HLA Qa match - how to treat?

iwanna

16 Posts
Reply HLA Qa match - how to treat? Posted on: Dec 4, 2011 at 9:10pm
Dr. Braverman, thank you for offering this service to everyone...I'm hoping you can offer some insight and hope that my husband and I could still have another bio child together, with me carrying - after being found to have an absolute HLA DQa match. I would love your advice on how to treat such a case....as I hear that you do not agree this dx is a lost cause & that our only option is donor sperm or gestational surrogacy.


Background:
My case is a bit unique and took a long time to figure out, because my husband and I have previous proven fertility together - we have 3 sons together, and I also have a daughter from a previous relationship. I was also a surrogate mother x 3!!! It was only after my last surrobaby birth in Nov 2005, that my husband and I began TTC another child together, and have experienced nothing but RPL - all super early losses before I've even missed my period. I'm an obsessive, early home pregnancy tester and have caught them all between 9-13dpo, and the +++ tests only last 1-3 days each time. Our first loss was detected in only our 4 month of TTC in July 2006 - so it seems we are still plenty fertile together, we just can't get one that stays with us.

To make a very, very long story as short as possible, since we began TTC in Feb 2006, we have been through many natural cycles, 13 IUI cycles, and 3 IVF's. All hormone levels are where they should be. I was found via laparoscopy to have stage 4 endo in Feb 2009 and lost my left ovary & tube. AMH this past summer was good at 1.4 with only ONE ovary. My AFC has ranged between 3 and 11 in the past 2-3 years. My uterine lining develops perfectly between 12-16mm triple stripe at trigger. We did a full (very extensive) RPL/immune panel the spring of 2010, and nothing too significant was found, only these:
elevated NK cells: CD56 = 14%
slightly elevated TSH - 3.35
slightly Protein S deficient - level was 55
heterozygous for MTHFR w/ one copy of C677T

After this testing, my RE started treating me *emperically* with intralipids, lovenox, and prednisone right away, and also put me on Synthroid 75mcg, and my TSH has remained around .76, but does drop too low when doing stim cycles. Since then 3 of our our IUI's and all 3 IVF's have been done with this immune treatment in place, though lovenox was only used in 3 of those cycles, and it was only started at the proper time in my last IVF cycle) The outcomes of those cycles were 2 more chemical pregnancies, and 4 BFN's. I did suffer 2 other chem pregs in a row, from natural cycles in Jan & Feb 2011, right in-between the 3 IUI's and 3 IVF's, when I was not doing any immune treatment, ugh.



After our 3rd failed IVF this past October, when we had everything as perfect as possible with immune treatment, along with it being my best response w/ IVF out of the 3, I was just devastated!! (and not ready to use donor eggs!!) So I reached out to Dr. Sher, and with ONE phone call, following a review of our history, he suggested testing for HLA DQa - and 2 weeks later we finally had our answer. We were found to have a partial (but absolute) HLA DQa match:
me: 3.0, 4.1
DH: 4.1, 4.1


I also had the full (k-562 target cell) NK Cell Assay done:

NKa Assay:
T:E 1:50 Native State % killed 10.0
T:E 1:25 Native State % killed 5.8
T:E 1:12.5 Native State % killed 2.3
T:E 1:50 w/ IL-2 stim % killed 10.2
T:E 1:25 w/ IL-2 stim % killed 7.6
T:E 1:12.5 w/ IL-2 stim % killed 4.5
T:E 1:50 w/ IVIG 12.5 % killed 8.7
T:E 1:25 w/ IVIG 12.5 % killed 8.6
T:E 1:12.5 w/ IVIG 12.5 % killed 6.1
T:E 1:50 w/ IVIG 6.5 % killed 9.1
T:E 1:25 w/ IVIG 6.5 % killed 6.8
T:E 1:12.5 w/ IVIG 6.5 % killed 4.6

Interpretation:
Abnormal NK Cell Activity
No stimulation with IL-2
Suppression with higher dose IVIG




NKa Assay w/ Intralipid:
T:E 1:50 Native State % killed 10.2
T:E 1:25 Native State % killed 4.6
T:E 1:12.5 Native State % killed 2.9
T:E 1:50 w/ IL-2 stim % killed 10.4
T:E 1:25 w/ IL-2 stim % killed 8.2
T:E 1:12.5 w/ IL-2 stim % killed 3.8
T:E 1:50 Intralipid 1:2000 % killed 12.8
T:E 1:25 Intralipid 1:2000 % killed 8.4
T:E 1:12.5 Intralipids 1:2000 % killed 4.1

Interpretation:
Abnormal NK Cell Activity
No Stimulation with IL-2
No suppression with INTRALIPID




As you can see, my actual NKa results don't appear too bad....but i'm wondering, could it be bcause I'm on 3600mg fish oil/daily? Also, this was done just 6 weeks following my last IL infusion (I actually had 2 IL infusions in Oct - one was 8 days prior to egg retrieval, and one was done 2 days before embryo xfer) and it was only 3-4 weeks after stopping 40mg/daily lovenox and .75/daily dexamethasone - so I was wondering, could those things have contributed to getting these results that don't appear that bad? (we assume the levels must skyrocket when an embryo enters my womb, seeing as how swift my body destroys them when they try to implant) would this be your assumption as well?

Also, at first I was very upset thinking intralipids don't work for me, but Dr. Sher explained that this is not the case, due to the limitations of this test and it being in-vitro, rather than in the body, where IL's are given ahead of NKa to PREVENT the activation from occuring. He said IL should work just fine for me, if we used donor sperm for example. Would you agree with this?


As for all possible treatments...I know there is LIT and other things, but we can't afford to do much more...whether it's more testing or more treatment. So...what should we do? Is there ANY hope at all for me to still carry my husband's child again? He is really struggling with the donor sperm idea, and we don't have a lot of money to work with anymore, after already spending SO much over the past almost 6 years, and depleting our savings.



Sincerely,
Holly

iwanna

16 Posts
Reply Re: HLA Qa match - how to treat? Posted on: Dec 5, 2011 at 7:24pm
Just to add info on the other testing that we had done:


Lab results from april 30, 2010:
DHEA-S: 306 = normal (range is 40-325)
DHEA: 417 = normal (range is 102-1185)
Lupus Anticoagulant: negative
Lupus PTT-LAC screen: 30 = normal (range is <40)
Lupus DRVVT screen: 27 = normal (range is <42)

Anti-Thyroid Antibodies/peroxidase: <10% = normal (range is <35%)
ANA - Anti-Nuclear Antibodies: negative
Thyroglobulin Antibody: <20 (range is <20IU/mL)

APA - Anti-phospholipid Antibodies - 9 part panel: NORMAL/negative --->
Cardiolipin AB - IGG: <10 (range is <10 GPL U/mL - negative)
Cardiolipin AB - IGM: <10 (range is <10 MPL U/mL - negative)
Cardiolipin AB - AGA: <10 (range is <10 APL U/mL - negative)
Phosphatidylserine AB IGM: <25 (range is <25 U/mL - negative)
Phosphatidylserine AB IGA: <20 (range is <20 U/mL - negative)
Phosphatidylserine AB IGG: <10 (range is <10 U/mL - negative)
B2 Glycoprotein I [IGA] AB: <10 (range is <10 U/mL - negative)
B2 Glycoprotein I [IGG] AB: <20 (range is <20 U/mL - negative)
B2 Glycoprotein I [IGM] AB: <10 (range is <10 U/mL - negative)

Natural Killer cells ---->
Absolute Lymphocytes: 1118 = normal (range is 850-3900 cells/uL)
NK Cells - CD3-CD16+CD56+ (ABS): 154 = normal (range is 70-760 cells/uL)
NK Cells - CD3-/CD16+CD56+: 14% = normal (range is 4-25%)





Lab results from tests on May 12, 2010:

Homocysteine = normal at 4.5 (range <10.4)
Protein C = normal at 102 (range70-180)
Protein S = LOW at 55 (60-140) (treating w/ lovenox for TTC and pregnancy)
Antithrombin = normal 103 (range 80-120)
MTHFR = positive for 1 copy of C677T and negative (normal) for A1298C
APC resistence/protein C ratio = normal at 3.8 (range is >2.1)
PT = normal at 10.1 (range is 9.6-11.3)
INR = normal at 1.0 (range is 0.9-1.1)



I've also had all the other basic stuff done too - in the spring of 2010 and again this past Jule 2011 - like a CBC and CMP - nothing else stands out.


On Nov 25, 2011 we ran these tests:
TSH: 0.32 (we lowered my dose of Levo from 75mcg/daily to 50mcg x 4 days and 75mcg x 3 days each week)
T4 free: 1.3
T3 free: 2.70
Vit D: 39 (added 10,000iu supplementation of Vit D3, daily)
Vit B12: 1672 (we have no idea why this is so high or if it's a problem?)
Vit B6: never received results, need to call and ask about it!!
ferritin: 30 (have yet to add anything extra to boost iron stores, background: I have suffered from low iron for many years even w/ religiously taking iron supps for YEARS - yet adding a children's chewable vitamin quickly brought my HGB up from 10-11 to an acceptable 12.7 almost 2 years ago - not sure why ferritin is still low, unless it was actually much lower after years of low iron, and is still on it's way up due to the addition of children's chewables)




Do you think adding Neupogen is something we should consider?

Dr. Braverman

1998 Posts
Re: HLA Qa match - how to treat? Posted on: Dec 5, 2011 at 7:46pm
ok just a few things here.

1. YOU DO NOT NEED SPERM DONOR(in caps so we are clear on that)

2. this is not an HlA issue with 3 successful pregnancies. I have seen some cases with two but not three. DQ alpha testing alone is useless as it only looks at 2 possible matches and our experience here(yes Ive had many successful with only DQalpha matches, never used a surrogate for that) is that at least 5 matches between the couple(and a few other things I wont get into are necessary to determine risk of a loss.
Your immune testing is really not significant to me, alot is missing however. (NKT cells, cytokines, activated T cells and others that we have recently added to our panel.) it is imperative regardless to track all the immune parameters prior to , during and after any miscarriage to get a true understanding of the immune systems involvement.
IL17, TH 17 , T regulator cells, subsets of all of the NKT cells(as some are regulatory and some inflammatory ) and without some type of fucntional assay everyone is just guessing. The problem is that most who are treating this do not have a complete understanding of immunology and its hard enough even when we get all the cells tested to decipher what is happening , it is near impossible to do with just a cursory few that many have gotten used to ordering.
we have to really complete your immune panel(yes i would still finish the entire HLA screen even though I think thats unlikely-but as sherlock holmes once said "when the likely is no longer likely ,it is time to consider the unlikely).
There is a lot of literature out now looking at mostly the conversion of stromal cells to decidual cells in the uterine lining and the "implantation window" , not an immune problem but a physiologic one that we have treatments for (nuepogen is one of them). There could be infection such as endometritis, and many times I find that the treatments patients were given to them for "immune" issues end up actually being the problem as oversuppression is just as bad as "inflammation"

I would be happy to guide you through all of this . Feel free to call my office and schedule a phone or skype consultation and Ill take you throught this. Dont loose hope and tell your husband to stick around.
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.

iwanna

16 Posts
Reply Re: HLA Qa match - how to treat? Posted on: Dec 5, 2011 at 10:19pm
Dr. Braverman, thank you for such a prompt, and detailed reply!!

I have a question based on our own concerns & thoughts, but prompted even moreso by YOUR reply...
Seeing as my husband & I never had problems before, and this all started immediately after giving birth to my last surrobaby (I birthed 2 children for this couple, one in Jan 2004, and the 2nd was Nov 2005 - which BTW, we went through A LOT to get these children here, including switching from gestational surrogacy to traditional surrogacy, and doing IVF to retrieve my eggs, due to the dad's male factor issues & their need for ICSI) do you think it's more probable that something significant was triggered based on possible matching issues with the Intended Father of the couple I was surrogate mother for?


My concern is, paying for ALL of this new testing you are suggesting for my husband and I - when, in such a unique situation, there are actually, possibly 2 paternal contributors to my RPL issues. Obviously my husband & I share the HLA DQa match, but yes, as you sa - it is quite confusing as to why it only became an issue 9 years after the birth of our last child together!! Especially considering our very first chem preg resulted from only our 4th TTC cycle. I just keep thinking that if it were just my husband & I, that it would not have presented so fast and so detrimetnal like that. I would think it would have taken more actual exposures to ongoing pregnancies to reach this level of swift and deadly attacking power - in the form of a full term pregnancy or bare minimum, true clinically dx'd miscarriages. I've always read of women experiencing miscarriages that present earlier and earlier with each exposure, and then ultimately presenting as super early chem pregs, or perhaps they don't even know they are still conceiving if they're not testing at home as obsessively as I do!

In fact, we arranged for the Intended Father to be tested for HLA DQa as well - having initially not expected to find any match with my husband & I. Due to the recent holiday and his business travel, he is just going to go tomorrow for this test, though - we planned on cancelling it, after getting our results and thinking we had our *answer*. But I still wondered if it was something with him that triggered this intense, immediate, and unrelenting RPL problem I've had ever since helping them as a surromom. What are your thoughts on his possible role in all of this?


Also, given the unusual circumstasnces surrounding my case...I must admit, we cannot move forward with testing for all of these new things for both my husband & I, AND the Intended Father. In fact, I'm almost certain my husband is going to say enough with the testing even for just us....because isn't the treatment essentially the same in cases like this - even if there were more HLA matching issues found?

We're just so ready to move onto whatever will work, and while my husband is uneasy about using donor sperm, he is even more uneasy about spending thousands more on more testing as well. If we could just get a clear cut, "You need to try X, Y, Z protocol" and we could move forward with it - even if it means paying for for you consulting services and to manage our care, he'd be much more inclined to say ok - let's pay for those meds & treatments & try it a couple times. Otherwise, it all just seems so daunting....and obviously, we're tired, and we're getting older, and we have other children to think of as well, in terms of spending every last dime we can on all of this. We just want a solid answer on what COULD work for us and we want to try it.


Your thoughts?

Dr. Braverman

1998 Posts
Re: HLA Qa match - how to treat? Posted on: Dec 6, 2011 at 4:24am
Ok so you want the "cut to the chase" special program. We just put that on our dollar menu this week. I completely understand where you are coming from and yes I can treat for what we suspect without spending all the money on testing. Its not optimal as I would be jumping to our best treatments without knowing for sure that you need them, but not that costly. Call me and we can discuss.
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.

iwanna

16 Posts
Reply Re: HLA Qa match - how to treat? Posted on: Dec 6, 2011 at 3:30pm
Dollar menu = perfect!!! LOL!!

So you are a Dr. with a great sense of humor AND expertise - I LOVE IT!!!!


Bottom line, I am a detail junkie too, and I would LOVE more answers, and to have left no stone unturned, but that's just not possible at this point. If money were no issue I'd say sign me up for any and all testing - for both my husband & myself, and the Intended Father of my surrobabes, and I'd write out the checks ASAP. But the bank account has run dry - so yes, I would be very interested in your new Dollar Menu!! LOL!!



That said....you mentioned earlier:

There is a lot of literature out now looking at mostly the conversion of stromal cells to decidual cells in the uterine lining and the "implantation window" , not an immune problem but a physiologic one that we have treatments for (nuepogen is one of them). There could be infection such as endometritis, and many times I find that the treatments patients were given to them for "immune" issues end up actually being the problem as oversuppression is just as bad as "inflammation"



How do you test for this?


Sincerely,
Holly

Dr. Braverman

1998 Posts
Re: HLA Qa match - how to treat? Posted on: Dec 7, 2011 at 5:18am
there are no good tests out know for the function of stromal to decidual cell conversion In the research they look at prolactin production and Insulin Growth hormones but no standard labs are doing this yet. We do perform and can arrange for an endometrial biopsy to try and assess endometrial cell function and it also looks at some immune cells to "try " and determine if this is immune or funcitonal . These tests are run at your Yale University laboratory and still in thier infancy as to trying to interpret such a small tissue sample and make heads or tales out of it.
And with that be with soft drink or without?
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.

iwanna

16 Posts
Reply Re: HLA Qa match - how to treat? Posted on: Dec 7, 2011 at 5:36pm
Haha!!! Well, I've given up caffeine, so can I just get a water with that?


Ok, since I would be a long distance/phone consult type of patient, how would you figure out for me if I've got something wrong with my uterine lining? Especially if the testing is not completely perfected? And - Is this the same thing as when I've heard women saying their lining doesn't *convert* at the proper time - say they find out their lining is 3 days BEHIND schedule for example, so when doing IVF they must freeze all their embryos, and come back later for an FET - is this what you're talking about? I believe I've read from those women, that the info was indeed gained via an endometrial biopsy.


Also, you mention that Neupogen is something you use to treat this uterine lining issue - if this was found to be an issue, can it be treated so that women can still be successful with natural or IUI cycles? We are really hoping to try more IUI (and natural cycles in-between) seeing as we have conceived both ways, several times.



You mentioned prolactin & insulin growth hormones as well - are you speaking of checking on these levels through simple blood tests? I know my prolactin level was ok at 13, when last checked. As for insulin growth hormones - I show no signs of PCOS, and don't appear to have anything else going on that would lead us to worry about this issue. So.....taking this very basic info into consideration, and seeing as I had no trouble conceiving and carrying prior to the year 2006, and considering the fact that our super early losses started occuring just 7-8 months post partum, on only our 4th month of TTC, also knowing there is (at least) the HLA DQa match between my husband & I, my hormone levels have ALWAYS been normal/good, and my uterine lining ALWAYS *behaves* - do you REALLY think this uterine lining issue could be my problem, or part of the problem?

I really don't want to move forward with any treatment if we're still missing something, but if the testing isn't precise on this issue, and if I don't necessarily fit into the categories that put me at risk for this uterine lining problem - I'd like to know if this is something you would pursue or not with me? In other words, what would make you decide for sure to have this tested?


Thank you again for your help - every bit of advice or info brings us that much closer to start treatment again, we just NEED to be sure of the expectations and ideas you have, and then we can prepare to get started!!


Sincerely,
Holly

iwanna

16 Posts
Reply Re: HLA Qa match - how to treat? Posted on: Dec 7, 2011 at 5:43pm
Just need to say - I am such a detail junkie, that having a typo in my *subject line* is really bugging me!! LOL

I do know that it is supposed to be HLA DQa - wish I could add the *D* in there and fix it!!!!

Dr. Braverman

1998 Posts
Re: HLA Qa match - how to treat? Posted on: Dec 8, 2011 at 2:50am
ok to clear up some confusion

the uterine lining issue Im speaking of has nothing to do with "out of phase" that is tested on endometrial biopsies. that is a progesterone effect this is more of a functional effect that in the research labs has been tested by looking at release of prolactin or insulin growth factors that are in no way related to blood levels of these hormones and therefore in no way related to PCOS. these functional tests of the decidual lining are not yet available in commercial labs so we still have to infer the existence of these problems. It becomes a diagnosis of exclusion, but I have done very well when treating it when I suspect it. (to suspect is what takes the years of experience and the many lost nights of sleep thinking about "what else could it be?"

Lastly many of my patients with just implantation issues are treated with IUI or natural cycles.
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.