Question 54. Who needs ICSI, and how can my reproductive endocrinologist be certain that I need it?

So as you may recall from Question 53, ICSI is that crazy technique that involves taking a sperm and inserting it into the egg to induce fertilization.....hard to believe that it works but there you have it.

Sometimes it is not that easy to figure out who needs ICSI and who doesn't. I have a nice couple that first came to me a few years ago with mild male factor infertility as the apparent cause. Ultimately they decided to pursue Natural Cycle IVF and were successful on the 2nd attempt of Natural Cycle IVF with ICSI. We used ICSI as they had no previous pregnancies and there was some mild male factor. We have tended to err on the side of ICSI with Natural Cycle IVF as there is only 1 egg and if we don't get fertilization then the cycle is a bust....

In any case, following delivery of a healthy baby from that first NC IVF cycle they returned last year for another round of NC IVF. However, we just couldn't get them pregnant. Several cycles ended in failed fertilization in spite of ICSI. They had no interest in any treatment other than NC IVF as they had moral/philosophical issues with the fertilization of multiple eggs.

So for NC IVF cycle #6, I made the bold recommendation to defer ICSI and go with just IVF. We got a nice egg, it fertilized, it grew, I did the ET of a perfect blastocycst and they are currently pregnant with Baby #2. Was it the IVF without ICSI that did it? Was it just a good egg? Was it the fact that DrG had been off that weekend and was well-rested for a Monday morning ET? Who knows? I am just glad that their persistence paid off.....

Another example of having to treat individuals and not applying cookie-cutter protocols to yoru patients....

So with all that said, here is the latest excerpt from our 100 Questions and Answers about Infertility book. Don't forget to respond to the poll so I can understand who besides my Mother reads this blog....


54. Who needs ICSI, and how can my reproductive endocrinologist be certain that I need it?


Most couples undergoing treatment with IVF do not require ICSI. The most common indication for ICSI is male factor infertility associated with an abnormal semen analysis. Thereore, men with unproven fertility whose sperm count, motility, or morphology is suboptimal are appropriate candidates for IVF with ICSI to ensure fertilization of the ova.

Another common indication for ICSI is unexplained infertility. In these couples, neither the man nor the woman has any apparent fertility-related problems. Their diagnostic evaluation is entirely normal, yet infertility exists. In such couples, traditional IVF may result in fertilization failure in 20-40% of IVF cycles. By using ICSI, the eggs are “forced” to fertilize, and the pregnancy rates are usually high. Fertilization rates with ICSI are usually 60-80% depending upon egg and sperm factors.

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To Tweet or not to Tweet..that is the question...

Although I am not an early adopter of technology, I am not a Luddite either. I have written this blog for a couple of years now and I think that at least 3 other people (besides my Mother) read my posts. I have usually focused on questions from our book on infertility but have commented on a range of other topics ranging from Princeton's epic win over Hahvahd at Yale earlier this year that secured an NCAA invitation for the men's basketball team to the reasons that some clinics fail to offer Natural Cycle IVF and so on.

I am now trying to figure out where Twitter fits into my approach to helping patients. Honestly, I am not really sure what the answer is to that question. I certainly have no plans to end up with a Weinergate type situation and I have had the experience of hitting "reply all" instead of just "reply" on email so I am aware of how embarrassing these miscues can be....

So in order to best serve my loyal base of almost 10 readers, I am asking for you to take about 45 seconds out of your busy days to participate in an anonymous survey about this blog. There is no way for me to identify you, nor do I have any desire to do so. I guess you can always tell me that you were the one who said that you think I should give up medicine and start selling Amway but I leave that to your discretion.

So please help me out here and as they say in Chicago: "Vote early and vote often!"

Click here to go to Survey Monkey and take the Poll. Thanks!

DrG

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Question 53: What is ICSI, and how does it differ from IVF?

In medical school at Duke I took a class in reproductive physiology taught by Dr. Patricia Saling. She was very engaging lecturer and the class was very interesting. During the class we had to memorize the sequence of events that included the fusing of the egg and sperm membranes, the release of the enzymes in the sperm acrosome and a bunch of other steps that I no longer remember. The possibility that you could get a baby from ramming a sperm into the middle of the egg with a micro-injector was just laughable....I would have flunked the class if I suggested it! So when the Belgium group reported on their experience with ICSI at the 1993 ASRM meeting in Boston no one could really believe it....seemed nutty. Yet here we are nearly 20 years later and ICSI seems totally banal! Hard to believe....

More on ICSI in the coming posts but here is today's Question of the Day from 100 Questions and Answers about Infertility, 2nd Edition.

53. What is ICSI, and how does it differ from IVF?

In routine IVF, eggs are placed in a laboratory dish in culture media together with prepared sperm. The eggs and sperm are allowed to spontaneously fertilize overnight. The fertilized eggs then develop and in the incubator until the embryo transfer procedure, which is usually performed 3 to 5 days after the egg retrieval.

Intracytoplasmic sperm injection (ICSI) differs from IVF in that each egg is individually injected with a single sperm using a tiny needle under microscopic guidance (Figure 4). The resulting embryo is then cultured similarly to an embryo produced in a non-ICSI IVF treatment.

ICSI was initially introduced by the IVF team working at the Brussels Free University in Belgium. At that time, assisted fertilization was being attempted through the insertion of the sperm under the eggshell (zona pellucida). The Belgian group took the extra step of injecting the sperm not only under the eggshell but actually into the middle of the egg itself. The first ICSI pregnancies were reported in 1992. Since then, tens of thousands of children have been born as a result of this unique procedure.

Both ICSI and non-ICSI IVF have similar pregnancy rates and outcomes. The embryos produced by either method should not be considered to be superior to those created with the other. ICSI is simply a method to ensure that the egg is fertilized. ICSI is a safe and proven IVF method that does not increase the likelihood that the child conceived in this way will have a birth defect.

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Question 52. Are there age or other restrictions on who should do IVF?

You know, Dear Reader, when I started in practice over 15 years ago I used to get the "you're too young to be my doctor." Now, not so much. Growing older is a fact of life. I personally find it very disturbing that the medical students that I teach at GWU were born in the 80s or even in the 90s (some Doogie Howser types). Unfortunately, the aging process is difficult to fight against. Some patients are now considering freezing eggs for future use, but this process has limitations and usually the patients seeking to freeze eggs probably should have done it 10 years ago but at that time they didn't think that they would need to freeze eggs for future use....

Fertility treatment success rates are age dependent and stimulated cycle IVF pregnancies in patients over 43 years old are very uncommon and usually limited to those patients who are still excellent responders to stimulation in spite of being on the other side of 40... FSH/IUI can be considered in patients with patent fallopian tubes and good sperm but what about the rest of the patients?

More recently we have used Natural Cycle IVF as an option for those patients unwilling to consider adoption or donor egg IVF. Some of these patients have succeeded including a 47 year old who had previously failed 4 stimulated cycle IVF attempts. We believe that patients should be offered the chance to pursue Natural Cycle IVF in such situations, although we are very clear in our expectations. We anticipate that rarely patients will have success. Those who fail to conceive still seem very appreciative that they were given a chance.

Imagine if Oncologists refused to treat cancer patients with a poor prognosis because it would hurt their statistics? I know that infertility and cancer are very different but both carry huge emotional and psychological costs.

So here is today's Question of the Day from 100 Questions and Answers about Infertility. An excellent book, according to my parents (see below), even though it was not written by any alumni of Tufts University or Tufts School of Medicine!



52. Are there age or other restrictions on who should do IVF?

Age restrictions for IVF vary from clinic to clinic. In general, women older than age 40 have a markedly lower chance for a live birth compared with women younger than 40 years old. Age is probably the most important factor influencing the outcome of an IVF cycle. Many clinics will not treat patients older than age 42, and some malpractice carriers dictate that physicians not perform IVF on patients older than 43 years old with their own eggs because of the poor IVF delivery rates related to advancing age.

A woman’s chances for successful stimulated IVF can also be predicted by measurement of her FSH and estradiol levels on cycle day 3. Elevations in either hormone are associated with poor IVF success rates, so many clinics impose additional restrictions once the FSH or estradiol levels are known to be elevated. The clomiphene citrate challenge test (CCCT) is another means by which to assess ovarian reserve and predict IVF success. Older women, those with elevated FSH levels on cycle day 3, and those with elevated estradiol levels may consider IVF with donor eggs or adoption.

Natural Cycle IVF has emerged as another treatment alternative for patients with diminished ovarian reserve. Remember that tests of ovarian reserve predict a patient’s response to fertility medications but no test exists to predict the presence or absence of a healthy egg in a given patient. The only true means to determine the presence of a healthy egg is that of delivering a healthy child – that proves that the patient had at least one good egg! Interestingly, the oldest woman to successfully conceive and deliver a healthy baby with her own egg using IVF was a patient who underwent Natural Cycle IVF and delivered at age 49.

Rebecca comments:
At over 40 years of age, I was fortunate that I had an RE that saw beyond my chronological age and aggressively worked with my husband and me to achieve a pregnancy and live birth using my own eggs. Our third and successful IVF resulted in boy/girl twins from eggs retrieved the day before my 42nd birthday. That said, our family building journey (two IUIs, three IVFs) was not an easy process, nor an inexpensive undertaking. It took an immeasurable amount of commitment on the parts of my husband and me; it was a journey best faced as a strong, unified team. We suffered heartbreaking losses and cycle failures. With each setback we had to regroup, reassess, reevaluate our finances, and discuss our options with our RE. We moved through the medical intervention 'process' gaining an understanding that we took a great deal of emotional and financial risk with every cycle. As we tried to establish realistic expectations from each cycle, we also tried to define the time point or cycle number where we might move on and explore different treatment or family building options. We had a firm belief that it was absurd to bring a child into a family situation that was emotionally and/or financially exhausted. Each patient must face making their own family building decisions, but it is important to consider all the issues (emotional, medical and financial) and enter into discussions with your RE (early and often!), when making decisions to move forward with IVF at advanced maternal age.

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Kindle Edition Arrives!

I really love June. It is my favorite month. The days are getting longer and school is out and the entire summer seems so full of promise. I would prefer to have a year with 3 Junes and no February or March and maybe a shorter November..... My love of the month of June and of early summer is my only excuse, dear readers, for the delay in posting to my blog. I have also been hard at work on a book chapter and some scientific papers but the honest truth is that I have been goofing off in the evenings....catching fireflies, throwing rocks at bats and trying not to be eaten by mosquitoes.

However, there have been some interesting developments with our 2nd Edition of 100 Questions and Answers about Infertility. No, there is no movie version or video game in the works. But there is now a Kindle ebook version available for purchase at Amazon.com! So as your friends and family get ready to head off to the beach tell them to download the Kindle ebook version of your favorite author's guide to infertility!

Next week I am heading up to Boston to check on the parents and participate in an event at Tufts Medical School. I will try to get some additional posts up this week...but if the fireflies are calling I may have to do it while stuck in Logan Airport!

DrG

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Question 51. How can you have an ectopic pregnancy after IVF?

Where does the time go? Here we are the last day of May and there are so many projects that I need to get to before June.....not looking so good here at 9:35 pm. Oh well, tomorrow is another day and I will just have to keep plugging away. Currently, DrD and I are working on several papers simultaneously including a chapter on Natural Cycle IVF for a textbook on infertility. I spent hours this past weekend slogging through paper after paper trying to extract the salient information as we reviewed the experiences with Natural Cycle IVF from clinics around the world (England, Japan, Slovenia, The Netherlands, Norway.....). All those places to visit and here I am unable to get away to New Jersey for the day because I am too busy. Traveling can be tough on anyone. But an embryo that travels out of the uterus following an embryo transfer after IVF can be heart-breaking. Although many patients are emotionally prepared for IVF to fail or for them to possibly suffer a miscarriage, the possibility of ectopic/tubal pregnancy is usually not on the radar screen.

Unfortunately, ectopics can occur following IVF (albeit rarely ~ 1-3%) in spite of all of our best efforts to place the embryo precisely in the uterus under ultrasound. Still it is a real disappointing end to a treatment cycle. Most ectopics can be treated medically with methotrexate but surgery still has a role in the management of ectopics. Years ago, before electricity, when I was a resident in Ob Gyn there was a saying passed down to junior house officers...."Never let the sun set on an ectopic." In other words, get that patient to the operating room now and don't mess around.

Seems a bit dated but not unreasonable advice in some cases....

So as we move to June here is today's Question of the Day...


51. How can you have an ectopic pregnancy after IVF?


The exact mechanism responsible for an ectopic pregnancy following an IVF procedure is unknown. Some believe that embryo migration up into the fallopian tubes occurs because of local cellular activity or fluid mechanics present inside the uterus. Sometimes the opening of the fallopian tube in the uterus is dilated because of disease, making it easier for the embryos to enter the tubes.

As described in Part 3, an ectopic pregnancy can occur within the section of the fallopian tube that passes through the muscle of the uterus or within the short segment of fallopian tube that remains after surgical removal of the tube. The incidence of ectopic pregnancy following IVF ranges from 0.5 % to 3%, but this figure may be decreasing. For the past several years, embryo transfer has been routinely performed using ultrasound to properly guide the embryo catheter to the optimal uterine location, which may help to reduce the risk of an ectopic pregnancy. However, even ultrasound guided embryo transfer cannot eliminate the possibility of an ectopic pregnancy after IVF.

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Question 50. How do I decide how many embryos to transfer?

Well, we are halfway done with the 2nd Edition of 100 Questions and Answers about Infertility. I am still waiting for my invitation to go on Oprah and the book is not on the NY Times bestseller list. I am thinking about having Audible produce an audiobook version but my attorney has warned me that I could be legally responsible for those listeners that nod off while playing the book in the car and then end up off the road in a car wreck. Oh well. Guess I will need to keep coming to work.

Deciding how many embryos to transfer is not an easy decision and raises many questions. Some patients are not comfortable with the concept of embryo freezing and thus elect to transfer all viable embryos. Obviously, the RE needs to be aware of this plan and such patients may need to restrict how many eggs are fertilized in order to avoid becoming the next Jon and Kate plus Eight.... Usually, 50-75% of the eggs will fertilize and half of these will develop into embryos that are good enough to transfer or to freeze BUT this is not always the case....I have seen 6 good embryos from 6 eggs and 2 good embryos from 23 eggs...go figure.

So how can we make educated decisions about the number to transfer? Well that is the Question of the Day!

50. How do I decide how many embryos to transfer?

Determining the number of embryos to transfer in an IVF cycle is a crucial decision that requires careful discussion between the patient/couple and the physician. The goal of every treatment cycle should be the delivery of a full-term, healthy, singleton baby. Although transferring more than one embryo will increase the pregnancy rate, at some point transferring additional embryos merely serves to increase the multiple pregnancy rate without altering the overall pregnancy rate. Several European countries have eliminated all discussion of how many embryos to transfer by mandating that all patients undergo only single-embryo transfers. Whereas elective (or mandatory) single-embryo transfer has been promoted heavily throughout Europe, it has not yet received widespread acceptance in the United States although this attitude may be changing slowly.

One of the major disadvantages of single-embryo transfer is that it leads to a decreased IVF pregnancy rate from the fresh cycle. Proponents of single-embryo transfer claim that the potential reduction in the overall pregnancy rate is well worth the marked reduction in the twin pregnancy rate. Twin pregnancies can be problematic because they are associated with higher rates of preterm labor and preterm delivery. Some couples, however, may desire twins or at least regard them as a neutral outcome. This view is especially prevalent among patients who are paying for the treatment themselves (rather than it being covered by insurance) and regard twins as a “two for the price of one” outcome. As noted in Question 49, the greatest risk to the health of children following IVF is the complications related to prematurity associated with multiple births. Despite the risks associated with multiple pregnancy, couples still tell us every day that they would “love to have twins.”

In the U.S., there is no question that the trend is to transfer of a single embryo in most patients. We fully embrace this concept. In fact, with the recent advances in embryo cryopreservation, such as vitrification our frozen-thawed embryos seem to be as likely to implant and produce a healthy pregnancy as embryos transferred in a fresh cycle. This, in the patients classified as “Most favorable prognosis” we see no need to transfer more than a single embryo and risk a multiple pregnancy when we can safely perform a frozen-thawed embryo using high-quality vitrified embryos. However, convincing patients has proved more difficult. One of the advantages of Natural Cycle IVF is that there is rarely the option to transfer more than a single embryo since nearly all patients produce only a single mature egg in a typical reproductive cycle. Some patients who had planned to undergo single embryo transfer will change their mind at the last minute and elect to transfer 2 embryos greatly increasing the risk of a twin pregnancy. With Natural Cycle IVF the temptation to transfer two embryos has been eliminated entirely.

The ASRM has published guidelines for making the decision of how many embryos to transfer (see Table 1). Patients who fall into the excellent prognosis category should transfer only one or two embryos, whereas those with an exceedingly poor prognosis—because of the woman’s age or multiple failed IVFs, for example—may undergo embryo transfer of five or more embryos.


The most problematic decisions concern those patients who fall between these two extremes. Couples who are paying out of pocket for IVF will often pressure their RE to be more aggressive in terms of the number of embryos transferred. Of course, the expense involved in caring for premature infants is many times greater than the cost of all of the fertility procedures used to initiate those pregnancies. The financial costs are merely one part of the picture, as caring for patients with preterm labor or premature infants is also associated with a variety of emotional, psychological, and physical costs.

If multiple pregnancies occur, a multifetal selective reduction procedure can be considered. This procedure is performed at approximately 10 weeks of pregnancy and involves injecting a salt solution into one or more of the gestational sacs. The overall pregnancy loss rate following this procedure is usually less than 5%. In patients who wish to avoid a triplet gestation (but who will not consider selective reduction), it is best to limit the number of embryos transferred to one or two.

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