Dear Dr. Sher: A Healthy Baby Followed by Multiple Miscarriages
This is one of a series of posts taken from questions that have been submitted to me via email, website, or discussion boards. This question is from a patient who had a healthy baby from her first pregnancy, but then went through a period of 6 consecutive miscarriages/chemical pregnancies. I have included her original post, followed by my responses along with the details of the patient’s eventual treatment.
Dear Dr Sher,
Thank you for this discussion board. It is a great help to those like me, who have feel like we are not getting the right answers, are floundering and quite frankly feel desperate. Here is my (sad) story…please help!
I am 37 years old and have had 7 pregnancies. The first one occurred 8 years ago and we have a beautiful little girl who is the light of our lives. The next two pregnancies also came without difficulty but both miscarried around the 8th to 10th week. So we went to see an RE who suggested that I was not ovulating properly…something to do with my hormone balance. He suggested IUI so we went through 5 of those using Clomid. I got pregnant once and this time miscarried at 6-7 weeks (a heartbeat was detected by ultrasound in each of these two cases). The next suggestion was IVF, which I have since gone through six times, with three chemical pregnancies.
My husband has normal sperm. He and I have had genetic blood tests which turned out to be normal. I have had a dye X-ray test, as well as a hysteroscopy and was informed that I have a normal uterus. I am told that even my uterine lining develops normally; measuring 12mm at the time I received the hCG trigger.
Frankly I am not getting any answers. None of this makes any sense to us. Why did I have a baby with no difficulty eight years ago and then have everything go downhill? Please give me advice….Help!!
Darla (Patient’s name has been changed)
My response in 2011:
Thank you for reaching out to me. I understand and empathize with your plight.
I have little doubt that your problem relates to embryo implantation dysfunction….most likely immunologic in origin. You ask why you would have had no problem with your first pregnancy, yet have so much trouble in ensuing attempts. Well, the likeliest explanation would lie in your having an immunologic implantation dysfunction (IID), which, based on history alone, is most likely to be alloimmune (rather than autoimmune) in origin. This type of IID occurs where both partners have DQ alpha or HLA genes in common. When this happens, there often occurs a progressive sensitization leading to activation of uterine natural killer cells (NKa)…over time.
In such cases – provided that pregnancy occurs early on in the relationship (i.e., before NK cells become activated) – a normal pregnancy with full term delivery (as was the case with you) can and often does occur. Thereafter, repeated exposure of the uterine immune system to DQ alpha/HLA matching embryos, NK cell activation develops progressively over time. Once this happens, the woman will often start miscarrying, with the losses coming ever earlier (again as with you) until ultimately, total implantation failure results (often regarded as “presumptive/unexplained secondary infertility”). Please read the two blog articles I posted on IVFauthority.com (Immunologic Implantation Dysfunction Part 1 and Part 2) in May 2011 as well as the one on Recurrent Pregnancv Loss.
The above could explain your situation. I suggest that you contact Reprosource (Boston, MA) or Reproductive Immunology Associates (Van Nuys, CA) and send your and your husband’s blood there for testing. Your blood should be tested for NKa (using the K-562 target cell test) and both your and your husband’s blood should be tested for DQ alpha and HLA genetic matching. Once you have the results, we certainly should talk. Might I suggest that you call 800-780-7437 and set up a Skype consultation with me for 14 days after blood has been dispatched for the above tests. In the interim, please complete the attached questionnaire and send me all your old records for review.
Geoffrey Sher, MD
[The patient underwent testing as I recommended and the results confirmed the presence of NKa as well as a partial DQ-alpha match. The letter below details my recommendations to the couple following our Skype consultation.]
As we discussed yesterday, your test results indicate the presence of activated uterine Natural Killer Cells (NKa) in your system. In addition, you and your husband do indeed have a partial DQ alpha gene match. As I told you when we consulted, this means that one out of every 2 embryos (resulting from his sperm fertilizing your eggs) will match your DQa genotype and as a result, upon reaching your uterus, will elicit the activation of NK cells there. The treatment of NKa is an infusion of Intralipid combined with oral ingestion of corticosteroids to overcome the NKa that occurs in a situation involving DQ alpha/HLA matching (such as you have). Since we presently have no way of determining whether the DQ alpha/HLA contribution to an embryo comes from you or from your husband’s contribution, I believe that our best course of action would be to proceed with IVF and to transfer a single embryo per attempt. My reasoning is that if we transfer more than one at a time, a matching embryo would likely “muddy the waters” by activating uterine NK cells and thereby prevent the non-matching one from developing into a healthy pregnancy.
Bear in mind that even in the absence of IID in a woman of your age, each advanced embryo (blastocyst) would likely have no more than a 30% chance of resulting in a birth. So with a partial alloimmune match compromising half of your embryos, I would estimate the chance of a live birth per transfer at around half that number (i.e., 15%). However, there is a way in which we could potentially double the chance of success in your case. This would require testing all your embryos for their chromosomal integrity (genetic “competence”) through CGH analysis and then transferring one chromosomally normal blastocyst at a time (under intralipid and corticosteroid cover) until a viable pregnancy occurs. I strongly recommend this approach for you.
Geoffrey Sher, MD
The patient decided to follow my recommendations and undergo IVF with CGH testing, combined with single blastocyst transfer. Eight (8) months later, after the second single blastocyst transfer, she conceived and subsequently gave birth to a full term baby girl without any complications.