Scholarly Series No.5: Protein Rich Diets Improve IVF Success

I normally wouldn't post a scholarly series on only a poster presentation, but this is especially timely... for me, because really, this all about me :). If we're going to step it up to IVF, it's especially important that we're doing everything in our power to make it as successful as possible. Unfortunately  there is lot of unsubstantiated advice floating around out there, based on rumor and superstition, rather than sound research. So for my next series, I will be working on debunking some of these myths and, more importantly, discovering sound research supported articles on complimentary medicine techniques. 

The following review is based on the press release from the poster presentation at the recent ACOG conference as well as the online radio show (Can Diet Affect IVF Success?) with that study's first author on CreatingAFamily.org, aired on November 28, 2012.

Russell, J.B, et al. (May, 2013). Daily Protein Content Correlates with Increased Fertility and Pregnancy Outcome. Presented at the Annual Clinical Meeting of the American Congress of Obstitritians and Gynecologists, Monday Poster #96 

Summary

Traditionally, research has shown that individuals with higher BMI (body mass index) have lower fertility success rates, especially once BMI >30. However, this author noticed several patients that were within the healthy weight range and still had little success, so began asking the women about their diet. He found that they were consuming a huge amount of carbohydrates and minimal protein (<10% of calories coming from protein). 

The study presented compared the embryo development quality and pregnancy rates among women with daily protein intake >25% of total calories confused with those consume less the 25% protein, based on 3 day food logs. They found improved embryo development (54% reaching blatocyst formation by day 5 compared with 38%) and improved pregnancy rates (67% vs 32%) for the high protein group vs the low protein group. 

In the radio show, the author elaborate on these findings. He reported that protein amounts did not seem to make a difference until you were consuming at least 25% and then the impact peaked at 30% (so that consuming 90% protein is not any more helpful). He also found that there was an added benefit to reducing carbohydrate calories to 40% or less of your daily caloric intake. 

The author commented that he has noticed that this effect we helpful in increasing fertility overall (vs just improving IVF rates) and that when they began instructing patients to follow these dietary guidelines, they noticed that many couples became pregnant in the month waiting for their IVF cycle. 

When asking about how long you would have to follow these eating guidelines before it having an effect, he reported that 3 months is usually what he recommends. He reports that it takes an egg approximately 2.5 months to go from dormant to mature and that he has noticed some benefit with following the diet for one month, more benefit after two months, and optimal benefit after three months. 

Review

It's a little difficult for me to review the soundness of this research, as many of the details are not available since it is not yet fully published. However, given that it's been highly endorsed by ACOG increased my confidences in the research methodology and conclusions. I did specifically ask my RE at our recent IVF consultation appointment about dietary recommendations and he told me that there wasn't anything specifically supported in the research. So maybe this isn't as well known or as solid of a study as I would have guessed. 

Either way, my RE said that it wouldn't hurt. I put this into the category of things that might be helpful and likely won't be hurtful. Plus, it is something that is very cheap/free (I have to eat no matter what). On the radio show, the author describes his theory about how protein is related to egg (and sperm) development, and it makes logical sense to me. So personally, I am making a commitment to focus on my protein and carbohydrate intake. Now that is research in action!

Scholarly Series No. 4: FASTT Trial

This clinical trial has been mentioned in some of the previous Scholarly Series  (here and here), so I had to look up the source itself. The attention it's been given by other researchers is primarily because it is one of the most recent and the largest, randomized control trials comparing different treatment models and has since been effective in changing policy in states that mandate insurance coverage. But I'm jumping ahead of myself with excitement.

Reindollar, R.H., Regan, M.M., Newman, P.J., Levine, B.S., Thornton, K.L., Apler, M.M., and Goldman, M.B. (2010). A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertility and Sterility, 94 (3), 888 - 899. 

Summary

This clinical trial randomized couples into one of two treatment strategies; standard approach versus an accelerated approach. In the standard approach, all couples initiated treatment with up to 3 trials of Clomid (100 mg, days 3-7) and IUI following a hCG "trigger shot". If this was not effective in three trials, they then received up to 3 cycles of gonadatropin/IUI, with the starting dose of 150 IU of FSH, which was adjusted based on the woman's response. If they were still not pregnant after these three cycles, the couples then received up to 6 cycles of IVF. In the accelerated approach, couples also initiated treatment with up to 3 trials of Clomid and IUI, in the same protocol as described above. Unlike the other group, if these couples were not pregnant after these three cycles, they then moved to directly to IVF for up to 6 cycles, skipping the FSH/IUI cycles completely.

All couples were considered unexplained infertility (i.e. no obvious tubal defects, regular ovulation, and normal sperm perameters) and were between the ages of 21-39. Couples were randomized into one of the two groups based on a stratified sample (<35 vs >/= 35) so that there would generally be consistency between these two age groups. A total of 493 couples initiated treatment cycles and underwent a total of 2,355 cycles.

The primary outcomes the study examined was "time to pregnancy" from initiating treatment and overall cost. They examined cost based on data from the insurance companies about how much was charged as well as adding in an estimated value of time lost from work ($17.43/hour based on 2007 national average wages).

In regards to time:

• They found a statistically significantly shorter time to pregnancy in the accelerated group, with the the median time to pregnancy in this group being 8 months, compared with the 11 months in the standard treatment group. 
• Per cycle pregnancy rates for Clomid/IUI, FSH/IUI, and IVF were 7.6%, 9.8%, and 30.7%, respectively, for each cycle. 
• Within each group, 20.6% of couples had a birth with one of the first three months of Clomid/IUI. An additional 25.4% of the remaining standard group couples (43 of 169 couples) had a live birth in one of the three FSH/IUI cycles, and then an average of 67.5% of the remaining couples in both groups had a live birth with the IVF cycles (73 of 111 standard group couples and 118 of 172 accelerated group couples). So total live birth rates by the end of the study was 74.9% for the standard group and 77.7% for the accelerated group. 
• Interestingly, 52 (14%) pregnancies occurred on cycles that couples were not receiving treatment. 
• Multiple birth rates did not differ significantly between the two arms (21% in the standard group vs. 23% in the accelerated group). 

In regards to cost effectiveness:

• The authors qualify themselves at the beginning of the article by stating that they would have needed approximately 800 couples to reach enough statistical power in order to detect meaningful differences. That being said, none of the differences that were discussed were statistically significant. 
• Total insurance charges for all of the couples analyzed was $9.4 million dollars. To be completely honest, the financially-oriented statistics are well beyond my scope of understanding, so I can't say that I completely understand the following results... 
• The authors looked at average total cost per delivery (i.e. they factored in improved success rates with accelerated track and divided the total cost for each group by the number of deliveries per group) and found that charges were $9,846 lower for the accelerated group (averaging $61,553) than the standard group (averaging $71,399). 
• When looking at the average cost per couple (not taking into account success of treatment), the difference was $2,624 less for the accelerated group (averaging $41,211) than the standard group (averaging $43,835). It's important to note that these differences were not considered statistically significant, but was definitely trending towards significance. 
• They also looked at the average amount of out-of-pocket costs, based on patient diaries and including time involvement, and found essentially no difference ($485 for the accelerated group vs. $495 for the conventional group*). 
• The authors used some fancy statistics to simulate cost differences based on different prices of treatment options and concluded that the cost of an IVF cycle would have to exceed $17,749 to have a lower cost per delivery. 

**I should note that this study was completed in MA, where insurance coverage for infertility is mandated. The out-of-pocket costs reflect time involvement and co-payments for drugs and physician visits. I appreciate that this cost is FAR BELOW what most of us have actually paid out-of-pocket and, frankly, sickens me a little.

Review

Phew, that was a long summary! Sorry. Or, you're welcome. I guess it depends if you find this as interesting as I do and are still reading this.

I have many reactions to this study and the implications, but first, some thoughts on the design of the study itself. Overall, it's a pretty solid study with a great design. The most optimal design is a randomized, double-blind, control trial and the only aspect that these authors were missing was the double-blinding. This is obviously understandable as it would be pretty impossible for people to be unaware of which treatment option they were giving or the doctors to be unaware of what treatment they were giving their patients (this is generally easier when it's just a simple pill and then you can give sugar pills and no one knows anything!). My only real beef with the study itself is that they had a lot of strong conclusions about the cost effectiveness based on statistics that were not significant at the 95th percentile. I completely understand why, that it would have been necessary to get an additional 300+ couples and that would have taken a lot of extra time, but I think that these results should be a little more cautioned.

Here are all of my other, random thoughts:

1. Eight months compared with 11 months is definitely a plus. No one can deny that. On the other hand, neither amount of time seems that exorbitant compared with what I hear about from others, or my current time-count for that manner. 
2. The accelerated group did have slightly better success overall, which is consistent with the research that suggests that the longer someone is in fertility treatment, the lower their success. This is also something for me to keep in mind. 
3. The fact that the authors concluded that the accelerated group had a (pretty significant) cost savings wasn't as important to me as just the knowledge that these two options are at least comparable. I had always assumed that IVF is so expensive so it would make sense to spend a lot of time and energy/expense on less expensive options before moving on. But this simplistic view doesn't account for the fact that IVF is also much more successful. I am reminded of the time that I went to an internist for migraines and she prescribed a sub-clinical dose of Imitrex. It helped a little, but when I finally sucked it up and went to a neurologist, I realized that there were WAY better options out there. 
4. Given these conclusions, I am still a little amazed at how many physicians still seem to encourage people to go through so many cycles of IUI before trying a more aggressive treatment option. I wonder if they think that this is what people want to hear. Or there is some other fatal flaw to this study that I'm not seeing. Ah!
5. I just have to bring this up again... couples with full insurance spent a total of $490 for their entire treatment! This makes me so angry at my state and place of employment and so jealous of the few people I know living in MA. I have honestly considered relocating to a state or at least company that offered infertility coverage. Not seriously, but I definitely did a mental pros/cons list on the issue. 

What are you reactions to this study? Will/would this influence your infertility decision making?

Scholarly Series No. 3: IUI is Valuable and Cost Effective

Continuing on with the medical community's debate on whether or not IUI is worthwhile, I now take on the counter-argument. For previous articles that initially sparked my interest in this topic, check HERE and HERE. In my last Scholarly Series post, I discussed the first of two chapters debating the merits of IUI and, frankly, it made a very strong argument against this approach. Now I take a look at the other side.

Moolenaar, L.B., Van Voorhis, B.J., van der Veen, F. (2013). IUI is a Valuable and Cost-Effective Therapy for Most Couples. in Biennial Review of Infertility: Volume 3. Eds Schlegal et. al., 185 - 188. 

Summary

Compared with the last article, these authors take a more moderate approach and begin by acknowledging that IUI is not the best approach for some diagnoses. They state that, unfortunately, many fertility decisions are made based purely on financial considerations rather than cost-effectiveness, a subtle but distinct difference. The authors do discuss a randomized control trial that compared 6 months of "expectant management" versus hMG and IUI that showed no difference in pregnancy rates and argued that that expectant management should be the "first line" treatment approach for most couples. 

They also discuss several studies comparing the cost-effectiveness of IUI to IVF. While some of these studies did conclude that jumping straight to IVF was more cost-favorable overall, the authors argue some key problems with the research methods in each of the studies. As for the FAST trial, that the previous article I reviewed spent a lot of time discussing, these authors point out that while the median time difference to pregnancy between the two groups was approximately 3 months, there was an equivalent rate of multiple pregnancies and that, ultimately, by 1 year, the pregnancy rate in both groups was equal. The other interesting finding that the authors point out is that, in each of these studies, 14-32% of the pregnancies were "treatment independent", meaning the pregnancies occurred during a break cycle. 

The authors conclude that current evidence show that expectant management for 6 months, followed by IUI is still more cost-effective, but that the duration of treatment with IUI before proceeding to IVF and the additional value of ovarian stimulation to IUI are still unclear. There is an upcoming study that compares IUI to IVF eSET to modified natural IVF, which the authors are hopeful will further clarify this issue. 

Review

The writing style of this article was definitely less compelling than the last article. To be honest, I found some of their arguments more confusing and harder to follow. But I think that might just be the point. Infertility is not a one-size-fits-all diagnosis and it is likely impossible that one, or even a handful, of studies can adequately capture each of the nuances that affect healthy conception and ultimately a healthy birth. There are too many different factors that cannot all possibly be controlled in a research lab, and if they were, would definitely not be generalizable to real-life.

The take-home point from this article that I gathered is that IUI can definitely be valuable to some couples, but trying this approach over and over will begin likely offset its value. Which is probably true with most other approaches/treatments if you think about it. So in other words, for many couples, it is definitely worth a try but not something to spend an excessive amount of time/money on.  

Scholarly Series No. 2: IUI - An Ineffective Treatment

In continuation of my nerdy pursuit of professional articles addressing topics related to infertility, I will be running a small section on the current debate over the whether or not IUI is worthwhile. This spawned from C and I needed to make a decision between Time Intercourse or IUI and me happening on the article I reviewed in my initial Scholarly Series post. In this book, two back-back-back chapters discuss each side of the argument and will be topics for my next two posts in this series.  

Johnstone, E.B. & Dorias, J. (2013). Intrauterine Insemination: An Ineffective Treatment. Biennial Review of Infertility: Volume 3. Eds Schlegal et. al., 173-183

Summary

These authors take a very pointed stance by clearly stating at the end of the first page that "IUI should no longer be a standard part of infertility treatment" based on several compelling arguments. The article begins by explaining how IUI performed and a little bit about its history (first published article on this was in 1962!) and the rationale for treatment, but then quickly veers into the arguments against its continued use. 

The first argument is that IUI is not significantly more effective than timed intercourse and/or controlled ovarian hyperstimulation (i.e. use of Clomid, Letrozole, Gonadotropins, etc.) and much less effective than IVF. They cited numerous studies, including many meta-analysis studies that analyze aggregated data from all previously published studies, finding that IUI was not more effective than these other approaches in both unexplained infertility and male factor infertility. Compared with IVF, IUI is becoming less beneficial over time as IVF success rates are continuing to increase but IUI success rates have remained stagnant. 

The second argument was made regarding cost effectiveness. They discussed two studies that compared the costs of "expectant management" (e.g. using OPKs, CM checks, etc.), Clomid, and IUI and found that the costs of IUI were significantly greater than the other two treatment options but without a significant increase in chance of live births. One really interesting study they discussed (which I may have to review separately at a later date), called that FASTT trial, compared unexplained infertility couples randomized to either three cycles of CC/IUI followed by three cycles of FSH/IUI followed by IVF (as necessary) to an accelerated track of three cycles of CC/IUI followed by IVF. The study found that not only were pregnancy rates increased with the "accelerated track" but there was also a cost savings of $2624 on average! They discussed several other studies that have concluded that cost-effectiveness data favors immediate IVF over IUI. 

The third argument proposed by the authors is that IUI is much riskier than other procedures and has more adverse events (e.g. discomfort of the patient and potential risk for infection). Infections were found in 1.83/1,000 women undergoing IUI. The biggest "adverse event" discussed was the risk for multiples. While most of the blame for multiples falls on ovarian stimulation (either oral or injectable meds), the issue with IUI over IVF is that you have much less control over how many eggs are mature, fertilized, and implanted. Multifetal gestations carry increased risk of numerous complications for both the mother (e.g. anemia, diabetes, preecplampsia, etc.) and the children (e.g. prematurity, cerebral palsy, visual and hearing deficits, learning difficulties, etc.). These risks are often minimized with IVF, especially with a single embryo transfer.

Review

This was clearly an argumentative style paper. I was surprised by how strongly worded the article was but I am also surprised that this was one of my first times coming across any negative thoughts or opinions on IUI. With both REs that I've consulted with with others that I have talked to, it seems like it is still the standard protocol to go through IUIs before moving on to IVF, especially in those "milder" cases. The idea that this was even up for debate in the medical community was a complete surprise to me. This makes me wonder if either A) the general medical community is slow to change their thinking with new scientific advances or B) these authors are a little extremist and making the mistake of throwing the baby out with the bathwater.

I do have to say that the arguments were very compelling. I would definitely recommend people read the whole article if you're trying to make related decisions. What I took away from it is that, for many couples, IUI does not add much and puts additional cost and time in the fertility journey so that it can be advantageous to just jump straight to IVF. For some couples, taking the gamble of trying IUIs first will pay off and you won't need to move to IVF, but this does't seem to be a statistical norm. I'm sure that there are some psychology studies related to the gambling mentality with all of this.

I purposely did not read the next chapter, the counter-argument that IUI is an affordable and effective treatment, but now I can't wait to see what the others are saying. Until then, I leave you in suspense.

Scholarly Series No.1: Timed Intercourse vs IUI in PCOS Patients

Over the past several infertility decisions we've have to make recently, my nerdy side has kicked in full-force and I have found myself turning to primary-source research articles. It's been very helpful to read the same scholarly journals that the professionals are reading and, given my background in research and statistics, I can actually understand most of it.

Because nerdism should be shared, I've decided to start a new series of posts, hereby known as the Scholarly Series, in which I will discuss an original journal articles. I will try to choose recent papers, likely ones that are relevant to my current situation or ones that I just find interesting. I may include some of the classics as well. In preparation for this, I've actually found several papers that I can't wait to share with people! So without further delay, here is the inaugural Scholarly Series:

Wisner, A., Shalom-Paz, E., Reinblatt, S.L., Holzer, H., and Tulandi, T. (2012). Controlled Ovarian Hyperstimulation in Women With Polycystic Ovarian Syndrome With or Without Intrauterine Insemination. Gynecological Endocrinology, 28 (7), 502 - 504.

Summary

This study evaluated the value of IUI among couples with PCOS and a normal semen analysis. It was a retrospective design, utilizing medical records review. The authors evaluated records of 156 women with PCOS treated with either Clomid, Letrozole, or gonadotropins in 2009 and 2010 and only looked at cycles that resulted in actual ovulation.  Women were given oral medications for three months and then moved on to injectables if not conceiving after this time. IUI was decided based on the physicians preference and was performed 36 hours after the HCG injection. If the couples used Time Intercourse (TIC) instead, they were instructed to perform TIC on the day of the HCG shot and then the following two days. The primary outcome was pregnancy, defines as having a gestation sac and fetal heart activity.

Of the total participants, 86 patients underwent a total of 145 cycles of IUI and the other 70 patients underwent 114 cycles of timed intercourse. Each couple was included in only group. The two groups were relatively similar in regards to the woman's age, BMI, number of dominant follicles, endometrial thickness, and semen concentration/motility/morphology. The results found that there were no significant differences between the Timed Intercourse group (17.5%) and the IUI group (16.6%) overall. In fact, the only variable that appeared to make a difference in pregnancy rates were whether patients used gonadotropins (38.8% for TIC couples and 25.7% for IUI couples) versus oral medications (14.1% for TIC couples and 7.5% for IUI couples). The authors concluded that IUI does not increase pregnancy rates compared with timed intercourse for this population (i.e. normal SA and PCOS).

Review

The study utiized a retrospective design, which isn't as strong as a prospective, randomized control trial because you are unable to control any of the variables or randomly assign participants, which could indicate that there is selection bias in the sample. Also, the study was based out of only site in Quebec, so it's not necessarily generalizable to other locations or populations. It also rubbed me the wrong way that the decision of IUI vs TIC was based on physician preference and did not mention patient preference, but I supposed you also have to consider the audience.

Despite this, the sample size was large and the results were very interesting to me. I previously assumed that IUI automatically added to your chances of success, but then with this article and a few others I came across, I realized that this is not always the case. In fact, one of the current hot topics in reproductive endocrinology is whether IUIs are a valuable tool at all. Based on this research and some others, C and I decided to forgo IUI for this cycle and instead go the Timed Intercourse route. The decision was made easier by the fact that we're still pretty early in the game, as I know it will become much more complicated when/if the decision shifts to trying IUI vs jumping straight to IVF. But alas, that will be the topic for the next Scholarly Series post.