How To Reduce The Risk Of OHSS

Question:

Hello,

I have been able to get pregnant naturally, but due to my kidney disease was not able to carry to term.  I have about 50 percent kidney function due to mild segmental mesangial sclerorsis.  I'm planning on pursuing surrogacy and would like to know what you would recommend for cycling treatment to reduce to the risk of OHSS (ovarian hyperstimulation syndrome) during the stimulation process?

Thank you, R. from California

Answer:

Hello R. from the U.S. (California),

First, I would choose a good IVF clinic.  OHSS is mostly due to overstimulation.  You'll want a doctor that is cautious, has a protocol to reduce the chances of developing OHSS and watches his patients carefully.

Second, OHSS tends to be most common in patients with PCOS where the ovaries are very sensitive to the stimulation.  If you don't have PCOS, then the chances of developing this problem are lower.

Third, patients at risk for OHSS get less medication than patients not at risk.  That is because their ovaries are so sensitive that they don't need much stimulation, and in fact, you don't want to stimulate them too strongly.  So a low dose FSH only or FSH/LH protocol is used.  I also don't use the "long protocol" in patients at risk for OHSS.  The long protocol is using Lupron injections starting from the luteal phase of the preceding cycle.  I use the antagonist protocol (the antagonist is to prevent spontaneous ovulation by suppressing the ovaries) which then allows me to trigger with Lupron instead of HCG (such as Ovidrel).

Finally, the estradiol levels and close monitoring of follicular growth are required so find a physician/clinic that works closely with their patients.  A large "factory" type of clinic is probably not a good choice. See this article regarding an American egg donor who underwent an IVF cycle through a Canadian clinic in 2011 to get an idea of the worst case scenario:  http://news.nationalpost.com/2013/03/28/kylee-gilman-sues-toronto-fertility-doctor/

Good Luck!

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

Monterey, California, U.S.A.

"What FET Protocol Do You Use For Difficult PCOS Patients?" UK Patient Asks

Dear Dr Ramirez,

Firstly, thank you so much in advance for taking the time to read my question.

Brief History: Dx with PCOS at 17 y/o. HSG clear. My husband has severe m/f, so our only chance of conceiving is through IVF with ICSI. On my fresh cycle in 2008, I had 30 eggs retrieved and due to OHSS, couldn't have an Embryo Transfer. We had 13 embryos, all of which were frozen at the 2PN stage. I have gone through six FET cycles since, but only got to transfer three times, b/c the drugs used to suppress my ovaries (ProstapSR, Buserelin, Synarel) have actually stimulated my ovaries, leading to OHSS a further three times!

My treatment is in the UK and I cannot switch clinics b/c a) my treatment is free and b) since it's free I can't choose where to have my IVF/FET's. The Drs at my clinic have put their heads together to try to come up with an individualized protocol for me, since I keep suffering these rare responses to the suppression meds. I am naturally frightened and sceptical about this new protocol since it hasn't been tried and tested in the UK as yet (but apparently it has in other countries with good success for challenging PCOS patients).

The new protocol would not involve the usual suppression medications. On day 3 of my period, I would inject a long acting Cetrotide shot (sub-q) and also commence 6mg Progynova (estradiol valerate). On Day 5, I would commence daily Cetrotide shots, whilst continuing daily with the Progynova. All in all, this protocol should only take around 13days, then I would commence Progesterone, 3-4days before Embryo Transfer. I am terrified of hyperstimulating again. Is this likely to happen with the Cetrotide at all? Have you had any PCOS patients who have ever responded like I have to suppression medications?

If you were my Dr (I wish you were :D ), what protocol would you suggest for a FET? It may be helpful to add that I have always been a slim PCOSer (BMI 21) and have an AMH of 98.5. I also got pg on our first FET with twins, which I sadly miscarried at 8 weeks. My subsequent two transfers resulted in a negative beta. Thank you so much for reading and for any input you may be able to give! G. from the U.K.

Answer:

Hello G. from the U.K.,

I have never heard of such as thing as OHSS with an FET cycle. I'll have to do some research on that and see if that actually happens. If not, your docs might want to write your case up as an unusual case. Since you have been using GnRH "agonists (stimulators)" in your previous cycles, it sounds like maybe the dosages were not high enough to suppress the hypothalamus (which is what they are supposed to do and prevent ovarian function), but instead stimulated FSH production and ovarian stimulation leading to the OHSS.

I think the change to an "antagonist" is certainly the best way to go. I converted to using the antagonist, Cetrotide and now Ganerelix, over 5 years ago (mainly because it is less injections). I have not used it with an FET cycle (because it is more expensive), but it can work just as well with the protocol you have outlined. The antagonist will definitely suppress any ovarian function, so you should not be able to mount an OHSS response. This is definitely a good plan.

I thank you for the compliment :) and wish that you could be my patient as well. For many reasons, such as the fact that some like you can get IVF for free where they live, patients feel that they are stuck in the clinic near their home. This cannot be further from the truth. I have a patient from Serbia and South Korea in my IVF cycle this month. I have patients come from out-of-state, one from as far as Montana, which is like the difference between the UK and Poland. You can travel to the best center to do your IVF, thereby saving you years of frustration & grief. I had one patient who failed five times at a Los Angeles center only to succeed the first time with us. It is not that difficult to do or arrange IVF afar. There are additional costs involved, which is the biggest factor, but heck, you could plan a vacation at the same time. The IF community calls this "Reproductive Tourism" or "Cross-Border IVF", I believe.

An IVF cycle can be done so that you only have to come here for the minimum necessary time, which for an FET cycle would be 1 week or less or 10 days for a fresh cycle. Also, remember the old adage, "you get what you pay for." Free cycles are all well and good, but as you mentioned above, you are stuck with one center, one protocol, one embryology lab (and there quality can differ greatly), governmental restrictions and that is unfortunate. In the U.S., particularly in California, we have few restrictions and can do embryo donation, donor egg, donor sperm, frozen eggs, surrogacy, and are given leeway on the number of embryos we can implant. I wish that I could just outfit a 747 jet with an IVF clinic and jet all over the world where patients want to see me. I think that would be fun as well :D !!!

Good Luck,

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.

Possible PCO Patient Adjusting IVF Antagonist Protocol For Fear Of OHSS: Decrease Gonal-F Dosage?

Question:

I am about to start my first IVF protocol (today is CD2). I am concerned about the recombinant FSH dosage prescribed and would like your opinion regarding appropriate dosage. I believe I am at higher risk for OHSS for several reasons (described below), however my recent ultrasounds are not showing definitive signs of PCO. Here is the protocol prescribed by my doc:

No pre-cycle BCPs (they make me very ill)
CD2: gonal-f 225
CD3: gonal-f 225
CD4: gonal-f 150
CD5: gonal-f 150
ultrasound on day 6
addition dosing determined following this ultrasound
Gonarilex to prevent premature ovulation

I called the doctor today because I was nervous about taking the first two days of 225IU gonal because of the risk of OHSS. After very little discussion, he switched me to 150IU for 4 days.

The difference between 225 and 150 is a big change. I wonder if I will get good results with a dosage that is this low. What is your opinion? I feel like there might be some sort of middle ground that is more appropriate? I would appreciate any thoughts. I would like to get the "best" results without complications of OHSS.

I believe I am at higher risk for OHSS than the normal woman for many reasons:

1) my ultrasound yesterday (on CD1) shows 9 follicles on right and 16 on left

2) I responded well to low doses of gonadotropins (6 IUI cycles some with letrozol/femera at 5mg/day?, others with clomid at 25mg/day all cycles gave 3-5 mature follicles on CD12),

3)I am petite (5'2", 100 lb.s)

4) in 2006 a doctor told me I had PCOS based on ultrasound results, a history of severe PMS, and moderate acne(two additional doctors I consulted with gave no diagnosis - I am not hairy or pear-shaped)

5) cancelled IUI due to elevated estrogen associated with a small complex cyst on cd2 (and another very uncomfotable IUI cycle when a different OBGYN proceeded with an IUI when I had a cyst at the start of my cycle).

6) grandma had type 2 diabetes

7)early male baldness runs in my family.

Answer:

Hello J. from the U.S.,

First of all, I have to caution you about trying to second guess your doctor. Sometimes that may not be good. I would presume that your doctor had a logical reason for selecting your protocol.

You were originally scheduled to be on a 3 down protocol (75IU x 3 for two days then decrease). That is a standard protocol and is on the low side. Because of your concern, your doc decreased you to 150IU and will make adjustments based on the response. The only down side to the lower protocol is that you may not recruit as many follicles as the higher dose, but there is no way to know this when it is the very first cycle. In most cases we determine the protocol based on an educated guess. The adjustment at CD#6 is still early enough to increase the dosage and recruit more follicles if necessary, and if you are indeed a PCO, then you will already have an increased number of follicles and the decreased dosage will be safer for you.

I am glad to see that your doc is using the "antagonist" protocol with ganerelix. I am a firm believer in this medication and its ability to decrease the risks of OHSS. With the antagonist, instead of using HCG to trigger ovulation, Lupron can be used to trigger and because of its shorter half-life, the risk of OHSS is dramatically reduced. This is the protocol I use with my PCOD patients to reduce their risk, in addition to careful monitoring, lowered FSH dosage, Drifting (if necessary) and Coasting (if necessary). My goal is to keep the Estradiol level less than 4000 at the time of trigger. With this protocol, I have had no incidence of OHSS in my center for the past 5 years. Most the reasons that you gave for being PCOD are not valid criteria, but my concern would be the same as yours based on the high number of antral follicles seen on ultrasound. I treat patients as a PCO patient if they have PCO-appearing ovaries even if they don't meet the strict criteria for PCO. And, I find that they do stimulate like a PCO ie have a high number of follicles (>25).

In your case, I think that being safe is better than being sorry and the lower dose is probably the way to go. I call your new protocol a 2up protocol and it is a standard protocol that I use with my PCO patients. I check estradiols at CD#5, however, and adjust from there.

Good Luck,

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.

OHSS: Ovarian Hyperstimulation Syndrome and the PCOS Patient

On Wednesday, February 24th, at 6pm EST, I will be interviewed by Sasha Ottey on her radio show. The subject: "The Real Deal about PCOS and Your Fertility" Join us at http://blogtalkradio.com/pcoschallenge.

Prior to my blog radio interview, I would like to publish a question from last year regarding OHSS, ovarian hyperstimulation syndrome, in a PCOS patient. In this year's January cycle I had a patient with PCOS at my clinic who had undergone IVF last year at another clinic in the Bay Area. There she developed severe, life-threatening OHSS, was admitted to the hospital and stayed there for seven days. Needless to say, that cycle failed. She returned to the same clinic to do a frozen embryo transfer, which also failed. She then came to me. I put her on my standard protocol for PCO patients, low dose stimulation (Lupron/Ganerelix) and carefully monitored her. I'm proud to report that this patient had no adverse reactions and is now pregnant after only her first cycle with us.

Typically, signs and symptoms of OHSS appear within the first 10 days after a gonadotropin injection, when the ovarian blood vessels have an abnormal reaction to the hormone and begin to leak fluid. This fluid fills the follicles, swells the ovaries and sometimes moves into the abdomen in large amounts. Fewer than 2% of women develop the most severe form of OHSS.

Here is a link to the Mayo Clinic's informative website regarding OHSS, definition and symptoms http://bit.ly/bYGk1R .

Question:

Dear Dr. Ramirez,

First I would like to give you some background information. I have PCOS and have been undergoing infertility treatment for apx. 2 years. First, I tried using drugs like Clomid and Follistem. After about 1 1/2 yrs of it not working, we decided to go the route of IVF.

On June 23 I had my egg retrieval. They retrieved 15. After the retrieval they recommended not doing the transfer due to the risk of over stimulation (OHSS). I ended up being admitted to the hospital on June 29 with severe OHSS and on July 1, they drained a little over a liter of fluid. I was sent home on July 2. I had my period on July 5. I went back on July 7 and still had a little fluid around my lungs and my left ovary was still swollen. They were able to freeze 7 fertilized eggs. How long should I wait to do the transfer and can I develop OHSS again with the transfer?

Thanks! I am from Missouri.

Answer:

Hello,

It is unfortunate that you developed OHSS with this cycle. It should have been expected and could have been prevented. There are measures/protocols an RE can take to reduce the chances of developing OHSS such as "coasting" using "antagonist + Lupron to trigger" and lowering the dosage of stimulation.

The Lupron trigger has been used extensively and written about extensively in Europe. It is better than HCG with hyperstimulation because it has a shorter duration, reducing the chances of developing OHSS. I use it with my PCO patients who have a tendency to hyperstimulate and are at higher risk of OHSS. I only given one injection, not two. Lupron used daily or in the higher doses can certainly suppress the ovary. It works indirectly but has the same effect as the Ganerelix. In low doses, it mimics HCG and triggers ovulation. I love the Ganerelix-Lupron protocol.

I have not had a case of OHSS in over 10 years by taking these precautions. In any case, you should not do the transfer until your ovaries have returned to normal. Pregnancy can exacerbate the OHSS. Once this resolves then you can go through the frozen embryo transfer cycle. You will not undergo ovarian stimulation with an FET. Only the uterine lining needs to be prepared. For that reason, you are not at risk of OHSS.

Good luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com