Second IVF Fails Despite Implantation: Thin Lining? Embryo Issue?

Question: Dear Dr. Ramirez,

I am here to seek your advice once again. I just found out my second IVF (in vitro fertilization) attempt finished with a chemical pregnancy. I tested HCG levels at 11dp2dt and it was 19,2 miu/ml (pretty low), and 48h later it was already 4,7 miu/ml.

I am nearly 37yo, have high FSH levels and my antral follicle count was 12 for this past cycle, 8 follicles grew, 6 were collected and 4 eggs retrieved. We got 100% fertilization and we transferred two 8-cell embryos with perfect morphology and no fragmentation.

I think my biggest problem is my endometrium. It is usually very thin. Although I still have 2 frozen embryos from my first IFV, two transfer cycles were cancelled due to thin lining that would never pass 6.9mm. I tried estradiol patches, vaginal estradiol (creme and pills) which resulted in poor endometrial growth (estradiol levels reached 3500pg/ml in one cycle) even after 3 weeks of use. I also tried vaginal viagra, vitamin E, baby aspirin, prednisone, and nothing worked... the endometrium would grow up to 5.5 to 6mm in the first 8-9 days of the cycle and then would take 14-21 days to reach 6.9mm. In one of the cycles it even decreased 1mm in one week.

Before my first IVF I did a hysteroscopy and everything looked fine. I have a couple small intramural fibroids, none projecting into the uterine cavity. I had a big fibroid removed 4 years ago, but it was intramural and the endometrium was not touched during surgery.

So, in my last IVF that turned out as a chemical pregnancy, my endometrium was 7.1mm at the 6th day of stimulation with FSH (Bravelle), which was really encouraging. However, 2.5 days later, it decreased to 6.4mm... Because at that time I already had bid leading follicles, my doctor wanted to triger that night. He then injected into the uterine cavity, using a catheter, 300 ug of filgrastim (G-CSF), since there are two papers from Dr. Gletcher that mention it as a possible treatment for thin lining. My RE explained to me it was experimental and I agreed to try it.

48h latter and on the time of egg retrieval, my endometrium was 7.6mm. Still not ideal, of course, but the best I got in a long time, so my RE advised us to carry on with the transfer (2 beautiful 8-cell embryos).

So my questions are:

1)What is more likely to be the cause of the chemical pregnancy: genetically abnormal embryo or my thin lining?? I know my age is a factor, but I have been taking Coq10 for nearly a year now. My embryos always look good and I have 100% fertilization rate.

2) Also, I wanted to know if it is normal to have a 8-cell embryo at the end of day 2 (I collected the eggs on Mon 9am and the embryos were transferred Wed 6pm).

3) Is it normal for the endometrium decrease during stimulation phase? What could have caused mine to go from 7.1 to 6.4mm in a little over 60h?

3) Do you think I should try filgrastim on my next transfer cycle? I don´t think my body likes synthetic estradiol though, it never responded well... so maybe a natural cycle (in which I usually reach 7mm) with filgrastim could work?

Taking my history into account, what would you recommend for my next FET in order to be suscessful in overcoming thin lining? Should I start to look into surrogacy?

As always, I really appreciate your time and expertise, and most of all the beautiful work you do here at your blog (for which I am a subscriber :)  C. From Brazil

Answer:
Hello C. from Brazil, Thank you for your kind words and for following my blog! Let me answer your questions in sequence to make it easier.

1. If endometrial thickness were the problem, implantation would not have occurred. Technically, the minimum endometrial thickness required is 6.5 mms so your lining was adequate for implantation to occur, which did happen. The miscarriage was most likely a genetic issue considering your age. Unfortunately, we do not have a technology to evaluate internal egg quality nor change the quality. Keep in mind that the CoQ 10 study was in mice and not humans so we don't know if that will work or not.

2. An 8-cell embryo on D#2 is not normal. That is a rapidly dividing embryo and may indicate that it is genetically abnormal, as has been found on preimplantation genetic studies in the past. Division rate is one of the criteria I use to evaluate embryos, in addition to the external quality.

3. The endometrium does not decrease. The difference in widths are variations in ultrasound measurements. Because we are dealing with mms, the difference between 7.1 and 6.4 (0.6) is within the margin of error and not significant.

4. I cannot comment regarding the "filgrastim" as I am not familiar with this medication or its usage. I would recommend that you consider the frozen embryo transfer in a natural, unmedicated cycle, but I would follow a natural cycle without transfer first to evaluate if your body growth the endometrium to adequate width. Then if it does, I would schedule to make do the transfer in the next cycle. I would still use supplemental hormones after the transfer, namely progesterone to help support implantation and the early pregnancy.

5. If the FET fails, despite everything that has been done, the only other recommendation I could make, if you are still going to try your own eggs, is to have preimplantation genetic screening done (trophectoderm biopsy) on a Day #5 embryo. Some studies have shown increased pregnancy rates in older patients when embryos are screened for normal genetics. That will at least give you an indication on the genetic health of the embryos you are making and whether or not you should consider donor eggs. I would only recommend surrogacy if you are absolutely sure that you cannot get implantation and in your case, you've had implantation. I think it might be more of an embryo issue.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.

High Responder Fails Two IVM and Two IVF Cycles: PCOD & Follicle Maturation Issues

QUESTION: Hello,

During the last year we did two IVM (in vitro maturation) and two IVF (in vitro fertilization) cycles at different clinics at Montreal, Canada. All failed. I'm 39 years old and my husband is 40. My FSH was 11.1 and AMH 2.2 two years ago. The first IVM was without stimulation, I was triggered when the lead follicle was 13mm, 11 eggs were collected, 7 managed to mature in the lab and 4 fertilized. By the day 3 we had transferred 2 embryos 6 and 8 cells (they did not give us their grade). Endometrium was 6.8mm by the day of collection. No pregnancy...

The second IVM I had 3 days light stimulation (about 150UI Puregon days 3-5 + Estrace from day 6). I was not aware of my hormone test that shown the E2 level fell on day 6. We had collected only 8 immature eggs from 17 follicles, the only egg fertilized and on the second day the weak embryo was transferred. Endometrium was 7.3mm. Of cause, no pregnancy.

We moved to another clinic and did there two IVFs. The first one I had stimulation from the second day: 225 Gonal-F + 75 Luveris. After 4 days dosage was increased up to 300 Gonal-F + 150 Luveris. On the day 13 I was triggered when I had one follicle about 22mm, 2 about 18mm, and many smaller ones. We collected 16 eggs, 12 were mature, 9 fertilized. My doctor decided to wait till day 5 for the transfer. We had one blast, the other embryos stopped developing. The lining was 8.2mm at the day of transfer. No pregnancy.

As the clinic doesn't work during weekends, the stimulation for our second IVF started on day 4 and lasted 9 days. It was more aggressive: 300 Gonal-F + 150 Luveris from the start and about 200 Gonal-F + 150 Luveris at the end as I had developed mild OHSS. I was triggered when my follicles were 1-19mm, 1-18mm, 3-16mm, and many 15mm and less. As I said the clinic doesn't work weekends. My collection was Friday. I asked to wait for follicle growing bigger and the answer was: no, they are big enough. We collected 25 eggs, only 13 were mature, and only 5 fertilized. They were stopping developing one after another. The last one stopped at day 6 on the morulae stage. The lining was perfect: 13.5mm. It was an epic failure: nothing to transfer... I was told that the issue is my egg quality (my husband has no issues with his sperm).

I see that I had the only follicle bigger 20mm at the collection and we had the only blast. So I really would like to understand whether it's not a coincidence? If there is a way to have more equal size of follicles by changing the protocol? If I'm a good responder and have many eggs and they usually fertilize good (if they are mature) but they stop developing - does it mean they are poor quality? Or they were not fully mature at the day of collection? As I'm getting older and we have no time to experiment with different protocols I would like to maximize our chances by using more effective protocol for our next attempt. It would be great to hear your opinion on it. Could the change in protocol give us better chance for success?

Thank you in advance! O. from Canada.

ANSWER: Hello O. from Canada,

I can't give you specific protocol recommendations because each doctor and each clinic do different things. There is no one way to do IVF as you have found out.

The latter stimulation cycles show that you are NOT a poor responder but a high responder with PCOD tendencies. That means your ovaries are very sensitive to stimulation and that is a good thing. Yes, your age and therefore your egg quality are issues. However, hope is not lost because there is a chance that you still have a few good eggs left. As long as your ovaries respond well to stimulation, your chances of finding the good eggs are high. However, it also means that you need to find the right clinic because pregnancy rates will vary highly depending on the skill of the clinic and factors such as when to retrieve. I think it is a mistake to go to a clinic that only does egg maturation, and a clinic that doesn't work weekends. Both clinics are short changing you. It's time to find a better clinic.

It is also known that when OHSS develops, the pregnancy rates also drops. Probably because the majority of the eggs are not adequately matured. So one goal would be to decrease the stimulation and try for fewer eggs and a longer stimulation to get higher quality eggs. That is my goal with patients that are high responders. One method I use to try to even out the stimulation is to use the "sandwich protocol" which is to use 2-3 days of antagonist prior to starting the stimulation (I don't use the long Lupron protocol)to suppress the ovaries so that the follicles all start at the same point. Not all doctors use this protcol.

One final note: I let my follicles reach 20 mms before trigger. In some cases, I'll go up to 24 mms on the lead follicles if there is some unevenness, the goal of which is to try to get as many mature eggs as possible. Again, these things/variations are what make clinics and doctors different. You need to find a clinic that has a respectable pregnancy rate for your age group (and that will stay open on the weekends) so that you don't waste any more IVF cycles.

FOLLOW-UP QUESTION:

Dr. Ramirez,

At first, thank you very much for your fast and detailed response.

I've forgot to mention that our infertility is unexplained and I always have a lot of follicles at any given cycle (the first time we asked medical help for infertility 4 years ago).

Today I've got some new details about my IVFs: first time the E2 was about 8000 at the day of trigger and progesterone was about 4. The second time E2 was more than 22000 and progesterone was 6.4 so that my doctor didn't wait anymore and triggered me when the lead follicle was still 19mm (and not because they do not work weekends, as he explained). Is it possible that the E2 level could compromise egg quality the second time?

My doctor told me that assisted hatching is not possible for a blast as it can be easily damaged. Do you agree with that? Is assisted hatching used for day 3 embryos only?

Also my doctor is tended to wait for a blast and do 5-day transfer as he believes it would give stronger embryo and higher chances of implantation. As I see we had many good-looking embryos on day 3 and 1 or no blast at day 5. Would it better to transfer at day 3 instead?

Thanks again for sharing your knowledge

Regards, O. from Canada.

FOLLOW-UP ANSWER:

Hello again,

You have to understand that my advice is my personal opinion and not necessarily the gold standard or generally accepted standard because there are many many variations in the stimulation portion of the IVF cycle. But let me give you my opinion.

Both cycles led to overstimulated cycles. If the peak E2's are correct, you went very very high and in the U.S., in general, we don't like the E2 to go above 4000. Yes, it has been shown that when hyperstimulation occurs, i.e. the E2 goes above 4000, there seems to be a decline in egg quality and pregnancy rates.

You don't necessarily have a diagnosis of "unknown" infertility. You have the "age factor" which means that your egg quality could be compromised based on your age. That is a diagnosis. My approach to transfer is to use D#3 transfers unless I have so many good D#3 embryos that it is harder to determine which ones to transfer. In that case I will proceed to D#5. I am not a big D#5 person because I don't think that it is an absolutely perfect technology and we probably lose some good embryos because of it (that has been shown by genetic testing of the embryos on D#3). Not all blastocysts are genetically good embryos. Because of your age, I don't think it makes any difference which day you transfer, but I would prefer to put back more and let nature decide that the lab. YES, assisted hatching can be done on blastocysts.

The only other option that might help you, is to consider preimplantation genetic screening so that only normal embryos are replaced. I would also recommend tranferring at least 4 embryos because of your age. PGS might decrease your pregnancy chances a little, depending on the expertise of the clinic, but can help you to distinguish the genetically normal from the abnormal. PGS can be done on D#3 or D#5.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com

Comment: Dr. Ramirez gives detailed and clear answers. He is extremely helpful and very knowledgeable.

40 Year Old UK Woman Trying IVF After Implantation Failures: Assisted Hatching & PGD?

PGD

QUESTION:
dear doctor ramirez, i am so glad to find you on this website and would very much appreciate your help. I will try to give you some background.

i have had 3 failed iui, then found problems with my fallopian tubes which led to bilateral salpingectomy, myomectomy, adhesiolysis and cornual tubal occlusion, left ovarian cystectomy, i also have fitz hugh curtis syndrome.


so then after recovery from the above op i had

one fresh ivf cycle - 18 follicles, 14 eggs collected, 8 fertilised, 3 day transfer of 2 embryos(8 cell, grade 2)on 18/10, started bleeding 30/10

fet - 19/3. 2 embryos transferred (5 cell grade 2 & 7 cell

grade 1-) Negative test 4/4

fet - 9/8. 2 embryos transfered (6 cell grade 3/3 & 3 cell grade 4/4) Negative test 24/8

on each occassion as you can see i had 2 embryos put back (blastacysts on the last fet) and all failed at implantation stage. these were in 2006 & 2007.

now in june 2012 i have started my ivf journey again. so far:

low amh result (i am 40 in october)

2 new fibroids found on ultrasound, advised to proceed anyway

down regulation extended 1 week as lining not thin enough

stim injections all went to plan

15 follicles (2 v large suspected to be cysts)

10 eggs retreived

7 fertilised

7 made it to blast but one left to perish as structure wasnt great.

2 fantastic blasts put back after using embryoscope which i was told had started collapsing which was explained as a very good development.

4 frozen.

so, 2 put back in and progesterone pessaries used one morning & 1 night.

day 5 post transfer sign of period.

evening of day 6 post transfer period definately started with heavy bleeding & clots, continued until today (day 9pt) flow seems to be slowing down.

negative test today 9dpt

clinic advised me to continue with pessaries and re-test on saturday (day 11 pt)
theres the background for you, so here are my questions:

1. why am i failing at implantation stage every time?

doctor says it just nature but i cannot help feeling something else could be wrong and i am running out of time

2. is there any kind of contraception or other medication that i could use to stop producing eggs, thus preserving the small reserve i have left?

3. what tests can i have done to rule out ANY other problems? ie immunology, uterine probs, endometrium probs?

4. fibroids-what should i do have them removed or is there any medication available that may shrink them before my next fet

5. assisted hatching-could this help?

6. pgd (preimplatation genetic diagnosis)?

7. having read my history but you advise i do????

if need be i will pay for any tests that they wont complete at my clinic. i feel if i can rule all other possible problems out then i can admit that yes it is in gods hands and just a matter of keep trying but at the moment i feel what if there is something else that is being overlooked?

many thanks for your help in advance doctor.

as you can see i am getting pretty desperate now!

lisa, uk

ANSWER:

Hello Lisa from the U.K.,

The term "Implantation failure" means that the last two steps of the reproductive process did not occur. These last two steps are natural steps and we do not have the technology to make them happen. That is why IVF is not a perfect technology. Once the embryo is placed into the uterus, the embryo has to hatch out of its shell and attach to the endometrial ining. Then the endometrial has to engulf the embryo (implantation). So either of these two steps could have been the source of failure. In addition, it is well know that pregnancy rates will vary from doctor to doctor and clinic to clinic because the transfer technique can play a significant role.

In your previous cycles, your embryo quality was poor. I am not surprised that they failed. In this last cycle, despite having good blastocysts, there is still a potential deficiency that they have. This is because of your age, or what I refer to as the "age related egg factor." We know that as the eggs age, the internal structures of the egg become more debilitated and so less likely to thrive. One of these deficits is the chromosomal structures are more brittle and can lead to chromosomal abnormalities as the cell is dividing. Without doing genetic testing, these cannot be detected. Even chromosomally abnormal embryos can turn into good looking embryos but not necessarily into pregnancies. That is another possible source of failure. IVF helps to overcome this problem by increasing the number of eggs retrieved and therefore, statistically, increases the chances of finding the perfect egg. But that does not occur every time. You will have to keep trying in the hopes of finding the perfect egg eventually. The good thing is that your ovaries are still very responsive (you don't have decreased ovarian reserve and stimulate well), which gives you a good chance.

In terms of your other questions, I would not do anything with the fibroids, any birth control pill can stop your ovaries from going through the ovulatory cycles and hopefully preserve your eggs and I can't think of any other testing. Without thoroughly reviewing your medical record, however, it is difficult for me to give you specific advice.

I would recommend assisted hatching as this has been shown to increase pregnancy rates in older patients. I would also recommend that you scrutinize your clinic, because of all the failures. Pregnancy rates can be very clinic and doctor dependent. You should try to find one that has good pregnancy rates for your age group. I am getting a 57% pregnancy rate in 40 year olds and many of the clinics in the U.S. are getting similar results. I would also recommend that you consider transferring more than two embryos (we allow up to 4 in 40 year olds).

You faith in God will help you through this, and eventually it will happen. You may have to change course at some point and look at a different approach, but your faith will get you to that dream of having a child. When I complete my embryo transfers, I say a prayer with each of my patients and ask God to bless my couple with fruit of the womb and grant their wish for a child. I am confident that he will do so as He wills it.

Good Luck

FOLLOW-UP QUESTION:
hi doctor

thank you so very much for your speedy and detailed response, it has set my mind at rest on a lot of points. it is interesting to be told that the quality of the embryos on our cycle a few years ago were of poor quality. although that is sad, at least now i can accept that maybe that is why we failed on those 3 occassions. i had been under the impression that the embryos were good quality, particularly on the first fresh cycle after egg collection.

i have read lots on assisted hatching and am glad you agree this may be a way forward for us.

can i please just take a few more minutes of your time to clarify my point on pgd & other test (point 3&6)

When you mention checking the quality of the eggs/embryos were you suggesting asking our clinic to go ahead with pgd for our next fet?

also what is your opinion on other testing such as Natural Killer cells, immunology, uterine/endo probs? Which of these or any other tests would you suggest i rule out before going ahead with our fet?

also you mention my ovarian reserve being good but i was under the impression that the AMH test i had done suggested i was on the bottom level in terms of my remaining eggs? this has confused me slightly?

thank you in advance.

many many many thanks for you time again. Lisa

FOLLOW-UP ANSWER:

Hello Again,

There are pros and cons about using PGS. It can help to identify embryos that are chromosomally abnormal so that you can be more selective in the ones that you transfer. The downside is that there is a decrease in pregnancy rates, probably because of the impact of the biopsy on the embryo.

I check certain immunologic testing on my patients that fail two or more IVF cycles. The tests I choose do not include natural killer cells because I don't believe in that concept as a source of implantation failure. Despite this testing, I also automatically place my patients on low dose aspirin, low dose heparin and medrol, as well as, increase the progesterone supplementation. The latter is the treatment for patients that have endometrial biopsy for beta integrins and find that they are deficient. I figure, why waste money on doing the test and just cover any ways, since increasing the progesterone is the treatment.

Remember that AMH is an "indirect" test for ovarian reserve and does not necessarily predict how you will respond. Your have already shown good response so it is not an issue.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.

How Can I Have A Year Of The Dragon Baby?

Question:
Dear Doctor,

We are a Chinese couple who would like to have a baby this year. We have been trying for many months in the natural way for timing the baby for the Dragon year but we are not successful so far. We are thinking that maybe we can make our chances better for a baby this year if we go see a baby specialist here in Hong Kong. My wife is 34 years old and I am 38 years old. We have been trying for six months now. If we try for test tube baby, can we choose for a boy or girl? What would you suggest would be the proper next step for us?

Thank you, you are very kind for your advice. L. from Hong Kong

Answer:

Dear L. from Hong Kong,

I appreciate the fact that many Chinese couples are looking forward to having a child in the Year of the Dragon. If you wish to time your wife's pregnancy for a delivery within this Chinese lunar year, you do not have much time to spare! In essence, since you have been trying to conceive already for six months, it may be time to look at alternatives. I will go over all your options, from least complicated to the most aggressive:

First option:

What I would suggest if you still choose to go the "natural way" for just this month, is that your wife begin taking prenatal vitamins that have at least 1 mg of Folic acid within it, and that you keep in mind that the actual fertile days are pretty narrow - 2-3 days. If your wife has regular and predictable cycles, you can predict ovulation by counting back 14 days from the period. That would show where ovulation probably occurred in the previous cycle and by counting from the first day of her period, gives you an idea of what cycle day ovulation occurred. Then with this information, you can use the calendar method by counting from the period the number of days where you can both expect ovulation to occur. You need to stop intercourse 5 days from that anticipated ovulatory day, then start intercourse two days prior and have intercourse daily, once per day, with having only one ejaculation per day for five days.

Second option:

I think that an IUI (intra uterine insemination or artificial insemination) is a better starting point and should be done right away, but you need to make sure that the appropriate treatment is being done to increase your chances. IUI's are better than trying naturally because the number of eggs ovulated are increased with fertility medications, timing is better known by ultrasound surveillance and the sperm is injected into the tubes to await the egg. Ideally, your wife should be ovulating 3 eggs per cycle, or have 3 eggs of ovulatory size (18-24 mms) so maximize the chances that an egg will find and get into a tube. You did not say if either one of you have been tested for infertility. In your age group (34yo), your chances of natural pregnancy are about 10% per month and with IUI, up to 24% per month.

At my center, typically, we do an hsg (hysterosalpingogram) to see if the woman's tubes are open and viable. We also do a semen analysis on her partner. A negative result in either of these tests would make it quite difficult for you to immediately succeed with either an IUI or naturally.

Third and probably best option:

Considering the fact that you do not have much time and that you are considering gender selection, then IVF (in vitro fertilization) or "test tube baby" may be the best choice if you wish to conceive within the next few months.

With IVF the woman can produce many follicles and as long as you get at least one good embryo, IVF has a better pregnancy chance than IUI because it is accomplishing 7 of the 9 steps your body goes through to achieve pregnancy (IUI only accomplishes one). The remainder have to be accomplished by your body. That is what gives IVF a pregnancy rate of 60-76% per cycle in your age group.

If you wish to do gender selection, then IVF with PGS (pre implantation genetic screening) is the only option you have. A microscopic biopsy of the trophectoderm (the outer cell layer of an embryo) is done by the embryologist and sent to a lab for analysis. Recently it has been shown that the pregnancy rates from a single PGS-selected euploid embryo were 58% and 60.7% compared to 42% and 40.7%, respectively, from a morphologically comparable but non-PGS-selected embryo. Interestingly, the miscarriage rates were seen to decrease to 6% and 6.3% from 12% and 12.5%, respectively. With transfer of one embryo, the risk of multiple gestation is essentially eliminated.

I know that in China, Korea and Japan, genetic screening for gender selection is not allowed. Here in California it is, though. We have had Asian patients come to us who have chosen to have PGS for gender selection and succeeded. Your chances would be reasonable if normal embryos were obtained and transferred. You can choose to freeze or vitrify some embryos and transfer one fresh (vitrification is a method of rapid cooling of embryos that minimizes ice crystal formation which has further improved success). If one is transferred and it takes (implants), I would expect that there would not be any abnormalities in the fetus or child.

I wish you luck in the Year of the Dragon and hope that you will find a good physician in Hong Kong or abroad that will be willing to work with you and help you succeed in your quest for a child this year.

I hope all this information is helpful.

Dr. 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.

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.

Follow Up Question From 30 Yr Old Austrian Who Failed 5 IVF Cycles & Is Trying Once Again

This is a follow-up question from a young woman with possible PCOS in Austria, who first wrote me in March. Please view the first two questions she posed in order to fully understand the problems she and her husband face. See the March 18th blog post: http://bit.ly/cqXqAp

QUESTION:

Dear Dr. Ramirez,

I had asked you a couple of questions two months ago, and thought of you now as we are preparing to do another IVF. I copy below what you suggested in terms of protocol for me (PCO-like stimulator), since I discussed it with my doctor and he is not sure that this kind of protocol can be done with the medicines available in Austria. You said:"Patients start at a low dose of Follistim 150IU for three days then the estradiol level is checked for response. If there is not a high response then I step up the dosage to Follistim 150IU + Menopur 75. We continue the same pattern of checking and adjusting the dosage as needed. I don't use Lupron agonist suppression (long protocol), but instead use the Antagonist Ganerelix. When the follicles are appropriate sized, I trigger with Lupron 0.5 mg instead of Ovidrel. These combination and protocol has been shown to be effective in preventing hyperstimulation syndrome"

The protocol he gave me last time (Dec. 2009) (starting on day 3 of cycle) was:Day 3-5 Gonal-f (150IU)Day 6 Gonal-f (112 IU)Day 7 Gonal-f (112 IU) + Cetrotide (one shot 0,25 mg)Day 8 Cetrotide (0,25mg) + Pergoveris shotDay 9 Cetrotide (0,25 mg) + Pergoveris shotDay 10 Cetrotide (0,25 mg) + Pergoveris shotDay 11 Cetrotide (0,25 mg) + Pergoveris shot Triggering with OvitrelleEven though this protocol was substantially reduced in quantity of medication, I still had 15 eggs and mild-hyperstimulation (enough for being 3-4 days uncomfortable to breathe and in pain and swollen all around).

The doctor is now proposing a similar protocol to this, but reducing from 150 IU to 112 IU to start and see what happens. I showed him your suggestion and he was receptive but I don't know if the medicines you suggested can't be found here or if what he is suggesting is similar to what you suggested. We are thinking of not having a treatment here anymore and moving onto a treatment in the States. In an ultrasound on day 19 of my cycle, he saw that I had ovulated recently and noted that I have/had around 15 follicles (or left overs of follicles) in my two ovaries. I was really shocked since I have been medication free for 6 months, so I didn't expect that's normal to have so many follicles on a natural cycle, he said that could mean I have a high ovarian reserve and could be a sign of why I hyperstimulate every time no matter what medicine they have given me.

My questions:

Is the protocol he proposes similar to what you wrote above?

What do you think about this empty follicles in my ovaries now?

Also, he has me taking Thyrex for my thyroid (one pill of 50 mg per day) since I started treatment with him over 10 months ago because my TSH level was over 4, and he wants to keep it at around 1, but am I supposed to take this pill forever? for Hypothyroidism? That's what he said, that until I achieve a pregnancy and give birth, I should be taking that pill.

Another question: What do you think about that? My TSH has been at around 1 since i started taking the pill. Regarding my husband's sperm (CF gene), they have been using his frozen samples for all treatments, saying that the freezing and thawing act as natural selection, whatever survives is better for ICSI than trying with fresh sperm. Do you think is better to use fresh sperm for ICSI? or frozen?

Finally, we are thinking of going to a US clinic because in Austria PGD is prohibited, and for us they have been doing polar biopsy of my eggs to only transfer the embryos which fertilized with the better eggs, but as you noted in your previous emails, the embryos should be checked as well to eliminate any effect by my husband's sperm...correct?

So thank you so much for your answers, we are about to cancel the cycle here which starts in one week and move on to make an appointment in the States with you or another clinic which can take us.

Receive my warm regards, L. from Austria

Answer:

Hello Again,

I am happy, yet surprised to hear that your doctor was receptive to my suggestions. I do not dispense recommendations with the expectation that patients will share it with their Physicians. It is mainly for patient knowledge. I do not mean to intrude on that doctor-patient relationship, nor your doctor's judgement, since they usually know you better, and many doctors will be offended.

The medications Gonal-f and Follistim are the same, but made by different companies. Cetrotide is the same as Ganerelix. Gonal-f and Cetrotide are made by Serono, whereas, Follistim and Ganerelix are made by Organon. They are interchangeable. Based on the protocol you showed me, you were already on a pretty low dose protocol. Since, despite this, you hyperstimulated, I would reduce the dose further to a starting dose of 75IU or 37IU Gonal-f. I would probably fight the inclination to increase the dose above this because you seem pretty sensitive and 75IU may be all that you need to get an adequate number of mature eggs.

The Pergoveris is the same as Menopur (FSH/LH). If it is added, as your doctor did previously, he might want to reduce the dose to 37.5 IU (half-dose), but it isn't absolutely necessary. Some studies have shown decreased hyperstimulation in PCO patients when the FSH/LH is left off because PCO patients tend to have an elevation in LH production.

Once your lead follicles reach 15 mms (at least 20% of the follicles), Cetrotide should be started at 0.25 mg per day and continued until the trigger shot. The Gonal-f may need to be increased because of this ovarian suppression, and you should expect a decrease/drop in the estradiol level initially because some of the smaller follicles will stop developing due to the suppression and stop producing estradiol. That is okay and the cycle should be continued (this is contradictory to current thought, where if the estradiol drops the cycle is usually cancelled).

The trigger should NOT be HCG or Ovidrel. Instead, Lupron 0.5mg (50 mcg) should be used subcutaneously as the trigger. This has been shown, in European studies, to be just as effective as HCG but because of a shorter 1/2 life (the amount of time the drug is in your system), there is a decreased incidence of hyperstimulation.

In addition, to the above, I will also sometimes use "drifting/coasting" if it looks like the estradiol level will go above 4000 before the lead follicles are at a mature size. This requires that the doctor predict the levels on a daily basis and the drift/coast is not started until the lead follicles are at least 16 mms. You doctor should understand what this technique is. But, just in case he is not familiar with it, it is where the stimulationn with Gonal-f and/or FSH/LH is stopped but the ultrasound surveillance continues until the lead follicles reach 18-24 mms, then the trigger is given.

Finally, your doctor is correct that the TSH (thyroid hormone) levels have to be in the normal range, otherwise this can have an adverse effect on your pregnancy chances. As I said previously, PGD is the only way to rule out your husband's CF gene from the embryo, as egg polar body biopsy only evaluates the egg (your genes), and frozen sperm is just as good as fresh sperm. I am flattered that you would consider us for a second opinion, thank you. If you do decide to come to the U.S. I would certainly enjoy meeting you and your husband and be assured that our center would do anything that it can to accommodate you and help you succeed.

In closing, tell you doctor that I have had patients where I even start the Gonal-f/Follistim at 37.5IU and step up to 75 or 150IU, so he might want to consider that in you since you are so sensitive.

The very best of 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.

German Woman Suffers Multiple Miscarriages Over Two Year Period - Proceed To Clomid Superovulation?

Question:

I´m 31 years old and writing from Germany. I have no children and have suffered four miscarriages. My husband and I have been TTC for 2.5 years now. After using the implanon hormone implant for birth control, I had it removed in 09/07 to begin TTC. In 11/07 I fell pregnant only to miscarry at about 5w3d. My hormone levels showed an hcg level of less than six. I was told to wait three months and try again, that I would have better luck. In March of 08 I fell pregnant a second time. At my first appt. at 8w5d it was discovered that there was a large sac with no fetal pole. I began to miscarry at 11 weeks and had an emergency D&C because I was losing so much blood. I asked that the tissue be analysed, but was told it was not done for a second loss and that this was in all likelyhood caused by a chromosomal problem. I was told to wait three months before trying to conceive again. Exactly 28 days after the D&C I got my period. I fell pregnant the next cycle, but did not realize it until I started miscarrying. My doctor did not do a blood test, only looked at an ultra sound, shrugged her shoulders and said I wasn't pregnant anymore, if I had ever been. She suggested that I could go for genetic counseling if it would make me feel better.

My husband and I went for genetic counseling, had kareotypes done, both of which came back normal, were tested for various thrombophilic conditions and immune disorders plus thyroid. My results came back as normal for everything but Leiden Factor V. I carry one copy of the gene. I was told by the geneticist that it would be good to start heparin at 8weeks in my next pregnancy and sent on my way.

In December of 08 I fell pregnant a fourth time, was given 100mg of aspirin to take starting at 4w5d. At 5w1d I began to bleed, but the ob/gyn felt that my lining still looked good, gave me progesterone supplements to take and told me to come back in five days for another ultrasound. On my return visit she could not find a sac in the uterus, and was unsure if she wasn´t seeing a sac in müllerin duct. I was told to stop the progesterone immediately and go to the hospital immediately should I have any sharp pains. Otherwise I was to report to the hospital in another five days for a beta draw. After stopping the progesterone I miscarried the next day. Three days later my hcg levels were drawn at the hospital and found to be 144, so I was required to come back every 48 hours for another draw to be sure that they were indeed falling. My levels fell nicely and I was sent home to wait three months before ttc again.We have been trying for a year now, and have not been able to get pregnant.

I have charted, used the clear blue fertility monitor and opk's to no avail. After six months I went to see an RE hoping that he would be able to give me some answers about my miscarriages, but he offered no ideas as to why, only said that my miscarriages were not a result of the Leiden Factor V. He did some bloodwork at CD13 to check my hormone levels, which he said looked very good, did a SA for my husband and a penetration test and said he saw no reason for us not to be pregnant. He suggested a doing a lap but made no further recommendations.

My regular ob/gyn was not in favor of the lap and suggested that I try a bit longer, and that if I wanted to we could try clomid and progesterone to get a stronger ovulation.I am unsure and very confused as what my next course of action should be testing and treatment wise, and if I really have a chance at having a biological child. I would appreciate any thoughts you might have on this subject. Thank you very much for your time.

Answer:

Hello L. from Germany,

Recurrent miscarriages are a difficult problem. The most common reason is because of a spontaneous chromosomal abnormality. That means it occurred when the egg was dividing, and not because you are carrying something. Hematologic disorders, such as Factor V, have been shown to increase the risk of miscarriage. Since you underwent evaluation and that was the only abnormality found, that is good because most patients with recurrent miscarriage due to spontaneous abnormalities will eventually be successful.

You mentioned that you were 31 years old, which is a good thing. Age plays a significant role in the risks of spontaneous anomalies and increases the risk of miscarriage with increasing age, especially after 35 years old. I call this the "Age related egg factor." Most patients that have recurrent miscarriages are because of age related spontaneous genetic defects. In your case, although there may still be "abnormal" or "weakened" eggs within your ovary, your chances of spontaneous defects are low. That means that your chances for success are high.

It sounds like your RE was addressing the issue of your infertility and not the recurrent miscarriage problem. Laparoscopy would be indicated to evaluate for infertility only. I don't think it is indicated at this point as well, but I wonder why you have not gotten pregnant after 1 year of trying. Something has changed and an evaluation is definitely warranted. I would go back to doing a full basic infertility evaluation and not make any assumptions, despite having gotten pregnant in the past. A hysteroscopy would be warranted to evaluate the uterine cavity because of your history of D&C. Therefore, you might also want to consider laparoscopy to complete an infertility evaluation, but not for evaluation of recurrent miscarriages.

If you don't want to do an evaluation but want to proceed with trying for pregnancy, then it is a little shot in the dark. Certainly doing Clomid "superovulation" is an option. This is where the fertility drug Clomid is used to increase the number of eggs that you ovulate per month. This can be paired with either timed intercourse or IUI. I might suggest the latter, IUI (Intra Uterine Insemination) for a higher pregnancy rate between these two. You might want to use low dose aspirin (81mg)per day and heparin (2000 units/twice per day) and medrol 16 mg per day starting from the beginning of the cycle, as well as, supplemental progesterone (vaginal or injectable) and estrogen.

The other option would be to proceed with IVF (in vitro fertilization). In this case, embryonic genetic testing, called PGS (preimplantation genetic screening) can be done to determine which are the normal embryos so that only these would be transferred. If you decided to pursue this option, I would recommend that you choose a clinic that has experience doing this and can do testing at the blastocyst stage (trophectoderm testing), rather than an earlier stage where they take one of the cells, and test with CGH (comparative genomic hybridization) .

I hope this gives you some information to consider.

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.

29 Yr. Old IVF Patient Told She Has "Bad Eggs", Husband Has Balanced Translocation

Question:

A bit of history...2 miscarriages in the last 2 years. We were referred to an RE who did testing and found that my husband has a balanced translocation. We were advised to do IVF with PGD - I had no apparent problems. Our IVF cycle resulted in 10 eggs, 7 fertilized, 3 made it to day 3 for pgd and stopped dividing later that day. The PGD revealed very abnormal embryos with multiple trisomies and some chromosomes with only 1 copy.

The dr said I must have bad eggs - he indicated he was very surprised because all my levels were normal and I'm only 29. he has suggested donor eggs. I'm wondering if I should try another protocol or just go along with the donor eggs. I feel like I'm too young to have bad eggs but since no embryos lived there must be something wrong right?

Any advice would be greatly appreciated!

Answer:

Your history is a little odd, because for someone your age, I would have expected a better outcome in terms of the number of embryos to test. It is most likely that the abnormal embryos are coming from your husband. Not you. I think, unless finances is a problem, I would continue trying. You will eventually have a good embryo, and hopefully, a subsequent cycle will give you more embryos to test. You were not stimulated very strongly and could be. Because of the poor embryo development, I would try to get you to produce 15-20 eggs. That will probably require more medications. PGD can be done to check the embryos with subsequent cycles to see if they are chromosomally normal or not. Keep in mind though, that recent studies have shown decreased pregnancy rates with PGD, probably due to embryo injury or affects from removing one of the blastomeres. In other words, you may harm a potentially "good egg".

If you go another 2-3 tries and still no normal embryos, then I would suggest you consider donor sperm with IUI. You could do IVF but that would be much more expensive. I would think that if you persist in having abnormal embryos it is because of the abnormal sperm. That is why I suggest donor sperm. If you are dead set on having a genetic child from your husband, then you will just have to keep trying using IVF.

I don't agree that your outcome in the first cycle is a sign of bad "eggs", especially at your age.

Good luck and try to keep in mind that you do have options.

Sincerely,

Edward J. Ramirez, M.D.

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/

Cystic Fibrosis Carrier and Infertility

Question:

I am a carrier of the Cystic Fibrosis gene. How does this affect my chances of becoming pregnant? I am 33 yrs old and am taking 5mg of folic acid to prepare my body. My husband and I definitely want a child, but we were for waiting at least until next year before trying. I have a very strong fear that conceiving is not going to be straight forward. Can you advise me on this issue? I have been advised to have children sooner rather than later.

Answer:
Hello Sharon,
Thank you for your question. First, I do advise sooner than later, especially after the age of 30. As you know, your fertility rate is decreasing with time. For instance, at 30, the pregnancy rate is 60% per year. At 35 it is 30% per year. You're in-between that rate. I wouldn't put it off.

In terms of your cystic fibrosis gene, it has no bearing on your pregnancy chances. It only impacts on the fetus, if and only if, your husband is also a carrier. In that case, you have a 50% chance of the fetus having cystic fibrosis, which is a fatal disease in children. If your husband is a carrier, and he should be tested if he has not, then you should undergo IVF with PGD (preimplantation genetic diagnosis) to exclude the embryos with the cystic fibrosis gene.

I hope this answers your question.

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.
Check me out on Facebook and twitter with me at @montereybayivf.