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A1. I have seen MF (low morphology) manifest at the morula stage causing embryonic arrest. It was not caused by the coasting. From the sounds of it, the cycle was managed fine. With 45 follicles growing, you are considered a "hyper-responder" and this kind of cycle is always difficult to manage. The slowing of development from Day 3 to Day 4 was not caused by culture conditions, as the lab appears to routinely culture embryo to the blastocyst stage. Maternal age problems usually manifest at the 4 to 8-cell stage. Since 3 embryos had gotten over the hump, it doesn't look like age played a role in the morula to blastocyst transition.

A2. No, I agree with your doc that it was better to wait until Day 5 to determine the development potential of the embryos.

A3. Usually, embryos proceed from the compacted morula stage to early blastocyst in about 12 hours. It is a relatively speedy process. About 90% of morula stage embryo progress to blastocyst. However, when the sperm morphology is poor, this can drop to about 60%.

A4. The remaining embryos were of poor developmental potential and it is no surprise that they did not proceed to the blastocyst stage. This is nature's way of "weeding out" genetically abnormal embryos. The fact that the remaining embryos arrested develop has absolutely no bearing on the developmental potential of the embryos that were transferred.

You still have a good chance. Try to put this stuff out of your mind until you get the results of the pregnancy test. All of this "stewing" may be for nought if your pregnant.

Best of luck.

Dr, Smith
Thank you for your response. It made me feel better and more hopeful. At least thinking that the one egg that was on its way to blastocyct stage would make it.

You mentioned in A1. response that " I have seen MF (low morphology) manifest at the morula stage causing embryonic arrest." If this cycle doesn't work out, should my husband have his sperm analyzed even further before we consider a second IVF cycle. While he was taking his vitamins for 3 months, he had a urologist, endocrinologist and reproductive endocrinologist run tests, including an MRI of the head. They found nothing wrong with him.
Well, on occassion his LH and FSH were on the lower side and other times normal. Just once his testosterone level came back low and the other times were normal and even high. Was it the lab? No one knows. They found no reason for his MF problem.
I think there is a problem that can be located. He doesn't produce a lot of semen and it is very thick. It doesn't liquify easily. What is odd is that the count is fine although morphology is quite low. The Urologist suggested that the sperm become defective since they can't swim around too easily.
Since we don't know what is the problem behind his MF issue and now we are seeing the outcome from this IVF procedure, do you think that more specific testing of my husbands sperm should be done? If so, what kind of Dr. should we go to for this testing?

One more thing...Since I was a "hyper-responder" with this cycle, does it mean that I will be a "hyper-responder" if we had to try another IVF cycle again? I am so bloated right now to the point where I look pregnant and not sure when the belly will go down. I have cut back a bit from all the gatorade because of the pressure in the belly area.

Thanks again.

Other than external heat to the testes, there is no other known cause for poor sperm morphology, hence no test available. The urologist was grasping at straws with the high viscosity causing poor morphology answer. Sometimes doctors have a problem with saying "I don't know". The DFI came down to an acceptable range after the varicocoelectomy, no further test is required there. In most cases of poor morphology, no one knows what caused it. Sorry.

The medications used to stimulate the ovaries can be modified to tame the stimulation a bit, but in the near future, you will always produce a lot of follicles on a stimulated cycle. Sounds like you are experiencing symptoms of Ovarian Hyperstimulation Syndrome. Make sure you stay in touch with your doctor especially if you feel short of breath or your urine is very concentrated.

Thanks again.
I guess there hasn't been much focus on MF as with women infertility issues. I should have made my point a little clearer in my last message. The s/a DH had done just detail the external physical atttributes and motility of the sperm. What I meant to say is that do you think that some of the sperm should be tested for abnormal DNA/chromosomes?

During my discussion about ICSI with the Embroyologist, he once said that the sperm is the vehicle that carries the chromosomes to the egg. Regardless if the sperm can penetrate the egg, by ICSI, they are simply injecting the chromosomes directly into the egg. BUT what if the sperm do not carry good chromosomes. Can that be tested? Is that what Karyotyping is?

By the way...there is a lot of controversy about icsi and the rate of mental development of the children being slower. What are your thoughts?

Sperm can be tested to determine the degree of DNA fragmentation. Spern DNA fragmentation can contribute to embryonic arrest, particularly at the morula-blastocyst transition. For more information on this test, see www.scsadiagnostics.com

Karyotyping evaluates the chromosome number in regular somatic (body) cells. This is not relective of what chromosome abnormalities the sperm may or may not be carrying into the egg. From a practical point of view, it is not possible to karyotype individual sperm prior to ICSI.

Controversy is good. ICSI was placed into clinical service without any long term effects studies. Data is now accumulating that ICSI may not be as benign as first thought. The data is not clear yet as to what subgroups of male infertility are associated with adverse effects. We need to remain ever vigilant to evaluate any potential down side to assisted reproduction.

Dr. Smith,
Thanks for the lead. I contacted the scsadiagnistics center for more information. Whether or not we do acheive pregnancy with this IVF cycle, it is important to know if DNA fragmentation exists, therefore contributing to miscarriage or fetal implications. I will discuss this with DH of course and perhaps have him proceed with a test.


There was one website that that mentions balanced translocation. It says that "healthy and normal individuals carry chromosome rearrangements that are referred to as balanced translocations. Balanced translocations typically do not cause any health problems for the person with the translocation. However, people with balanced translocations are at increased risk for infertility, miscarriage and more serious chromosome problems in their children. Approximately 1/400 individuals in the general population are carriers of a balanced rearrangement of their chromosomes."
Do you know if this testing can be done by a blood test? If not, what kind of test?

I don't mean to be a nag but I feel that you are helping me understand things more clearly.

Regarding ICSI, it seems that although thousands of children are born via this method, these children are the testing group. Science is playing with natural law, it can't be all that perfect. Seriously, I, like many others do have concerns even though we go through the process.
Do you have any credible sites that would provide more information about ICSI?
Can it be possible that out of the 1% good sperm there were a few normal looking ones that can be chromosomally balanced and successfully bring about a healthy, nornal and fertile baby?

Sometime I wonder if more information about MF isn't provided because it will keep the clinics flourishing. My DH was tested for several things other than the actual composition of the sperm (DNA fragmentation). Shouldn't that test have been routine? I mean, if there is serious fragmentation, it can lead to failed IVFs, miscarriages and babies with disorders. We were only told that if it does work that we should have genetic testing on the embryo. Why go there if the odds are so great.

Your comments are welcome.

Regards,
Maria G.

Dr. Smith,

I am also getting ready to embark on an ICSI cycle and have some concerns about the long-term effects of this procedure.

Question 1
In your previous post, you wrote, "Data is now accumulating that ICSI may not be as benign as first thought." Can you provide more details or point me to some articles?

Question 2
I am all for ICSI if it is the last resort, but I'm not convinced that it is necessary in my case and sometimes I wonder if RE's suggest ICSI because it has such a high rate of success. For our case, our first RE said do 1/2 ICSI, 1/2 IVF as a form of treatment as well as diagnostic tool (IVF would help determine the fertilization problem). A second RE's opinion was to do all ICSI.

We're 31 yrs old. My tests were normal except 25% ASA. My DH has 11.9% DFI, 25% HDS, normal semen parameters except for 21% morphology and lower sperm concentrations (26 and 33 mil on last 2 SA's with only 9 mil and 8 mil post wash). We're 1 year past a bi-lateral varicocelectomy with 4 failed IUI's before the surgery and 2 failed IUI's 10 months after the surgery.

Given the above, does this sound like a case for IVF or do we need to move straight to ICSI?

Dr. Smith
I did further research regarding www.scsadiagnostics.com"
Your quote above:
"Sperm can be tested to determine the degree of DNA fragmentation. Spern DNA fragmentation can contribute to embryonic arrest, particularly at the morula-blastocyst transition. For more information on this test, see www.scsadiagnostics.com"

After reading the entire website I realized that the scsa test only tests approx 5000 unwashed sperm. Well with a normal sperm count of less than 1% isn't it obvious that there will be great chances of DNA anmormalities / fragmentation? Therefore, proving that the sperm is highly likely to lead to infertility problems.
I guess my question is that with ICSI, supposidly the lab injects the most mobile and normal looking sperm they find in the wash, basically select from the 1% normal sperm. Shouldn't the scsa be testing the DNA of washed sperm rather than 5000 random unwashed sperm? Chances are that the majority of the sperm will have defects therefore giving us results that we already know, especially after going through one IVF/ICSI cycle.
I am just wondering if the test is a viable one. We know the sperm is damaged but how can we know if there is a chance that there are a few sperm that have normal DNA and therefore have normal embryonic development that will not arrest in Morula-blastocyst stage or later on in miscarriage?

Am I missing something about this test that you can shed some light on?
a. do abnormal sperm have normal DNA, therefore capable of producing healthy babies? By this meaning that out of the 5000 unwashed sperm, the test will more-or-less let us know if the DNA is a problem in general or do all abnormal sperm have abnormal DNA?
b. does the scsa test allow enough conclusive information about the 1% normal sperm potential for good DNA in spem, therefore leading to successful embryonic development?

I cheated a bit and took a pregnancy test today. Negative! I figured but I will go for the Dr. prenancy test in 2 days and hope that there is a follow-up. I have a ton of questions about the sperm that was injected and the quality of the eggs, although I was told 3 grade 4 good quality eggs were transferred. I am afraid that they won't have answers and say try again without further research of the sperm. I would try again but then again I don't know if it is worth it. Five good eggs and all arrested in the morula-blastocyst stage. Well, three of them were transferred (one was compacting) but I think they had the same fate as the other 2 in the dish that arresseted on Day 6. IIt is tough, my insurance does not cover and so I have to be careful with wasting time (age 38 factor) and money. Last thing I want is to get prenant and have defects with the fetus. We are seriously thinking that with the IVF/ISCI results (morula-blastocyst arrest of 5 good eggs) that perhaps it is best to consider a sperm donor. What would you suggest. Should we test for scsa, or balanced translocation or the y chromosome deletion? I feel that I need answers in order to see what to do next. Most Dr.'s dont say much and I am surprised that there is such limited information about MF.

I hope to hear from you. In the mean time, I am doing a lot of research trying to understand what may be going on with the sperm issue. Is there any data I can look at that speaks to MF being the issue with Morula - blastocyst arrest on day 5. We both think the issue with the arrest (and as you suggested) is MF related although my age is 38. What does one do in this case?

Again, thank you for your assistance. I hope we can gain information from this that can help others with similar issues as well.

Regards,
Maria



BTW, where are you located?

The SCSA has only been clinically validated for ejaculated sperm. However, your idea of analyzing washed sperm is a good one. I will forward your comment to Dr. Evanson at SCSA Diagnostics. Unfortunately, the results of the SCSA test do not give absolute answers. They describe the [i]possibility/probability[/i] of success. There's really no clear-cut answers anywhere in infertility treatment. I wish we could advise patients with more specific answers to their questions, but we'd be lying if we did.

If your husband is open to the idea of using donated sperm, I think that's the way to go. Spending additional money on testing that will leave you in the same uncertain place you are in now would not be productive. Time's a wasting. The advangae to using donated sperm is that you will not have to spend a lot of money to achieve a pregnancy. Its low-tech and fairly inexpensive (compared to IVF/ICSI). If, after you achieve a pregnancy through the use of donated sperm, and you have the financial resources to pursue additional treatment, then you could try another run at IVF/ICSI.

I don't think the specifc arrest at the morula stage in MF cases has been published, but we published a paper a few years back on the impact of MF of blastocyst development. We observed the major impact of MF in the 5-8 cell stage, but also observed arrest at the morula stage and poor quality blastocyst stage embryos. See below:


The effect of intracytoplasmic sperm injection and semen parameters on blastocyst development in vitro.

Miller JE, Smith TT.

Hum Reprod. 2001 16(5):918-24.

The present study compares the development and quality of blastocysts derived from conventional oocyte insemination with those derived from intracytoplasmic sperm injection (ICSI). Oocytes were collected from patients undergoing ovarian stimulation with human menopausal gonadotrophins for IVF. Patients with normal semen were assigned to conventional oocyte insemination while those with progressive motility <20% and/or normal sperm morphology < or =4% were assigned to ICSI. Resulting embryos were cultured for up to 6 days. The mean number and percentage of embryos reaching the blastocyst stage and the mean number and percentage of blastocysts of high quality on days 5-6 were assessed for both treatment groups and compared. The influence of paternal factors (sperm concentration, motility, progressive motility, morphology) on blastocyst development and quality were assessed by regression analyses. Significantly more ICSI-derived embryos arrested at the 5- to 8-cell stage (P = 0.024) concomitant with the activation of the paternal genome than those derived from conventional oocyte insemination. Significantly fewer ICSI-derived embryos reached the blastocyst stage on days 5-6 (P<0.001) and significantly fewer ICSI-derived embryos were of high quality (P = 0.002) compared with conventional oocyte insemination. When treatment groups were combined and evaluated by regression analysis, progressive motility and sperm morphology were significantly correlated with diminished blastocyst development and quality (P < 0.05). From these data, we conclude that paternal factors and/or performing ICSI in cases of severe male factor infertility may have a detrimental effect on blastocyst development and their quality.

Dr. Smith
I am glad to hear that you will forward my comments/ Quite frankly, I believe that most couples going through these issues can provide first-hand feedback for institutions. Who ever discovers treatment(s) for unknown MF is going to become quite renowned.

Thanks for sending the above article. It further validates MF contribution to arrested development. Did the test take into account the status of the egg? I would assume the ages of the women must have been under 35 and in good (fertility) health in order to get the best statistical results regarding MF issue.

After doing even further online research, I read in several articles about MF arrest in Morula-Blastocyst stage. A very interesting article that I thought you may find interest in is:
http://www.biolreprod.org/
cgi/content/full/68/4/1470
Rea
d
the last part called "Discussions" if anything.

I will keep reading in order to understand the issue as a whole and who knows, perhaps see where the root of the problem lies. I get the feeling that something can be done to treat (or cure) at least some cases of MF. And most likely is not as difficult as it seems. From what I have heard over the last 8 months and read, there just haven't been enough studies yet almost half of all infertility cases are caused by MF. Is it a funding problem? Can't help but think that if there were easy treatments then the Dr's and clinics would lose a lot of business. This was a very expensive test (IVF/ICSI) for us to go through only to find out that it is sperm DNA problems probably caused during spermatogenisis. Instead, we could have found out about Sperm DNA problems with a test beforehand.

Would you know which are the best organizations to contact for information rearding MF issues?

Reagrds,
Maria

Thanks for the reference. It makes an interesting point that ICSI was put into clinical use without prior animal studies to determine efficacy and safety. We should have done many more animal model studies before implimentation of ICSI. You'll notice that the researchers are in Canada. Much of the research we depend on comes from abroad.

The problem with determining the causes of MF infertility is funding. The National Institute of Child Health and Development (NICHD) is responsible for funding research into infertility. It is consistantly one of the poorest (if not the poorest) funded institute at the NIH. I used to be a sperm (MF) researcher in academics before moving to clinical practice. It was virtually impossible to secure NIH funding for research into MF infertility. I gave up and decided I could do more good on the front lines of infertility treatment.

ICSI provides us with a work-around, but all clinicians would prefer a "cure" to a "treament" (even if it means a drop in revenue). The lack of adequate research on MF is not do to a lack of motivation, just a lack of funding.

The SCSA is not considered a routine test during the male workup although this has been proposed in several publications. Unfortunately, the SCSA has not been accepted by all clinicians and is still considered controversial by some. As a "sperm guy", I see nothing controversial about DNA integrity and embryo development. FYI, the SCSA test is only about 4 years old, so it may take more time for full acceptance.

And yes, in our study, all female factors (age, number of mature eggs retieved, diagnosis, etc.) were matched in both groups. My only regret is that we didn't wait for more patients and therefore had to use non-parametric statistics to show statistical significance. I'm old school and would like to use parametric stats to show the significance of a finding, but that would have taken many, many more patients and a significant delay in publication. I've been told that there are three kinds of liers: white liers, damn liers, and statisticians. (apologies to any statisticians reading this :))

Dear Dr Smith,

I am 33 and my husband is 31. I am in the 2 week wait period and I find the shared journey very comforting and supportive. I have one question.

1. 9am on day 5 we transferred a morula. We had an ICSI done 5 days ago late afternoon. The embryologist said the embryo was a morula and showing early signs of a blastocyst at 9am. What are the odds of our embryo progressing to a blastocyst stage?

Many thanks.

Hi Sammy,

We are in the same boat - we also had morula (3 of them) transferred on Day 5. I am concerned now if they will develop further.

I am hoping you can share with me what happened to your morula - did it grow into pregnancy?

Thanks for the help