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!

Use Of Prednisone And Lovenox For IVF Cycle With Donor Eggs: How Long?

Question:

Dr. Ramirez:

I am a 44-yr old with a history of numerous IVF attempts. Miraculously, cycle 1 (2007) with my own egg (yes, only one egg was retrieved) resulted in a healthy baby. 1 additional IVF attempt (2009) with my own egg - unsuccessful. Subsequently, 4 IVF attempts with two different donors (some fresh, some frozen cycles) were also unsuccessful. With each attempt, the blastocysts were high-grade, and other recipients of same donor's eggs resulted in pregnancies.

For my current cycle, which begins this week, we will be using a cryopreserved embryo, and physician is adding two medications: Prednisolone 25 mg daily, starting 10 days before transfer, and Lovenox 40mg daily, starting 2 days prior to transfer. If successful, plan is to continue both meds (along with Estrogen and Progesterone injections) for the first trimester. This seems like an extremely large dose of prednisolone and lengthy duration. I am concerned about the potential side effects on me, as well as the developing fetus, assuming a positive outcome. Do you have any experience and/or information regarding the prednisolone and Lovenox? Thank you, C. from the U.S.

Answer:

Hello C. from the U.S.,

In my patients that fail 2 IVF cycles, I automatically add prednisone, Heparin (lovenox can be used as well). All my IVF patients get the prednisone (I use medrol), low dose aspirin, progesterone and estrogen, so in reality the only thing that is new is the heparin/lovenox. Because of the potential effects on the developing fetus, I do not use the prednisone longer that the first pregnancy test. The heparin, aspirin, progesterone and estrogen are continued until the patient reaches 10 weeks gestational age. In patients that have a history of recurrent miscarriages, I will sometimes continue the medications until 12 weeks gestational age.

I start the heparin (lovenox) with the start of the IVF cycle, just like I do with the prednisone and aspirin.

Incidentally, your experience with a pregnancy in the first IVF cycle with only one embryo transferred, at the age of 40, is the reason why I DON'T ever cancel a cycle if there is only 1-3 follicles. My belief is that this one egg may lead to the one perfect embryo left and I would hate to lose the opportunity to get a pregnancy from it. It may be a lower chance, but it is still the best chance that you've got. So I am glad to hear that your docs continued the cycle and did not cancel it like so many do!

Good luck with your upcoming donor cycle.

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 very much for your expert opinion and extremely timely response! I greatly appreciate your time and expertise.

40 Yr Old German Woman With Great Ovarian Stim Fails IVF: Likely Abnormal Embryos, Try Again!

Question:

Dear Dr. Ramirez,

My name is A. from Germany, 40 years old, never pregnant before. I had 2 failed IVF this year (1 in March, 1 in June). My FSH=10.6, AMH=0.8. progesterone level is normal.

The 1.IVF had 6 eggs (2 embryos were transferred: 1 grade 1 and 1 grade 2) and 2.IVF had 7 eggs (3 embryos with grade 1 were transferred in July).

The 2.IVF was done in North Cyprus. Do you think the failure was caused by taking airplane back home on the 2.day after transfer? It was just about 3.5 hours flight.I will try the 3.IVF this year.

How long should I take a break before trying the 3.IVF? Because I heard that the hormone level, uterus lining and ovary need time to get back to normal. Are these correct? I have also read an answer of yours regarding implantation failure.

You wrote in March this year:

"My approach to patients with implantation failure is to add the following medications:
1. Aspirin 81 mg per day beginning at the start of the cycle.
2. Heparin 2000 units twice per day beginning at the start of the cycle.
3. Medrol 16 mg daily until transfer then 8 mg from that point until positive pregnancy, then stop.
4. Increase progesterone to 50 mg injection plus Endometrin 100 mg twice per day vaginally. The injections starts on the day of the retrieval and the suppositories start the day after the transfer. "

My questions are:

1.what for an effect is the heparin in the case of repeated failure? I did not have this in the last 2 IVF. Do I need this, even I do not have thrombosis problem?

2. Do I need to increase my progesterone level even I have a normal level?

3. I will do an autoimmune test next month. Which tests should I do in addition?Thank you very much for your time. Best Wishes. A.

Answer:

Hello A. from Germany,

I was impressed to see that your ovary stimulated well and gave you an adequate number of embryos despite your age and elevated FSH levels. One thing to keep in mind is that despite having a good IVF cycle with reasonable embryos, IVF is not a perfect technology. The last two steps, embryo hatching and attaching to the endometrium and implantation, must occur naturally. This does not always happen. Also the embryos have to be completely genetically and otherwise normal. There is a higher chance of abnormal embryos with increasing age. That is what is called the "Age factor."

What that means for older women (35 years and older) is that it may take a lot more attempts to achieve a pregnancy, but as long as the ovaries still respond and put out eggs and embryos, then you have a good chance. Also keep in mind that pregnancy rates are highly variable among clinics so the clinic you go to is very important.

With multiple failed attempts, I add the protocol that you cited. There is a saying in the U.S. called "throwing in the kitchen sink" which basically means doing everything you can possibly do. That is the reason for this protocol. These medications are mainly used in patients that have recurrent miscarriages. But in IVF failure patients, it seems to work as well.

The Heparin and aspirin are at low doses so they are mainly targeting very small clots that occur in the micro-vessels that feed the implantation site. It is not enough to prevent a large clot in your vasculature. At that level they also have an anti-immune action to prevent failure due to an increased immune response from your body. That is also the reason for the Medrol or prednisone. It is an anti-immune drug. Some women are found to have an increased immune system when an antiphospholipid antibody screen in done (21 points). Finally, the increased progesterone is to insure that adequate progesterone is reaching the endometrium because this hormone is vital to implantation and survival of the pregnancy.

Travel is not an issue. I have many patients that come to me from far away places, yet they have been successful. Studies have shown that travel has no impact on pregnancy rates. What is more important is finding a good IVF center that uses state of the art techniques and has good pregnancy rates in your age group. I have many patients that come from Europe so that is always an option as well.

Good Luck,

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