Immune FAQ

[agate]

21   T
21.1   Tests
21.1.1   Which tests do I really need?
That’s a very difficult question and in the end you will have to make your own decision based on what your consultant says.  Dr Gorgy will allow you to ‘opt out’ of any tests you don’t want.   
•   Any lady with fertility problems will need their day 1-3 FSH, LH, prolactin and estrodiol (and ideally AMH) run and also their progesterone (about seven days before your period is due/seven days after ovulation). 
•   Any male partner will obviously need a semen analysis (there is no point trying to conceive if your partner turns out to have no live sperm).
•   Initial female fertility testing will usually include some anatomical tests e.g., HSG/lap&dye to check for tubal blockages, ultrasound scan to check for normal ovaries.  If your tubes are blocked, there is almost no chance of conceiving naturally (or with IUI) but a good chance of conceiving with IVF.  If the scan reveals swollen, distorted tubes (hydrosalpinx), your chances of conceiving naturally will be reduced as it is likely that your tubes may be too damaged to allow the egg to travel down to the uterus.  A large hydrosalpinx is also associated with reduced chances for IVF success due to inflammatory chemicals and toxic 'wash' from the hydro.  Some docs think that treating the hydro during your cycle with steroids and antibiotics may be enough, but others prefer to remove or clip the non-functioning tube.  This is a difficult decision, as its not impossible (but possibly unlikely) for a swollen tube to unblock itself given time.  Surgery to open tubes (recanulation) typically has a fairly low success rate. 

If your ovarian scan reveals more than about 12 follicles per side, that will indicate PCO which could mean that you might benefit from metformin and possibly drugs to stimulate ovulation (like clomid).  This is because egg production is a competitive process, so large numbers of follicles mean that it can take a very long time for one follicle to compete and dominate the others in order to successfully ovulate.  If your ovarian scan reveals an antral (mini) follicle count of less than 2 per side, that could be a sign of diminished ovarian reserve and might mean that you need to either hurry to have IVF before ovarian failure is complete or might need (eventually) to start thinking about donor egg treatment if you don't manage to get pregnant naturally.
•   A saline contrast ultrasound (SIS, aquascan) will identify any major uterine anomalies (e.g., large fibroids, septa, polyps etc  - having enough space in your uterus that isn't impinged by scar tissue or fibroids is necessary to allow an embryo to implant successfully and to grow - these anomalies can often be resected (cut away) if needed and will improve your chances.   Different docs disagree about how large a septum or fibroid or how numberous polyps need to be to cause a problem).    A saline contrast ultrasound can sometimes give an indication of whether your tubes are open or not.
•   A hysteroscopy & laproscopy will identify (and hopefully treat) any fibroids, septa, polyps, scarring, endometriosis, adhesions etc.  A hysteroscopy (and particularly a laproscopy) is considered to be more major surgery than an aqua scan or HSG, so it is usually reserved for cases where there are risk factors for tubal blockage, scarring or endometriosis (e.g., abdominal pain, hystory of PID infection, chlamydia, abnormal uterine ultrasounds, visible hydrosalpinges on ultrasound).
•   Most ladies will ask their GP for the level 1 tests (see level 1).  The most critical tests are probably the thyroid hormones (TSH and FT4, antithyroid antibodies and a thrombophilia (clotting) panel including antiphospholipid antibodies.   TSH levels outside the range of 0.4-2 together with low normal FT4 are associated with significantly lower chances of live birth e.g., with IVF.
•   Male and female karyotyping tests are expensive and rarely available on the NHS unless a couple have had 3+ miscarriages.  Karyotyping anomalies are rare so most couples who have them will find their results are completely normal.  However, for affected couples, it may mean that their chance of having a healthy baby is very low - or that it can be improved a lot by having IVF with PGD
•   All ladies seeking full immune treatment will have the NK cytotoxicity assay run  - or possibly a CD69 test or a NK biopsy (see NK assay)
•   Almost all immune docs will want to run the TH1:TH2 cytokine ratio test (see cytokines).
•   Most immune docs would recommend the tests for inherited thrombophilias (e.g., MTHFR) - see thrombophilias.
•   Dr Gorgy, Beer Centre and Dr Sher would usually recommend testing for DQa (unless using sperm donor – where the need for it is less obvious - see DQa).
•   Dr Gorgy and Beer Centre would usually recommend testing for LAD (although it is more difficult when using sperm donor) - see LAD.
•   Dr Gorgy is now recommending testing for infection in both partners - see Chlamydia, ureaplasma and mycoplasmas.
•   Some doctors would recommend testing for sperm DNA fragmentation.

21.2   Thrombophilias – MTHFR, PAI-1, Factor V Leiden, APLAs
21.2.1   What are they?
These are conditions which cause the blood to be ‘sticky’ and therefore have more propensity to form clots.  They can be genetic (inherited) e.g., MTHFR, PAI-1, Factor II Prothrombin and Factor V Leiden and also Protein C and Protein S deficiencies or they can be non-genetic (acquired) e.g., all the antiphospholipid antibodies e.g., anticardiolipins(collectively known as APLAs).  Pregnancy also raises the risk of acquired thrombophilia.

Thrombophilias may cause difficulty in getting and staying pregnant due to microclots compromising the blood flow (nutrition and oxygen) to the uterine lining and to the placenta.  This can result in a poor lining and/or slow failure of the pregnancy leading to miscarriage.

Thrombophilias may also be a significant health risk leading, for example to stroke.

21.2.2   How are they tested for?
MTHFR, Factor II Prothrombin (202010), PAI-1 and Factor V Leiden are tested for using genetic tests (on blood).  APLAs are tested for by measuring antibody levels in the blood.  The general tendency to clot is tested by doing physical clotting tests like the APTT.  As well as the genetic test for the mutation which tends to cause elevated PAI-1 levels, the actual PAI-1 levels in the blood can also be tested (elevated levels mean that the body has an impaired ability to breakdown clots).  Tests for APLAs and general clotting are usually available on the NHS.

Because chromosomes are always paired (one from mum and one from Dad), you can have one copy of the genetic thrombophilia mutations or two.  MTHFR, for example, can be homozygous (where the patient has two copies of the 'faulty' MTHFR gene) or heterozygous (only one copy).   Having only one copy of the gene is usually less serious than having both copies. 

MTHFR polymorphism (having the ‘faulty’ MTHFR gene) is very common.  More than half the UK population have at least one copy of the MTHFR gene.  Having a single copy (heterozygous) is considered to be less of a problem than having two copies (homozygous).    There is a Yahoo Group for MTHFR ladies (see Resources, below).  PAI-1 polymorphism is also very common - about 20% of the population are homozygous 4G/4G and about 30% are heterozygous 4G/5G (the rest of the population are negative i.e., 5G/5G.  The PAI-1 mutations are more common in ladies with PCOS.

Example results:
MTHFR – gene mutation C677T                                         negative/positive heterozygous/positive homozygous
Factor V Leiden: Factor V G1691A mutation                      negative/positive homozygous/positive heterozygous
Factor II Mutation- Prothrombin Factor II G20210A            negative/positive homozygous/positive heterozygous
PAI-1                                                                                negative (5G/5G)/positive heterozygous 4G/5G/positive homozygous 4G/4G

Dr Gorgy charges £250 for the genetic tests for Factor V, Factor II and MTHFR (PAI-1 is available at an extra cost).

Care charge £118 for the test for Factor V, £118 for the test for Factor II, £136 for the test for MTHFR and £153 for the test for PAI-1 4G/5G.

Dr Economou in Athens charges 260Eu for screening of genetic thrombophilias (MTHFR, PAI-1, Factor II, Factor V) and acquired thromophilias including antiphospholipid antibodies (see my thread on serum clinic).
21.2.3   How are they treated?
For fertility they are generally treated with blood thinners e.g., clexane (20-100mg) during fertility treatment and pregnancy - see above (or other low molecular weight heparins), and sometimes additionally with aspirin (started before fertility treatment and continued through pregnancy - in some cases, continued for life) - see above.   

In addition to blood thinners during treatment, for MTHFR homozygous, folic acid (5mg), B6 (20-50mg) and B12 (0.05-1mg) are usually prescribed (for MTHFR heterozygous, most ladies take at least 800mcg of folic acid but not necessarily the whole 5mg dose indicated for homozygous MTHFR and not necessarily extra B6 and B12. B6 and B12 absorption can also be impaired with the MTHFR mutation which is why supplementation with B6 and B12 is often suggested as well as folic acid.  Bear in mind that B12 deficiency is high among vegetarians and B6 and B12 deficiency are sometimes implicated in luteal phase deficit.  MTHFR causes problems in absorbing/using folic acid, so sometimes even a 5mg dose may result in deficient blood levels.   Methyl folate (e.g., solgar methylfolate or femibion containing methylfolate) may be much more absorbable but is more expensive and not available on the NHS in the UK.

For PAI-1, metformin (850mg twice daily started 3 months before fertility treatment), folic acid 5mg, vitamin B6 20-50mg and vitamin B12 0.05-1mg are often prescribed but weight loss can also be important for ladies who have elevated PAI-1 or the genetic mutation which tends to lead to it.  Some docs do not believe that metformin treatment is justified unless a test reveals high fasting glucose or insulin resistance.

Where a significant clotting issue is identified, you would normally need to see your GP, and if necessary a haematologist to understand and treat any long term implications. Mild thrombophilias may not be life threatening but could still prevent a healthy pregnancy. 

Once you have transferred to the care of an obstetrician during pregnancy, he should be responsible for managing your clotting risks later in pregnancy and immediately after baby is born.

21.2.4   Where can I get more information/support?

There are several support groups for ladies who are trying to conceive with thrombophilias

e.g.,
http://health.groups.yahoo.com/group/FVL-PG/ for factor V leiden
http://health.groups.yahoo.com/group/MTHFRPG/ for MTHFR

The treatment protocols are described above (under clexane).

There are some helpful articles about PAI-1 on this blog by Dr Trofatter:

http://www.healthline.com/blogs/pregnancy_childbirth/labels/PAI-1.html

21.3   Thyroid tests
21.3.1   Do I need my thyroid activity testing?
An over or under active thyroid can significantly reduce your chances of conception even if it is still within the ‘normal’ range for the NHS.   For example, the NHS will currently not treat a TSH level of 4 mIU/mL (= 4 IU/L) as requiring any medication for hypothyroid (because of its cost/benefit analysis).  However, studies have shown that anything over 2 mIU/ml (=2 IU/L), especially where anti-thyroid antibodies are present is associated with a lower chance of a live birth. 

e.g. http://www.ajog.org/article/S0002-9378(06)00365-6/abstract
http://www.gghjournal.com/volume26/1/pdf/ab14.pdf

http://www.thyroid.org/professionals/publications/clinthy/clinthy_v237.pdf

So in my opinion, infertility patients should ask their GP for a basic thyroid screen and if, for example the TSH comes back at over 2 mIU/ml (2 IU/L) or high levels of antithyroid antibodies are present, seek advice from an endocrinologist who has experience with infertility or an immune fertility doctor as you may need to be prescribed thyroxine to reduce your TSH to below 2 mIU/ml.   In the study above, where IVF patients had a TSH level greater than 2.5 mIU/ml and did not have FT4 levels in the high normal range, they were prescribed 50mcg per day of levothryoxine from the first day of IVF stimulation which lead to greatly improved pregnancy and live birth rates (reduced miscarriage rates) compared to similar ladies who where untreated.

DURING PREGNANCY the American Thyroid Association recommends TSH is maintained to:

First Trimester, TSH 0.1 – 2.5 mIU/L

Second Trimester, TSH 0.2 – 3.0 mIU/L

Third Trimester, TSH 0.3 – 3.0 mIU/L

http://thyroidguidelines.net/pregnancy/results
The presence of antithyroid antibodies, even if TSH levels are normal, appears to be associated with a reduced chance of pregnancy/IVF success, but at least one study has shown much improved results if patients with antithyroid antibodies are prescribed thyroxine together with aspirin and corticosteroids. The doctors used this protocol:  levothyroxine 50 mcg/d orally + 100 mg oral aspirin + 10 mg Prednisolone from the first day of IVF stimulation.  The prednisolone was increased to 30 mg/d for 5 days starting the day of embryo transfer, and then dropped back down to 10 mg/d and continued until at least 10 weeks of pregnancy.

http://www.rbej.com/content/7/1/137

This study showed a reduced miscarriage rate and a higher rate of embryo quality where ladies with subclinical hypothyroid were prescribed thyroxine  http://www.fertstert.org/article/S0015-0282(10)02928-6/abstract

Both pregnancy and IVF can affect your thyroid hormones and increase the body's need for thyroxine so ladies with thyroid issues need their thyroid levels monitoring regularly in pregnancy, and if you have recently been through an IVF cycle you may want to wait a few weeks afterwards before (re)testing your levels to get an accurate baseline measurement.

The NHS CKS knowledge summary on managing subclinical hypothyroidism (where free T4 is normal but TSH is elevated) in pregnancy or when trying to conceive tells GPs to "Aim for a TSH concentration in the low-normal range (0.4 mU/L to 2.0 mU/L) and an FT4 concentration in the upper reference range."   Please note that the CKS system is supposed to be being replaced soon but I don't think this invalidates the information on the database for the time being.

http://cks.nice.org.uk/hypothyroidism#!scenariorecommendation:6

However, the NHS guidelines (unhelpfully) do not go as far as the logical next step of telling GPs to make sure that all ladies who are pregnant or trying to conceive should have TSH in the 0.4-2 range (only that if their TSH starts off higher than 4.5, to get it down to the 0.4-2 range).

Thyroid-stimulating hormone (TSH) 0.9–4.0 mU/L (aim for between 0.9 and 2.0 mU/L) - some ladies will feel fine with TSH down to about 0.4 and it will not cause any fertility problems, but most ladies feel better if TSH is closer to 1.
Free thyroxine (FT4) 9.0–25 picomol/L (aim for high end of this range e.g., 19-25 - but bear in mind that some women can't achieve this without dropping their TSH too much - so also  be guided by how your feel and where your TSH is)
Free triiodothyronine (FT3) 3.5–7.8 picomol/L (aim to be in range)
Total thyroxine (TT4) 60–160 nanomol/L (aim to be in range)
Total triiodothyronine (TT3) 1.2–2.6 nanomol/L (aim to be in range)

Thyroxine supplementation will raise FT4 (and T3) which causes TSH to fall.     Your doctor will normally start you on a low dose e.g., 25-50mcg per day and gradually tweak it upwards, retesting your TSH and FT4 every 4 weeks until you are on target.  Thyroxine has a fairly long half life, so if you are in between doses, its quite common for doctors to put you on alternate day dosing e.g., 50mcg one day and then 75mcg on alternate days to 'average out' the dose that you need.

Once you do get pregnant, its important to follow the guidance on monitoring thryoid in pregnancy (i.e., blood tests on bfp and then monthly) because you may need to drop your thyroxine slightly in early pg and then start to raise it.

If you are TTC with stimulated own egg IVF, it is probably more critical to try to get your TSH below 2 and your FT4 up to the high normal range because during stimulation, the high levels of estrogen can push down your FT4 and raise your TSH so if you start with levels above 2, you are more likely to end up with levels well above normal (e.g,. 5) by the time you get to embryo transfer.    In one study, 44% of women with a TSH below 2.5 had a rise in TSH when doing an OE IVF cycle.

http://www.fertstert.org/article/S0015-0282(11)02907-4/abstract

21.3.2   What is thyroid peroxidase?  What is thyroglobulin antibody
Thyroid peroxidase is one of the common anti-thyroid antibodies (ATAs).  The second most common ATA is (anti) thyroglobulin antibody.  Having an elevated level means that you have antibodies in your blood that attack your thyroid gland meaning that it is likely that now, or sometime in the future, your thyroid will be damaged and not produce the right amount of thyroid hormones (e.g., Hashimotos thyroiditis).  It is an autoimmune condition and it is associated with an increased risk of having elevated natural killer cells.   Even for ladies whose thyroid hormones fall within the normal range, chances of a live birth with IVF are reduced if it is not treated with a combination of thyroxine, blood thinners (e.g., clexane, aspirin) and corticosteroids (e.g., prednisolone).

http://www.rbej.com/content/7/1/137

However, some ladies who are diagnosed with ATAs decide to have level 2 immune testing so that they can access more aggressive treatments e.g., intralipids, IVIG, humira, on top of the basic treatment (thyroxine, blood thinners and corticosteroids).

21.3.3   What thyroid tests do I need?

If you are concerned about thyroid activity for fertility you need to know

- your TSH level (you are wanting this to be around 1 (between 0.4 and 2) for optimum fertility
- your FT4 levels (you want this to be in the top third of the normal range for optimum fertility - but see comment above)
- antithyroid antibodies (e.g., thyroid peroxidase, thyroglobulin antibody)

If your results show any problem you would want to ask for T3 and iodine to be tested.   Its normal to feel some side effects when you first start thyroxine e.g., jitteryness but this should settle and you start to feel ok. If you do not start to feel ok, and still feel hypothyroid (overtired etc) after about 4 weeks on thyroxine, despite your TSH and FT4 getting into the normal range, you may need to check T3 because some patients have a problem converting T4 into T3 and occasionally, T3 supplementation may be necessary. 

Knowing your iodine level will help you determine whether iodine is causing your thyroid problems and whether you should be on iodine supplements/changing your diet. If your results show a problem with antithyroid antibodies, you probably want to also ask for selenium, so you can determine whether you need extra selenium. A dose of 200-400mcg of organic selenium is often suggested.   Bear in mind that too much iodine can make hashimotos (autoimmune thyroid disease) worse, particularly if selenium is low - so you must not take iodine containing supplements without a doctors' permission and ensuring your selenium is ok first if you have hashimotos. Too much selenium is toxic and linked to increased risk of diabetes, so you should ideally get your levels checked especially if you intend on taking a high dose for a long period.

Bear in mind that estrogen binds to T4 so high levels of estrogen will reduce Free-T4.  After an IVF cycle, pregnancy/miscarriage or being on estrogen containing medication, you might need to wait for at least 4 weeks to get an accurate T4 level.   Also, remember that the thyroid system is supposed to be dynamic - your body uses TSH to lever up and down your Free-T4 levels in order to set the body's 'thermostat'.   So it should respond to extra demands by changing your TSH and FT4.  Its therefore normal for your thyroid results to keep changing.  What you are looking for is to get them into a good place before your fertility treatment starts, to give you some headroom in case estrogen pushes up your TSH and down your FT4, then to make sure they stay adequate when you are pregnant to give baby the right supply of thyroid hormones, particularly in the early weeks of pregnancy before baby can make his own thyroid hormones.

Steroids like prednisolone sometimes suppress TSH, so your doc is supposed to pay more attention to your FT4 level and possibly ignore an artificially low TSH level if you are on pred.

21.3.4   What causes thyroid problems?

- the main cause worldwide is iodine deficiency - a recent study on schoolgirls in the UK found mild deficiency in 51%, moderate deficiency in 16% and severe deficiency in 1% - so its safe to say that iodine deficiency is common in the UK - but excessive iodine can also cause/exacerbate thyroid disease (particularly if there is a selenium deficiency).
- another major cause is autoimmune disease of the thyroid gland caused by antithyroid antibodies (hashimoto's or grave's disease).

Soya protein, brussels sprouts, broccoli, rutabaga/swede, turnips, kohlrabi, radishes, cauliflower, African cassava, millet, cabbage and kale are called goitrogenic foods and can also exacerbate thyroid disease.

21.3.5   What are the symptoms of under or overactive thyroid?

Bear in mind that underactive thyroid that is sufficient to be reduce the chance of getting/staying pregnant may be symptomless.   Overactive thyroid that is severe enough to reduce your chances will normally have obvious symptoms.  You can get a list of the symptoms here:

http://thyroid.about.com/cs/basics_starthere/a/symptoms.htm

21.4   TNFa – see cytokine ratio above or

21.5   Timescales for immune treatment
21.5.1   What sort of timescale is typical for immune testing and treatment?
For a hypothetical patient who, after testing with Dr Gorgy finds she has virtually every issue that there is (almost no-one is that unlucky), your experience might go something like this:
1)   Attend first consult, decide to get Chicago tests done, decide to test for Chlamydia and get swabs done for mycoplasma and ureaplasma and a semen culture test.
2)   Go back to your GP and get any missing basic tests run there (if possible)
3)   Wait for your period to send Chlamydia sample for testing
4)   When all results are back, have follow up appointment
5)   If Chlamydia and other infection tests are positive start on antibiotics (both partners)
6)   Wait for your second period after finishing the antibiotics to retest and make sure the infections are gone
7)   Have hysteroscopy and endometrial biopsy if you need that (a lot of ladies don’t) and follow up on any issues
8)   Have two shots of LIT (if needed), four weeks apart and start on Humira (if needed), possibly in between the shots of LIT.
9)   Wait 1-3 weeks before retesting LAD and/or cytokine ratio (if needed).
10)    Wait up to one week for results to come back before following up and getting any prescriptions that you still need.
11)   Start your fertility treatment cycle and start taking aspirin (you should already be on a prenatal vitamin plus any extra folic acid, B6 and B12 that you have been advised to take if you are MTHFR positive)
12)   Start clexane and prednisolone (if prescribed) on day 5/6/7 of your stimulation
13)   Have IVIG and/or intralipids (if prescribed) 7-14 days before your planned embryo transfer
14)   Stop your clexane from trigger day until the day after egg collection.
15)   Start your gestone after egg collection
16)   Confirm your pregnancy with a beta HCG test about 14 days after egg collection (and follow up with a second test 48 hours later to confirm that your levels are rising sufficiently – see Two Week Wait, below)
17)   Have another IVIG/ILs asap (if prescribed) and have a LAD retest if not already done.
18)   If LAD is still poor, book another LIT asap
19)   Have your first ultrasound scan at 6.5 weeks (4.5 weeks after egg collection) to confirm a heartbeat and a further IVIG/ILs asap
20)   Wait 7-10 days after the drip before retesting NKa
21)   Wait one week after the retest for the results to come back and have a follow up consult to decide what the plan should be for future drips.
22)   Have next drip in about four weeks (if prescribed), then a retest after 7-10 days, then a follow up one week later and repeat, possibly up until 31 weeks – if your retests are problematic.   If your consultant feels its necessary, possibly have scans every four weeks.
23)   Have your NHS nuchal scan and tests at twelve weeks
24)   Stop your gestone at 12-16 weeks and start tapering off the prednisolone at twelve weeks (or as directed by your consultant).
25)   Have your NHS anomaly scan at 20 weeks and further scans as your NHS OB dictates.
26)   Stop your clexane at 31 weeks if you are cleared to do so by your consultant and your NHS OB.

Obviously, actual treatment plans may vary considerably from this.

21.6   Tocolytics - atisoban, nifedipine, ritodrine - 'womb relaxants'
These are a group of drugs that were developed to try to reduce pre-term birth by stopping the uterus from contracting.  This class of drugs are now being used by several clinics prior to and after embryo transfer in ladies who have experienced cramping on previous embryo transfers or where hypercontractility (excessive contractions of the uterine muscle) has been observed by their doctor during previous gynaecological procedures.   These drugs act to reduce spontaneous uterine contractions (cramps), and it is hoped that by doing this, they may make the uterine environment more favourable for implantation.   Ladies who have experienced cramping during ET and for up to about 3 days after ET in previous failed IVF's might like to discuss the possibility of taking these drugs for their next ET.


21.7   Treating empirically
21.7.1   What is treating empirically?  Can I just take immune meds without testing?
Treating emprically means taking medication by common usage rather than after testing and scientific proof.
Lots of clinics worldwide will consider empirical immune treatment for ladies who have had repeat IVF failures or repeat miscarriage.

Emprical treatment for this often takes the form of continuous low dose daily aspirin (for possible clotting issues and/or low dose daily clexane (e.g., 20 mg) either from the mid-follicular phase (day 5/6/7) or, sometimes from ovulation/egg collection, or even from positive pregnancy test and/or low doses of corticosteroids (e.g., 5-15 mg prednisolone or prednisone or 0.75-1.5mg dexamethasone) from the mid-follicular phase, or from ovulation/egg collection, or from positive pregnancy test, and/or additional progesterone e.g., 50mg gestone injections from ovulation/egg collection.

From the point of view of supplements, Vitamin D3 is the most obvious supplement (see Supplements) to take as Vitamin D3 deficiency is very common in UK/northern Europe and Vitamin D is a potent immunoregulator.

The advantage of empirical treatment compared to comprehensive immune testing and treatment is basically cost (and the difference in cost between empirical treatment and comprehensive testing and treatment can be very, very large), and for some ladies practical access to treatment.   These drugs are very commonly used and many doctors are happy to consider prescribing them after several IVF failures/miscarriages.  For avoidance of doubt, I am not suggesting that anyone should take any medication without medical advice from their doctor.

The disadvantages are:
1) the treatment may have no benefit - e.g., you may be given blood thinners when you have no clotting or NK issues and they may not help you get/stay pregnant.
2) the treatment will always carry some risks e.g., immune suppression from taking steroids, or small increased risk of cleft lip/palate for baby - and these risks may be unnecessary if you don't need the treatment
3) the treatment may be at too low a dose to be effective.

Nevertheless, this type of treatment does seem to help a lot of ladies get/stay pregnant after they have failed to without it and it may be worth discussing with your doctor, but it won't be appropriate for everyone e.g., steroids may be very risky for ladies who have immunosuppression problems and blood thinners could be dangerous for ladies with other medical conditions. Ladies with significant known autoimmune issues may be more likely than average to require more comprehensive immune treatment to get/stay pregnant, some ladies will not want to to take the time to try empirical treatment before having more comprehensive testing or will be uncomfortable with taking medication which is not tailored for them on the basis of  issues identified by comprehensive tests.   Personally, I think it would be inappropriate to consider these sorts of treatments unless you do have a history of miscarriage and/or multiple IVF failures or are diagnosed with issues through comprehensive testing because they do carry some risks to you and to the fetus and it would not be justifiable to take them unless you need to.

Before starting a cycle using empirical treatment, personally, I would:
1) ask for an FBC to screen for any obvious immunosuppression - that would suggest taking steroids may be risky for you
2) ask for blood test screening for diabetes and thyroid issues (including antithyroid antibodies) in case they need treatment first
3) ask for rheumatoid arthritis and lupus blood test screening to identify if you are at high risk of having diagnosable autoimmune issues
4) ask for blood clotting (thrombophilia) tests  - because if these reveal issues you may need blood thinners for medical reasons or at a higher dose.

essentially, these are the so-called level 1 tests.

5) consider whether to have infection screening particularly for Chlamydia with the greek test (see Chlamydia above) because that may be the undiagnosed root cause of many immune issues, lining issues and IVF failures and the test and treatment (aggressive antibiotics) seem particularly cost effective compared to full immune testing and treatment

6) decide whether you would prefer to try this route first, even if it fails, or would prefer/are able to go straight to comprehensive testing and treatment bearing in mind the relative cost of comprehensive testing/treatment and the financial and emotional cost of another cycle.

7)get your doc to have a good look in your uterus for problems like adenomyosis, septa, polyps, fibroids, scarring, adhesions.   An aquascan will pick up some of these, and a hysteroscopy may pick up the rest.

21.8   Trying again
21.8.1   When should I try for another baby after my immune pregnancy?

Autoimmune issues run in families and I strongly believe that breastfeeding gives baby's immune system the best chance of being normal in the future, so I would hope that most ladies would want to give their special baby the benefit of breast milk for as long as possible - at least for 6 months, preferably for longer. Some immune related conditions e.g., diabetes and asthma, appear to be an increased risk for babies exposed to the antigens in formula milk.  Breastfeeding is not always easy, especially if baby has health problems, but babies can always have the benefit of your milk if you express with a good quality pump.

However, getting pregnant naturally or with fertility treatment whilst breastfeeding is less likely due to elevated prolactin levels even if your natural cycles return and the risk of miscarriage is higher whilst breastfeeding.  If you do find you are pregnant whilst breastfeeding, you may need to take the decision to stop breastfeeding if you have a history of miscarriage etc.  Fertility treatment is not normally permitted whilst breastfeeding because of the risks to the breastfeeding baby due to the medication, the reduced chance of success and increased risk of miscarriage.  Most clinics will recommend waiting for at least 2 normal periods after you stop breastfeeding or 1 period and a normal prolactin level by blood test before you restart fertility treatment.

However, Dr Beer used to say that the immune system reset for around 1 year after a successful pregnancy, so you may want to try again within a year for an improved chance.  For example, you could breastfeed exclusively for 6 months whilst building up a stock of frozen expressed milk to reduce the need to expose your baby to formula milk whilst weaning.

21.9   Two-week wait (between ovulation and pregnancy test)
21.9.1   Any do’s and don’ts during the 2ww and pregnancy?
•   Don’t exercise too much – your ovaries may be swollen after IVF and can twist causing damage if you try to do more than your body is very used to.
•   Do drink plenty of water and ensure sufficient protein intake to help prevent OHSS and reduce constipation.
•   Try to avoid baths, swimming pools, Jacuzzis etc – they can cause overheating/dehydration which is unhelpful for your embryos and there is a small risk of infection – stick to a warm (not hot) shower.
•   Do try and avoid anyone you know is ill with anything contagious like colds or flu– especially someone with chickenpox (unless you have checked that are immune with a blood test) – you may be slightly immunosuppressed due to steroids or Humira, and if not, you don’t want to catch anything that will then cause your NKa and TNFa to rise.
•   Do try to eat sensibly – to provide protein, avoid saturated fats that may increase TNFa and to reduce the constipation that comes with taking progesterone.
•   Do try to rest more than usual – ‘normal’ ladies do get pregnant without resting during their 2ww but ‘immune Tx’ ladies need all the help they can get to keep their immune system calm and quiet.
•   Do avoid caffeine (coffee, tea, chocolate, cola, red bull, iron bru, energy drinks etc).  Studies suggest four cups of coffee don’t raise the miscarriage risk in ‘normal’ ladies, but I think ladies with immune issues need all the help they can get, particularly as they may suffer from impaired blood flow to the uterine lining which caffeine will exacerbate.   I wouldn’t drink more than two cups of (green) tea. (I would avoid decaff tea as the processing to get the caffeine out leaves traces of chemicals – decaff coffee is safer.)   In addition, risk of blood clots rises significantly during pregnancy and drinks like red bull in particular have been shown to also raise clotting risk, so I think they are too dangerous to drink during pregnancy.
•   Personally, I would avoid artificial sweeteners (especially aspartame, acesulfame-K, sodium cyclamate and saccharine) because some practitioners say that they are unhelpful for fertility so I’d rather not take the risk.  Research into their safety is very contradictory, with many studies saying that they are safe, but a few others saying that they are not safe, for example linking consumption of aspartame to risk of premature birth and there is strong evidence that sodium cyclamate affects the urinary tract and saccharine crosses the placenta.  Sucralose and sugar alcohols like malitol or xylitol may be safer options but it still seems to me that you should try to keep intake of these low.
•   Personally, I would keep sugary foods to a minimum to avoid swings in blood sugar level and only drink fruit juices which are diluted with plenty of water.
•   Personally, there are chemicals that I avoid in shampoos etc e.g., methyl and ethylparaben and pthalates because some sources say that they reduce fertility.  I also decided not to dye my hair (bleaching, light colours and highlights are safer), because dark coloured dyes (no matter what claims they make about having no peroxide or ammonia or whatever) contain chemicals which can be absorbed all the way through your body into your bladder – and that is just too close to baby for me to feel that it’s a good idea.  I try to avoid BPA (a feminising hormone that is in plastics and the lining of food tins – but its very hard to do so because its hard to find out which cans are BPA free - but my understanding is that most food tins contain BPA.  I also gave up tuna fish because its mercury content is more variable than say, mackerel.
•   I have been asked before for suggestions about what to do with darker moustaches that seem to appear in pregnancy (particularly around the end of the first trimester).  Personally I would stick to facial bleach and use it cautiously i.e., put some bleach on and if it starts to feel warm, wash it off with cold water then wait until your skin is completely calm again before having another go and repeating as necessary – on the basis that I want my whole body as calm as possible.
•   Where there are avoidable things that you are allergic to e.g., a friend’s cat, you may want to try and minimise exposure especially during stimms, 2ww and early pregnancy - purely on the grounds of keeping your levels of inflammation as low as possible.  If you normally take antihistamines to deal with an allergy, you should speak to your consultant about whether they are safe to continue to take when you may get/be pregnant.
•   Some ladies choose to eat brazil nuts (see Selenium under Supplements, above) in the two week wait.  Other ladies choose to drink pineapple juice, but I’m not convinced about that one.

21.9.2   When should I do a pregnancy test?
Many IVF clinics suggest waiting until at least 14 days after embryo transfer and then using a home urine test. They discourage ‘early’ testing because they have no interest in early losses/early biochemical pregnancies, but this is not the case for immune docs.  Most immune docs recommend testing by a blood test (betaHCG) about 14 days after EC, and if this is positive, following up with a second blood test 2 days later.   The second test is to check that your HCG levels are rising as they should do in a healthy pregnancy.  They should rise by at least 66% in 48 hours (or to double in 72 hours).  If you cannot get the tests done exactly 48 hours apart, then tests done at a slightly different interval can be interpolated (mathematically corrected) to estimate the value at 48 hours – there are several HCG calculators on the internet to do this.  Testing early this way, is important for immune patients:
the sooner you know you are pregnant, the sooner you can get your consultant’s advice on any immune tests/treatments (e.g., drips) that may take time to organise, and this timing may be more urgent in early pregnancy; 
abnormal rises in HCG may indicate a problem e.g., an ectopic or molar pregnancy that needs to be addressed urgently;
if unfortunately the pregnancy does not proceed, your consultant will have gained some information that may inform his future treatment for you.

Dr Beer used to advise using a urine test stick each morning starting a few days after embryo transfer but then watching the stick for around an hour in case there was any hint of a line – as that might give information to help determine whether you are dealing with repeated very early losses or not.  You could still do this, particularly with a sensitive brand like First Response but it may be pretty stressful as clearly the first few tests could be positive due to HCG from the trigger shot, then if you do get pregnant you could see several days of negative tests first before the positive.   Having a blood test seems less stressful to me and a lot more accurate as urine test sticks are not designed to be used in this way.

Your consultant may advise you to have further b-HCG tests until your first heartbeat ultrasound scan.

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22   U
22.1   Ureaplasma urealyticum
22.1.1   What is ureaplasma?
It is a fairly common STD that is rarely tested for unless there are overt symptoms which are rare and all other STDs have been ruled out.  However, it is associated with higher rates of infertility and miscarriage in the few studies that have been done.  One theory is that although ureaplasma may be relatively harmless in most women as it is kept in check by the natural acidity in the vagina, but that if it grows out of control it can cause BV (bacterial vaginosis - an infection of the vagina with a typically fishy smell, particularly after sex) or, if it reaches the uterus, endometritis (inflammation) and possibly even scarring.  In men, it can cause urethritis (inflammation of the urethra) and seems to be associated with poor sperm morphology, presumably if the infection reaches the testes.

http://www.bellaonline.com/articles/art10667.asp/zzz

22.1.2   How is ureaplasma tested for?
In women, the most accurate test for ureaplasma in the vagina is a PCR vaginal swab specifically for ureaplasma.  A swab culture test is an alternative but is slightly less sensitive as it relies on the laboratory being able to grow (culture) live bacteria from the swab.  In men, the most accurate test is a semen PCR test specifically for ureaplasma.  A semen culture (and antibiotic sensitivity test) is an alternative but it is slightly less sensitive.  A high vaginal swab test through Dr Gorgy for mycoplasma and ureaplasma (together) is currently about £75.  Semen PCR tests are about £75 and semen culture tests are £50.  Locus Medicus in Athens will also test menstrual fluid samples for mycoplasma and ureaplasma (see under Chlamydia, above) for approximately 90Eu each.  In theory, the menstrual fluid test may obtain a sample not just from the vagina, but from higher up e.g,. in the uterine lining, so it may reveal bacteria that have moved higher up in the genital tract.

***Serum have introduced a new 7 in 1 PCR test from LifeCode laboratory in Athens.  This tests for Mycoplasma hominis, Mycoplasma genitalium, Ureaplasmas, Gardnerella vaginalis and Atopobium vaginae as well as an 'ordinary' test for Chlamydia and a test of total bacterial load which measures whether there is a normal population level of 'good bugs' (lactobacillae).   The 7 in 1 test can be done on menstrual fluid or semen and can be sent by post.  It costs €170 so its probably better value for money than doing the locus medicus tests for Mycoplasma and ureaplasma separately.***

22.1.3   How is ureaplasma treated?
Getting rid of ureaplasma from the vagina should be easier if the vagina is kept acidic. The cheapest way to do this is to use natural live yoghurt and apply it to the vagina using clean fingers.   However, most pharmacies sell specially formulated vaginal acidity gels which are sold as products for preventing recurrence of BV e.g., Biofem acti-gel or Rephresh.   These need to be applied over several days to have a good effect as aim is to return the vagina to its normal acidic state and make it a more hostile environment for BV bugs.   Acidity is likely to be reduced if you are close to ovulation (or stimming for IVF etc) as fertile egg white cervical mucus is not as acidic as mucus at other times of the month.  Acidity can also be compromised if you have reduced cervical mucus or after having sex as semen is not acidic.

The usual treatment is a short course (7-10 days) of doxycycline 100mg twice a day.

http://www.sciencedirect.com/science/article/pii/S1201971209001568
http://jac.oxfordjournals.org/content/62/5/1027.short
http://www.ingentaconnect.com/content/maney/joc/2012/00000024/00000002/art00004

22.2   Uterine biopsy
22.2.1   How is uterine biopsy done?
Unless you can get the biopsy done whilst you are sedated/anaesthetised for another procedure it is usually done whilst you are awake without anaesthetic, so you may want to take something like paracetamol codeine (or any other painkiller recommended by your consultant) in advance of the procedure.  Your doctor may also give you some prophylactic antibiotics just in case of any infection risk.  The doctor will use a speculum to visualise your cervix and then insert a biopsy instrument up through your cervix to take a sample from your uterine lining.  You may be instructed that you need a full bladder for this procedure so it is best to check in advance.  It usually needs to be done about two days before your period to ensure that the lining is mature but is not yet coming away.

22.2.2   What is it for?
A biopsy will provide a sample usually to determine whether you have elevated uterine NK cells (CD57+) or diminished Fox P3 (regulatory) cells, and whether your lining looks healthy and normal.  A biopsy sample can also be used for infection testing.  Elevated numbers of uterine NK cells and reduced numbers of FoxP3 cells are associated with a reduced chance of a live birth.  Looking at the sample under the microscope can also reveal problems like having a lining which is underdeveloped for that day of your cycle (e.g., due to hormonal or blood clotting problems).

22.2.3   Please explain my uterine biopsy results?
The report will normally say whether you have excessive NK cells, whether you have sufficient Fox P3 cells and whether there is anything unhealthy evident in the stroma (the uterine lining tissue) e.g., hyperplasia (overgrowth),  necrosis (dying tissue), atrophy (lining too thin and underdeveloped).
Example report:
Endometrial biopsy shows:
1.   Late secretory endometrium POD 11-12 The secretory phase is the time after ovulation (when the corpus luteum - the follicle that has just ovulated - is secreting progesterone).  POD stands for post-ovulation-day i.e, it was approximately 11 days after ovulation that this sample was taken 
2.   2 CD57+ cells identified/high power field CD57+ are uterine NK cells – having as low a number of them as possible is ideal
3.   4-5 FoxP3+ cells identified/high power field FoxP3+ are regulatory cells that help keep immune activity under control.  It is healthy to see at least some of these cells in your specimen
4.   no evidence of inflammatory change seen it is healthy to see no inflammation
5.   no evidence of necrosis it is healthy to see no necrosis (dying/dead tissue)
6.   no evidence of hyperplasia or atypia it is healthy to see no hyperplasia (overgrowth)and no neoplasm (cells with indications of possible cancer)

22.2.4   How much does uterine biopsy cost?
I think it is about £350 with Dr Gorgy.

22.2.5   Should I have a uterine biopsy?
Unless you have had problems with developing a normal uterine lining on previous cycles, or you have the opportunity to get a biopsy sample taken during another procedure (e.g., hysteroscopy), I think I would wait to find out the results of your cytokine ratio (Chicago) test first.  This is because the biopsy can be quite uncomfortable, and if your TNFa ratio comes back high, you may decide to have Humira treatment – which is the same treatment that Dr Gorgy usually prescribes for elevated uNKs.   If your TNFa ratio comes back normal, then it might be worth having the biopsy done to see if you have uNKs and therefore would still benefit from Humira.  When you have a biopsy, there is a small risk of scarring and/or contracting or stirring up an existing infection.  You may want to check with your doctor in advance whether you should take some strong painkillers e.g., paracetamol codeine beforehand and some prophylactic antibiotics afterwards.

22.2.6   How are uterine biopsy problems treated?
High uterine NK cells are normally treated with humira and/or corticosteroids and/or IVIG and/or intralipids.

Low FoxP3 cells are normally treated with IVIG and/or intralipids.

If infection/inflammation is detected that may need antibiotics.

22.2.6   Which labs will do a uterine biopsy?

Repromed in the US is most often used.   The sample needs to be sent in a bottle/tube containing 10% formaline solution.

http://www.repro-med.net/repro-med-site2/index.php?option=com_content&view=article&id=5%3Aimmune-pathology-of-endometrium&catid=2%3Apages-ett&Itemid=25&limitstart=5

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23   V
23.1   Valtrex/valaciclovir
Some fertility docs believe that, just as recurrent surges of bacterial infection like chlamydia can cause problems with implantation failure and early pregnancy losses e.g., due to increased levels of NK activity and/or TNFa ratio, recurrent viral infections may have a similar effect.   Some clinics, e.g., Serum in Athens, appear to trying valtrex (an oral antiviral) during IVF for patients who either have a history of herpes varicella zoster (the chickenpox and shingles virus which is also linked to Bell's palsy) or herpes simplex (a virus which causes cold sores on the lips and genital herpes). 

There is some support for this idea in research studies which suggest that symptomless herpes infection may cause inflammation (e.g., increased inflammatory cytokines like TNFa) leading to reduced sperm count in men and lead to implantation problems in women - and that treatment with antivirals may reverse these effects - although it should be noted that antivirals cannot permanently eradicate herpes infections, just prevent them from surging or reduce the severity.

http://www.ncbi.nlm.nih.gov/pubmed/9706490

http://www.ncbi.nlm.nih.gov/pubmed/19459485

The regime which is being used at Serum is apparently 500mg of valtrex or the UK generic twice a day from day 3 of stimulation/estrogen administration to pregnancy test day.  Some ladies have mentioned that the UK generic version which can be sourced by pharmacies like Rigcharm (see Resources) is apparently cheaper than branded valtrex which can be bought in the UK or in Greece.

23.2   Viagra – see Lining issues (above or click here)

23.3   Vitamins – see Supplements (above or click here)

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24   W
24.1   Weight/BMI/visceral fat
24.1.1   Is it worth the effort to lose any excess weight before my treatment?
I would say yes because
Excess visceral/abdominal fat is associated with elevated TNFalpha (which is unhelpful for fertility) and abnormal hormone levels.
Higher BMIs are associated with an increased risk of miscarriage (particularly after IVF), stillbirth, gestational diabetes, pre-term birth, emergency C-section, DVT (life threatening blood clots), intra-uterine growth restriction, neonatal death.
Excess visceral fat increases the chance that the egg recovery team will not be able to access all the follicles you develop during IVF.
Higher BMIs are associated with adverse health risks for baby for the rest of their life.
Higher BMIs are associated with PCO which can result in lower egg quality.

That being said, dieting during fertility treatment is likely to reduce your chances, so you need to deal with any weight issues as much as possible before your cycle starts.

24.1.2   But heavy ladies, smokers, drinkers and other people with unhealthy lifestyles get/stay pregnant all the time, so how can weight and lifestyle factors be so important?

If you are very fertile, your body can cope with some adverse lifestyle factors and still get/stay pregnant.  If your fertility is already compromised by other issues (male factor, egg quality, lining issues, clotting, immunes, infections, general health etc), lifestyle factors can make a significant contribution.

24.2   Why?
24.2.1   Why do I have immune issues?
Alloimmune sensitisation problems (see alloimmune issues above) only arise where you have a DQalpha match with your current or a previous partner, and you had either a successful pregnancy, early losses, chemical pregnancies or miscarriage(s) with them.

Autoimmune problems often have a combination of causes.  You are likely to have a genetic tendency (so you may find your genetic family have some kind of autoimmune disorder), but it is often either triggered or exacerbated by some kind of stress e.g., an infection (for example, chickenpox), high physical demands on your body or long term emotional stresses.   A very readable book with a lot of background on the link between stress and immune problems is “Why Zebras don’t get ulcers” by Robert Sapolsky.  Unfortunately, autoimmune issues tend to cluster, so if you have one autoimmune problem you are at higher risk for developing others and the risk rises as you get older. 

Clotting issues can have several causes, for example the genetic thrombophilias (see above), or acquired thrombophilias e.g., due to alloimmune sensitisation (see above), or health/autoimmune problems e.g., diabetes.

24.2.2   Why did my fertility treatment not work?
We are purely biological machines and we are built to reproduce so if that fails, in my view, there must always be a biological explanation.   The difficulty is in pinpointing the problem.  The types of problems I would consider are:
1) karyotyping (permanent genetic) problems of either the patient or the partner – can be ruled out with a karyotyping blood test (see Karotyping).
2) genetic problems with the specific egg/eggs resulting from your fertility treatment – more likely if you are older, have high TNFa, if you have PCOS, or if the embryology is not done carefully – can only be ruled out for certain by genetic analysis of the specific egg or the embryo prior to embryo transfer e.g., PGD/array CGH testing.
3) genetic problems with the specific sperm used in your fertility treatment – more likely if sperm DNA fragmentation is poor and/or sperm count is very low (e.g., below 1 million/ml) and/or motility/morphology are poor – but can only be ruled out for certain by genetic analysis of the individual embryo(s) prior to embryo transfer e.g,. array CGH testing i.e., DNA fragmentation can give an indication of the likelihood of sperm causing a genetic failure of pregnancy but it can never tell you for certain whether or not you will be able to have a healthy pregnancy with that father.
4) anatomical problems in the uterus e.g., septa, polyps, fibroids, scarring – can only be ruled out by physical examination e.g., hysteroscopy or sometimes a saline scan.
5) inflammatory problems in the uterus or tubes e.g., ‘toxic’ fluid wash from unclipped hydrosalpinx (swollen tubes), endometriosis, uterine infections (e.g., Chlamydia - my advice on this is to ALWAYS consider infections even if you have had very few sexual partners - Chlamydia rates can be as high as 1 in 5 in the infertility population and mycoplasma rates can be as high as 3 in 5 - and these infections can be present for many years with no symptoms, and you can get false negatives on tests - see Chlamydia, Mycoplasma and Ureaplasma)
6) alloimmune problems (DQa match) that have not responded to immunosuppressive/immunomodulatory treatment.
7) autoimmune problems causing, for example uNK, NKa or TNFa elevation, or failure of blocking antibody (LAD) levels to rise leading to immune attack on the embryo.
8) untreated clotting (thrombophilia/ 'sticky blood') issues leading to the lining or the placenta not getting enough nutrition to sustain the embryo.
9) untreated unfavourable hormonal environment e.g., TSH too high, progesterone too low, estrodial too low or too high, glucose levels too high.
10) unfavourable lining (too thin, poorly developed (no ‘triple-stripe’ appearance) or embryo transfer done poorly or too late/too early compared to the development of the lining (for example, some studies have shown that the time window for receptivity of the lining may be shorter where estrodial levels are very high or where antagonist medications have been used)
11) ‘unknown causes’ – I believe that there is always a cause, but all these areas are developing, including the reproductive immunology field, so further clues may be constantly emerging from research studies.

You may want to have a follow up consultation with your doctor or seek one or more second opinions from different doctors before you decide how you and your partner want to proceed.   You will often get very different opinions from different doctors which can be stressful and confusing, but you may turn up a suggestion for a test or treatment or ‘tweak’ to your protocol that makes all the difference and saves you from distress and disappointment in the long run.   You may decide to take a different route to having a child e.g., donor egg/sperm/embryos, surrogacy or adoption.  Some couples may decide at some point that they are no longer able or want to contemplate further fertility treatment – however, if donor egg treatment remains a medical possibility for you, that is a decision that you may be able to reverse, even several years in the future.

24.2.3   Why did my pregnancy not continue?
Personally, I do not believe in simple ‘bad luck’.  If a pregnancy does not continue, in my view, something in the biological reproductive machine has failed.  The difficulty is in knowing what the problem was so that you can try to prevent it or reassess your situation.  The issues I would consider are basically similar to the preceding question.

1) Karyotyping problem of that pregnancy (which could be due to a karyotyping problem in one of the partners if that has not already been excluded by their testing) or could be isolated to that specific pregnancy – more likely if either partner is older – can only be ruled out by karyotyping the failed pregnancy.
2) Less obvious genetic anomalies in the pregnancy causing anatomical failure – very difficult to diagnose or rule out unless it is physically obvious in the failed pregnancy.
4) anatomical problems in the uterus e.g., septa, polyps, fibroids, scarring, thin/undeveloped uterine lining – can only be ruled out by physical examination e.g., hysteroscopy/biopsy.
5) inflammatory problems in the uterus or tubes e.g., ‘toxic’ fluid wash from unclipped hydrosalpinx (swollen tubes), endometriosis, uterine infections (e.g., Chlamydia)
6) alloimmune problems (DQa match) that have not responded to immunosuppressive/immunomodulatory treatment.
7) autoimmune problems causing, for example uNK, NKa or TNFa elevation, or failure of blocking antibody (LAD) levels to rise leading to immune attack on the embryo, which has not been treated/responded to treatment.
8) untreated clotting issues leading to the lining or the placenta not getting enough nutrition to sustain the embryo.
9) untreated unfavourable hormonal environment e.g., TSH too high, progesterone too low, estrodial too low or too high, glucose levels too high.
10) ectopic pregnancy can result even from IVF – but usually is a sign of existing tubal damage, potentially on a microscale.  It is normal for an embryo to potentially drift up from the uterus to the tubes, but if the microscopic structure of the cilia on the walls of the tubes is intact, the embryo should be wafted back down to the uterus.  If this fails to happen, it is likely that there was some damage to the cilia (which probably implies a previous history of infection) even if the tubes themselves are open.

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13   Overspill from the L section!

13.5   LIT
13.5.1   What is LIT (Lymphocyte Immune Therapy)?
LIT is an injection of washed white cells which is normally placed just into the skin on the inner arm in a series of pinprick jabs.  The white cells usually come from blood freshly donated by your partner (or donor, see below).  The aim of LIT is to stimulate your body to produce anti-paternal blocking antibodies (antibodies to cells from your partner) as measured on the LAD test (see above).  Several studies found that women who had multiple miscarriages tended to have lower levels of anti-paternal blocking antibodies than women who had successfully carried a baby to term.  This lead to the theory that antibodies to the father’s DNA were necessary to help the mother’s body recognise their embryo’s cells to give a protective response rather than an aggressive response.   

The cells that are expected to be responsible for the aggressive response are NK cells, particularly uterine NK cells.  Everyone has a population of NK cells in their body which are ready to deal with cancerous cells and viruses. The problem for trying to conceive and carry a baby to term arise when these cells are too aggressive or the body fails to identify embryonic cells as harmless.   Dr Beer’s theory was that repeated exposure to embryonic cells (by failed implantation or failed pregnancy) when anti-paternal antibodies are low was likely to lead to increasing NK cell activation and higher levels of TNFa both of which make the conditions for an embryo to implant and grow into a healthy baby very difficult.    The aim of LIT is to expose the mother’s immune system to the father’s DQa markers (using injections of white cells from him or from a donor) in a way that is less likely to be treated as a threat by the mother’s immune system, to prompt her body into increasing her anti-paternal antibody level, so that the next time an embryo is introduced, it is recognised and protected rather than attacked.

13.5.2   Why is LIT controversial?
Any transfusion of blood products carries some risk (although, for paternal LIT, if you are having IVF with your partner’s sperm you will be exposed to a very similar risk during the IVF and resultant pregnancy because viruses can be transmitted via sperm and embryos).  All doctors who perform LIT will insist that the partner (or other blood donor) is screened for infectious viruses e.g., HIV and Hepatitis etc.

Where you provide the donor, you can make sure that the screening tests are done, but where you pay a doctor to give you blood from an unknown donor, obviously you are taking it on trust that the doctor has chosen the donor from a low risk group (not a drug addict etc) and has carefully screened them by insisting on regular blood tests – bearing in mind that the incubation time for viruses like HIV is up to three months.   

Whenever you have any treatment involving puncturing the skin, you are also taking it on trust that the doctor has adequate training and procedures to ensure their equipment is sterile.  There is also a potential risk with any blood product of some very rare but serious side effects like graft versus host disease (but most LIT doctors say that these side effects are theoretical because they have not actually encountered them when doing LIT).

In the US, LIT was banned several years ago because of the risk of infection and because of a large study (the Ober study) that showed no benefit from giving LIT in reducing miscarriage rates.  However, advocates of LIT including Dr Beer said that the Ober study was not done correctly, e.g., the blood was refrigerated before use, and women with untreated thrombophilias were included in the study.  Other studies have shown a significant improvement in miscarriage rates for ladies who have LIT.  Ladies who want LIT in the US now tend to travel to Nogales in Mexico to have their LIT treatment.

13.5.3   What are the alternatives to LIT?
You could decide to try other immune treatments first and only think about LIT if that doesn’t work, but its possible that you might need a greater number of IVIG/intralipid drips to try and manage any flares in your NKs or TNFa, and particularly if you have a DQa matching issue, you could find that further failed pregnancies sensitise your body more to produce more TNFa and a higher NKa.

You could stick to paternal LIT to minimise any infection risk to you.

13.5.4   Do I have to have LIT?  Will I get pregnant/stay pregnant without it?
The total number of ladies having LIT around the world is still very small.  Presumably, the number of ladies with low LAD numbers is fairly large, yet, we assume that a lot of them will get pregnant/stay pregnant.  In the studies of multiple miscarriages, it has been shown that these ladies tend to have lower LAD numbers than ladies who stay pregnant, but it does not mean that ladies with low LAD will never pregnant.  LIT is an option but its up to you whether you want to try that route. Its very possible you will be able to get pregnant and stay pregnant without it, but some studies (not all) have shown a very great improvement (a doubling of the chances of a live birth) in ladies who have paternal LIT, particularly for ladies who have had repeat miscarriages but no live birth.

13.5.5   Which immune doctors support LIT?  Who doesn’t promote it? (see below for where you can have LIT performed)
Dr Gorgy at the Fertility and Gynaecology Academy in London currently recommends LIT to his patients who have low LAD and/or DQa matches.

Dr Armstrong at the Portland recommends LIT to his patients who have low LAD and multiple miscarriages.

Dr Ndukwe at Zita West will refer patients for LIT if they request it.

Dr Sher at SIRM in the US does not refer patients for LIT and is strongly anti-LIT.

The Beer Centre in the US refer patients for LIT to Nogales (or Athens).

Dr Braverman in the US occasionally refers patients for LIT to Nogales (or elsewhere).

Penny at Serum in Athens recommends LIT but only to a particular group of patients - patients with low LAD who have had repeat miscarriage or who have immune issues and a low LAD despite previous pregnancy.  She seems to think that LIT probably doesn't reduce implantation failure but may reduce miscarriage rates for repeat miscarriage sufferers.  Serum don't offer donor LIT as such - they are happy to give LIT with the male partner's blood, but in cases where that is not possible e.g., because double donation with both egg and sperm needs to be used, they may be able to provide LIT with blood from the egg donor.

I don’t believe the ARGC recommend LIT, but some of their doctors appear to be supportive of ladies who choose to have LIT.

I think very few IVF clinics in the UK are aware of or support LIT.

13.5.6   How do I decide whether to have paternal or donor LIT?
There is no simple answer but things to bear in mind are:
1)   In studies, paternal LIT has been associated with higher success rates than random donor LIT.
2)   If you have significant DQa matches with your partner, it is more likely (but not impossible) that your body might have a lesser response to paternal LIT, so donor LIT (especially pooled donor where you are given white cells from more than one donor mixed together) might provide more stimulation – but even so, paternal LIT might still be effective or even better than donor – you cannot know until you try LIT and then retest LAD.
3)   Can the clinic provide you with a donor that is likely to give you the maximum benefit?  If you have no DQa matches with your partner, then theoretically, your partner should be the best donor for you (and if you choose to have donor LIT in a no-match situation, you would probably want a donor who has the same DQa as your partner.  Depending how unusual his DQa is, it might be hard to find an ideal donor.  If you have a partial match, it is possible that the best donor for you would be someone who shares one of your partner’s numbers (the one that is different from yours), but not the one that matches you.  If you have a significant match with your partner (e.g., (1.1, 1.1)you, (1.1,1.1)him or (1.1, 1.2)you, (1.1, 1.1)him or (1.1, 1.2), (1.1, 1.2) the ideal donor would probably be someone who has DQas which are anything other than yours and his.  It is probably easier to find a donor who does not have a specific DQa rather than to find a donor who has it.  So finding a donor in a total match situation is probably easier than trying to find a matched donor, just because the population of unmatched people will be higher than the population that matches.
4)   Paternal LIT is theoretically safer because you won’t be exposed to any viruses that you aren’t being exposed to already through other fertility treatment with your partner.  If you decide to have LIT when you are already pregnant, you might particularly want to stick with paternal LIT for safety.
5)   In a sperm donor, double donor or embryo donation situation, having pooled donor LIT might be the best way of ‘hedging your bets’ as you are unlikely to know the DQa of the father, but in a double donor situation, the egg donor might be able to provide a safer source of blood for LIT.
6)   Donor LIT is sometimes cheaper if the donor’s screening tests are included in the price, and your partner doesn’t have to travel with you for the LIT.
7)   Not all clinics have access to blood donors for LIT.
8)   If you use donor blood for LIT, unless you can get blood from the same donor to repeat the LAD test, you may not be able to tell whether the LIT has improved your anti-paternal blocking antibodies.  It would not be impossible to generate lots of antibodies to the donor's white cells after LIT, but still not have many antibodies to your partner's white cells.

13.5.7   What is pooled donor LIT?
White cells from the blood of more than one donor at a time is called pooled donor LIT.  Pooled donor LIT is sometimes referred to as double or triple donor.

13.5.8   How long does LIT last?
Dr Tsagaris says it usually lasts 6 to 9 months, which should be long enough to have 1 or 2 IVF cycles and to establish the pregnancy to the point at which LIT is no longer needed.    However, many ladies decide to have their LAD retested if they get a positive pregnancy test so they can decide whether to have a ‘booster’ shot of LIT in early pregnancy.  For ladies with a normal response (basically ladies who don't need LIT), LAD levels may stay raised for years.

13.5.9   I still don’t understand LIT or donor LIT?
You can try this analogy:  Imagine you were a tiny bit allergic to peanuts but for some reason you wanted to make yourself more allergic. That is, you wanted to have more antibodies in your blood to peanuts (you want to have anti-paternal antibodies so that your body is ‘trained’ to recognise your partner’s DNA – so it can protect an embryo that carries it rather than attacking it). 

Having a shot of LIT is like eating some peanuts to try to increase your peanut allergy by making peanut antibodies (anti-paternal antibodies).  For some ladies, their body might ignore the peanuts (paternal LIT) and not react – it might be as though some of the peanuts are not even nuts, they just turn out to be peas (possibly, allele matches) and don’t increase their peanut antibodies (antipaternal antibodies).  Those ladies might want to try eating a bag of walnuts (donor LIT) because nut allergies overlap so if you can increase your walnut antibodies, your peanut (antipaternal) antibodies will probably go up too.  You are not interested in having walnut antibodies (because you don’t care about getting/staying pregnant with somebody else’s embryo), but if they make your peanut antibodies go up (antibodies to your partner’s cells) you’ll eat the walnuts.  If you want to hedge your bets, you might try a bag of mixed nuts (pooled donor blood) to give you even more chance of finding a type of nut that elevates your peanut antibodies (antipaternal antibodies).

13.5.10   Would I still want LIT/LAD test if I am using egg donation?
Probably yes, if you are interested in having LIT.  The immune risk arises from the match between the host mother and the embryo (so the host mother is still important).  If your partner is going to be the embryo’s father, then it is just as important to have a blocking antibody response to his cells as if you were having own egg IVF.   If you are having egg donation, it may be that the egg donor might be able to provide you with the blood you need to have LIT done.

13.5.11   Would I still want LIT/LAD test if I am using donor sperm?
It would be more difficult, but theoretically you could have it.  Either you’d need to persuade the sperm donor to give his blood for the LAD test and for paternal LIT, or you could choose to have LIT with your partner as blood donor, or a third party donor, or pooled donor blood.  However, if you had the LAD test, unless you have access to the sperm donor’s blood (or can find out his DQa and get a donor with the same DQa to stand in for him), you wouldn’t necessarily get meaningful measurements.  You could test whether you have blocking antibodies to your partner (or your LIT donor)’s blood but you wouldn’t know for certain whether you have antibodies to the sperm donor’s blood (and he is the one who will be providing half the genetic material to the embryo – so its his cells that you would want your body to learn to recognise – because they represent half of the embryo’s markers).  However, it is likely that if you have a good level of blocking antibodies to one person’s DQa, you also have a good level of antibodies capable of recognising other DQas.

13.5.12   Can I have LIT if I am pregnant or during the two week wait?
Usually it is recommended that you have LIT before conception (to give you the best chance at getting pregnant), but LIT is commonly given to ladies who discover they have low LAD when they are already pregnant, or want/need booster LIT treatments in pregnancy.  After about 18- 22 weeks LIT is less likely to be required.  Because of the increased risks to you and the baby during pregnancy (when immunity and defence against infection is naturally reduced) paternal or known donor LIT might be preferable if you have the option.  If you are taking steroids during two week wait or early pregnancy this may reduce the effectiveness of LIT, and, particularly if your immune issues are severe you may decide you would rather risk compromising the effectiveness of LIT (possibly meaning that you may require additional LITs) rather than reducing/stopping the steroids at a critical time in your treatment/pregnancy - alternatively you may decide to reduce your steroids just for 1 day either side of your LIT or even stop them for a short time, but it is not always obvious what the best option is, and different doctors may give different advice about this.

13.5.13   Where can I get LIT?
There are centres all over the world. The largest one is probably at Nogales in Mexico.   UK ladies usually go to see Dr Tsagaris or Serum in Athens or Dr Armstrong at the Portland Hospital in London or Dr Gorgy.   Dr Gorgy has recently started a London LIT clinic and an occasional Saturday LIT clinic in Cairo.  There is also a clinic in London called Clinicheck in Harley Street who are offering LIT, but I don’t know many details about them, although I believe that they are more expensive than Dr Gorgy or Dr Tsagaris and I am not sure whether they use a comparable quantity of white cells for the infusion.   In making your decision between the different providers you need to consider the overall costs including travel.   You also need to factor in the cost of screening blood tests for the donor.  Overseas, there tends to be no time limit expiry on the donor’s blood screening tests, but in the UK there is a strict 30 day time limit which makes the timescales for having two shots of LIT 28 days apart critical.  If you then need a third dose, you would need the tests redone unless you go outside the UK for your third dose.  Some GPs will be very helpful and let you have the screening tests done on the NHS but the timing may not work to enable you to get the results back on the NHS within the 30 day window, so it may require you to visit a private lab with a faster turnaround time e.g., TDL in London.  Some tests can be done by sending blood by post to TDL in the appropriate tube, but other tests e.g., CBC or liver function tests can only be done on blood which is less than 4 hours old.

The doctors all use slightly different protocols.  Dr Tsagaris tends to use a larger quantity of white cells than Dr Armstrong which he puts just into the skin as per Dr Beer.  Dr Tsagaris also recommends at least 2 shots of LIT 4 weeks apart. He then suggests you retest LAD to see if your levels are now ok, which gives you the opportunity to get a 3rd shot of paternal/donor/pooled LIT before you try to conceive or you can opt do a third dose after 4 weeks without retesting LAD, or you can choose to cycle regardless and then retest your LAD when you get pregnant and then book in a third dose at that point if you need it. The disadvantage of leaving booster LIT until you get pregnant is that a lot of ladies are on steroids by that point as part of their immune fertility protocol which reduces the effectiveness of a shot of LIT so you are more likely to need a fourth LIT. 

Dr Gorgy's method of LIT is similar to Dr Tsagaris except that he injects the LIT into both upper inner arms rather than just the left arm.

Serum apparently offer 3 alternative methods. They offer a similar method to Dr Gorgy and Dr Tsagaris using about 20mls of paternal blood (or possibly egg donor's blood if both egg and sperm donation are being used), or they offer a 'double dose' of 40mls.  However,  their strongly preferred method is to start with 20mls, separate out the white blood cells and then culture them in the lab for 24-48 hours to increase the cell concentration and then give the LIT.  They prefer this method as they feel it gives good results with an added safety precaution in that they can check that the cells behave normally in the laboratory before they give the LIT.  In the rare case, that the cells divide abnormally, they can suggest you abandon the treatment.  They also prefer to spread the injections out over your body (both arms and both hips) as they say this gives less chance of scarring and a bigger effect on the immune system.  Typically they inject in both upper outer arms and on the hips.  They only offer paternal LIT (or possibly LIT from the egg donor where double donation (egg and sperm) are being used. 

Serum will allow you to bring your partner's blood with you for LIT if that is more convenient.  This entails getting his blood screened for infections and then the donation blood is drawn just before you fly to athens (blood is carried in your hand luggage). Vials for the blood containing a little pharmacutical grade heparin can be posted to you from Serum (but in an emergency you might be able to arrange to substitute plain tubes from the uk and obtain some heparin yourself in the uk - but its better to get the approved tubes from Serum).   Please note that in the UK, staff are used to working with tubes that use a vacuum to fill the container with blood rather than to take blood using a syringe, but to fill the tubes from Serum, it may be necessary to use a syringe, and in any case, the tubes may not be the same size as the vaccutainers used in the UK.

On arrival you take the blood straight to Serum (by taxi or by metro) who prepare it so you can have the LIT 24-48 hours later (Serum are open most days from 8am to 8pm - but are closed for August).  The blood needs to be delivered to athens within 24 hours of it being drawn and is carried in your bag.  In hot weather you may need an insulin wallet e.g., Frio (large size), or a small cool pack with ice.  Ideally, the blood should be refrigerated (but must not get colder than 4degC) but for the journey itself a Frio pack should be enough (be very careful to read the Frio instructions if you've not used one before - it needs to be soaked for a specific length of time and carried so the air can get to it).  Alternatively, your partner travels to athens and has his blood drawn (and screened for infections if you haven't already done that), and then you have the lit 24-48 hours later.  Serum are easy to contact and easy to get an appointment with by phone or email (particularly on weekday afternoons 2-4pm greek time).  A lady called Vasso deals with most of the LIT arrangements.   It may also be possible to freeze a sample of cells to use later - but serum will culture them after the defrost and check that they are reproducing well before using them.

Dr Armstrong uses a smaller dose of white blood cells. He only does 4 skin injections which are quite deep compared to Dr Tsagaris and he puts most of the sample into your vein.  He also only offers one dose and prefers to give it at the start of your cycle which does not give you time to retest LAD if you want to.  Dr Armstrong only offers paternal LIT.  I am not sure whether Dr Armstrong is offering LIT at the moment.   

It can be very difficult to contact Dr Tsagaris from the UK/other countries to make an appointment as his staff do not speak English (he speaks excellent English but is usually impossible to get hold of as he is running all sorts of other immunology clinics apart from those related to LIT) and he only attends the fertility clinic on LIT days (fortnightly on a Tuesday afternoon). If you do try to contact him by phone, bear in mind that working hours in Athens are different to the UK and it is common to have a long ‘siesta time’ from about 12pm until later in the afternoon, when doctors often reopen about 5pm until about 9pm. 

Not being able to contact Dr Tsagaris when you need to make travel plans and fit in with your IVF cycle, is stressful, so ladies wanting an appointment in Athens or to ask queries tend to make contact through Fertility Friends (on the ‘LIT needed’ thread in the ‘investigations and immunology’ section) with those ladies who are going out for LIT in the next clinic and ask them to raise any queries face to face, to hand over copies of DQa and LAD results and contact details and to book appointments.  This system seems to work quite well because you have the reassurance of knowing that one of the Fertility Friends ladies has seen your name written up in the LIT diary so you know your appointment is confirmed.  Alternatively, if you just need a straightforward appointment and know which day the clinic is operating (e.g., from the ‘LIT needed thread’), then if you email to request an appointment that should be sufficient especially if you only need paternal LIT – but Dr Tsagaris rarely sends a response to confirm.

It is easy to contact Serum in Athens - you can get the phone number or email from their website (see Resources, below) and either phone up and speak to Vasso (the lady who deals with most of the LIT and speaks english) or email.  You can book in for LIT via Dr Gorgy's secretary - although sometimes there is a long waiting list for LIT appointments with Gorgy.

13.5.14   Do I need to worry about my Rh- status or having a different blood group from the donor when having LIT?
If you are Rh- and you are going to receive LIT from your Rh+ partner, Dr Armstrong used to give/gives an anti-D injection.    This should only be necessary if the LIT contains red blood cells (the cells which carry the Rh antigen). Dr Tsagaris and Dr Gorgy are confident that their procedures are more than adequate to ensure all the red cells are washed out, so anti-D is not required, and neither do they suggest you need to test your Rh status before LIT as far as I am aware.   Dr Tsagaris's clinic use very careful washing procedures and as a backup step, they check the washed sample under a microscope before administering the LIT to make sure that it contains a good enough white cell concentration and to make sure the washing has removed all the red cells.   

Depending on your and your partner's blood groups, as well as Rh exposure (for Rh- ladies), it may increase the risk of you developing other antibodies to your baby's group if you are exposed to red blood cells (e.g., if you are group O and your partner is group A) which can cause problems for the health of your future baby.  It is likely to be a very small risk, but, personally, I would try to avoid any LIT practitioner who cannot give assurances that all red cells are removed from the LIT preparation.

13.5.15   What medication can reduce the effectiveness of LIT?
Dr Tsagaris recommends that you do not take corticosteroids like prednisolone and dexamethasone or antihistamines like piriton for at least one week either side of LIT as they may reduce its effectiveness.  Similarly, its normally not recommended to have LIT in the same week as taking Humira.  According to Dr Tsagaris, some antibiotics should not be taken within one week of LIT but tetracycline antibiotics like doxycycline are not a problem.  Other practitioners’ views may be different.

13.5.16   Who can be a donor for LIT?
Theoretically, any healthy person (male or female, related or unrelated) can be a LIT donor but they must have the required screening tests and you would want to get their DQa tested to find out whether they would be likely to be a useful donor for you. If you are using egg donation, the egg donor might be a good source of blood for LIT - as she will be infection screened (and you are already accepting any risk of infection from her by accepting her eggs) - and she will be providing half of the genetic material for the embryos. 

For example, if you have been advised to try donor LIT because you have a lot of DQa matches with your partner, there would probably be little advantage in using a donor who had the same/very similar DQa as your partner (e.g., his sister), whereas if you are looking for a donor who has a similar DQa to your partner (say, because he can’t travel with you on the date you need LIT), his brother or sister, might be a good suggestion (because they might match him).  Your parents, brother or sister probably would not be a good donor for you (as they would probably match you).  Apparently, Dr Tsagaris does not permit one donor to give blood to two ladies at once (unless it’s a pooled mixture) because it needs too large a sample for one person to give.   It might be possible to trade your partner’s blood with another lady’s partner who is having LIT on the same day if the DQas are advantageous to both of you and you are happy that the donor has been properly screened.   As I understand it, it is this system that Dr Gorgy is using for donor LIT in London (i.e., he is finding couples whose partner’s have suitable DQa to ‘trade’ donor blood – as otherwise it may be difficult to find donors).

13.5.17   What screening tests does my partner (or donor) need?
The key tests (HIV, HTLV, Hep B, Hep C) are the same for all LIT providers, but they all have different requirements and their requirements have changed over time. It is best to get an up to date list from the provider or from someone who has just had their LIT.  The 30 day rule for blood tests in the UK is a strict requirement.  If you miss your LIT appointment through illness or some other reason and cannot have the LIT done before the blood tests expire, in the UK you will need to pay for all the infection tests again before you can have LIT (unless your GP will let you have them on the NHS).   For Dr Gorgy and Clinicheck you are probably best to arrange the screening tests through them due to the 30 day rule and their own requirements.

This list is current as at Feb 2010 for Dr Tsagaris only (the comments have been added to help you – but they were not provided or checked by Dr Tsagaris):

1.   HIV I+II - the virus that causes AIDS
2.   CMV (IgM, IgG) = cytomegalovirus - a virus which can be hazardous if you are exposed to it for the first time at the start of/during pregnancy
3.   EBV (IgM, IgG) = epstein barr virus - a virus which can be hazardous if you are exposed to it for the first time at the start of/during pregnancy, but its ok if your husband only has a past infection and not a current one as this is unlikely to be transmissible
4.   HTLV = human T lymphocyte virus - a virus that can be like HIV
5.   Anti-HAV (IgM+total) = antibodies to Hepatitis A - probably not so important as its normally transmitted by poor food hygiene and is rarely transmitted by blood products - past infection is very common, but not a problem for LIT
6.   Anti-HCV = hepatitis C = a virus that can damage your liver
7.   HBsAg = hepatitis B surface antigen = if positive it means active infection which would be transmissable to someone else through white blood cells (including LIT)
8.   Anti-HBsAb = antibodies to hepatitis B surface antigen = if positive it either means you have been successfully vaccinated against Hep B, or you have previously had hepatitis B and recovered (this test might not be quite so useful as the other Hepatitis B tests for determining infection status)
9.   Anti-HBcAb (IgM) antibodies to hepatitis B core = if positive it means you either have infectious hepatitis B now, or you have had it very recently (there is a similar test which measures total antibodies to hepatitis B core rather than only the IgM antibody - but that one only tells you that you've had hepatitis B in the past, rather than telling you how recent the infection was/is)
10.   SGOT (AST) = liver function test - EBV and hepatitis can damage the liver
11.   SGPT (ALT) = liver function test - EBV and hepatitis can damage the liver
12.   GGT = liver function test - EBV and hepatitis can damage the liver
13.   VDRL = syphilis test - other syphilis tests can substitute for this one
14.   CBC = FBC = full blood count = general test of health - doesn't give you any specific information and can come up 'abnormal' for lots of different and trivial reasons e.g., recent flu, pregnancy, steroids

It may be worth seeing what test results you already have on your IVF file (if you are having LIT outside the UK), and whether you can get any of them through your GP to reduce the cost.

As at August 2010, the list of tests for paternal LIT with Dr Gorgy was:
- rubella (both partners)
- HIV
- Hep C
- Heb B (surface antigen & core antibody)
- Syphilis (VDRL)
- full blood count
- HTLV 1 & 2

Serum Athens require: HIV 1&2, Hep C, Hep B and Syphilis.

13.5.18   Are the test requirements strict?
Where you are having paternal LIT, Dr Tsagaris expects you to get all these tests done and to let him know in advance if any of them show a problem.  Where you are providing the donor, it is essentially your responsibility to determine that he/she is properly screened.  Dr Tsagaris does glance at the test results when you have your first LIT, and its possible that he MIGHT still agree to treat you if some of the less critical tests are missing from your results (the HIV, HTLV, Hep B and Hep C tests are clearly essential) but he does rely on you to ensure your partner (or any known donor that you bring) is properly screened.  If you are having third party donor LIT, then it is obviously his responsibility to ensure that the donor is properly screened.

Nogales are apparently strict on their test requirements.  Dr Armstrong is very strict on test requirements and, presumably Dr Gorgy will be too as he needs to keep his UK licence.  I understand Cliniccheck require you to do all your blood tests ‘in house’ with them.

For LIT at Serum its possible for your partner to have the screening tests the day before LIT for a fairly low fee (110 Euro).

13.5.19   How much does LIT cost?
I think it is £1500 for 2 shots of paternal (or donor if that is available) LIT with Dr Gorgy but blood tests are around £270 on top of this.
I think it is £2680 including blood tests for 2 shots of paternal LIT with Cliniccheck in London.
I think it is €600 per shot of paternal LIT with Dr Tsagaris in Athens – blood tests are around £400 but could potentially be cheaper if you have already done some of the tests as part of your IVF (e.g., Hepatitis B, C and HIV).  As there are no time limits on the expiry of screening test results, you might be able to get your GP to do some/all of them.
I think it is €700 for 1 shot of single donor LIT with Dr Tsagaris (no blood tests needed) and €750 for pooled donor LIT.
It is €245 per shot of paternal LIT with Serum in Athens.


13.5.20   How do I retest my LAD after LIT?
You would probably want to wait 3-5 weeks before retesting to give your body chance to show a reaction.  Depending where you live, it may be cheaper to get you and your partner’s blood drawn and fedex it yourself to RFU Chicago (the blood test request forms and shipping instructions are on their website here http://rosalindfranklin.edu/DNN/home/CMS/Microbiology/CILab/CITests/tabid/1311/Default.aspx

You need to send 1 yellow SST tube of your blood and 3 green lithium heparin tubes of your partner’s blood.  Your partner’s blood has to be less than 48 hours when it gets to Chicago so you need to check with fedex about the timing of their pickups and coordinate with your GP or (private) hospital about getting the blood drawn.

You need to bear in mind that the blood needs to arrive in Chicago on a weekday during working hours and avoid any bank holidays in the UK or US.

It is probably easier to go through Dr Gorgy (or another consultant), and ask his clinic to organise the test for you by post or go to TDL on a mon-wed morning to get the blood drawn there.  If you ask for a post pack – it will be posted to you and include the right tubes and a completed requisition form (you can double check by comparing the colours of the tube tops against the coloured ‘spots’ shown next to the tests on the requisition form in the pack – but normally TDL get that right).  You need to take these to your GP/local hospital to get the blood drawn preferably on a Monday or Tuesday afternoon just in time to take it to the post office where you need to pay for special delivery next day by 9am service back to TDL.  TDL will then Fedex it to Chicago in their daily Fedex run and fax the results back to Dr Gorgy/other consultant.  If you are in any doubt about the timings, you should phone TDL pathology and speak to their Referrals Department to check with them the timing of their fedex run to RFU for that week.

The results are normally back within 2 working days of the blood arriving in Chicago.

You can also have your LAD retested in Athens if you are going to be there for treatment. 

13.5.21   How can I book in with Dr Tsagaris in Athens and ask any queries?
Dr Tsagaris is notoriously difficult to get hold of or to get email answers from.  You can try all his various emails and phone numbers.  The easiest way is to try to contact someone through Fertility Friends (‘LIT needed’ thread) who is about to go to Athens for LIT and ask them to ask your questions for you and book you in.  She will need to take all your contact details, DQa and LAD numbers with her to give him.  Dr Tsagaris will write your name in the LIT diary (which your friend will see) and that is confirmation of your appointment.

Dr Tsagaris’ contact details are:
[email protected]
[email protected]
mailto:[email protected] [email protected]
mailto:[email protected] [email protected] (Dr Tsagaris’s assistant)
Telephone 00302108993200
Fax +0030107214222  00302109658442
00306944513332 mobile

The website for the fertility clinic where Dr Tsagaris runs the fortnightly LIT clinic is www.infertility.gr (but its in greek so you will need to use google translate or similar).

13.5.22   Where are the LIT clinics in Athens?  What’s the procedure? How long will it take?
Dr Tsagaris’ clinic is at 43 Ypsilantou which is near Evangelismos metro station (on the airport metro line and the X95 bus route) and Evangelismos hospital.   If you take the metro, follow the signs for the hospital and it will bring you out near some steps up into a small park.  Go up through the park which brings you out in front of the hospital.  Turn left, walk past a newspaper/snack kiosk and cross the road – there is a pharmacy on the corner of Ypsilantou and the clinic is next door to that.  Find the middle column of bells and press the 3rd up from the bottom.  When the buzzer sounds you can open the door and go up to the 1st floor. There is another buzzer there to get into the clinic.   In the clinic you need to write your name and address on a card and say whether you are there for ‘husband blood’ or ‘donor blood’.  Take a seat and wait (it can be a very long wait).  All the donors’ blood is taken first before the ladies are called in one by one for LIT.   There isn’t an appointment system, but the clinic starts at about 2.30pm and runs until everyone has received their LIT.

If you are rushing to meet a plane, you will need to try and ask to be seen as a priority but there are no guarantees about when you will be finished and you need to bear in mind that the receptionists do not speak English, although Dr Tsagaris does.

When your partner is called, he will be taken to the treatment room by a nurse and up to a pint of blood will be taken by syringe.  He will be given a carton of juice to drink afterwards by the nurse, but it is better if the donor is well fed and hydrated before he gives blood (not fatty food though). You can buy drinks and snacks at the kiosk near the clinic or from other shops nearby.

Later in the afternoon, when your name is called, you will go into the treatment room (with your partner), sit down and roll up your left sleeve.  Dr Tsagaris will want to see your partner’s screening results if you are having paternal LIT and will chat to you whilst the LIT is given – its about 12 pinpricks on the inner arm. After which you will be bandaged with a big sticking plaster and told to leave your arm alone for 24 hours.   Then you go back out to reception, pay your bill (in cash) and you are free to leave.
If you want to make another appointment for yourself or someone else, you should ask Dr Tsagaris before leaving his treatment room so he can instruct the receptionist to book the appointment and you can see it written up in the diary for the right day (and the right name).

By the time the bandage is taken off the following day most ladies will see a patch of what looks like insect bites which may be itchy, but it may take a few days to reach its maximum skin reaction.  The marks will then gradually fade but are often still slightly visible even after a few weeks.

With other doctors, the exact procedure may be slightly different (e.g., using the other arm or both arms) but the basics of having the blood taken earlier in the day, then receiving the injections later the same day will be the same.

For Serum, you can take a taxi (print off a copy of the clinic's address from their website so you can hand it to the taxi driver at the airport) for about 40eu, or you can take the metro (very easy!)for 6eu  to, say, Ampelokipoi and walk from there (about 15 mins) - print off a map from google before you go.  The clinic is at 8 Evinou (parallel road to Evrou).  You can also catch the N95 bus for 4 eu.  Serum operate an appointments system and the staff speak English - there is an English nurse, Sharon too. Although, as with all clinics, appointments are often a bit delayed - so take a book and preferably make contact with someone else from Fertility friends to chat with.

13.5.23   Is it difficult travelling to Athens and getting to the clinic?
It was easier than I expected and it is nice to meet up with other fertility friends ladies there.  If you want company to travel with, you may well find someone travelling out on the same day as you on the ‘LIT needed’ thread on Fertility Friends or try the Serum thread on the Greece section. The metro service from the airport to the clinic and to the centre of Athens is easy to negotiate because the signs and ticket machines have instructions in English, otherwise you can take a taxi (but that is more expensive) or the X95 bus to Syntagma (which is even cheaper than the metro).  Most ladies who decide to stay over in Athens choose hotels in Syntagma, Plaka, Acropoli or Kolonaki because they are close to the clinic and avoid the more ‘down at heel’ area around Omonia. 

Hotels near Serum include the Alexandros, the Athinais and the President.  It may be cheaper to buy a hotel and flight together online from sites like BA.com, expedia.com or lastminute.com.  Some ladies make a day trip to Tsagaris from Heathrow using the first and last BA flights there and back (I think the Easyjet flights from Gatwick no longer have a helpful timetable, but this can change), but this can be stressful if the clinic is particularly busy and it is a long day.  You do need to pay in cash for Tsagaris because the clinic doesn’t take credit cards or UK cheques but there are cash machines nearby – pickpockets are apparently a problem in all big cities now – so its been suggested that you might want to carry cash in your bra, for example.  There are many cafes and restaurants in Athens but if you want to find somewhere particularly nice, the ladies on the ‘LIT needed’ thread or the SERUM threads on the Greece section of the board often have tips to pass on.


13.5.24   When should I have LIT?

Most docs recommend 2 shots of LIT at least 2 weeks apart (4 weeks spacing is ideal but you can leave it longer, although having shots closer together than 4 weeks might mean that you don't give your body enough time to get the maximum benefit from each shot).  A few docs e.g., Armstrong only give 1 shot of LIT and some protocols specify several shots e.g., I've seen a Japanese hospital protocol where shots are given every 2 weeks until there is no longer any skin reaction.  So assuming you are following the Beer protocol using 2 shots, ideally you want to have it in advance of your fertility treatment so that you have time to have at least 2 shots of LIT, then a retest of your LAD 2-5 weeks (ideally at least 4 weeks) after the 2nd shot to make sure your LAD has risen as expected, so that you can book a booster shot if not before your cycle.  However, some docs feel that the benefit of LIT is mainly in protection from miscarriage rather than improving implantation rates, so some ladies decide to wait until they get a positive pregnancy test and then retest their LAD, and arrange a booster shot then if necessary (or not retest LAD and just have a booster shot anyway).   However, that could be more stressful as you would obviously want to get a shot of LIT almost immediately on BFP which will be difficult due to the time it takes to get your LAD results back and to arrange a rushed trip to, say, Athens. 

13.6   Lovenox
13.6.1   What is Lovenox?
Lovenox is the US version of clexane (see clexane, above).

[SunshineGem]

Agate
As you can see from my thread I have been through the ringer and really don't know where to go and what to do next, this morning another BFP. I know zita and George are the best but I'm scared something is being missed. We even had IMSI this time as DH morphology has gone down dramatically, even though he's taking every supplement going!!
Any ideas




Sunshine
X

[MistyB]

19   R
19.1   Recurrent pregnancy loss – see miscarriage (above or click here)

19.2   Resources and links

Yasser Latif at Rigcharm pharmacy (used to be called Ali's pharmacy), London yasser latif <[email protected]>  0207 790 9150
Central Homecare pharmacy (mail order pharmacy - tend to be cheap for IVF drugs) 01420 543400
Healthcare at Home fertility  (Jade Herrington) 08702 400518
london medical diagnosis laboratory (cheap and easy access blood tests) http://www.medical-diagnosis.co.uk/o-nas

Agate

Just a copy of updates, Rigcharm pharmacy does still go by the name of Ali's pharmacy.  They have been having trouble with their landlines so mobile number is 07957472457 or email [email protected]

Also the link to London Medical Diagnosis Lab doesn't work, and if you remove the text after the / it takes you to a polish site, not sure if they are still in business or have changed their website address.

Thanks
Misty

[Devonrocks]

Hi there,
Is anyone able to point me in the direction of information on neupogen?

Thank you
Alice

[agate]

Under GCSF