> >that all of our doctors
> >who have taken such great
> >care of us throughout this
> >pregnancy are on the same
> >page for the final stretch.
> ***********
>
> Studies
> ***********
> 4.
>
> American Journal Of Reproductive Immunology
> Volume 49 Issue 5 Page 308 – May 2003
>
> Pro-inflammatory Maternal Cytokine Profile in Preterm Delivery
>
> M. Makhseed, R. Raghupathy, S. El-Shazly, F. Azizieh, J. A. Al-Harm,
> M. M. K. Al-Azemi
>
> PROBLEM: The objective of this study was to determine the levels of
> cytokines produced by maternal peripheral blood mononuclear cells
> (PBMC) upon stimulation with a mitogen, with autologous placental
> cells and with a trophoblast antigen extract.
>
> METHOD OF STUDY: Peripheral blood mononuclear cells from 54 women
> with a history of successful pregnancy and 30 women undergoing
> preterm delivery (PTD) were stimulated with the mitogen and antigens,
> and the cytokine levels in mitogen-stimulated culture supernatants
> assessed.
>
> RESULTS: Significantly higher levels of the type 1 cytokines,
> interferon (IFN)- and interleukin (IL)-2, were produced by the PTD
> group than by the normal pregnancy group, which on the contrary
> showed significantly greater production of the type 2 cytokines, IL-
> 4, IL-5 and IL-10. A comparison of the ratios of type 2 to type 1
> cytokines is indicative of a type 1 cytokine bias in PTD.
>
> CONCLUSIONS: These data are suggestive of a maternal type 1 cytokine
> bias in PTD.
>
> **********
>
> 6)
>
>
>
> Transactions of the Twenty-Second Annual Meeting of the Society for
> Maternal-Fetal Medicine
> Role of tumor necrosis factor- in the premature rupture of membranes
> and preterm labor pathways
> Sephen J. Fortunato MD, Ramkumar Menon MS and Salvatore J. Lombardi
> MD
>
> From the Perinatal Research Center of the Women’s Health Research and
> Education Foundation.
>
> Available online 19 December 2002. Abstract
> Objective: To further delineate the differences between the preterm
> labor and premature rupture of the membrane pathways, we investigated
> the role of the inflammatory cytokines as activators of matrix
> metalloproteinases 2 and 9 in human fetal membranes.
>
> Study Design: Normal amniochorionic membrane that is maintained in an
> organ explant system was stimulated with interleukin-1, tumor
> necrosis factor-, or interleukin-6. The expression and activity of
> matrix metalloproteinases 2 and 9 in amniochorion was documented with
> reverse transcriptase-polymerase chain reaction and specific
> substrate activity assays. The matrix metalloproteinase inhibitor,
> tissue inhibitor of metalloproteinase-1, concentration was measured
> by enzyme-linked immunosorbent assay.
>
> Results: Interleukin-1, tumor necrosis factor-, and interleukin-6
> induced the expression of matrix metalloproteinase-9 messenger RNA,
> whereas matrix metalloproteinase-2 expression was constitutive in
> control and cytokine-stimulated tissues. Matrix metalloproteinase-2
> activity did not change after cytokine stimulation. Active matrix
> metalloproteinase-9 was significantly higher in tumor necrosis factor-
> stimulated tissues, which conversely were not changed after
> interleukin-1 or interleukin-6 stimulation. Tissue inhibitor of
> metalloproteinase-1 levels were decreased after interleukin-1 and
> tumor necrosis factor stimulation but changed after interleukin-6
> stimulation.
>
> Conclusion: Only tumor necrosis factor- increases matrix
> metalloproteinase-9 activity in amniochorion. (Am J Obstet Gynecol
> 2002;187:1159-62.)
>
> *************
>
> 7)
>
> Am J Obstet Gynecol. 1992 Oct;167(4 Pt 1):920-5.
>> Tumor necrosis factor-alpha in midtrimester amniotic fluid is
> associated with impaired intrauterine fetal growth.
>
> Heyborne KD, Witkin SS, McGregor JA.
>
> Department of Obstetrics and Gynecology, University of Colorado
> Health Sciences Center, Denver 80262.
>
> OBJECTIVE: To investigate whether abnormal immune system activation
> is involved in the pathogenesis of some instances of impaired fetal
> growth, we compared tumor necrosis factor-alpha levels in
> midtrimester amniotic fluid samples obtained from appropriate-for-
> gestational-age and small-for-gestational-age pregnancies. STUDY
> DESIGN: In a case-control study with the sensitive and specific WEHI
> cell assay, bioactive tumor necrosis factor-alpha levels in amniotic
> fluid samples from 24 gestations resulting in small-for-gestational-
> age infants were compared with levels in 35 samples obtained from
> gestations resulting in the birth of a term, appropriate-for-
> gestational-age infant. The two groups were not significantly
> different with regard to indication for amniocentesis, maternal age,
> race, smoking history, parity, or other factors. RESULTS: Elevated
> amniotic fluid tumor necrosis factor-alpha activity was associated
> with small-for-gestational-age birth, p = 0.028. With a threshold of
> 10 pg/ml, elevated amniotic fluid tumor necrosis factor-alpha had a
> sensitivity of 48% for the detection of small-for-gestational-age
> birth, with a specificity of 83%. CONCLUSION: Elevated tumor necrosis
> factor-alpha in midtrimester amniotic fluid is associated with
> impaired intrauterine fetal growth. Abnormal immune system
> activation, as manifested by increased amniotic fluid tumor necrosis
> factor-alpha activity, may mediate impaired fetal growth in some
> cases.
>
> PMID: 1415426 [PubMed – indexed for MEDLINE]
> **************

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13 responses

21 10 2012
7 01 2014
The Antihistamine Protocol | From 2 to 3 Kids

[…] A very detailed post on immunological research. Information on the protocol is about half way down under “CCRM’s anti-inflammatory/anti-allergy cocktail” […]

20 02 2014
Hannah

Thank you for the very informative page regarding Nk Cells and lowering imflammatory. However, i have made notes regarding everything that is on here, and some of it is contradictory… i.e Grapeseed Extract (you say avoid, then you say take it as it’s an active ingredient in Maxi Flavone), Soy (which is genistein), Estrogen (no less than 2 paragraphs apart you say that it is good, and then you say to avoid it! Estrogen is also soy…). Dong Quai was also avoid and then take….

Hinderance or help is the question regarding this page. I am left no more informed from your write up than when i started unforunately… Are yuo able to clarify these points??

20 02 2014
Georgette

Sorry, it’s frustrating isn’t it? I’m reporting what I’m told, but I’m not a doctor. I would ask Dr Braverman on his site’s forum. Sorry I’m not more helpful!

21 02 2014
Hannah

Ha…yes very frustrating. I think the main thing i’ve picked up from what you’ve written/shared, is that there is actually a difference between inflammatory and high Nk Cells and unfortuntely it has all been jumbled around on here… You were spot on the mark when you wrote Bluberries are good for inflammatory but increase Nk cells… if there had been more of this type of explanations it would of made it easier for the reader to know what was best for them and what to avoid.

Apologies, not triyng to put down anything you’ve written because I am incredibly grateful to have found all this information…but perhaps if you ever get time, you could reorganise it in sections..

But again, thank you so much and for also getting back to me. 🙂

21 02 2014
Georgette

I will add it to my list 🙂 do not hold your breath though!

I will suggest joining FertilityFriend, though, because there is a group in the forums specifically for immune issues, and I have learned a LOT from those ladies (and copypasta’d a lot of it here.) Also there’s a yahoo egroup for immune infertility…. not everyone there is very scientific or very well read, so your mileage may vary, but there are some gems to be found.

21 02 2014
Georgette

One more thing. I don’t care what you read on the internet, it will NEVER be a substitute for advice from Dr. Kwak Kim or Dr Braverman. Problem is these fields are making progress on a daily basis. Since I have pretty much checked out of my fertility focus for now, this stuff here is terribly dated. I HIGHLY recommend you call Dr. B (tell him you are a friend of Georgette’s) and see what he advises.

21 02 2014
Hannah Clark

Wow! Thank you so much for all of this! Really really grateful! I’m based in the UK so do you think he’d take my call and help?

21 02 2014
Georgette

I know he would, he has helped other gals in Europe, and I believe he works with a reproductive immunology doc in Spain very closely… he will also work with your doctor if your doc is willing to be guided. It’s so frustrating how asinine all this territoriality becomes. I have heard about an RI in France, Dr. Ledee, as well…

21 02 2014
Georgette

GOOD LUCK 🙂

1 02 2015
Alice Good

Thank you Georgette for taking the time to research this, most informative

6 02 2015
Shona C

Hello – post re Dr Nathalie Ledee
What specific tests did you do with Dr Ledee? Thinking of going to see her.

18 04 2015
Abigail

Has anyone been to Dr Nick Lolatgis in Melbourne? He’s quite well known for NK cell tests etc & treatments.. though I’m still going through the journey trying all myself.. Hopeful but nervous of any risks.. curious more in the immunity side.. (I have a sesame (food) allergy for example as well). Otherwise would say Im mainly healthy & exercise moderately. Might try reducing gluten, dairy, sugar & coffee.. Are the anti-inflamatory notes the ones we’re meant to increase? I already take spirulina.. Many thanks for the posts & detail 🙂

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