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/

You Can Do IVF With A Low AMH !

Question:

Hello Dr. Ramirez,

I am 36 and have been unable to conceive for 3 years. The diagnosis we have been given is diminished ovarian reserve. I have tried 3 IUIs (intra uterine insemination) with clomid. Each time I ovulated only 1 egg (I already ovulate on my own). I decided to move on to IVF. I went to a new clinic because they have very high success rates (30% higher than my current clinic). Over the last year, my antral follicle count has only been between 6 - 8. FSH has been between 7.6 to 9.5 (my very first cycle a year ago it was 12.5, but that was tested on day 4, so I'm hoping that made a bit of a difference). Estrogen is always low on day 3, so my FSH is not artificially suppressed. The new RE insisted on an AMH test (my previous clinic offered it, but I declined as it is not covered by insurance and wouldn't have changed my treatment plan - only possibly caused more worry - my previous clinic was okay with my decision).The AMH test came back with very bad results (2.4 pmol/L - I understand there are 2 units for measuring this and for pmol/L this is very low). The new RE says there is no point doing IVF with that AMH result. He said my chances of success are less than 2%. He said you usually get half the number of eggs of your AMH (so I would be lucky to get 1). He would only do IUI with injectables if I wanted to, but recommends I move straight to donor eggs based on the AMH test.

I am wondering if the new clinic has such great results because they exclude patients from IVF that may not respond so well OR if the doctor really does know what he is talking about and I would just be throwing money away. Obviously, I would prefer to have a chance at a biological child and wanted to move to IVF ASAP. In your opinion, should I visit another clinic that would allow me to do IVF (understanding with low AFC and low AMH, my results may not be positive) or do you think this doctor is right and it would be a waste of time to try my own eggs and move to donor eggs immediately. I know donor eggs would have a better success rate, but there is not a time limit on this option (as there is on my own eggs) so that could be a future option. Thank you very much for your time, L. from Toronto, Canada

Answer:

Dear L. in Toronto

It always angers me when Doctors draw these type of conclusions. A recent study that I read showed that despite a low AMH number or an elevated FSH, there is still a pregnancy rate of about 20%. What that basically shows, as I have always argued, is that it only takes ONE good egg to be successful. When a woman tries on her own naturally each month, she only has one egg to work with. I often get letters from patients whose doctor has cancelled their cycle because they only have 1-3 follicles. But, what if the perfect egg was in one of those follicles? FSH levels and AMH are only indirect measures of ovarian function. They are NOT measures of egg quality or your chances of pregnancy. Please see more on AMH here: Understanding Infertility: Age Factors.

Naturally, part of the statistical chances with IVF occurs from being able to get many eggs to work with i.e. more eggs increases the statistical chances. Imagine that you have a dice and want the number 6. If you only have one dice, you have a 1 of 6 chance. Two dices double your chances, three dices etc. So with IVF, since we can't predict if the egg that is retrieved will be the perfect egg, and because we don't want to have to do this over and over again due to cost, we want to have lots of eggs. But that doesn't necessarily mean it won't work if you have fewer than is ideal. It might take more than one try (statistically). But, as I ALWAYS tell my patients, who are usually older than you, it only takes one good egg to be successful.You might want to find a clinic that is more willing to work with you instead of make decisions for you. I can see that you are good at analyzing the situation and I am confident that you will make the right decision.

Good luck and don't give up!

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

Follow-Up To This Post:

Please scroll down to November 6, 2013 to see this writer's good news and how by persevering she conceived with a low AMH :)!

"I am the one that originally submitted this question to you and I want to thank you for being positive as even with the low AMH we did end up getting pregnant and are currently 4 months away from meeting our 'miracle' baby."

31 Year Old With DOR Advised To Keep Trying: Adjust Protocol To "Mixed" FSH & FSH/LH

QUESTION:

Hi Dr Ramirez

I am on my first round of IVF and my day 9 scan showed no follicles on left ovary and 3 tiny follicles on right. I am on 375 menopur which has now been upped to 450. Priot to starting treatment i was on the combined pill for irregular periods. I am 31 years old with FSH level of 6. My question is, can being on the pill interfere with follicles growing and am i on te right meds? When they scanned me prior to starting treatment i had more follicles than when doing IVF which doesn't make sense to me? I am having treatment in London, England.

Thanks, N. from England

ANSWER:

Hello,  N. from England,

With your age and FSH level, I would have expected a much better stimulation response. I think you are not being adequately stimulated. Menopur is not adequate. There needs to be more FSH in my opinion, but keep in mind that each doctor does things differently and one way is not necessarily better than another. If you were my patient, my preference is to use a "mixed" protocol using both FSH (Follistim or Gonal-f) and FSH/LH (Menopur or Repronex). I would have started at 300IU Follistim and 150IU Menopur (450IU total of FSH), then possibly decreased to the dosage you started at. But, that is my personal preference (and of course something that makes each clinic different with different results).

The pill should not and does not interfere with ovarian stimulation. I presume that you are also on a Long lupron protocol? Lupron will suppress the ovaries as well.

I have also been surprised by the lack of stimulation in a younger patient, such as your doctors were pretty surprised. Sometimes it is hard to predict what will happen. If the cycle fails, then I greatly increase the medications in the next cycle. Such a finding is called a "poor responder". But keep two facts in mind:

(1) each cycle is unique and the stimulation results can vary from cycle to cycle. One does not necessarily predict the next.

(2) it only takes one good embryo to be successful.

Good Luck!

Follow-Up Question:

Hi Dr Ramirez,

Thank you so much for your prompt reply. I carried on with the 450 Menopur until day 16 and they decided to cancel the cycle as the one follicle was not responding as they would have liked. The consultant at the IVF clinic told me that my chances of conceiving are zero per cent even with IVF. To say I was shocked was an understatement. I spoke to him about the possibility of a different protocol or different meds but he was adamant that I shouldn't try again. I don't quite know where to go from here. I have been under the care of a gynae at my local hospital for fertility investigations for 5 years and he kept telling me IVF was the answer. I got pregnant with Clomid two years ago but now I am at zero fertility, I mean not even 1% according to the IVF consultant.

My question to you would be, in America do you do things differently? I spoke to him about Gonal F and he said it wouldn't have made a difference. I also said about Synarel and he said it wouldn't have made a difference. I have low ovarian reserve and that is that. He is a highly regarded doctor here in England (Mr Tim Child) so I am sure he wouldn't have said zero if he didn't believe it. I know it's hard for you to give an opinion without knowing my full history, but have you seen seomeone with such a poor first reposne go on to do better second time around or should I just draw a line under it all?

Thank you so much for your guidance on this, as my husband and I are a bit shell-shocked. Over here in the UK we always consider the Americans to be further forward in medicine and cutting-edge treatments. We would be prepared to travel if we thought it was worth it. If only one follicle is growing very slowly under high stimulation, would you be inclined to say zero chance too? I appreciate your honesty.

Kind regards, N.

Follow-up Answer:

I am sorry for all the grief you have had to endure. I am afraid that I don't completely agree with your doctor. First of all 450IU is not the maximum dose of medication. You certainly have "decreased ovarian reserve", which means that your ovaries don't stimulate well, but given your age, I would expect you to have a good chance even with only ONE egg. So I would recommend trying with a higher protocol and even if there are only a few follicles, you should continue the cycle and give it a try. It stands to reason, if the cycle is cancelled you certainly won't get pregnant, so in my opinion if there is a follicle present the patient deserves to give it a chance.
In terms of decreased ovarian reserve, there have been several studies, including one that was just published, that showed that ovarian response will vary even in patients with decreased ovarian reserve. Therefore, it is still recommended to continue trying in a patient with decreased ovarian reserve. The next cycle may be completely different than this one, especially if a different protocol is applied.

In addition, I am a firm believer that there is a difference between a mixed protocol (using FSh + FSH/LH such as is found in Gonal-F or Follistim (pure FSh) and Menopur (FSH/LH). I know that there is no standard protocol and studies contradict each other, but FSH is the hormone that stimulates follicle growth (that is why it is called follicle stimulating hormone)and LH is not. In a normal natural cycle, the LH does not rise until just before ovulation whereas the FSh is rising all of the first half of the cycle.

I would encourage you not to give up.. . at least not yet anyway. It is possible that down the road you might have to resort to using donor eggs, for instance if your ovaries shut down completely (premature menopause/premature ovarian failure) or you have failed several attempts with your own eggs, but until then, hope is not lost, every cycle is a new and different cycle and every egg is a new and different egg; all with their own potential. I will never tell a patient that there is "zero" chance because there are always exceptions to the rule and I also believe in miracles. I've seen them happen many times. If you wish to come to California, I would be pleased to assist you in the best of my abilities.

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/

Diminished Ovarian Reserve, First Time IVF: Low Estradiol (E2) Levels During IVF Stim Cycle

Question:

K. from NYC:

So, I took your advice and immediately wasted no time, and moved directly to IVF (in vitro fertilization). Dx: DOR (diminished ovarian reserve) @ age 35, one previous live birth 2 years ago, natural conception, (baby came from left ovary) after 12 months of trying @ 32 years old.

My recent HSG showed tubes open, but right tube slightly dilated. RE said not to worry about it at this time, as it was only slightly dictated and still spilling. Always have right ovary pain w/ ovulation, never left. I had b/w done on day 3 of my cycle before my ivf. FSH 10.4, e2 45, AFC 10, AMH 0.87. I started bcp's (birth control pills) for 21 days prior to stims. My AFC (antral follicle count) dropped to 6! ugg. For the last year i monitored my cycles very closely. 26 day cycles when i had ovulation pain on my right ovary, and 30 days when I had no pain from my left ovary. In my humble opinion I don't think my right ovary functions like it should.

Last month was my left ovary's turn, the month I had an AFC of 10 (6 antrals in left and 4 in right). This month it is my right ovary's turn and I only have 3 AFC in each #small too!~bcp's?. I also ovulate on cd 18 with my right ovary and cd 16 with my left, not sure if that is relevant.

My stims are NOT going well. I am on 300 follistim and 150 Menopur, I took no meds between ending BCP's and starting Follistim/Menopur 3 days later. On my the morning after my day 3 stims my e2 was a whopping 32.5! My clinic said to continue on my meds, no changes. Come back in 3 days for b/w and u/s. Per the nurse, "some people take a little time to get going". My questions are: why didn't they increase my meds? Did they expect a low e2 because I am DOR? Could this be over suppression with bcp's? Since I normally ovulate later in my cycle and not earlier like most DOR, could this just be my norm~my body taking it's time to develop the eggs? My cd3 e2 have always been between 30-45, I thought that was good for stimming? Could this be due to decrease blood flow to ovaries? I was told to stop my fish oil/baby asa/vitamin e before stims b/c they are blood thinners, but i thought these could help during stims?

This is my first IVF. Do you think they are just riding this out to see how I stimulate for next time? I am waiting for RE to call me back, but I want all the opinions I can get.

ANSWER:

Hello K. from New York.,

If I am understanding you correctly, your CD#3 E2 with this cycle was 32.5. That would be your baseline E2 for this cycle and does not necessarily indicate that you are not stimulating. The first estradiol level to check for stimulate would be four to five days after starting the stimulation (Follistim/Menopur) and you would be monitored approximately every three days after that to determine your progress. It is at the second E2 that you doctor might adjust your protocol and increase it if their protocol is not already at the highest. Some clinics use 450IU of medication (300IU Follistim/150IU Menopur) as their highest protocol. I go a little higher with 450IU of Follistim and 150IU Menopur. Because of your decreased ovarian reserve, it is expected that your ovaries will probably not stimulate strongly, but you will have to wait and see how things go. The goal is to have a peak E2 of around 2000 (when the follicles are ready to trigger).

I use low dose aspirin in all my IVF cycles, but not the Vit E or Fish oil. There is no problem with that.

It is certainly difficult to know how a person is going to respond in the first IVF cycle. There is a little guess work in determining how much medication to use with each patient. Your doctor has probably chosen this protocol as a good place to start and may make adjustments henceforth. You'll have to be patient and wait and see how things turn out. You may want to ask your doctor if you are on their highest protocol.

Follow-Up Question:

I never asked what my baseline e2 was, but the 32.5 was after 3 nights of stimulation. I had an u/s today (after 6 nights of meds) and NO CHANGE to baseline u/s, 6 unmeasurable follies. Waiting on new e2, but suspect it is going to be the same. I feel like I was completely suppressed. My cycle prior to this my CD3 u/s showed 10 juicy follicles, 6 in left and 4 in right. I know that this is a low count but I can't help to think that if i started my stims on that cycle I would have produced some eggs.

I am sure I will be cancelled on Monday. I hope my ovarian function returns. When they call w/ my e2's from this AM and if they don't increase my dose, I will ask why. I was told not to take any blood thinners (and listed: ASA, VitE, Foil due to risk of bleeding w/ ER.) When I suggested not using BCP's next time if needed they said ok, switch to Lupron, but wouldn't that suppress me too? Why can't we just start meds on CD3?? Thank you so much for your time!

Follow-Up Answer:

Hello Again,

Thanks for the clarification. The E2 on the third day of stimulation is called the CD#5 E2 level. It is the first check to see how you are stimulating, and you are correct, it shows that you are not stimulating at all. I don't do an ultrasound on that day because it is too early and the follicle sizes will still be small. The next check is usually done on CD#9 and an ultrasound is done with that visit. If you were in my clinic and the E2 were only 32 on CD#5, I would have increased your Follistim to 450IU. That is my maximum protocol (450IU Follistim/150IU Menopur). Then we would see how it goes from there. However, you have to understand that every clinic and every doctor is trained differently and uses different protocols. No protocol is better than any other. Your doctor's max protocol may only be 300/150. So you'll have to ask.

In terms of your decreased response, I don't think that it is due to the birth control pill, but there are some studies that show a decreased response if not enough days are given after the last pill and the start of stimulation. Basically, not enough time is given for it to leave your system.

In DOR (diminished ovarian reserve) patients I will usually want 6-7 days off the pill before starting stimulation. Again, you are correct that Lupron would also suppress the ovaries (this is known as the long protocol), and in fact, it will suppress the ovaries stronger than the birth control pill. I don't think that is any better.

The non-pill cycle that you are referring to is following the IVF cycle after a natural cycle. There are some clinics that do that but scheduling and making sure everything is suppressed appropriately, stimulated appropriately and timed appropriately is harder after a natural cycle. Some older studies also showed a better response if the ovary has been suppressed with the birth control pill for at least three weeks in the preceeding cycle. I always precede a cycle with birth control pills. That allows me to control the ovarian response. Decreased ovarian reserve or DOR basically means that your ovaries will not respond well to stimulation. That is to be expected. But, you should have had at least one follicle developing and that may mean that you are not being stimulated hard enough.

Good luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

37 Yr. Old IVF Patient With Decreased Ovarian Reserve or DOR: Continue Trying Or Use Donor Eggs?

Question:

Hi there,

I have just turned 37 years old and this year have been through two IVF cycles both of which were abandoned prior to egg collection due to lack of response to the drugs (only 2 follicles matured and they would only go ahead with 4 min). My consultant has diagnosed low ovarian reserve (DOR, decreased ovarian reserve) without further testing. My FSH level was 7.5 in October when the cycles began and I have not been tested since (they wanted to but I was going on holiday so they used my previous result).

The first IVF converted to IUI but did not work. The next month I fell pregnant naturally but miscarried (very early so was probably a clinical pregnancy). The second cycle we did not convert to IUI as my consultant wanted to wait until I developed a LH surge and then we would have gone to IUI but I didn't surge (probably due to my poor body having had so many drugs!). Anyway, now I am left feeling very down about the whole thing and I think the next meeting I have with the consultant will be the donor egg discussion. I just wanted to know whether you agree with all of this or whether I should try something else first?

Please ask if you need more details but I seem to be rambling on here. Thank you!

Answer:

Dear Adrienne,

Thank you for your question.

You diagnosis of decreased ovarian reserve or DOR is based on the poor response to stimulation during your IVF cycles. We call that "poor responder." Despite a relatively low FSH level, your ovaries did not respond well. This could also be dependent on the amount of medication that you received. I presume you received a high protocol? I go up to 600IU per day with my poor responder patients. Some physicians will not use this high a dose, however.

There are differing philosophies regarding whether or not to proceed with the IVF cycle if there are only a few follicles. Some physicians, like yours, will cancel the cycle if there are not sufficient numbers. I, on the other hand, always complete the cycle. I have had many pregnancies with only 1 egg/embryo. In a natural cycle you only ovulate one egg anyway. IVF is definitely more efficient at achieving pregnancy than a natural method such as IUI so I proceed. I think it gives the patient a better chance for pregnancy. I have heard that in the states where IVF benefits are mandated, such as in Massachusetts, the physicians will cancel because there is a limit on the number of IVF cycles that can be done. In this case it is not the patient's best interest that is being served but economics. That is the problem with government regulations.

Certainly, if your doctor has determined that because you are a poor responder you should not continue trying on your own, then donor eggs is the only option. It is really your choice as to what is the best option for you. I think that each individual has to be emotionally and psychologically ready to go to donor eggs. That is, you have to have resolved that you cannot do it with your own eggs. When my patients have not reached this point, I allow them to continue trying on their own (with their own eggs). You see, my feeling is that I am here to HELP patients achieve their goal, not to dictate what they should or should not do. I don't want to force them into a choice that they are not prepared for or want (some IVF clinics do mandate the choice).

I hope this answers your questions.

Sincerely,

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.