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.

Egyptian Fails One Fresh & One Frozen IVF Cycle: Advice On How To Improve Lining Thickness

Question:

Hi, I am 28 years old, married since 3 years, trying to get pregnant since 2 years. I had ectopic pregnancy since 15 months which ended by right laparoscopic salpingectomy. Then I tried clomid for 3 cycles, HMG induction for 2 cycles and I tried fresh IVF (in vitro fertilization) with long protocol.

I took 1 amp menogone , 1 amp fostimon 75 mg, 1 amp fostimon 150 mg/d. there was 36 mature follicles , all fertilized well, then 4 good embryos were transferred on 3rd day but ended badly on 5th week by blighted ovum.

Then I tried frozen embryo transfer by thawing the embryos and let them grow to the blastocyst stage. We got 14 good blastocyst from 19 embryos, then 2 hatched blastocysts were transferred. I took estrogen valereate 6 tab/d till endometrium thickness 8cm, then progesterone supp 800 mg/ d , aspirin 75 mg/d. but again a negative BHCG on due time.

Some history:

a) semen analysis is good with no abnormal forms or motlity
b) patent left tube by hysterosalpigogram
c) history of endometriosis discovered during laparoscopic salpingectomy.
d) good hormonal profile FSH, LH, TSH, prolactin, anti-phospholipid tests

Now I am planning to repeat but I still have 12 frozen blastocysts, but I need your advise because we thawed the 3rd day embryos from the first ivf , then let them grow till the blastocyst stage , then did the transfer the last time , then refreezed them again.

My question:

I am undergoing a new frozen cycle now. I take 6 tablets oral estrogen valereate/ day, 200mg sildenafil (viagra) vaginally/ day and vitamin e, aspirin, and after the endometrium reached 8.5 mm thickness on the 10th day stimulation, it decreased on the 13th day to 6 mm although I still take the same dose with no discontinuation, sure of the expiry date.

What is your explanation please, and what can I do to prevent cancellation of the cycle? If I continued the same dose is there any hope for restoration the thickness?

Please answer me because I am frustrated and breakhearted.

N. from Egypt

Answer:

 Hello N. from Egypt,

This is a protocol question, which I do not answer because protocols can vary widely and there is not only one way to do things. That being said, there is some general information that I can provide.

First, keep in mind that you have been pregnant with IVF and so can get pregnant again. IVF only gives you the opportunity to become pregnant, it cannot make you pregnant because there are still some natural steps that must occur on their own. Studies have shown that if you have gotten pregnant in the past, your chances of getting pregnant with IVF are higher. Also keep in mind that, just like trying to get pregnant on your own each month, it does not always work. Sometimes it can take several attempts before it is successful.

Second, it is well documented by studies that the best way to deliver hormones for IVF is either by injection, by patches or by vaginal delivery. Oral tablets can be used vaginally (you just push them to the very back). This helps with maximum absorption of the hormone and delivery to the uterus. Oral intake has been shown to be the worst way to give hormones for IVF because most of it is lost when it passes through the liver. I personally use patches, which most US doctors use, but tablets used vaginally is also a good option.

I would not necessarily cancel the cycle, because time can be taken to develop the endometrial lining further. It is only finalized once the progesterone is started. That is what determines the timing of the transfer, which for a blastocyst, should be on the 6th day after starting the progesterone. If you have not started the progesterone yet, you can keep using an increased amount of estrogen to get the lining to 9 mms.

Good Luck,

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

American In The UK Taking Clomid & Has Thin Uterine Lining: Needs A Specialist

Question:

Hi Dr. Ramirez,

I will try to keep this as concise as possible. I am very healthy, slim and 29 years old, and have never had issues with my periods. My husband (29 years also) and I conceived on our first try last year, but unfortunately had a missed M/C at 12 wks (fetus stopped growing at 8 wks). Tests confirmed non-recurring genetic abnormality. After the D&C I had only spotting, until 5 days after when I had a very heavy bleed with large clots lasting only one day. Then I got my first period 6 weeks later. The 3 subsequent cycles were 42-45 days.

Pelvic ultrasound revealed PCOS, hormone levels were all normal, including thyroid. Lining on this ultrasound was only 5.5 on day 40, just before I started my period. I have just completed one round of 50 mg Clomid unmonitored due to travel, and BBT shows clear ovulation on day 18 with 12 day luteal phase. This cycle I have had my first follicle tracking on day 11 which showed dominant follicle at 15 mm, but lining of only 4 mm. My questions are:

1. Could the thin lining be due to problems from the D&C?

2. My gyn prescribed Progesterone pessaries for the second half of this cycle to help thicken the lining- is this the appropriate treatment?

3. When should I consider seeing a fertility specialist?

Thank you for your time- I am writing from London. M.

Answer:

Hello M. from the U.K.,

A thin lining could certainly be due to an over-vigorous D&C, leading to scarring in the uterus. This is called Asherman's syndrome. A procedure called hysteroscopy can be done to evaluate the uterus cavity for this. However, that being said, it is not very common to develop this with D&Cs. The more common possibility is a thin lining due to the use of Clomid.

Clomid is an estrogen receptor blocker and so blocks estrogen receptors at the endometrium (uterine lining). For that reason, many patients have to use extra estrogen given vaginally in order to overcome the blockage from the Clomid, or they use a different medication such as Femara or injectables.

Progesterone is NOT the hormone that thickens the uterine lining. Endometrial thickening and priming is dependent on ESTROGEN in the first half of the cycle. The fact that your doc told you the wrong info makes me skeptical that he/she clearly understands the physiology of this treatment. So, I think you should go see a fertility specialist instead. Without proper estrogen priming, the uterine lining will not be ready for implantation. The progesterone, which is given after ovulation, is to convert the endometrial lining to develop the "pinopodes" that are necessary for implantation. (See diagram up above, the "pinopodes" are small finger-like protrusions in the endometrium) Without the proper priming, the pinopodes will not develop.

Good Luck and keep trying, you should succeed with the right treatment path,

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.

Comment: Thank you Dr. Ramirez! I am very grateful to have your opinion, which confirmed to me that I need to see a specialist. As an American living abroad, it can be daunting to find the same quality of health care that we take for granted in the US. Again, I really appreciate your help.