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Understanding Immunologic Implantation Dysfunction Part 2: A Rational Basis for Selective Intralipid & IVIg Immunotherapy in IVF

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ALLOIMMUNE VS. AUTOIMMUNE DYSFUNCTION

Alloimmune Implantation Dysfunction

Every human being has two DQ-alpha genes. One is contributed by the father and the other by the mother. In a small percentage of patients undergoing IVF, paternal-maternal DQ-alpha gene similarities occur.In such cases, following repeated exposures to such genetically matching embryos, this will provoke activation of the decidual immune system. In most cases, through the mechanisms described above, this will lead to NK/CTL activation and reproductive failure (i.e.; infertility, and pregnancy loss).We refer to this phenomenon as alloimmune implantation dysfunction.

This is how alloimmune implantation dysfunction happens:Immunogenetically triggered HLA-G signaling by the embryo leads to a reduction in Treg cells, and eventually to a destabilization of NK/CTLs with domination of TH-1 over TH-2 activity. The severity with which this occurs determines whether total implantation failure will occur, or whether there remains enough residual trophoblastic activity to allow the pregnancy to limp along until the nutritional supply can no longer meet the demands of the pregnancy, at which point miscarriage or pregnancy loss occurs.

With paternal-maternal DQ alpha matching, it often takes several pregnancies for natural killer cell activation to build to the point that a woman with alloimmune implantation dysfunction will present with clinical evidence of implantation dysfunction. Sometimes it starts off with one or two pregnancies surviving to the birth of a baby, whereupon NK cell activity later starts to build, leading to one or more subsequent early miscarriages. Eventually the NK cell/CTL activity is so high that subsequent pregnancies can be lost before the woman is even aware that she was pregnant at all. At this point she is often diagnosed with secondary “unexplained” infertility.

Autoimmune Implantation Dysfunction:

With autoimmune implantation dysfunction, NK cell activation is already well established by the time the embryo reaches the uterus. Accordingly, in such cases the pregnancy is usually lost before its presence can be established by a blood pregnancy test or an early ultrasound examination (i.e., it presents as a negative pregnancy test or a chemical gestation).

So how is autoimmune implantation dysfunction established?The initialrecognition of the non-DQ alpha matching embryo as “friend” or “self” sets the stage for the cells/tissues of our bodies not coming under immune attack. However under certain circumstances, genetic, infective, toxic and degenerative influences can result in our own body’s proteins coming to be regarded as “non-self” (“foe”). When this happens the immune system starts to produce antibodies that are directed against our body’s own proteins. These so called autoantibodies then start attacking the body’s own cells/tissues/organs, creating pathologic states (diseases) such as can be seen with certain (autoimmune) diseases (e.g.,lupus erythematosus, autoimmune hypothyroidism [Hashimoto’s disease] and rheumatoid arthritis).

There are also certain reproductive diseases such as endometriosis, where cell membrane phospholipids are often altered by the disease process, and then combine with proteins to evoke the production of so called antiphospholipid antibodies (APAs)Certain types of APAs can both directly damage the trophoblast and can also lead to a reduction of Treg lymphocytes, culminating in activation of NK/CTLs.

This type of reaction, albeit due to a predisposition to autoimmune diseases such as lupus erythematosus, Hashimoto’s disease, etc., or reproductive conditions such as endometriosis, is referred to as autoimmune implantation dysfunction. Autoimmune implantation dysfunction is much more common than alloimmune implantation dysfunction. In fact, it is probably responsible for more than 85% of reproductive failure attributable to immunologic implantation dysfunction. The most common autoantibodies involved are:

1) antiphospholipid antibodies (APA)

2) antithyroid antibodies (ATA)

3) antiovarian antibodies (AOA)

Since autoimmune implantation dysfunction is often genetically transmitted, it is not surprising that this condition is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus, scleroderma, clinical or subclinical hypothyroidism, rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis.

As previously stated, autoimmune implantation dysfunction is usually immediately lethal to the implanting embryo and accordingly most often presents as “unexplained “ infertility and/or “unexplained” IVF failure, rather than as miscarriage.This is because NK/CTL activation is present prior to implantation and as such, the embryo’s root system is severely damaged from the get-go. Autoimmune implantation dysfunction isreadily amenable to reversal through timely, appropriately administered, selective immunotherapy (see below).

Diagnosing Immunologic Implantation Dysfunction:

Whether alloimmune or autoimmune in origin, it is only once specialized immune cells in the uterine lining known as Natural Killer (NK) Cells and Cytotoxic Lymphocytes (CTL), become activated and TH-1 cytokine dominance is established that IID occurs. Thus, a full evaluation of immunologic implantation dysfunction requires that DQ alpha, APA, ATA, as well as NK/CTL activation be evaluated. This involves highly specialized blood testing and possibly also endometrial tests that can only be performed in a handful of reproductive immunology laboratories in the United States.

Alloimmune ID is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes. A sufficient degree of matching clinches the diagnosis. Since matching DQ alphas will rarely cause reproductive failure unless there is concomitant NK/CTL cell activation, it is important to test the embryo recipient for NK cell activation (the K-562 target cell) test and CTL activation (by a blood immunophenotype and HLA-DR measurement). Some reproductive immunologists might also test blood Treg cell concentration and/or recommend an endometrial biopsy to histolochemically evaluate uterine NK cells or assess the local TH-1/TH-2 balance. The performance of blood TH-1 and TH-2 cytokines to assess for TH-1 dominance is controversial and is of unproven value.

Treating Immunologic Implantation Dysfunction

In the United States, effective treatment of NK/CTL activation associated with either alloimmune or autoimmune implantation dysfunction requires the administration of Intralipid or IVIG. Such treatment is usually much more likely to be successful in the case of autoimmune implantation dysfunction where the NK/CTL activation is present in advance of the uterus being exposed to the embryo. It is not nearly as effective for the treatment of alloimmune implantation dysfunction where a DQ alpha matching embryo will exert a sustained activation of NK/CTLs over several months of gestation. It is presently not yet possible to identify paternal DQ alpha in the embryo. Accordingly, in cases where the paternal DQ alpha gene only matches with one of the mother’s DQ alphas (i.e. a partialmatch) there is a one-out-of-two chance that a transferred embryowill inadvertently be a match with at least one of the mother’s DQ alpha genes. Thus Intralipid or IVIG therapy will only prove half as likely to propagate a viable pregnancy in cases of partial DQ alpha matching as it can achieve in the treatment of NK/CTL activation associated with autoimmune implantation dysfunction .

For this reason, I prefer to transfer only one (rather than multiple) embryo at a time in such cases,for fear of there being one DQ alpha matching embryo in the mix and so “muddying the waters” for the non-DQ alpha matching that otherwise might have propagated a healthy baby.

A real problem arises in cases of a complete DQ alpha match, where both paternal DQ alpha genes match with at least one of the mother’s DQ alphas.Here, every embryo will express a paternal DQ alpha gene that matches that of the mother’s. In such cases, Intralipid and/or IVIG therapy will rarely work. The reason is that such treatment cannot match the sustained provocation of NK/CTL activity brought about by an ever-present DQ alpha “clash.” In cases of complete DQ alpha matching (with associated NK/CTL activation), where all the embryos will inevitably carry one or both paternal DQ alphas that match the mother, there is in my opinion little hope of success, even with Intalipid/IVIG/steroid therapy. In such cases, gestational surrogacy or the use of non-DQ alpha matching, donor sperm may offer the only reasonable chance of a successful IVF outcome.

Some patients ask whether using an egg donor might not offer another solution in such cases. The answer is no! The matchup is between the paternal DQ alpha contribution (in the sperm) and the mother’s uterus. It is not between the sperm and the egg.

IVIG/IL therapy should preferably always be administered in combination with corticosteroids at an adequate dosage, starting 7-14 days prior to planned embryo transfer. With alloimmune implantation dysfunction shuch treatment should be repeated every 2-4 weeks through the 1^st half of pregnancy. The goal is to down-regulate NK /CTL activation and thereby reinstate a TH-1: TH-2 cytokine balance in advance of a “competent” non- DQ alpha matching embryo reaching the uterus. When it comes to autoimmune implantation dysfunction Intralipid and/or IVIG (with corticosteroids) need only be administered twice; (once, 7-14 days prior to embryo transfer, and the second administratio should be given when the beta hCG blood level has shown evidence of an appropriate rise, thereby suggesting that healthy implantation is likely to be in progress). Supplementation with heparinoid (see below) is indicated when there is evidence of concomitant APA’s

Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of heparin twice daily or low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation and continued until the end of the 1st trimester), can improve IVF birth rates in women who test positive for APAs.

What About Taking a Baby Aspirin a Day?In my opinion, aspirin has little if any value when it comes to IID, and besides, could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or resulting in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.

IVIg and Intralipid Therapy: In the past, the only effective way to accomplish the aforementioned immunologic down-regulation was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). However, the administration of a blood product raised understandable concern with regard to the possible transmission of viral infections such as HIV and hepatitis C.

Several years ago, researchers at SIRM and its (then) affiliate reproductive immunology program in Chicago, IL reported on the use of Intralipid (IL), a synthetic product which, upon being administered intravenously a week or longer prior to embryo transfer, elicits a similar down-regulatory effect on Nk / CTL activation as IVIg. We subsequently conducted confirmatory internal trials, and in 2007 I began prescribing IL preferentially for patients with CTL/NK activation.. To date we have treated more than 400 cases in this way and results have been very encouraging. Against this background I have now all but abandoned the use of IVIg for immunologic implantation dysfunction associated with NK/CTL activation, supplanting it with IL. On very rare occasions, where IL alone does not achieve the desired result I might recommend combining IVIg with IL therapy.

IVIg is very expensive and in about 20% of cases its use is indeed associated with immediate and delayed side effects and complications. Intralipid, on the other hand (provided that it is prescribed and administered appropriately), is virtually devoid of risk and/or significant side effects. It is also safe to the developing conceptus and it comes at a fraction of the cost of IVIg.

Corticosteroid Therapy (Prednisone, Prednisilone and Dexamethasone): Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation overall. This is more than likely to an overall immunomodulatory effect. Some IVF programs prescribe daily oral methyl prednisilone (Medrol) while others prefer prednisone or dexamethasone, commencing a week or two prior to egg retrieval and continuing until pregnancy is discounted or until after the ultrasound confirmation of pregnancy.

TH-1 Blockers (Enbrel, Humira): I was one of the first to suggest using the TH-1 cytokine blocker, Enbrel (and Humira) forNK cell activation, only to find it to be relatively ineffective in the IVF setting. To date, as far as I am aware, there have not been any convincing reports showing TH-1 blockers to be of real benefit in patients undergoing IVF. These blockers might well have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but in my opinion, not in the IVF setting. The reason is that the very initial stage of embryo implantation requires a cellular response involving TH-1 cytokines. To block them (rather than simply restore a TH1: TH-2 balance as occurs with IL or IVIg therapy) so very early could, in my opinion, compromise rather than benefit implantation.

Leukocyte Immunization Therapy (LIT): The subcutaneous injection of husbands lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation, thereby improving the decidual TH1: TH-2 balance.Thus, there could be a therapeutic benefit from such therapy. However, in my opinion, such benefit is no greater than can be achieved through the use of IL plus corticosteroids. Besides, Intralipid is much less expensive and the use of LIT is prohibited by law in the United States.

The evaluation for immunologic dysfunction as well as other factors that can affect implantation should form part of the evaluation of patients preparing to undergo IVF, and especially so in women with endometriosis, recurrent pregnancy loss (RPL), women with a personal or family history of autoimmune conditions, and women with “unexplained” infertility or unexplained IVF failure(s).

Tags: alloimmune, autoimmune, DQ alpha, Immunologic Infertility, IVF Authority, recurrent miscarriage, unexplained infertility

52 Responses to “Understanding Immunologic Implantation Dysfunction Part 2: A Rational Basis for Selective Intralipid & IVIg Immunotherapy in IVF”

ladybug says:

August 23, 2011 at 6:01 am

Dr. Sher,
It's hard for me to interpret the DQ matching data. My husband and I share the 4.1 and 6 others. Does this leave us little hope? I've had 7 miscarriages (no live births). One made it to 8 wks (the 3rd pregnancy). ONly got this dx recently so no pregnancies on immune treatments.

Reply
Geoffrey Sher, MD says:

August 23, 2011 at 10:33 am

WE should probably talk. I think I can give you some constructive input.Call 800-780-7437 or 702-892-9696 and set up a phone consultation at no cost.

Geoff Sher

Reply
hedger says:

October 14, 2011 at 12:58 pm

Could DQ matching be my problem?

37 years old
4 failed IUI's
2 failed IVF's – (2010 and 2011) there was no response to Gonal-F (1 follicle but no eggs and then second time, no follicles).
FSH was 14.1 at last IVF, took DHEA FSH went to 12.5, now 8.3
AMH is 5.9

Diagnosed with Hashimoto's, positive antithyroid antibodies.
Immune testing =
very high Thyroid Antibodies >3000,
mildly positive ANA speckled pattern,
upper range CD3% 85.3% (60-85) and CD56% 11.6 (2-12)
and very high CD19+, CD5+ cells 22.2% (2-12)
Awaiting LAD, hidden C, DQa results
Hysteroscopy and laparoscopy 15th oct

Reply
Geoffrey Sher, MD says:

October 14, 2011 at 4:41 pm

It could be, but more likely the Hashimoto's (autoimmune) is causing NK cell activation. Even more concerning is the diminished ovarian reserve.

Read the 2 articles on this blog posted on May 10th and May 16th. Also read the one I posted on November 22nd 2010.

Feel free to call 800-780-7437 if you wish to discuss further with me.

Geoff Sher

Reply
Irina says:

June 1, 2012 at 12:57 am

Dr. Sher,

First of all Thank you for an amazing resource for all infertility patients!

I am a healthy 35 y.o. with secondary unexplained infertility. I’ve had 12 picture perfect IUIs and 1 pregnancy on a break cycle, miscarried at 5W5days.

As a last resort my Dr. tested for reproductive immune issues (Chicago labs) and it was found that my NK levels are elevated – CD56+CD16+ at level 17 (norm 0-11).
The rest of the tests were all normal.

From your experience, will prednisone help implantation failure in my case?

Reply
- admin says:
  
  June 2, 2012 at 6:25 am
  
  The concentration of NK cells in your blood is not relevant. It is NK cell activity as measured by the K-562 target cell test that is important. And, if this is where the problem lies, then prednisone alone will not suffice.You will need down-regulation of NKa with Intralipid.
  
  Good luck!
  
  Geoff Sher
  
  Reply
Gemma says:

June 22, 2012 at 10:19 pm

I have had 4 miscarriages, 2 at 6 wks and 2 at 8 not found til 10weeks. My husband and I have a partial DQ alpha match for the 0501 gene plus I have the MTHFR C677T mutation gene.
My nk cells are slightly raised nut not hugely.
For my last pregnancy I was on steroids, clexane and intralipids but still miscarried. Do you think it’s possible to conceive naturally and go full term or is IVF more likely to be successful?

Reply
- Geoffrey Sher says:
  
  June 23, 2012 at 4:52 am
  
  I really would need to know much more to comment properly. Please go to the home page on this site, find a “search bar” in the upper right hand column and type in “Immunologic Implantation Dysfunction” (2 articles posted on May, 10th and on May 16th respectively)into the bar. Read this carefully and then I recommend we talk. Call 800-780-7437 and set up a telephone consultation with me to do so.
  
  Geoff Sher
  
  Reply
Sarah says:

September 23, 2012 at 1:25 pm

I have been trying to get pregnant for 11 cycles now. I have 3 IUIs under my belt ( all medicated) plus an additional couple of medicated non IUI cycles. Months and months of nothing happening and I had a chemical pregnancy cycle number 9. I just had what I was hoping to be a very successful IUI cycle ( cycle 11) only to have it end in another chemical pregnancy. I am conerned because I have type 1 diabetes which is an autoimmune disease. I am now wondering if my unexplained infertility and two recent chemicals may be due to autoimmune implantation dysfunction. Do you think it would be wise for me to undergo some sort of testing? I plan on bringing this up to my RE but i have a feeling he is not going to take me very seriously.

Reply
- Geoffrey Sher says:
  
  September 24, 2012 at 11:11 am
  
  Clearly there is something that has been (probably inadvertently) missed here. It could be an immunologic implantation dysfunction but that is speculative at this time. I would need to know much more before I could comment substantively. You might consider calling 800-780-7437 to set up a free video-conference call with me to discuss.
  
  good luck!
  
  Geoff Sher
  
  Reply
Danielle says:

October 20, 2012 at 7:29 pm

Hello … thank you so much for such helpful information! I am 32 and have 2 children, age 3 & 5, both conceived naturally the first month trying. We have been trying for another child for 20 months, and last year I lost 3 babies … one at 5 weeks, and twins at 8 weeks (1 twin had actually passed away very early on). The 2 RE’s I’ve seen are not very familiar with reproductive immune issues, and I have not been tested for NK cells, etc. However, I am convinced this is what my issue is. I am currently 11 weeks pregnant, and so far so good. I am on 1mg of dexamethasone per day, and my RE said I need to wean off now. I am nervous to do that, especially if my issue is alloimmune. Is dex safe to stay on, and if so, how long should I keep taking it? Is 1mg the proper dosage? I would love the opinion of an expert in this area. Thank you so much!

Reply
- Danielle says:
  
  October 20, 2012 at 7:45 pm
  
  ps. Yesterday and today I’ve only taken .5mg dex to start the weaning … now I’m worried about the baby. Should I go back to the full dose of 1mg?
  
  Reply
  - Geoffrey Sher says:
    
    October 21, 2012 at 10:03 pm
    
    I think you will be fine . Stay the course.
    
    Geoff Sher
    
    Reply
- Geoffrey Sher says:
  
  October 21, 2012 at 10:02 pm
  
  I agree with your RE. There is no benefit continuing longer.
  
  This having been said, I frankly am not convinced that you do have an immune issue. However, if this pregnancy fails, then you should consider arranging for us to talk.
  
  I will be praying for you!
  
  G-d bless!
  
  Geoff Sher
  
  Reply
Sharon says:

November 12, 2012 at 6:20 pm

My husband and I share some of the same Alpha genes. We have 1 biological child, born in 2010. I got pregnant on the first IVF cycle with him. When I was pregnant with my son, my antiphospholipid antibodies were high but I delivered a healthy baby boy!

Last year, 2011, we tried for another child. We did 3 IVF’s and after the third failed cycle, the RE recommended donor sperm. For one of the IVF’s I did IVIG. I did have a chemical pregnancy for the first cycle I did in 2011.

I am now 45 years old and am interested in using a donor embryo. With this issue, is it a viable option? I also have an underactive thyroid and take synthroid. Please advise if you would recommend donor embryo.

Thanks so much for your discussion on this issue!

Reply
- Geoffrey Sher says:
  
  November 12, 2012 at 9:59 pm
  
  I urge you to have an NK cell activity (NKa) blood test (the K-562 target cell test). If you have NKa then with donor embryos and intralipid/steroid therapy you should be OK!
  
  Good luck!
  
  Geoff Sher.
  
  Reply
- Geoffrey Sher says:
  
  November 13, 2012 at 8:52 pm
  
  Donor embryo -IVF is a good option because it will break the DQa match. However, if yopu have NK cell activation (by the K-562 test), you will need to use Intralipid even with donor embryo.Please go to http://www.IVFauthority.com and when you get to the home page find the “search bar” in the right hand column. Type in “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively).
  
  Geoff Sher
  
  Reply
Sharon says:

November 15, 2012 at 6:33 pm

Thank you Dr Sher. I read this article and really appreciate your feedback. When I read it I knew that this is exactly my/our situation! We are not sure what we are going to do at this point. It seems as if it will be very difficult for me to carry/have another baby so we are looking into different ways to add to our family. We had a wonderful experience the first time around with our clinic and Dr here in NYC. He knew right away what our issue is. My husband is very opposed to using donor sperm but is open to a donor embryo. It’s a lot of money though and there seems to be a strong possibilty that it may not work as well.

Reply
- Sharon says:
  
  November 15, 2012 at 6:50 pm
  
  Dr. Sher,
  I forgot to mention that I have 2 frozen embryos. Do you think I should just forget about them? When I did the 3 cycles last year, I transferred at least 3 embryos each time. Because I did the cycles back to back, I had 6 embryos in some of the cycles. Do you think it’s worth trying a FET? Thanks again.
  Sharon
  
  Reply
  - Geoffrey Sher says:
    
    November 15, 2012 at 10:37 pm
    
    I guess it might be worth a try!
    
    Geoff Sher
    
    Reply
- Geoffrey Sher says:
  
  November 15, 2012 at 10:36 pm
  
  Good luck Sharon!
  
  Geoff Sher
  
  Reply
gurke says:

November 26, 2012 at 2:18 am

Hi,
have you heard that IL is not made out of SOY anymore? Apparently they decided to go with Olive Oil instead.
<< Does it still has the same effect now??

Plus what is your oppinion that IL is PRO-inflammatory (I herad this) – isnt that contrary to use for a hyer active immune system?

cheers,
Bee

Reply
Grace says:

December 4, 2012 at 8:50 pm

My husband and I were unable to conceive naturally due to PCOS. After 1 IUI with meds, we got pregnant with quads and lost 1 early. We went on to have healthy triplets. In the past 2 years, I have had 3 failed IVF transfers. For the 3rd cycle, we used donor eggs. A couple days after the transfer I had cramping off and on, as well as cervical mucas and a few bright spots of blood. I did notice around that same time, I developed a sore throat and my glands became swollen. Could this be coincedence or possibly an immune disorder? Is it possible for this to develop after having a healthy pregnancy? Thank you!

Reply
- Geoffrey Sher says:
  
  December 5, 2012 at 10:15 am
  
  I doubt is the sore throat is an indication of a compromised immune system…pure coincidence.
  
  Likewise the spotting a few days after ET also means nothing specific.
  
  Good luck!
  
  Geoff Sher
  
  Reply
sweetie pie says:

January 13, 2013 at 7:14 pm

I’ve had 4 IVF failures with 2 chemical pregnancies using donor eggs. RE said I tested positive for Anticardiolipin and included predisone for 5 days before and including transfer but then stopped. I was also given doxycycline with the predisone. And baby asprin of course. Based on what you’ve written, it looks like I need to be on predisone longer than 5 days pre-transfer? Do you also prescribe anything like doxycycline with it?

Reply
- Geoffrey Sher says:
  
  January 14, 2013 at 6:25 am
  
  Thank you for the post,
  
  More important than the length of time on steroids is to determine whether you have activated uterine natural killer cells (NKa). I suggest you have your blood drawn for a K-562 target cell test. Bear in mind that the concentration of NK cells in your blood is unimportant. It is the NKa that matters. There are about 3 Reproductive Immunology Labs in the U.S.A that can perform the K-562 test adequately in my opinion.I suggest you contact Reproductive Immunology Associates (RIA) in Van Nuys, CA or Reprosource in Boston, MA.
  
  Please go to the home page of this blog, (www.IVFauthority.com). When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
  
  1. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
  
  2. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
  
  3. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
  
  4.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
  
  5. “IVF success: Factors that influence outcome”
  
  6. “Staggered IVF”
  
  7.“Embryo Banking”
  
  8. “Egg Donation”
  
  Consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail.. While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.
  
  Geoff Sher
  
  Reply
Hope2012 says:

January 14, 2013 at 9:49 pm

Hi Dr. Sher, Is dexamethasone only needed until confirmation of pregnancy in ultrasound as you mention in your article or until 10-12 weeks as it shows in my protocol? I did get a confirmation and saw a heartbeat already, so can Dex be stopped after 1st successful ultrasound?

Reply
- Geoffrey Sher says:
  
  January 15, 2013 at 6:31 am
  
  I personally advise tailing it off over a 7-10 day period, after the 10th week of pregnancy.
  
  Geoff Sher
  
  Reply
Joslyne says:

January 17, 2013 at 4:33 pm

Hi Dr. Sher,

My husband and I are both 30 years old. My husband has no issues. We have been trying to have a baby for almost 2 years. We have had 3-4 IUI cycles and 1 IVF (which produced 3 embryos in total). In one of the IUIs, I had a chemical pregnancy. After the unsuccessful IVF (where two good quality embryos were transferred), we decided to do a laparoscopy. The doctor found out that I had low stage endometriosis and she fixed everything. The next cycle we decided to do a natural cycle, but it didn’t work. So this cycle we will use our remaining frozen embryo from the IVF. We have decided that I will take an intralipid for this cycle and would very much appreciate your thoughts about this decision.

Reply
- Geoffrey Sher says:
  
  January 18, 2013 at 8:33 pm
  
  Good decision Jocelyne, but it would have been even more judicious if you first determined that you had activated natural killer cells by the K-562 target cell test. The reason is that 12/3 of women with endometriosis will have activated NK cells requiring IL therapy 1-2 weeks prior to ET.
  
  Good luck and please keep me in the loop.
  
  Geoff Sher
  
  Reply
Andrea says:

January 28, 2013 at 3:43 pm

I am 41 years old and had 3 failed IUIs. Although I know the biggest factor is age in my infertility I feel something goes wrong with the second part of my cycle. I have slightly increased testosterone level, thyroid antibodies and possible luteal phase defect (I got a second ovidrel shot on my last iui after I asked for it). I feel these issues should be addressed in order for me to have a better chance with iui or ivf. Do you think these are valid concerns or should I just go into ivf and hope to find out more? Does Sher Institute’s Westchester, NY center address these issues?
Thank you.
Andrea

Reply
- Geoffrey Sher says:
  
  January 28, 2013 at 6:44 pm
  
  Indeed they ate valid and yes we would address these issues in our Westchester center.Please go to http://www.IVFauthority.com . When you get to home page, look for a “search bar” in the upper right hand corner. Type the following subjects into the bar, click on it and it will take you to all the relevant articles posted there.
  
  1. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
  
  2. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
  
  3. “Thyroid autoimmune disease and IVF”
  
  4.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
  
  5. “IVF success: Factors that influence outcome”
  
  Good luck!
  
  Geoff Sher
  
  Reply
Katherine says:

February 9, 2013 at 9:44 am

I have been through 2 IVF cycles that did not result in a pregnancy. first cycle produced a fever for several hours after a five day transfer of 3embryos. dr said he never heard of anyone having a fever after transfer unless there was an infection. There was not. Second cycle was with Braverman who did immune testing. Husband andI turned out to have a few matches on HLC… Don’t have a copy of tests. Anyway, used his protocol of Neupogen and Lovenox. Dr. Let me stim for too long and only got 2 eggs, both transferred on day 1. Same kind of fever 48 hours later. I have Hashimoto’s. Have you ever heard of women having these fevers and can anything be done to stop them? Thank you ver much.

Reply
- Geoffrey Sher says:
  
  February 9, 2013 at 11:23 pm
  
  Katherine, you also should see the post in answer to Emily’s query above (regarding Hashimoto’s disease. I am NOT a believer in Neupogen. There is as yet no strong data to support a real benefit. As for the fever, it sounds as if you experienced some type of reaction to a drug given. Perhaps to the oil used in the progesterone, but admittedly that is speculative. What is clear is that you did not respond well to stimulation. You probably need a real protocol reassessment before trying again (see below). Again, I am not a believer in a benefit from Neupogen. Also HLA-C does not feature in my book when it comes to developing an immunotherapy regime.
  
  Please go to http://www.IVFauthority.com . When you get to home page, look for a “search bar” in the upper right hand corner. Type the following subjects into the bar, click on it and it will take you to all the relevant articles posted there.
  
  1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
  
  2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
  
  3. “Agonist/Antagonist Conversion Protocol”
  
  4. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
  
  5. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
  
  6. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
  
  7.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
  
  8. “IVF success: Factors that influence outcome”
  
  9. Thyroid Autoimmune Disease and IVF”
  
  Consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail.. While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.
  
  Geoff Sher
  
  Reply
Katherine says:

February 10, 2013 at 7:45 am

Thank you Dr. Sher. I will schedule a consult. There were details I did not mention that would have made this post very long!

Reply
- Geoffrey Sher says:
  
  February 10, 2013 at 7:46 pm
  
  Better we talk.
  
  Geoff sher
  
  Reply
Zita says:

February 20, 2013 at 5:57 am

Hello Dr Sher,
I have had 4 recurrent pregnancy losses in the last 2yrs andthe 4th being ectopic. Im 30 yeas old and I have done several tests for Recurrent pregnancy loss were carried out on me, including karotype, lupus anticoagulant, clotting disorders, Antithrombin, MTHFR mutation, Prothrombin, Protein tests, mixing studies and other tests relevant tests for RPL And all tests came back normal between my husband and I.

Im worried and wondering if IVF with PGD is for me since I have lost one of my tubes to the ectopic pregnancy

Reply
- Geoffrey Sher says:
  
  February 20, 2013 at 7:04 am
  
  Hi Zita,
  
  Your issue is not very dissimilar to that of “Aviva” (see above) Please read my response to her and also the advice given.
  
  I would be happy to talk to you too, so please call and set it up.
  
  Geoff Sher
  
  Reply
Jodi says:

February 23, 2013 at 7:40 am

Hi Dr. Sher,
My RE unexpectedly decided to do NK cell testing after starting this FET cycle. We have 1 failed IVF that was a chemical pregnancy but with lots of heaving spotting from the day of suspected implantation (7dp3dt) and really low starting betas. I am already on Lupron for this cycle and my FET is scheduled for 3/20/13. We have mild MFI (borderline motility and low morph) but no issues found with me so far. I have been reading and noted that there can be a correlation between high NK cells an endo. I have suspected endo, but my RE has never been interested in investigating the possibility and I’ve never had a lap. If my NK cell test comes back abnormal, is further investigating the possibility of endo wise? Or would just the Intralipid therapy be sufficient? My RE only mention doing the NK cell testing, but your article discusses several other autoimmune problems that could be tested. Should we be testing for all of these things at this point? Thanks for your help and advice.

Reply
- Geoffrey Sher says:
  
  February 23, 2013 at 8:53 pm
  
  Remember, it is not the concentration of NK cells that matters (the more the merrier) and in endometriosis the blood concentration is often even reduced. It is about their toxicity as measured by the blood K-562 target cell test or by uterine cytokine assessment. There are only 2 labs in the country that I would recommend for this. The one is Reprosource in Boston, MA and the other is RIA in Van Nuys, CA.
  
  Feel free to call 800-780-7437 if you wish to discuss.
  
  Geoff Sher
  
  Reply
Geoffrey Sher says:

March 5, 2013 at 6:25 pm

Gina, I invite you to give me a call and let me go through your case history in detail.Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail.

Geoff Sher

Reply
Jason says:

March 15, 2013 at 5:06 am

Hello Dr. Sher,
I would like to follow up on Jodi’s question/comment from Feb 23. We (wife=32 and husband=32 great sperm) also had a chemical pregnancy following an IVF fresh cycle with 1 good embryo from an 11 embryo litter all by ICSI (6 good and 5 fair). (hCG level=8 on 14 days past 5 day transfer {using progesterone and estrogen until blood test} and hCG=3.5 on 16 days past 5 day transfer) My wife has confirmed stage 2 endometriosis. We have been naturally trying to conceive for 4.5 years with absolutely no hint of pregnancy until the IVF failure. We are scheduled for a FET within the next 2 months. Do you think that we would benefit from any additional testing (immunological or other) before proceeding? We are in the Philadelphia area.
Thanks,
Jason

Reply
- Geoffrey Sher says:
  
  March 15, 2013 at 10:59 am
  
  Yes indeed I do think that such testing should be done..but I am not certain that her RE would concur or agree.Please go to the home page of this blog, (www.IVFauthority.com). When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
  
  1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
  
  2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
  
  3. “Endometriosis”
  
  4. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
  
  5. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
  
  6. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
  
  7.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
  
  8. “IVF success: Factors that influence outcome”
  
  Feel free if this does not work out, to call 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case further.
  
  Geoff Sher
  
  Reply
p song says:

March 21, 2013 at 2:03 pm

I got pregnant quickly at the age of 29. We’ve been trying for baby #2 for two years now. All my blood work checks out great as does husband’s. I did two rounds of clomid (good response) and one with follistim (great response) but still no baby. Husband’s sperm has been mediocre (low morphology), not the greatest but during follistim, his sperm analysis showed that everything was awful. He has a small and medium sized varicocele. One of the IUI’s, his morphology was good but count was a little low.

I have an indeterminate blocked left tube as well. One MD says blocked, one says muscle spasm and the other says can’t tell. No hx of STDs, PID or anything like that. I’ve also been having cyclical (around ovulation and menstruation) right upper thigh pain that may be associated with endometriosis but no other symptoms of endomet are present. Periods are not long, painful or heavy. There are also no cysts on my ovaries and cycles are always regular around 28 days. One ob recommended I could try laparoscopy but he’s unsure if that would be of much benefit to me since my leg pain is relatively minor and not unbearable.

I’ll be turning 34 soon if that makes any difference. Husband is 36. Any advice you have would be really appreciated. I’d like to know what to do next so I don’t keep blowing through my savings. Thanks for your time!

What would you recommend next?
1. Another round of IUI? (we were able to freeze a sperm sample that happened to be one of his best)
2. Remove the varicocele? His sperm analysis has been all over the map but the frozen one was good on all levels.
3. Should I get a laparoscopy?
Other questions-
4. How many rounds of IUI before IVF? Does it count as a round when sperm is bad?
5. Does freezing sperm affect quality?
6. Can you tell tube spasm versus true blockage on HSG?

Reply
Sam says:

April 24, 2013 at 10:02 am

Dr. Scher,

Thank you for providing so much helpful information. After 3 miscarriages (all natural conception), my husband and I did many tests and the only thing my doctor found was an identical HLA-C match between my husband and myself. We are thinking of trying intralipids but above you indicated that intralipids rarely work for identical matches. Does that include identical HLA-C matches?

Thank you.
Sam

Reply
- Geoffrey Sher says:
  
  April 24, 2013 at 9:13 pm
  
  No it might not apply.
  
  Feel free to call 800-780-7437 if you would like to discuss your case with me via Skype.
  
  Geoff Sher
  
  Reply
KBK says:

April 30, 2013 at 5:21 pm

Dr. Sher,

With someone who has Hashimoto’s, would going gluten free in turn decrease the toxicity of the NK cells??

Reply
- Geoffrey Sher says:
  
  April 30, 2013 at 7:39 pm
  
  I doubt it!
  
  Geoff sher
  
  Reply
simran says:

May 8, 2013 at 12:47 pm

Dr Sher,
i am 31 and my partner is 36. we have previously undergone 3 failed ICSI cycles . everytime i had 2 grade A embryos transferred but result BFN. i have recentlybeen advised to to get a hysterescopy to check if i have implantation issues. do u think it would be helpful to get thos procedure done? would appreciate your input on this matter.

best regards
simran

Reply
- Geoffrey Sher says:
  
  May 8, 2013 at 3:43 pm
  
  I do think it would be helpful but even more important would be to test for an immunologic implantation dysfunction (IID).
  
  Please go to the home page of this blog, http://www.IVFauthority.com. When you get there, look for a “search bar” in the upper right hand corner. Type the following subjects into the bar, click on it and it will take you to all the relevant articles posted there.
  
  1. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
  
  2. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
  
  3. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
  
  4.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
  
  5. “IVF success: Factors that influence outcome”
  
  Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail
  
  Geoff Sher
  
  Reply
simran says:

May 8, 2013 at 12:51 pm

sorry for the typos.. also would like to add that we opted for ICSI due to male factor infertility

Reply
- Geoffrey Sher says:
  
  May 8, 2013 at 9:04 pm
  
  Copy!
  
  Reply

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