Genetic Defect In Husband's Sperm Leading To IVF Failure: Screening With CGH Recommended

(If the blog radio program turns on, go to the Oct. 1st blog post and pause it...I will be keeping the show up for the month of October.)

Question:

Dear Dr. Ramirez,

My husband and I have been infertile for two years. The second year, we began IVF. We have completed 3 IVF rounds. The first was not successful. The second resulted in a chemical pregnancy / early miscarriage at 6 weeks. The third resulted in an ectopic pregnancy. My husband and I are both in good health, with no known infertility factors (endometriosis, etc.). We do not have antisperm antibodies. All our bloodwork was good. On our second IVF round, 1/2 of the eggs were fertilized by standard IVF and none of them merged. 1/2 of the eggs were fertilized by ICSI and did very well. On our third IVF round, all the eggs were fertilized with ICSI and did very well. We have 9 frozen embryos waiting.

After this ectopic pregnancy, we had genetic testing done. Mine were normal. My husband's were abnormal. The interpretation was:

"A male karyotype with a small supernumeray bisatellited marker chromosome was noted in all metaphases analyzed. The majority of bisattellited markers are derived from an inversion duplication of the pericentromeric area of chromosome 15. Apparently this market carries minimal with no phenotypic significance to the patient; however it may lead to decreased fertility, repeated pregnancy loss, or chromosomally abnormal offsrping. Parental follow up chormosome studies are recommended to determine if the marker is familiar or de novo in origin, and to further evaluete its clinical significance. De novo markers are associated with an increased risk for phenotypic abnormalities. Genetic counseling is recommended."

We are going to receive genetic counseling in the future, but what is your opinion about this chromosome 15 abnormality and its effect on conception and offspring? Thanks! A. from the U.S.

Answer:

Hello A. from the U.S.,

Unfortunately I am not a geneticist and will usually go by what the geneticists advise me in terms of the consequences of chromosomal abnormalities.

However, in general, this is what it means to me. Your husband is carrying a genetic abnormality that is "recessive" in nature, meaning that it does not necessarily present itself as an abnormality. Because his sperm can contain this trait, it is possible that this can result in abnormal embryos, which will lead to early embryo death (and lack of implantation) or an early miscarriage. The ectopic pregnancy you had was for a different reason and does not need to be considered in this discussion.

What I would recommend is that the embryos be tested by the relatively new CGH (Array Comparative Genomic Hybridisation) process or PGS (Preimplantation Genetic Screening) prior to transfer. Last year, in England, a 41 yr. old woman who had failed IVF 13 times had her embryos tested with CGH and in September delivered a healthy baby (see article here). If your embryos are D#3 embryos, they should be thawed, and biopsied for genetic testing done by CGH. They would then be cultured to blastocyst and transferred at that time. If they are already blastocysts, then they would need to be thawed, biopsied then frozen again for a later transfer. In any future IVF cycles, the embryos should be similarly tested to look for the normals so that the abnormal embryos are not transferred leading to a negative pregnancy, miscarriage and further disappointment.

Not knowing how the genetic transference of this abnormality is done i.e. does it occur every time with every embryo, or is there a chance that some embryos will not have the disorder? it is hard for me to give any more specific recommendations. Once you have your genetic counseling, they will be able to answer these questions for you, which will help to determine a more specific strategy.

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.

Comment: Thank you. You are an angel for helping with this guidance.

Did Childhood X-Ray's Affect My Fertility? Queries Australian Woman...

Question:

Hi,

I was born with Perthes Disease (a disease of the hip). From the ages 5 - 15 I would have had well over 100 X-rays, concentrated on that area - most taken from above my body looking directly down at my hips.

I have never been able to keep a pregnancy beyond weeks, and tests have come back saying the last one included the extra chromosome 15. I have been under fertility treatment for 2.5 years. Tests are going to be carried out on my latest "failed pregnancy" within the next 4 weeks. The X-rays took place from 1971 - 1986. I have been in 2 long term relationships since 16 years old. (The current one being 13yrs) and there is no history of infertility in my family - all 4 siblings successfully having multiple children. I believe my eggs may have been damaged as a result of these X-Rays.

Regards. K. from Australia

Answer:

Hello K. from Australia,

I have to agree that there could have been egg damage from the proximity of the X-rays that is now causing the embryos to have genetic abnormalities. There is no treatment that can be done to repair eggs, but one option you might want to consider is to do CGH in association with an IVF cycle. With CGH (Comparative Genomic Hybridization), polar body biopsies can be done on the eggs at the time of fertilization and thereby evaluate the genetic complement of the eggs. This will immediately allow you to eliminate the abnormal eggs and hope that there is a normal one that survives and can be transferred. There is always the chance that there are some good eggs left and that is the goal. It may take several IVF attempts before finding that good egg, but in the end it will be well worth it. There is no price you can put on a child.

If you don't want to go through this option, with the potential risks of failure, your alternative then would be to proceed with Donor eggs and IVF.

I was just at a National OB/GYN conference and one of the topics discuss was a new program in the U.S. called Oncofertility Consortium. This is a group of specialists in the field of infertility, oncology, therapists, etc. that are promoting fertility preservation in patients facing various cancers or treatments such as radiation, chemotherapy, etc. The reproductive outlook for women cancer patients is becoming as good as for men, who long have had the option of banking their sperm. It is our hope that patients, such as you, will undergo counseling for fertility preservation and be given the option of preserving your eggs or ovarian tissue prior to undergoing treatments. I know that this is not going to benefit you now, but we hope that it will benefit people like you in the future. For more information on this group from the American College of Ob/Gyn's website, go to: http://bit.ly/axAePh.

Thank you for your question. I will be keeping my fingers crossed for you!

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

43 yr. old Trying To Conceive Needs High Stim Protocol

Question:

My Medical History: TTC 4.5 yrs. (3.5 with RE) Many IUI's & IVF's. 3 chemical pregnancies - 2 with IUI 1 with IVF. AMA - 43ys young.

Had a Coagulation Panel done - Mutation found -

heterozygous MTHFR C677T

Results negative for Factor V mutation

Factor II DNA Analysis

Results WNL for

ANA

APA

Lupus anticoagulant

Homocystein

Elevated levels for

Protein C Functional (187)

Factor II Activity (133)

Plasminogen (161)

B2 Glycoprotein (low positive)

Do I need to supplement my prenatal with extra folic acid and b vitamins? Baby aspirin? If so - can I just add extra supplements or do I need an Rx for something like Folgard?

Could this be the reason for all of my failed IUI's, IVF's and chemicals? Before finally agreeing to do this testing, my RE kept telling me that immune issues are too controversial and that the risks of their treatment outweighed their assumed potential benefits. I don't know what his thoughts are now as I couldn't get a Dr. callback for 3 weeks.

Many thanks, Dr. Ramirez, for so graciously donating your time in answering our questions! Your services are invaluable! Oh, yes - I am located on the east coast.

Answer:

I'm afraid I am in agreement with your RE, although for slightly different reasons. We do know that the immune system does contribute to miscarriages, although I am not sure that is the problem that you have. There are definitely some very controversial treatments, such as IVIG, which are very expensive and have not been shown to be of benefit in multiple studies. However, the alternative, which I try with all my patients is low dose aspirin (81 mg) per day, progesterone (injections and suppositories) and low dose heparin 2000 U twice per day. This regimen has been shown to help with recurrent miscarriages and is very low risk. That is why I use it. I have had some successful pregnancies in patients with recurrent miscarriages using this cocktail.

However, although you are still very young in my book, your fertility age may be the basic problem. You have shown that you can get pregnant. The problem is an egg problem. It is what I call "age related egg factor." We know that because a woman is born with all her eggs, and they age with her, and the lifetime of the eggs are about 43 years old, they deteriorate with time and age. This deterioration causes internal problems in the egg, including fragile chromosomes. This leads to bad embryos that either don't progress in their development, don't implant or end in miscarriage. There is a 40% chance of miscarriage with each pregnancy in your age group. Chromosomal abnormalities is probably the major reason for your losses.

There are only two ways to mitigate this increased risk: you can keep trying until you are successful (and hopefully you will be eventually) as long as your ovaries are still functioning well, or you can do preimplantation genetic testing (PGD) to identify the normal embryos prior to transfer (however, keep in mind that this is a new experimental technology, is very expensive, and does lower the implantation rate because of the "injury" to the embryo.).

I think that if you were to present to me, I would continue to recommend IVF with a high stimulation protocol and put you on my cocktail. I don't necessarily recommend PGD. I think nature will take care of that. The key would be to keep trying if you are determined to have a baby. There have been successes in your age group but time is running out for you.

I hope this helps,

Edward J. Ramirez, M.D.

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF program

http://www.montereybayivf.com/

40 Year Old With Multiple Miscarriages Needs Correct Specialist

Question:

I have been trying to conceive for 3 years, have had 3 miscarriages, all between 6-9 weeks (one was trisomy 22, the other two are unknown. Two pregnancies required progesterone suppository supplementation). I am 40 years old, hypothyroid, insulin resistant, have a bicornuate uterus, my DRVVT came back Borderline (lupus anticoagulant, recommended re-test in 12 weeks), positive for ANA's, 1:320 titer, speckled), and compound heterozygous MTHFR gene mutation (variants C677T and A1298C). I am getting ready to try again. I was already taking synthroid 88, and 850 mg metformin twice a day.

My doctor has put me on folgard in addition to my Prenate DHA prenatal vitamin, baby aspirin, 10 mg prednisone twice a day, and I am taking 1 tbs Maca Magic, as well as 1 tsp royal jelly. Should I be taking low dose heparin as well? Lovenox? Start the progesterone suppositories immediately after ovulation?

My high risk pregnancy doctor recommended I not do IVF, because he said that at 40, my eggs are much too fragile to undergo retrieval, fertilization, analysis and reimplantation. He also indicated I would have a harder time getting pregnant after this (likely) failed. Please let me know your thoughts on this. Also, do you have any research you can direct me to, indicating that only 1 in 40 or 50 of my eggs are normal at 40 years old?

Would love to know your thoughts. I can't bear to go through another miscarriage. Thank you.

Answer:

You seem to have lots of reasons for having miscarriages, but probably the most common and predominant reason is your age. This "age factor" leads to spontaneous chromosomal aberrations that lead to abnormal embryos and subsequent miscarriage.In terms of your immune factors, just to cover those bases I would recommend either low dose heparin or lovenox. The progesterone should be started right after ovulation and continued until the pregnancy test is negative or 10 weeks gestational age.

Although you are able to get pregnant naturally, the only method that would increase your chances of a successful pregnancy is IVF. The reason is that multiple eggs can be extracted thereby increasing the chances of having a good egg (normal). It is not for sure, but will statistically increase your chances. At your current age, you probably have 1 out of 40 to 50 eggs that are normal. (When this post was published in 2009 no one really knew how many "good" eggs exist in the 35+ woman...and although it is still not 100% certain, a recent 2013 study has come out with some answers. The study found that 2 out of 20 eggs retrieved from 40 yr old women were chromosomally sound and had the potential of fertilizing and implanting successfully.) When you go through a natural cycle, you are only ovulating one egg at a time, so you can see that your chances that it will be normal is low and the chances of being abnormal is high. That is where IVF can help. With IVF you could get anywhere from 10-20 eggs at a time, depending on your ovarian function. Because time is against you, that is what I would recommend. The aforementioned medications should be used in conjunction with the IVF cycle.

As far as what your high-risk (I assume perinatologist) ob/gyn has recommended, I think you need to decide who knows fertility better. A fertility specialist or a high risk pregnancy perinatologist. As a fertility specialist, I have to disagree with your perinatologist as to your chances of pregnancy. As mentioned previously, IVF is the treatment of choice at your age. He is correct in that the chances of pregnancy are reduced because of the age related egg factor, which means that the majority of your eggs are no longer viable and prone to genetic abnormalities (spontaneous breakages), but is incorrect in saying that IVF will worsen your chances because the "eggs are too fragile for retrieval, fertilization or implantation."

In order to educate yourself regarding age related infertility and egg quality, your best source is ASRM's new website, reproductivefacts.org, sart.org or the CDC website. Each of these have the information you are asking for regarding the age-related reduction in infertility.

Good luck in your journey and don't hesitate to look for the right approach by seeking a second opinion.

Sincerely,

Edward J. Ramirez, MD, FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF

http://www.montereybayivf.com/