39 Year Old With Recurrent Chemical Pregnancies

Question:

Hello there! I’m writing to you from Florida. I have recently suffered two miscarriages. One in Oct of 2012 and one in March of this year. Both occurred at about two weeks so very early. I guess the term is chemical pregnancy when it is that early. I don't know how I know I am pregnant so early but I just know. My body is sensitive! I am 39 years old so my Dr. watches me closely and had me do the clomid challenge test to check the fsh which I think tests egg quality. Mine was 7.6. I also had a vaginal ultrasound and everything looks perfect. No fibroids or cysts. Then in March 2013 I got pregnant again and I was immediately sent for an hcg blood test. My hcg levels kept going up and down 241 to 119 over the course of three weeks and it would not leave my system completely so I ended up having to have another ultrasound that found nothing as they were worried about an ectopic pregnancy but did not find a sac or anything. I ended up taking a methotrexate shot.

Finally my levels went back to zero and 6 weeks later I did a complete recurrent miscarriage blood panel test and they found that I tested positive for two copies of the mthfr CT677 gene. I also was out of range for the PAI-1 test which was 51. Everything else was normal. My Dr. put me on foltx and a daily aspirin plus I take my prenatal vitamins and she told me that as soon as I find out I am pregnant again I need to start administering lovenox injections and progesterone suppositories. Right before delivery it would change to heparin. I enjoy reading your blog and appreciate all of your knowledgable answers. I would like to know what your thoughts are about the regimen she has planned for me and if there is anything else I should be doing. I am a bit nervous to try again. We really want to have a baby!  

Thank you, M. from Florida

Answer:

Hello M. from the U.S. (Florida),

The CCCT is to check for ovarian reserve (ability of the ovary to respond to stimulation) and not egg quality.  Thought you should know that.

It sounds like your Ob/Gyn doctor is well versed in the evaluation and treatment of recurrent pregnancy loss, which makes her a little better than the average Ob/Gyn doc.  One thing to keep in mind, however, is that you have the "age factor" which means that your eggs are old and debilitated and therefore have a propensity to forming abnormal embryos.  In most cases these embryos will not continue and lead to a miscarriage (especially before 8 weeks gestational age).  The age factor is the main factor that you are trying to overcome.  There is no treatment that can make eggs better.  The good news is that your ovaries are still functioning well, and you know that you can get pregnant.  Now it is just a matter of getting a perfect egg.

The increased folic acid, low dose aspirin, low dose heparin or lovenox and progesterone supplementation are all reasonable and acceptable treatments for recurrent pregnancy loss. What I would recommend is that the heparin/lovenox start immediately with the start of your period, NOT once you become pregnant.  It should already be in your system when implantation occurs to help with increased blood flow at the implantation site, and decrease the immune response to the embryo.  Starting after pregnancy would defeat the purpose.

Based on your age, I would agree with the above regimen, add CoQ10 600 mg per day (found to help with egg quality in mice.  No human studies yet but it can't hurt) and strongly recommend that you consider IVF rather than continuing to try naturally.  I know that you are able to get pregnant naturally, and it may eventually happen, but the only way to increase your chances of success (overcome the age factor) is to increase the number of eggs and embryos you have to choose from.  With IVF, you have a better chance of finding the perfect egg.  I explain it to my patients with the following analogy: imagine that you have a bucket of blue balls and a few red balls. There are mostly blue balls and only 4-5 red balls.  The red balls represent your good quality eggs and the blue balls the poor quality eggs.  These balls are all mixed up together and you lift the bucket above your head so that you can't see inside.  Now you have several options.  You can take one ball out at a time (like you would in a naturally ovulatory cycle) whereby you will eventually get a red ball, but you can see that it will take a long while; or you can take out a handful of balls out at a time (like using superovulation with fertility drugs); or you can dump out a bunch of balls at a time (like doing IVF).  You can see that the latter method is the fastest for getting to a red ball.  That is why IVF (in vitro fertilization) is the recommended treatment.  With a red ball (good quality egg) not only will you get pregnant, but you will have a successful pregnancy because a normal embryo will develop.

Sorry for the extremely long explanation, but I hope my answer has been clear.

Good Luck,

Edward J. Ramirez, M.D.
Executive Medical Director
The Fertility And Gynecology Center
Monterey Bay IVFwww.montereybayivf.com

Monterey, California, U.S.A.

32 Yr. Old Losing Hope After One IUI Miscarriage and One IVF Chemical Pregnancy: I Say Don't Give Up!!!

Hello, I don't even know how to begin because my infertility process has been so exhausting. I suppose I have diminished ovarian reserve. My last FSH check was 8.5. My AMH is 1. My stimulation cycles response seem to change--one time will be a nice response and the subsequent ones won't be. I started my first IVF this year and I fear repeating the same pattern as last year. Last year, my first IUI on 75 follistim/femara produced 4 mature eggs. I conceived, hcg was high, but ultimately a miscarriage due to trisomy 3. Did a complete RPL work up (I had a chemical pregnancy unmedicated 6 mos earlier). Nothing was abnormal, even karotyping. I had two more IUIs after that, producing 2 eggs, then only 1 egg. No success. I battled recurrent simple follicular cysts for about six months (would bounce from one ovary to next, two cyst aspirations and they would still come back) and finally had a cystectomy and laparoscopy in early February 2013. He found very mild endometriosis and treated it. I had started birth control pills in early January, on for 5 weeks, and then carried on with an antagonist protocol later in February with 150 follistim/75menopur. My day 4 E2 was over 700, thought I had another cyst, but instead had several follicles, dropped follistim to 75, then E2 dropped to 500, then up to 100 follistim and eventually my growth balanced out. Ultimately, I had 14 follices, 12 mature, 9 eggs retrieved, 6 fertilized, 4 day 3 embryos, then 2 highest grade blastocysts, 1 morula. Transferred the two blasts. Positive beta, 175 14 days after transfer. But my 48 hour beta dropped to 77. So I'm having another chemical pregnancy/miscarriage. This is exactly a year from my last miscarriage. I am terrified that in continuing IVF I will repeat this same pattern--that the next IVFs will not work. I just don't know what to do. I don't want to be 32 and have bad eggs when I know I don't have a translocation. I feel like I do respond to lower doses of medications, which should be indicative of decent reserve, but I don't know why I would keep having such problems likely due to embryo abnormalities. I suppose my uterus may have not been ready after the surgery and it wasn't the embryo but I took the good stuff-PIO, vivelle, dexamethasone, prednisone. Anyway, can these protocols be causing me an increased risk for aneuploid embryos? What could be changed? Any comforting words that I won't face the same fate with more IVFs that I did with the repeat IUIs? With it happening the same way all over again, I am believing I'll never have a baby. Last year was so hard, this IVF was hard. I’ve had to miss so much work, surgeries, U/S, procedures, etc. And I love my husband so much. I hate that I put him through this. Thank you, L. from Oklahoma Answer: Hello L. from the U.S. (Oklahoma), First let me clarify and emphasize to you that the IVF cycle worked, and you certainly have a good chance that it will continue to work in the future.  Your doctor probably did not explain that IVF only gives you the "chance" to get pregnant.  It, in fact, cannot MAKE you pregnant because the last three steps of the reproductive process are still beyond our technology to make happen.  These steps have to happen naturally (that part is still in God's hands).  So the fact that you got pregnant on your first IVF cycle is significant because it shows that you can get pregnant!  It is unfortunate, however, that it ended as a miscarriage. In terms of going through all of your previous pregnancies and this one, that would involve a more comprehensive analysis and explanation, that is beyond this venue.  I can do that by private consultation only. Second, I think you need to get the terms "decreased ovarian reserve" and "never" out of your vocabulary.  You DON'T have decreased ovarian reserve.  Keep in mind that in IUI cycles, we only want up to three mature sized follicles so that you don't get triplets, quadruplets, etc.  So, your responses were appropriate.  With your IVF cycle you were on a very low dose protocol and the yield was appropriate. . . not too strong and not too light.  You certainly could have been stimulated a little stronger, but it looks like your ovaries are very sensitive to the fertility medications so some care needs to be taken, as your doctor did. Finally, there is no technology that can predict or evaluate for internal embryo quality.  We can evaluate chromosomes so one option you certainly could consider with IVF is to have preimplantation genetic screening (PGS).  If you decide to do PGS, I would recommend a D#5 biopsy to reduce harm to the embryo, but your embryos would need to be frozen and transferred at a different cycle.  But that would allow you to evaluate the genetics of the embryo prior to transfer.  Your doctor would also need to stimulate a little stronger to have more embryos to work with and test since surely some will return abnormal.  This will then allow you to transfer normal embryos. All clinics, doctors and the protocols they use differ and that is what influences the pregnancy rates which vary from clinic to clinic.  There are other treatment protocol options; for example, I use low dose aspirin and low dose heparin in my recurrent pregnancy loss patients.  It has been well documented to help.  You might want to discuss that with your doctor. I want you to not lose hope.  You are young, your ovaries are still responsive and you've been pregnant, so now the goal is just to get a perfect embryo so that you can have the perfect baby.  Statistically, your chances are very very high, so you will eventually be successful.  You just need to hang in there and get the best treatment that you can.  Then once you have your baby, let me know so that I can celebrate your success as well.  You are on the road to success.  The only way you will surely fail, is if you deviate from than road.  Like Law school, this is a hard road, and it may not be fair, but in the end, it will be the most wonderful experience you've ever had in your life!  Greater than falling in love.  It was for me, and I thank God for his blessing that gave me my beautiful soon to be 16 year old IVF daughter.  Keep the faith in your path and in yourself.  Sorry for the long answer...good luck! Dr. Edward J. Ramirez, M.D., FACOG Executive Medical Director The Fertility and Gynecology Center Monterey Bay IVF Program www.montereybayivf.com

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.

32 Year Old With Two Failed IVF Cycles With Positive Beta's: Chemical Pregnancies?

Question:  Hi Doctor,
I live in Idaho where we only have 1 IVf (in vitro fertilization) clinic, so I don't have the option of a second opinion and can't decide if it's worth the six plus hour drive to find out if anyone else would do anything different so I really appreciate you reading this.

A quick medical run down is my infertility was both blocked tubes which 3 years ago I had opened, since they've been open I developed endometriosis which I had cleared last September. I am 32 years old with no medical issues. I have had 8 failed IUI's before finding the endo and then 4 failed IUI's since clearing it. I did have one pregnancy with the IUI but they thought it was ectopic and it aborted itself. I have just completed my second failed IVF. By the way DH has all "normal" counts and morphs for his samples. Both protocols for meds were the same I took Doxycycline and Medrol right after ER (embryo retrieval) and started Progesterone vaginal inserts day after ET (embryo transfer) and was on prenatals and baby asprin the whole time. Both transfer's were done with guided ultrasound with no complications.

1st IVF-September 2012. 10 eggs,10 matured, 4 embryo's fertilized (no ICSI) 1-six cell, 3-eight cell all grade 2's. Two embryo's transfered, last 2 died on day 6 before making it to blast. First beta was 9, second 32, then on day 11 I started spotting,cramping and clotting. Day 13 beta was 7.

2nd IVF-November 2012. 21 eggs, 18 matured, 13 fertilized with ICSI, 1-eight cell grade 1, 6-eight cell grade 2, 4-seven cell grade 2, 1-nine cell grade 2, 1-two cell grade 3. Transfered 2 embryo's back (one was hatching) and cryopreserved 6. Beta test 1 was only a 3 and then the second beta nothing improved. I started bleeding day 11 again.

I have not yet met with my RE but I am trying to gather all the info I can before meeting with her. This last fresh cycle will have been the last one that I think I will do just because the stress on my body of being on meds off and on for 3 years now I think is too much. So the 6 frozen are very important to me to use wisely. I read that you said a chemical pregnancy is not an implantation problem so does that mean that you think it would be a problem with the embyo's? My RE felt last time that there was no need for genetic testing and that my endo was not an issue. I'm just lost as to what my next step should be, what to test for or what I should do with my remaining embryo's (gestational carrier or gamble with them). Thank you again for your time, your blog's have been so much help for me while searching for answers. M. from Idaho, U.S.A.

Answer:

Hello M. from the U.S. (Idaho),

Once you get a positive bHCG, that means that implantation occurred. To be more specific, it means that after the embryo was transferred into the endometrial cavity (the limit of what IVF can do), the embryo progressed in its development, hatched out of its shell, attached to the endometrial lining and the lining grew and enclosed the embryo. These last steps are all natural steps that we do not have the technology to make happen. They have to happen on their own. The take away message from this is the knowledge that you can achieve a pregnancy with IVF. The ensuing problem, of miscarriage, is a pregnancy issue. Whether or not the embryo progresses to developing a successful pregnancy and ultimately a normal and healthy baby is based on the pregnancy alone.

Miscarriage is a more common occurrence than people think. We know that up to 50% of pregnancies can end in a miscarriage, many of which are chemical pregnancies like you had. In most cases of early miscarriage, the reason is because of an abnormal embryo, meaning the embryo had some sort of genetic abnormality. In most of these cases, it is a spontaneous abnormality that occurred at the time of embryo division and not something that you carry. But just to make sure, you and your husband might want to undergo genetic testing if you have not already done so.

One other thing I noticed is that your embryo quality, based on its external appearance because we don't have the technology to know the internal quality, was not optimal for someone your age. This could be related to an inherent problem with the eggs, sperm or lab conditions. In a woman under the age of 35, I would expect most of the embryos to be 8 cell, grade 1 embryos. Genetic testing in the embryos, PGS, is an option but I too would not have recommended it in your age group. In addition, PGS may do some harm to the embryo thereby reducing your pregnancy chances. You'll need to discuss this further with your doctor.

I don't think that any of this has to do with your endometriosis, which is not an issue with IVF.

Ultimately, because you have achieved chemical pregnancies, you have to keep in mind that the IVF can work. Now it is just a matter or time, or more specifically, a matter of getting the perfect embryo. That will take continuing to try and ultimately I am confident you will be successful. It is unfortunate that you only have one option for an IVF clinic in your area because pregnancy rates vary highly from clinic to clinic. That may be another option i.e. travelling to another clinic. We call that distance IVF where patients travel to another state to have the IVF done. It is easily coordinated and arranged so you don't have to limit yourself to one option only. There is more that can be said or advised, but a thorough review of your medical records would be required.

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: I was amazed at the timely response and all the information given. I feel confident that the Dr. is giving a knowledgable response as well as very honest without pushing his own clinic which was comforting. Thank you again for your time.

Severe Allergy To Progesterone During IVF Cycles

QUESTION:

Dr. Ramirez, I have a problem with progesterone but my symptoms are not typical of an allergic reaction. My husband and I have done 3 IVF cycles, all failed. They were all chemical pregnancies

1st cycle: The day after the first progesterone in ethyl oleate injection, I developed chills, a high fever, blood pressure drop and an elevated heart rate. The doctor thought it was an infection but the lab results were negative. I was then switched to Endometrin which caused intense vaginal itching and burning. So the RE put me on Crinone which also resulted in intense burning and terrible headaches.

2nd cycle: I was put on compounded progesterone capsules. After 5 days, I developed severe redness, swelling and pain. So I was then put on compounded suppositories which looked like white bullets. These caused burning and bleeding. The RE then had me try progesterone in sesame oil injection. About an hour after the shot, I became flushed and felt like I was going to pass out. I also developed a fever, drop in blood pressure and an increase in my heart rate.

We then did a mock cycle with the compounded progesterone capsules along with Zyrtec and Singulair. When the vaginal redness, swelling and pain returned, I was put on Benadryl. Unfortunately, that didn't work either.

3rd cycle: The RE had me do daily HCG injections along with oral Prometrium 200 mg three times daily. I had no problems with that protocol but it was not successful in achieving a pregnancy.

Prior to my mock cycle, an allergist tested the various progesterones to which I had an adverse reaction. The prick test was negative for all but the intra-dermal shots induced a wheal (9 & 10) and flare (both 12).

Is there a way to either prevent symptoms from developing or are there other progesterones which will not induce a reaction in the first place? Thank you! S. from Michigan

ANSWER: Hello S. from Michigan,

I think that you should avoid compounded progesterone. Instead, you could try an injectable progesterone made with an oil other than sesame oil so that would be one option, or a pharmaceutical formulated progesterone such as Crinone 8% or Endometrin would be alternatives. I use a pharmacy called MDR who makes an progesterone in a different oil that is less viscous and more easy to inject. I presume that the injectable that was tested by your allergist was with sesame oil. It is most likely that the allergen was the "oil" and not the progesterone itself, since the oil is a protein. You might want to have him check that.

Crinone and Endometrin are both used vaginally which has been shown to be the optimal method for delivering progesterone to the endometrium. Oral progesterones have been shown to be ineffective because most of the drug is lost in the first pass through the liver. Only injectable, vaginal or dermal have been shown to be effective.

Although there are no pharmaceutical companies that sell transdermal progesterone products on the market, there are a lot available through health stores and the internet, and also can be compounded. I don't use them so can't attest to their effectiveness or dosage but have seen some studies looking at them. It is possible that MDR can compound one for you.

The alternative for luteal phase support would be low dose HCG injections, like your RE has done. That has been shown to be effective. As a last resort, a surrogate could be used. Although expensive, it is an alternative that some of my patients have used with success when they could not carry the pregnancy for whatever reason.

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.

Young Canadian With Hydrosalpinx And Endometriosis Complicating IVF Cycle

Question:
Hello Dr. Ramirez,

I am 27 years old and last year stage 4 endometriosis was discovered and I had 2 large cysts removed from both my ovaries, one was 12cm and and the other was 5cm. My left ovary is almost completely gone and both my tubes are not functional. My hormones as far as I know it are normal and my antral follicle count is 8.

My first IVF with ICSI (my husband has blood in his semen due to unknown reasons) was last November with an antagonist estrogen priming protocol. I had 10 eggs retrieved, 5 mature, 3 fertilized, and ended up with 1 good quality day 3 embryo to put back. The cycle ended with a chemical pregnancy. I was on 400 puregon and 75 repronex.

I did my second IVF cycle with ICSI this month on the exact same protocol. They saw 11 follicles before my retrieval and 6 was retrieved, but none fertilized at all. My RE said that egg quality was very poor and may not suggest another cycle for me.

My questions are:
1. Is my endo the cause of bad eggs?

2. Will changing the protocol help better egg quality?

3. They noticed 2 small cysts on a recent ultrasound, and also a hydrosalphinx on the left. Would it help to have another surgery?

4. Do I have any hope in becoming pregnant with my own eggs?
Thank you so much for your information!

Thanks... A. from Canada

Answer:

Hello A. from Canada (Ontario),

I don't think that endometriosis is causing the egg problem, but that is certainly debatable. There are some studies showing better results if the IVF cycle is preceded by 3 months of Lupron depot in stage 3 and 4 endometriosis. There is definitely an effect if there are endometriomas that are penetrated at the time of egg retrieval. These endometriosis debris has been found to be detrimental to egg quality. Because of that, I am very careful to avoid the endometrioma at the time of retrieval, or if it is penetrated, I replace the needle and tubing before continuing.

In terms of protocol, you certainly seem to be stimulating well, which is the goal of the protocol and there are many variations that can be used. Each doctor has their own preferences. There is not one protocol that is better than another. However, I would probably use a stronger protocol if you were my patient (you are currently using a 475 combination protocol# such as a 600 IU combination protocol #450 FSH + 150 FSH/LH (Menopur)). Changing the protocol will not improve egg quality, but having more eggs may help with getting more embryos to work with.

If you have a hydrosalpinx, you definitely need to have that surgically removed or excised from the uterus. Numerous studies have shown a reduction in pregnancy rates with IVF by 50% if a hydrosalpinx is present. In the U.S. it is now considered the standard of care. The cysts are not an issue.

I am always hopeful for my patients, in terms of your last question, even those that have a minimal chance because they are way too old. I see exceptions all the time and believe in miracles.You are only 27 years old. Your chances should be much much better and I am leery of the results you have had thus far. Frankly, it doesn't make sense to me, but I would have to review your medical records to see what might be going on. At your age, you should not have an egg quality issue and fertilization should be at least 60%. In my clinic, your age group has a 76% chance of pregnancy per attempt. That makes me worried about the quality of the clinic you are going to. You may want to seek a second opinion.

Good luck and don't hesitate to keep me updated,

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.

Fourth IVF Cycle Ends In A Chemical Pregnancy: What Can Be Done?

Question:

Hi Dr. Ramirez,

I have been on a rollercoaster ride for the past week and I am hoping that you can offer me your opinion.


I received a positive beta after my 4th IVF on Monday (11dp3dt). It was 14.3 and my RE said that it was quite low. I held out hope as I am convinced that I tend to implant a little later than others. In a previous cycle I had a negative beta 12dp3dt and found out that I was pregnant a couple of weeks later. I tested 3 days later and my beta was up to 52.8. I was so excited and felt so much better about things. I am scheduled to go back on Sunday morning for another beta.

I am currently taking Crinone 2xday. For the past week, I have had dark brown Crinone gunk(sorry for TMI). Last night and this morning there was some red blood on the applicator tip. At 1st I thought it was just irritation but for the past couple of hours, when I wipe there has been more red blood. I am also getting some minor cramping.

I am freaking out and I am so worried that things are moving in the wrong direction. I called my clinic and they said that they cant know anything until Sundays beta. They said it could be start of a miscarriage given the low beta #'s or it could be irritation from the Crinone or even pregnancy spotting.

I was hoping that you could offer some advice as I remember in the past that you prescribe Crinone to your patients.

Is RED spotting normal? How much spotting is normal? Was I foolish to be hopeful after my #'s doubled? Do you think its likely that this will end in miscarriage?

Any insight would be greatly appreciated. I dont know if i can hold out until Sunday's beta.

Thank you,

D. from Boston, Mass.

Answer:

Hello D. from the U.S.(Massachusetts),

The advice that your doctor gave you is completely correct. It could be from the Crinone, and I have seen an increased incidence of spotting in my patients using Crinone), it could be implantation spotting or pregnancy spotting or it could be indicating an abnormal pregnancy. There is no way to know which of these is the correct diagnosis. In general, I reassure my patients not to worry about spotting. I only worry if the bleeding is bright red flow like a period with accompanying cramping. The only way to determine the fate of this pregnancy at this point is to continue to follow the bHCG's every other day. This trend will then give you a better idea of how the pregnancy is doing. AS long as the bHCG is rising, then you can be reassured. If it plateaus or drops, then that is not a good sign.

Follow-Up Question #1:

 Dr. Ramirez,


Thank you for getting back to me. Unfortunately, my beta level dropped on Saturday so it looks like I will be having another chemical pregnancy. I am devastated of course. I was hoping that you might be able to provide me with some insight as to an explanation as to why this keeps happening.

A little history:

Me: 31 years old- normal FSH but AMH is .8

Husband: Very low morphology (less than 1%)

This was our 4th IVF cycle and 3rd chemical pregnancy. I have had tons of testing... RPL work-up, HSG, genetic testing, uterine biopsy and all came back normal.

I am a low responder and in previous cycles have had poor egg quality. I just switched REs and had a better response with an Estrogen Priming Antagonist protocol. He used a low dose HCG with Gonal F. Quality and ICSI fertilization rate was much better so I was hopeful that this was it.

My RE said that it was likely a chromosomal issue with the embryo and probably because of poor egg quality and we just need to keep trying and hopefully will get that “one” good egg. I don’t know if I am comfortable with that answer. We only have 2 insurance tries left and I want to make sure we are exploring all options before proceeding again. What would you recommend for your patients at this point? Do you think that it is worth doing a Sperm DNA fragmentation test?

What could be the reason for all of these chemical pregnancies?

Any insight is greatly appreciated.

Follow-Up Answer #1 :

Hello Again,

The exact reason cannot be known, of course but the most common reason for chemical pregnancies are a genetic abnormality in the embryo. With poor morphology in the semen analysis and your young age, definitely the genetic weakness could be from the sperm. I don't recommend the sperm DNA fragmentation test because it only gives the indication for the batch of sperm that it tests and not the sperm as a whole. In addition, the treatment recommendation is to use ICSI, which I presume you are doing already. So you won't gain anything from that test. If we suspect the sperm, other than ICSI you have the choice of either using donor sperm the next time or maybe try using a supplement for three months before doing IVF again. The supplements that your husband can try, which might help with sperm quality, are either Proxeed or Fertility Blend (vitamins) and CoQ10 600 mg per day. He will have to wait three months because sperm are on a 90 day cycle #the sperm made today won't be expressed for 90 days.

The only other options I could give are what I would do with my patients who have recurrent miscarriages (which is what you have even if it is a chemical pregnancy). Studies have shown the benefit of these meds and it is standard of practice to use these with recurrent miscarriages.

I would add: aspirin 81 mg per day, Medrol 15 mg per day until transfer then decrease to 8 mg per day, Heparin 2000 units twice per day and CoQ10 600 mg per day, all starting with the start of the cycle (CD#2). The Aspirin and Heparin are withheld from the day of HCG trigger until the day after the retrieval. The only other option you might want to consider is genetic testing of the embryos prior to transfer, called preimplantation genetic screening (PGS). That way you will know if the embryos are normal genetically or not. The downside of using PGS is I have observed and some studies have shown a drop in pregnancy rates after this. Some of my colleagues say that if it is done by a very experienced embryologist who does lots of these procedures, the pregnancy rate does not drop.

You'll have to discuss these options with your doc. I'm afraid there are no exact answers to your dilemma. But, studies on patients with recurrent pregnancies have shown that eventually these patients are successful. So, hang in there, even if your insurance coverage expires.

Follow-Up Question #2:

Thank you so much for your thorough response. I really appreciate it.

I am only 31 years old but I do have a low AMH (only .8) so along with that and the fact that I am a low responder, my RE suspects that I may have a diminished ovarian reserve. So, unfortunately, both my husband and I seem to have issues.

Do you think that the low AMH and dimished ovarian reserve contribute to the repeat miscarriages? Or do you think it is likely a sperm issue?

Is there any way to tell who is main contributor to this issue? We are not ready to talk about donors at this point and will continue to try with our own eggs/sperm for now but in the event that we need to explore other options, it would be helpful to know if we would be more likely to succeed using donor egg or donor sperm.

My RE has given us the impression that it is more a egg issue but hasn't given us any explanation of why.

Any help with this would be hugely appreciated.

Follow Up Answer #2:

Hello Agian,

There is no way to know what the exact cause of the recurrent miscarriages is. It could be egg or sperm derived since the genetics of the embryo come from both. Considering that you are ONLY 31 years old, I would suspect that it is NOT an egg issue but there is no way to be sure.

It is definitely not related to AMH or low ovarian reserve. The AMH is a measure of follicle availability and low ovarian reserve is a description of ovarian response to stimulation.

Good Luck,

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

Implantation Problems & Causes Of Chemical Pregnancy

Question:

Hi again, it's K. in NY. I have written to you in the past about my difficulties staying pregnant. I have had 7 chemical pregnancies in the past 18 months and one miscarriage at 9 weeks after using femara (you felt it was probably due to a respiratory virus I contrated around 6 weeks). I tested positive for MTHFR mutation heterozygous but also this didn't appear to be the issue.

I guess I have a 2 part question for you. The first would be related to causes of chemical pregnancies. My progesterone levels have been on the low side of normal (even during the pregnancy that ended in miscarrige) and I really thought that was the cause. I was placed on 50 mg suppositories 2 months ago and I did get a positive result this month (8 DPO Hcg 12, progesterone 18.8, took femara and progesterone) but my HCG level was back to <5 on 10 DPO.

Are there other implantation issues that could be my problem besides chromosomal abnormalities and low progesterone that lead to a pregnancy not progressing? I know I shouldn't test early, but I was trying to establish if low progesterone levels were the cause of my losses.

Part 2: is it possible to just have an underlying HCG level that elevates above 5 regularly, and if so, what would that signify? As you may remember, my old RE wrote off the HCG values as me eating too much cereal and developing an antibody to HCG that triggers pregnancy tests. I will be visiting a new RE soon and want to be sure to ask the right questions and supply the best information.Thank you very much for all of your insight and for volunteering your services. Merry Christmas!

Answer:
Hello K. from the U.S. (New York),

Let me take the second question first since it is the easier of the two to answer. The answer is NO, you can't have an underlying HCG level from cereal or any other source other than pregnancy. Serum pregnancy tests are very sensitive and testing for the beta subtype (bHCG), so there is no cross reaction even if the cows you were using the milk from were given hormones for some reason (I presume that is what your old RE was thinking as a source. A little far fetched if you ask me).

In terms of your chemical pregnancies, that is a difficult problem to answer. If you have already undergone a complete recurrent miscarriage evaluation (hormones, infectious diseases, anatomical, genetic, immunologic) then we may not have the technology to find the exact cause. However, the hormonal is easy to check through blood tests, and I automatically place my patients on progesterone supplementation just in case; anatomical testing would take an ultrasound and hysteroscopy, again an easy test; and infectious diseases and genetic are also easy to test. The only one that is difficult and not completely understood is the immunologic component. Many authorities have looked into many different immune factors.

If you look at a website by Reproductive Immunology Associates, who have made a practice of the immunologic causes of miscarriage, you will see lots of different test that they recommend. Because this component is so difficult to define, experts have conflicting opinions.

If you were my patient, I would put you on a protocol that I use and, for the most part, have been successful with. It involves taking aspirin 81 mg per day starting at the beginning of the cycle, medrol (prednisone) 16 mg per day taken from the beginning of the cycle then decreasing to 8 mg after ovulation, progesterone vaginal suppositories beginning after ovulation and, finally, heparin 2000 units twice per day subcutaneously beginning at the start of the cycle. The aspirin, medrol and heparin treat for subclinical immunologic problems and the aspirin and heparin also help to increase blood flow at the microvascular level at the implantation.

Good Luck & Merry Christmas to you too :) ,

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.

Comment: Thank you SO much for your opinion. I will definitely have to look into these additional things. Glad to hear that I am doing all that I can do on my own and that I am advocating for the right things. It makes a HUGE difference when you have an idea what direction you should be headed so that you can work with a doctor to get there. Merry Christmas!

37 Yr. Old Malaysian Woman Gets Chemical Pregnancy With First IVF: How Did Her First Cycle Look And What Are Her Chances With The Second?

Question:

Dear Doc, I would appreciate an opinion on this current IVF cycle I'm on and my previous failed cycle. I'm 37. My period is regular ie 28-32 day cycles. This is my second IVF. I started suprefact on day 21, 40 units for 13 days, 15 units from the 14th day onwards. 300 iu Gonal F on the 16th day for 4 consecutive days now. I will be seeing my RE tomorrow. My period came on the 10th day I was on Suprefact, 30 days after my previous period.

My first IVF also started on day 21, I was on suprefact for 14 days @ 40units. I started puregon 350iu on the 15th day-was on 350iu for 11 days, 250iu on the 12th day and 225 on the 13th day; suprefact was at 15 units. 13 eggs retrieved, 9 fertilised but only 4 left on the 3rd day when the transfer was done. 13dp 3dt my HCG was 375. At 18dp 3dt, my HCG was 2065. I was bleeding lightly post transfer and when the time came for the ultrasound, no sac was found and my hcg level had dropped to 117-end of my BFP. What do you think my chances are for this second cycle? I would appreciate any advise you might have. A. from K.L., Malaysia

Answer:

Hello A. from Malaysia,

Thank you for writing me all the way from Kuala Lumpur! Let me comment on the information that you have given me. The first IVF cycle looked pretty good except that the embryo development was poor. If 9 eggs fertilized, you should have had 9 embryos formed. Despite this, you were able to get pregnant, which proves that this treatment plan (IVF or in vitro fertilization) can work for you. The miscarriage has nothing to do with the IVF. Once the pregnancy occurred, it becomes an independent entity and will either progress or miscarry on its own. In your case, a chemical pregnancy occurred leading to a miscarriage. Most miscarriages occur because of spontaneous genetic/chromosomal abnormalities that occur at the time of cell division. Because the embryo was abnormal, a fetus did not develop, thus leading to the miscarriage. This was probably due to the "age factor."

As a woman ages, more and more of her eggs become weakened/debilitated leading to abnormal embryo formation. Therefore the miscarriage rate increases. Keep in mind that IVF can only give you the opportunity to get pregnant. Whether or not implantation and pregnancy occur are up to your body's and the embryo's natural processes. We do not have the technology to make that happen. It has to happen on its own. So the fact that those processes occurred is a very good sign :) and all you need now is to get a good and healthy embryo into position. Then you'll have a successful pregnancy.

I'm glad to see that you are now in another IVF cycle. Since you had a chemical pregnancy, I am confident that you can achieve pregnancy eventually. Because of your age, it will just require persistence on your part.

Good Luck on your second cycle,

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.

Multiple Failed IVF cycles

Question:
Dear Dr Ramirez

Welcome back from your holiday ! I’m Australian but am writing to you from sunny Singapore, one degree north of the equator, which is where I work and where I am now having IVF (after 6 failed cycles in Australia).

I had metastatic cancer (melanoma) at 35 so had no choice but to stop trying for a baby back then, and I received the "all clear" to try again just before my 41st birthday (this would be my first/only). I tried 3 IUI cycles (because my hormone levels were apparently great) but when they failed, I went to IVF with ICSI and assisted hatching. I am now 43 and trying for what will probably be my last (or next to last) attempt. I very much want to try with my own eggs (my medical history makes me ineligible to adopt).

I wasn’t told, but have recently discovered, that I have what appears to be very high E2 levels (I’ve discovered that from the web sites I’ve visited…..my first clinic just told me I was "too old"). My D2 bloods this month were similar to every other non-stim month: FSH 6.5, LH 5.6, E2 168.8, P4 .76 and Prolactin 12.8. Those numbers have changed little since my first tracking cycle in Jan 06 and it’s common for me – at ovulation – to have E2 levels of 900-1800 on unstimulated cycles. On stimulated cycles (I’m using 250IU Puregon with Nafarelin/buserelin as downregulation) I’m getting E2 at trigger of 9000-21 000 (21000 was on a flare protocol). I get good response usually (10-17 eggs so far, with about 70% mature and about 75% of those fertilise) but apart from one chemical pregnancy, no good outcomes despite some AA grade blasts last year. I usually get mild OHSS but last cycle, it was so bad I had trouble breathing (due to the abdo swelling….it made it hard to expand my lungs).

The only other significant background I can think of is that my periods became light to non-existant (spotting only some months) after the first IVF cycle and despite the excellent efforts of my naturopath and acupuncurist who work together and work with my new clinic), they’re still really light. Even after the chemical pregnancy ended, there was no bleeding. I had some spotting as the HCG hit 500 but then as the numbers went down, nothing. I just ovulated again 2 weeks later (confirmed with a P4 blood test) and it seems to me you can hardly expect a pregnancy with minimal endometrium. I’m otherwise really healthy – normal weight, and work out 3 times a week with a personal trainer.
　
My questions are
1. If I have such high E2, why aremy periods so light ? My P4 at 14 days post transfer is usually 40 (with crinone pessaries) but is that too low in view of the high E2 ?
2. My new doctor has suggested birth control pills (Gynera: gestone + estradiol) for a month to quieten down my ovaries and then a long downreg to try and suppress the E2 level. His plan is that if E2 becomes too high, we can just freeze any embryos and transfer later but I don’t expect that to do much more than kill any embryos, so any suggestions you have for controlling the high E2 would be great. (not sure if there is a particular type of BCP/downregulation that’s better than others ?) 3. What protocol would you suggest for someone with that profile ?
Thanks for any help you can suggest. I realise we’re going through a lot in the hope of "one good egg" but I want to make sure I’ve tried everything possible before I give up. I’ve been reading your previous responses (to make sure I don’t ask something you’ve already answered !) and have been quite cheered up by your "20% chance of success" stats. That’s more than I’d expected and a little under the chance I was given of surviving 5 years from metastatic cancer, so I hope to be "queen of the small percentages" one more time ;) Thank you so much for volunteering your time for this – I guess you can tell that it’s enormously appreciated.

Warmly

Alison

Answer:
Hello Allison,

Thank you for all the information. You are certainly in a tough spot because you are trying to "beat the odds", but since your ovaries respond so well to stimulation, there is certainly hope. The major obstacle for you at this point is the age related changes to your eggs. This passage of time has rendered them quite debilitated, and therein is the problem. Finding that one good egg will be difficult and make take many more attempts. Fortunately, you provide your clinic with lots of eggs to work with and that increases your chances.

It is curious that your baseline estradiol is elevated, and certainly not normal. I am surprised your doctor has not tried to find the source of that elevation. It is not normal, and something has to be producing the estrogen. In most cases it is an ovarian cyst, but that would easily be seen by ultrasound. Ovarian tumors can do the same. That certainly needs to be followed up in an unstimulated cycle. If your doc is going to proceed anyway, I would definitely recommend suppression with the birth control pill for at least three weeks prior to the start of the cycle. That, hopefully, will suppress the estrogen and it should be under 100 at the start of the cycle. If it starts out elevated, how can the clinic know exactly what your real estradiol level is to make decisions. By the way an estradiol of 21,000 is the highest I have ever seen. I watch my patients very very carefully to prevent hyperstimulation syndrome, which is the most dangerous complication of IVF, so I have never had a patient get so high.

In term of protocol suggestions, other than the BCP, I can't think of any specific protocols for your situation except the following:
1. Your doctor might want to consider using an antagonist instead of the "long protocol" with Naferelin (a GnRH agonist) such as Ganerelix or Cetrotide. This uses less medication, and is used extensively in European protocols, but the major advantage, and the reason I use it in high stimulators, is that Lupron can be used to trigger, instead of HCG. Since Lupron has a shorter half-life, there is a significantly decreased incidence of hyperstimulation syndrome. Lupron is a GnRH agonist so it can't be used when you are already on one.
2. I would recommend post-retrieval day # 3 transfer and NOT blastocyst transfer. I am not confident that culturing to blastocyst is entirely perfected yet and your good embryos may not make it to the point. There is not change in pregnancy rates between the two transfer dates, but you lose more embryos going to blastocyst. In addition, I don't know if they allow it in Singapore, but they should put back up to 8 embryos to give you the best chances. The chance of a super-multiple (>2) is low at your age.
3. Because of your age, you are at an increased chance of miscarriage, which includes chemical pregnancies, due to spontaneous chromosomal breakages. That is part of the age factor. You'll have to be prepared for that if you use your own eggs.
4. Because you have gotten pregnant before, that is a big positive on your side. That means that if you can get a good embryo into your uterus, you have a good chance of having a successful pregnancy. That is the hard part. Instead of adoption, have you ever considered using donor eggs? Is it allowed where you are. I think that if you switch to donor eggs, and this can be done at any age because the uterus does not age, you would have an excellent chance of pregnancy. In our center the pregnancy rate is 62% per cycle with donor eggs. It would be genetically your husband's and biologically yours, since you would be pregnant, nurture it in utero and deliver the child. No one would ever dispute that it isn't your genetic child. It is a better alternative to adoption, and would give you the highest chances of success. It is an alternative that you should keep in mind.

I hope this helps,
　
Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
Monterey, California, U.S.A.

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