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      • IVF Failure With “Good Quality” Embryos: What Went Wrong?

      Dr. Geoffrey Sher Recommends

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      According to the Society for Assisted Reproductive Technology (SART), IVF success rates have been improving over the last decade. In 2007, the live birth rate in the United States was in the order of 33%. However, there is a very wide variation in program to program IVF live birth rates, ranging from as low as 10% to well over 50%. Based upon these statistics, the majority of women undergoing IVF in the United States require more than two attempts to have a baby.

      IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infective, anatomical and immunologic factors that influence embryo implantation are at least equally important.

      Even though this post will focus on IVF failure in spite of transferring “good quality embryos”, I feel compelled to briefly address the issue of embryo quality. In my opinion, many cases of “unexplained” IVF failure are due to the fact that many (if not most) embryos judged through conventional microscopic grading as being optimal in quality, in fact have numerical chromosomal defects (aneuploidy) that render them “incompetent” (incapable of producing a healthy pregnancy). Such incompetent embryos are thus often erroneously regarded as being of high quality. While embryo aneuploidy occurs in women of all ages, its incidence increases from about 60% in women under 35 years of age to more than 90% by the age of 45. It is for this reason that blastomere biopsies, with comparative genomic hybridization (CGH) which identifies each and every chromosome, might be regarded as a valuable diagnostic tool in many cases of unexplained IVF failure.

      Another problem pertaining to distinguishing viable (“good quality”) embryos from non-viable (“poor quality”) ones, lies in the fact that virtually all IVF centers culture embryos in groups in petri dishes. This practice precludes careful individualized evaluation of those morphologic and/or biochemical changes in early embryo development, which can help predict implantation potential of each embryo. In the year 2,000, we introduced the Graduated Embryo Scoring (GES) System where we grow (culture) each fertilized egg separately rather than in batches (as is most commonly done in most other IVF centers). By so doing we are able to better assess the embryo’s developmental milestones and so more competently evaluate its potential to propagate a viable pregnancy.

      One of the most important procedures conducted during an IVF cycle is the actual embryo transfer. Embryo transfer differs from most other steps involved in the IVF procedure, which attempt to mimic mother nature. In “normal” conception, the blastocyst reaches the uterus 5-7 days after ovulation, via the Fallopian tubes. In the United States, in the past , we most commonly performed embryo transfer 3 days after the egg retrieval. As such, embryos were prematurelybeing placed in the uterus via the cervical canal. In attempt to overcome this “dissynchrony” and improve pregnancy potential, many IVF programs opt to either replace a greater number of embryos on day 3 or to transfer fewer embryos on day 5 or 6 post-fertilization – as blastocysts.

      Equally important as performing embryo transfer on day 5-6 is the actual embryo transfer technique itself. This needs to be performed delicately with minimal trauma, and under ultrasound guidance so as to insure proper placement of the embryo(s) in the mid-uterine cavity. The need for such ultrasound guidance cannot be overemphasized. The embryo recipient is instructed to have a full bladder. We use a soft catheter, which is introduced gently via the cervix into the uterine cavity. An abdominal ultrasound probe allows for the visualization of the tip of the catheter and the transfer of embryos into the center of the uterine cavity, preferably without touching the fundus of the uterus

      But, even with “good quality” embryos and excellent embryo transfer technique, implantation can be thwarted by such factors as:
      • anatomical abnormalities in the uterine cavity (e.g. scarring, polyps and encroaching fibroid tumors)
      • a thin endometrial lining
      • immunologic rejection of the embryos.

      Several studies performed both in the United States and abroad have confirmed that a dye X-Ray or hysterosalpingogram (HSG) will often fail to identify small endouterine surface lesions (in about 30% of cases). This is significant because even small uterine lesions have the potential to adversely affect implantation. Hysteroscopy is the traditional method for evaluating the integrity of the uterine cavity in preparation for IVF. It also permits resection of most uterine surface lesions, such as submucous myomas, intrauterine adhesions and endometrial or placental polyps. All of these can and indeed often do, interfere with implantation by producing a local inflammatory response, similar in nature to that which is caused by an intrauterine contraceptive device.

      Sonohysterography (a saline ultrasound examination) has all but supplanted hysteroscopy to assess the uterine cavity in preparation for IVF. Here, a small amount of a sterile saline solution is injected into the uterine cavity, whereupon a vaginal ultrasound examination is performed to assess the contour of the uterine cavity.

      In 1989 we became the first to report on the fact that ultrasound assessment of the late proliferative phase endometrium following ovarian stimulation in preparation for IVF, permits better identification of those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >9mm and that a thickness of less than 8 mm bodes poorly for a successful outcome following IVF.

      Then in 1993, we were able to show that sildenafil (Viagra) introduced into the vagina prior to hCG administration can improve endometrial growth in many women with poor endometrial development. Viagra’s mechanism of action is improvement in uterine blood flow with improved estrogen delivery…thereby enhancing endometrial development.

      Immunologic factors also play a role in IVF failure. Some women develop antibodies to components of their own cells. This autoimmune process involves the production of antiphospholipid, antithyroid, and/or antiovarian antibodies – all of which may be associated with activation of Natural Killer (NK) cells in the uterine lining. Activated NK cells (NKa) release certain cytokines (TH-I) that if present in excess, damage the trophoblast (the embryo’s root system) resulting in immunologic implantation dysfunction (IID). This can manifest as “infertility” or as early miscarriages). In other cases (though less common), the problem is due to alloimmune dysfunction. Here the genetic contribution by the male partner renders the embryo “too similar” to the mother. This in turn activates NK cells leading to implantation dysfunction. These IID’s are treated using combinations of medications such as heparin, Clexane, Lovenox, corticosteroids and intralipid (IL).



      “In the pursuit of optimizing outcome with IVF, the clinician has a profound responsibility to take an individualized approach aimed at favorably influencing the biological environment for both egg/embryo maturation and implantation. Doing so will maximize the chance of a pregnancy and promote the noble objective of optimizing the quality of life after birth.”

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      15 Responses to “IVF Failure With “Good Quality” Embryos: What Went Wrong?”

      1. Susan says:
        December 4, 2009 at 4:56 pm

        awesome article!! I will be seeing Dr. Kwak soon for my autoimmune dysfunction.

        Reply
      2. Geoffrey Sher, MD says:
        March 8, 2010 at 10:25 pm

        Thank you Susan.

        Geoff Sher

        Reply
      3. Noha Adel says:
        May 22, 2011 at 8:03 am

        very helpful article, thank you so much… I actually had IVF on 24/4/2011… my B-HCG was 230 on 8/5/2011, then I had brownish spotting so I repeated it on 12/5 and was 626 then spotting continued so I took I.M Progesterone together with the progesterone suppositories I have been taken since the IVF , but I had an attack of vomiting about 8 times with severe abdominal pain, and bleeding (about half a pad of fresh blood) My B-HCG was 1020 on 16/5 & bleeding discontinued & was followed by brownish spotting.. my B-HCG on 18/5 was 717….. I just wonder what is the cause of my IVF failure…

        Reply
      4. Geoffrey Sher, MD says:
        May 23, 2011 at 12:33 pm

        It could be an embryo issue or an implantation issue. However, I would need an opportunity to review your records in detail to be more specific.

        However be sure to have your RE rule out an ectopic (tubal) pregnancy.

        Good luck!

        Geoff Sher

        Reply
      5. Noha Adel says:
        May 24, 2011 at 3:19 pm

        Thanks alot Dr. Sher for your kind reply and your kind wishes…. The pain was more at the right side of the abdomen and so I think it may has been an ectopic pregnancy but my dr. performed an U/S and he didnt mention if he thinks it was an ectopic or not…. I'd like to ask you one last question Dr. Sher if you dont mind.. What can be the earliest time to try again?… I really cant wait & want to try as soon as possible.. Should I have to wait for a new menstrual cycle and start again after ovulation following that cycle or is there an ovulation after this bleeding of abortion that I can start with.

        Thanks alot Dr. Sher

        Reply
      6. Noha Adel says:
        May 24, 2011 at 4:11 pm

        Thanks alot Dr. Sher for your kind reply and your kind wishes…. The pain was more at the right side of the abdomen and so I think it may has been an ectopic pregnancy but my dr. performed an U/S and he didnt mention if he thinks it was an ectopic or not…. I'd like to ask you one last question Dr. Sher if you dont mind.. What can be the earliest time to try again?… I really cant wait & want to try as soon as possible.. Should I have to wait for a new menstrual cycle and start again after ovulation following that cycle or is there an ovulation after this bleeding of abortion that I can start with.

        Thanks alot Dr. Sher

        Reply
      7. Geoffrey Sher, MD says:
        May 26, 2011 at 11:52 am

        You need two periods before you will be ready to try again.

        Consider calling 800-780-7437 to arrange for a free medical telephone consultation so we can discuss.

        Geoff Sher

        Reply
      8. Dlewis says:
        November 29, 2012 at 10:53 pm

        Dr Sher, what kind of test to find out if I have immunogic issue?
        I read about the blood test rejection too, said if the mother has blood type O and father is other than O will be rejected. Is that the same?
        Thanks a lot

        Reply
        • Geoffrey Sher says:
          November 30, 2012 at 12:55 pm

          You will find the information you seek in the articles listed below. Simply go to the home page on this site (www.IVFauthority.com) , find a “search bar” in the upper right hand column and type in the following subjects into the bar and it will take you to all the relevant articles I posted there.

           “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
           “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
           “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
           “A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
           “IVF success: Factors that influence outcome”

          You might 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) 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
      9. Dlewis says:
        November 29, 2012 at 10:58 pm

        Dr Sher,
        what kind of test to find out if I have immunogic issue?
        I read about the blood test rejection too, said if the mother has blood type O and father is other than O will be rejected. Is that the same?
        Thanks a lot

        Reply
      10. Serena says:
        February 1, 2013 at 7:38 am

        Dear Dr. Sher,

        I have read with keen interest various articles you have posted on your website, in particular related to unexplained IVF failure, and I would like to ask your view on my situation:

        I (44 yrs, no identified egg issues, except age; no identified uterus issues) and my partner (41, slightly low sperm motility, but fixed with ICSI) have undergone the following treatments in Belgium:
        * 6 failed IVF/ICSI cycles in 2010-2012 with own eggs, each time 7-9 fertilized embryos, 3-6 embryos transferred each time (on appearance high quality embryos); 2 x chemical pregnancy
        * July 2012 IVF with donated eggs (26 yr old donor, with history of donations resulting into several successful pregnancies), 1 fresh ET (3dt), 2 FETs (3dt) and 1 FET (5dt), all with 2 ‘very high quality’ embryos (or in the last case blastocyst) transferred, but did not result even to a chemical pregnancy.

        Before moving to DEs, our doctor thought that despite appearance, the cause of implantation failure would have been age-related poor embryo quality. However, even with DEs, the result was nil, so the cause for failure seems to be implantation-related and not related to embryo quality.

        I had hysteroscopy in April 2012 to check any uterus-related issues. My one tube was badly damaged and the other somewhat, so we decided to put clips on both of them to avoid any possible leakage that could interfere with implantation. (Thus rendering IVF the only remaining option for conception, but that seemed to be the best option anyway due to my age.) I have had slight endometriosis in the past, but that had been fixed already in a previous hysteroscopy in March 2010 before starting IVF cycles, and no additional problems were found in April 2012. Also my uterus lining seems to develop normally during the cycle (8-10 mm around ovulation; supported by Utrogestan and Progynova starting from the transfer). We have also had karyotype analysis on the sperm, and everything is fine. So we are completely at loss for the cause of the implantation failure.

        Our doctor in Belgium is rather sceptical about the concept of Immunologic Implantation Dysfunction and not really forthcoming in trying to have it tested and to find treatment options. We still have 5 frozen embryos left, but do not want to proceed to yet another failed transfer attempt before checking whether immunology issues could be the culprit. The tests that I have had done (in France) are as follows:
        - urea plasma: tested positive, treated with antibiotics
        - chlamydia: negative
        - AC phospholipides: <10 UA/ml
        - Proteine C: 106 %
        - Proteine S: 100 %
        - Mutation Factor V Leiden: absence of mutation
        - AC Anti DNA and anti lupus (anticorps anti nucleaire): <15 UI/ml
        To my understanding all the above test results are normal.

        From your excellent website I understand that the research and treatment of immunological causes of implantation failure are more advanced than in (continental) Europe. I would therefore ask your advice on what test you could recommend (I have seen references to the so-called "Chicago test", but I am not quite sure what they contain) and on where I could get such tests done (e.g. if tests are not available in Europe, can samples be sent for testing to the US?).

        I am very grateful for any advice you might be able to give. Thank you again for this excellent website, which is a true wealth of information!

        Reply
        • Geoffrey Sher says:
          February 1, 2013 at 11:40 am

          First,there is definite possibility of an Immunologic Implantation Dysfunction. One third of women with endometriosis (whether treated or untreated and regardless of its severity) have activated uterine NK cells that thwart implantation. If have NKa+ then, regardless of the quality of the embryos transferred, whether own or donor-egg derived, will be highly unlikely to propagate a viable pregnancy.

          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.

          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”

          Since to my knowledge there are no Reproductive Immunology Reference Laboratories in Europe that do the required tests, your blood and your husbands’s blood should be sent to Reprosource in Boston, MA for the following testes:
          a) Your blood for natural killer cell activity using the K-562 target cell test; Full antiphospholipid antibody panel; Antithyroid antibodies; and Immunophenotype and for DQ alpha/HLA
          b) Husband’s blood for DQalpha/HLA

          Consider calling 702-699-7437 to arrange for a telephone or Skype consultation 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 would suffice.

          Geoff Sher

          Reply
      11. neetu says:
        April 15, 2013 at 11:44 am

        sir.my doctor transter 2 blastocyst & 1 morula
        I found no symptoms. my beta hcg is negative. my dr
        can’t teii me the reason of failure .he just told that embryo not grown
        shelll I continue the 2 cycle of ivf or icsi

        Reply
        • Geoffrey Sher says:
          April 15, 2013 at 10:25 pm

          It could well be just bad luck. 1 cycle is often insufficient because not all embryos, regardless of how good they look willm be “competent” to make a baby.

          Geoff Sher

          Reply

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      My IVF Cycle Failed – What Went Wrong? Question #18: My Fertility Clinic Reports a High Success Rate – How Could I Have 2 Failed Cycles In A Row?
      This is no. 18 in a series of answers to common questions about failed IVF. While it is true that IVF failure can be due to preventable factors, it is as important to understand that optimal medical care does not always equate with an optimal outcome... more
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      My IVF Cycle Failed – What Went Wrong? Question #17: Why Didn’t I Get Pregnant When I Used a Young Egg Donor and Had Good Quality Embryos?
      This is #17 in a series of answers to common questions about failed IVF. For women whose advancing age and/or ovarian resistance make having a baby with their own eggs unfeasible or unlikely, IVF using donated eggs from a young donor (under 35 years)... more
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      My IVF Cycle Failed – What Went Wrong? Question #16: Why did my hCG levels stop rising properly?
      This is the 16th in a series of answers to common questions about failed IVF. Immediately following implantation, the root system (trophoblast) of the embryo begins to release the pregnancyhormone, human chorionic gonadotropin (hCG) into the surround... more
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      My IVF Cycle Failed – What Went Wrong? Question #15: Might My Mental State Have Played a Role?
      This is the 15th in a series of responses to common questions about failed IVF There is little doubt that stress and emotional lability plays a role in the normal physiological/hormonal regulation of the menstrual cycle.After all, Eskimos often stopp... more
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      My IVF Cycle Failed – What Went Wrong? Question #14: Could it Have Been Due to Inadequate Hormonal Support After the Egg Retrieval & Embryo Transfer?
      This is the 14th in a series of answers to common questions about failed IVF. In vitro fertilization establishes an abnormal hormonal environment in the uterus.In some cases (especially older women and those with a diminished ovarian reserve), high o... more
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      My IVF Cycle Failed – What Went Wrong? Question #13: Did the Number of Embryos I Had Transferred Play a Role?
      This is the 13th in a series of answers to common questions about failed IVF. Virtually everyone recognizes that pregnancy with multiples (especially triplets or greater) is associated with a high incidence of premature delivery that has serious cons... more
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      My IVF Cycle Failed – What Went Wrong? Question #12: Might the Timing of Embryo Transfer – Day 2-3 (Cleaved) vs. Day 5-6 (Blastocyst) Play a Role?
      This is the 12th in a series of answers to common questions about failed IVF. (Note: I’ll be hosting a live video chat on Aug. 2 on the topic of Failed IVF where I’ll discuss the issues addressed in this series of posts and take your ques... more
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