By Drew V. Moffitt, MD
My big manila envelope arrived. I must admit I don’t really get that excited about it. It is one of those things that is not necessarily fun, but is good for you in retrospect. I am talking about my Maintenance of Certification Part II REI ABC examination packet. I am a board certified obstetrician and gynecologist (Ob/Gyn) with subspecialty certification in reproductive endocrinology and infertility (REI). What all that means is that in addition to going to medical school, residency, and fellowship training, I had to take a written test, collect cases for two years, and take an oral test to become an Ob/Gyn, and then do that all over again to become an REI. Once that was done, I now get to “Maintain” that certification by doing several things each year including reviewing specific scientific publications selected by the American Board of Obstetrics and Gynecology (ABOG) and taking a test (open book!). The good news is that most of the articles they select for us to review are actually very good and important for us to know. The bad news is that it is not always easy to find the time to do it. I usually review the articles at 6 am while I am exercising on a recumbent bike at the gym. I do it then because I don’t really like riding the recumbent bike…. Ok it’s complicated.
Anyway I got the big manila envelope with the articles to start out the New Year and the first one was on a topic I know pretty well and was actually quite important so I thought I would share it with you as well as the journal club last week. It has to do with progesterone. Now there are a lot of things to say about progesterone. We talk about blood levels of progesterone at certain times and we talk about supplementing progesterone at certain times and we talk about how not having enough is bad. We also talk about how maybe too much of a good thing at the wrong time is bad. Many years ago (in the early 90’s) this topic was really hot. Some authors published findings that suggested that if the progesterone level was above a certain level right before the eggs are removed in an IVF cycle that could be bad. They suggested that it caused the lining of the uterus to not be receptive to implantation of the embryo. They felt so strongly about this that they suggested not transferring any of the embryos into the uterus at that time. Instead, they recommended freezing all of the embryos and then transferring them at a future time when the lining has not been exposed to the elevated progesterone. That seemed a little extreme to many of us. In response to that, I published a study looking at the same topic and essentially showed that people with progesterone levels above the suggested cut off did just fine. In fact some of the higher levels came from the patients that produced the most eggs and had the best chance of getting pregnant. Well the debate has gone on for years and I guess has never quite been put to rest. The article we reviewed was by E. Bosch in June of 2010(1) and was notable for two things. One, it was a really big study. The other thing is that, partly because of the size of the study, they were able to look at many different levels of progesterone and come up with a cut off level that is probably more clinically relevant than the one we all used in the earlier studies. The results of the study were that, if you have a progesterone level above the cut off they suggest, you have about a 20% absolute drop in your chances of getting pregnant. For example, a drop from a pregnancy rate of 43.9% to 24%! That is the kind of difference that gets people’s attention! That difference is still valid regardless of the number of eggs produced. The good news is that this is a rare problem the way we stimulate patients with only about 5% having a level above the cut off. The question now is if it is worth testing 95 people with a normal blood progesterone level to find the 5 with an elevated one that will experience a 20% drop in their pregnancy rate if we don’t detect them. Remember, that drop is only for the fresh transfer of eggs into that uterus exposed to the elevated progesterone. If a person has lots of embryos and you are only putting back a few, perhaps the impact on that couple’s overall chance of having a baby is minimal since they will have additional chances in frozen embryo transfer cycles from that one egg retrieval. If a person only has enough embryos for one transfer, then clearly the implications are greater.
The second article dealt with what to do when a patient is not responding very well to the medications to stimulate egg production. These patients are called poor responders, and can produce only a few eggs despite receiving lots of very expensive medications. When they are trying to do in-vitro fertilization, the response can be so low, that the benefit of proceeding with the full cycle can be so low that it might not make sense to continue with the IVF cycle. Many cycles are cancelled around the world because of this problem. These investigators (2) tried to look at what really happens after the decision is made to continue the cycle or not to better guide us as to what recommendations to make. They looked at three groups of patients. All of them had gone through the entire stimulation and had only one or two follicles (these were really poor responders!) Group 1 decided to go ahead with the IVF cycle. Group 2 converted to an intrauterine insemination, avoiding the procedure to get the eggs and the laboratory process to fertilize the eggs and grow the embryos. Group 3 “abandoned” the cycle, meaning they did not do what the first two groups did but rather tried on their own after the stimulation. The surprising thing is that the group that just tried on their own after stimulation did about as good as those that decided to go ahead with the IVF process (around a 5 to 7% pregnancy rate). The group that did the worst was the group that did the insemination. It is hard to draw too many conclusions from this information because we don’t know the reasons why the different people had the different treatments. The data showed that the people that “abandoned” the cycle were younger and needed lower doses of stimulation medicine so it could be that they were better prognosis patients and cancelled because they thought they could do better in another cycle whereas the ones that did IVF, did so because they felt it was their last and only chance.
One thing they don’t really address in this article is the economic decisions that are behind a decision to cancel a cycle. This study was done in London with a nationalized health care system so the financial issues were not as critical as they can be for patients in the United States. We do not have a mandatory cancellation policy, but we try to be as realistic as we can with our patients so that they are able to make wise choices about how they spend their resources. For our patients, we try to give them an idea of how they are doing much earlier in the stimulation than was done in this study so that if they decide to cancel, they do so at a time when they have incurred only a minority of the expenses involved in an IVF cycle. The big story of this article in my opinion is that, even when things are looking very difficult and the cycle is cancelled, there is still a 5 to 10% chance of a baby, even if the couple just has 1 or 2 mature follicles and tries on their own. In other words, “it ain’t over ‘till it’s over”.
(1) E. Bosch et. Al., Human Reproduction, Vol. 25, No.8 pp. 2092-2100, 2010
(2) J. Nicopoullos et. Al., Fertility and Sterility 2011;68-71
Drew V. Moffitt, M.D., FACOG, is the co-medical director of the Arizona Reproductive Medicine Specialists (ARMS), the director of the Division of Reproductive Endocrinology and Infertility at Good Samaritan Regional Medical Center and an assistant professor at the University of Arizona. He is now president of ARMS and director of the Division of Reproductive Medicine and infertility for the residency program at Good Samaritan Regional Medical Center. Dr. Moffitt has significant clinical experience in assisted reproductive technologies and reproductive surgery.
