Question 60. My reproductive endocrinologist has recommended a protocol that uses birth control pills. Why would birth control pills be used in IVF?

Last night I was speaking to a group of high school students that are interested in medicine as a career. I have spoken to such groups many times over the past 5 years and sometimes I feel like I am on the TV show "Kids Say the Darndest Things." Sometimes they get hung up on asking about transgendered individuals. Sometimes they ask about multiples like John and Kate plus Eight or the Octomom. Last night we got sidetracked into a discussion of the NuvaRing and oral contraceptives. These are high school kids I remind you....When I was in high school I spent most Saturday nights watching the Love Boat....I certainly was not wondering which girls were on forms of oral contraception. But amazingly enough I was able to eventually date, marry and reproduce...it gives me hope that geeks everywhere will be able to overcome social adversity...just look at Leonard on the Big Bang Theory as another success story!

Ok. So it's Friday afternoon and I am off this weekend so I am a bit punchy....What does all this have to do with IVF? Well some IVF protocols actually use oral contraceptives as part of the medication recipe. Personally, we don't use a lot of OCPs except in high responders. Recently I had a patient that came in for a second opinion prior to stimulated IVF. Her planned protocol was OCPs plus luteal Lupron and then stimulation drugs. She was 38 years old with an AMH of 0.5 and I recommended against that approach because I thought she would be over suppressed. Ultimately she went back to the original clinic, followed that recipe and never came close to egg collection as her stimulation was a total bust. She called me up and we discussed the plan over the phone and she was very upset....why did that clinic use OCPs on everyone? I told her that I couldn't answer that question and she should ask her RE at that clinic. She said that she was calling me since they never return her calls! Oh well. Hopefully next time she will have a better response...

So here is today's Question of the Day from 100 Questions and Answers about Infertility, Second Edition...

60. My reproductive endocrinologist has recommended a protocol that uses birth control pills. Why would birth control pills be used in IVF?

Birth control pills or, more correctly, oral contraceptive pills (OCPs) can be used as a part of the IVF stimulation protocol in several different settings.

First, in patients who are known or suspected to be high responders, OCPs may help mitigate the risk of ovarian hyperstimulation syndrome (OHSS). Second, in patients without predictable regular menstrual cycles, OCPs can be used in combination with Lupron to initiate an IVF cycle. In our practice, we usually start OCPs in such cases after confirming with a blood test that the woman has not recently ovulated. Then, after 1 week on OCPs, we add Lupron. After 1 more week, we stop the OCPs and continue the Lupron and wait for withdrawal bleeding. Once a patient has bled, we begin the gonadotropin stimulation.

Some clinics use OCPs as part of the protocol for microdose Lupron (MDL) flare, traditional flare, or GnRH-antagonist (Antagon, Centrotide) cycles in the hope that pretreatment with OCPs will prevent one follicle from growing faster than the other follicles once the stimulation has begun. We have not routinely used OCPs with our MDL flare patients, as we have rarely had problems with the emergence of a single dominant follicle compared with the more common problem of oversuppression and a cancelled cycle. Given that prolonged OCP use can lead to oversuppression in low responders, we use these medications very carefully.

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Question 59. What is natural cycle IVF? And why does my fertility clinic not offer this treatment?

As readers of this blog are well aware, we have a particular interest in Natural Cycle (unstimulated IVF). All I can say is that the past 4 years have been filled with outcomes that I would never have believed if these were not my own patients. Although it is not surprising that young healthy women with tubal factor infertility can conceive with Natural Cycle IVF, it is the patients that we thought were clearly long-shots that stick in your memory.

Once recent patient was B.W. (not her initials) who was a 41 year old whose husband had a vasectomy reversal 3 years earlier but had failed to conceive. Her evaluation revealed an FSH of 23 and an AMH that was < 0.16 (essentially zero!). We discussed donor egg and donor embryo and adoption. She was really not interested at this time in pursuing those options even though the success rates were clearly markedly superior to those with her own eggs.

So we elected to attempt NC IVF and during the treatment cycle her day 3 FSH came back at 40! I wasn't even sure if she would have normal follicle development but she did and we were able to get a mature egg. It fertilized with ICSI. It grew into a perfect looking blastocyst. She had an easy ET and her first beta was very positive. She currently has a normal ongoing pregnancy. I actually just called her this morning and she had her 20 week anatomy scan and all looks well!

If you made up cases like this, then no one would even believe it because it seems to fly in the face of conventional wisdom. So here is a bit of conventional wisdom from 100 Questions and Answers about Infertility, 2nd Edition...

59. What is natural cycle IVF? And why does my fertility clinic not offer this treatment?

Natural-cycle IVF (NC-IVF) has been proposed as a means of reducing the risk of multiple pregnancies, eliminating the costs and risks associated with fertility drugs, and reducing the stress and time commitment needed for traditional stimulated IVF. This approach has been espoused by a number of leaders in the field of IVF, including Dr. Robert Edwards, whose pioneering work along with Dr. Patrick Steptoe’s led to the birth of the world’s first IVF baby, Louise Brown, using NC IVF in 1978.

NC-IVF avoids the use of expensive ovarian stimulation drugs and their associated cost of about $4000 per treatment cycle. With NC-IVF the risks of ovarian hyperstimulation, multiple pregnancy, and the issues of cryopreserved extra embryos are avoided as only one embryo is produced. Total cost of Natural Cycle IVF is about 20% to 25% of the total cost of a conventional IVF cycle.

However, NC-IVF has its own set of disadvantages. For example, by not using fertility drugs, unexpected premature “LH surging” or ovulation can occur, leading to cancellation of the planned egg retrieval. This occurs in about 10% to 15% of treatment cycles. In such cases, if the fallopian tubes are open, the doctor may recommend converting the treatment to an intrauterine insemination (IUI) and possible a successful pregnacy. Furthermore, because only one egg and one embryo are produced, the chances for pregnancy are less than with conventional IVF when two or more embryos are transferred. Proponents of NC-IVF expect the “cumulative” pregnancy rate for NC-IVF to be similar to a single cycle of conventional IVF within one to three treatment cycles of NC-IVF.

The best candidates for NC-IVF are patients with regular menstrual cycles who are less than 36 years old and have normal ovarian reserve. Patients with tubal-factor infertility or male factor infertility may be good candidates for NC-IVF before resorting to conventional IVF. Older patients, patients with previous stimulated cycle IVF failures, patients with poor ovarian reserve or unexplained infertility all can be considered for NC-IVF but may experience lower pregnancy rates compared with younger patients with well defined fertility issues and no previous fertility treatments.

Many European fertility centers routinely use NC-IVF with good success rates. For a variety of reasons, the availability of NC-IVF in the United States has been limited. We believe that NC-IVF will soon become increasingly available as patients demand less stressful and less costly fertility treatments that utilize little to no fertility drugs with good pregnancy rates. In our clinic we have routinely demonstrated pregnancy rates of 25% per successful egg collection and 30-40% pregnancy rate per embryo transfer with NC-IVF. We have seen success in patients who had previously failed stimulated IVF and were told that donor egg IVF was their only option so NC IVF may represent a viable treatment option for many infertile couples even those with a poor prognosis with stimulated cycle IVF.

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Happy Thanksgiving 2011

Happy Thanksgiving to all!

I usually post this on Turkey Day but honestly I was so busy at work this past week that I never got around to doing it. At my mother-in-law's house in North Carolina we always go around the room before saying Grace and ask everyone to say what they are thankful for this year. It never hurts to count your blessings. In face, several medical studies have indicated that those individuals who have a positive attitude about their life and situation are healthier than those who always see the glass as half-empty. On the other hand my Dad has always been a glass is half-empty guy and he is still hanging in there at 88 years of age.....

I am thankful for my family...they are a source of love, support and joy...even the teenagers.

I am thankful for my health...although I would like my hair loss to slow down.

I am thankful for my career...I remain stimulated and enthusiastic about my profession.

I am thankful for my partners and staff...Couldn't ask for a better partner than DrD (12 years and counting) and Dr Reh and Dr Payson and all the employees at Dominion.

I am thankful for my patients...They have always been my best teachers.

I am thankful for my church....2 years on the Senior Pastor Search Committee failed to dampen my support for the National Presbyterian Church (still there is no politics like church politics!).

I am thankful for God from whom all these blessings flow (just like in the song)!

So that's my list and I am sticking by it!

Hope everyone had a Happy Turkey Day! I will try to get to those recent posts....

DrG

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Question 58. Which types of drug protocols are used in IVF, and how is the most appropriate protocol selected?

So last August I developed a wicked (note Bostonian roots given use of this adjective) toothache while on vacation at the Outer Banks. Naturally, I did what most physicians do...I started myself on antibiotics and ibuprofen and didn't call a dentist. By the next Monday I was not a happy camper and went to my general dentist only to be told I needed a root canal. Ugh. What a way to return from vacation. I took the recommendation of a local specialist and he did a fantastic job. Took 40 minutes and the next day I felt great! Last week it all started again and I went to my general dentist who said that I may need another root canal (different tooth). He proposed doing it himself without a referral to the specialist. I was in the chair already and it was 4:45 PM so I agreed to let him try. In retrospect, this was not a good decision. He found 2 of the 3 roots but ultimately quit the procedure at 6 PM and told me that I needed to see the specialist the next day anyway. I should have gone there first and next time I will. Dr. DiMattina scolded me for not knowing better....

REs are the specialists in this story. Many generalists are truly excellent physicians but infertility work represents only a small percetage of most general Ob/Gyn practices. Your RE only treats infertility and as a result I think that the advice and approach is superior. Of course, I have a jaded view being a specialist but I should have gotten out of that chair and high-tailed it back to the root canal specialist...Think about this carefully before taking 6 months of clomid with your Ob/Gyn!

Not all patients are created equal. Some patients are destined to be high-responders and some are low responders. This past year I had a patient who had PCOS and I was planning on using a lower dose stimulation. She went to another clinic because of insurance and was hit very hard with stimulation meds and ultimately the cycle was a bust. When we tried stimulation again I had her on one of the lowest doses that I had ever used for IVF but it was successful and we were all much relieved that the OHSS did not materialize. More recently we have been using the GnRH-antagonist protocol with Lupron instead of HCG to trigger for retrieval. This approach is very reasonable in the PCOS patient at risk for OHSS but care must be taken to support the endometrium following retrieval as the estrogen levels tend to drop like a rock and that may affect inplantation.....yup, no such thing as a free lunch.

So here is today's Question of the Day...

58. Which types of drug protocols are used in IVF, and how is the most appropriate protocol selected?

Although several drugs and protocols are available to stimulate the ovaries to produce extra eggs for IVF, most clinics utilize only a few of these stimulation protocols.

One of the more common IVF protocols is called luteal suppression (or long luteal or simply just long) and involves suppression of the ovaries using a GnRH-analog (Lupron) during the luteal phase of the menstrual cycle preceding the planned IVF treatment cycle. Once the ovaries are suppressed, ovarian stimulation is accomplished with daily injections of gonadotropins (e.g., Gonal-F, Follistim). Lupron is usually continued until the day of the hCG trigger shot. A common variation of this protocol is to stop Lupron at the time of starting stimulation. Not surprisingly, this protocol is called “stop Lupron.”

Another common protocol is called flare stimulation. In this case, the woman does not take any medications until the second day of her menstrual cycle. At that time, a microdose (most commonly) of Lupron is used to “flare” the pituitary gland and induce it to release its store of FSH and LH. Simultaneously, gonadotropins are started, producing a “one–two punch” in terms of ovarian stimulation. Premature ovulation of the eggs rarely occurs despite the low dose of GnRH agonist utilized in this protocol.

A third, more recent option is GnRH-antagonist stimulation, in which GnRH antagonists are added later in the stimulation to prevent premature ovulation. In this method, the gonadotropins are started on cycle day 2 of a normal menstrual period. Once the follicles have reached a specific size (usually 12 to 14 mm), the woman begins the GnRH-antagonist medication, which almost instantaneously prevents the pituitary gland from generating an LH surge.

Some reproductive endocrinologists prescribe oral contraceptive pills to their female patients prior to beginning the actual ovarian stimulation drugs, but this practice varies between patients and fertility clinics. We have found that the use of birth control pills often results in oversuppression of the ovaries and cycle cancellation except in those patients known to be high responders (women with PCOS, in particular).

The type of protocol selected for any patient (i.e., luteal suppression, flare stimulation or GnRH antagonist) depends on the individual patient and the philosophy of the fertility clinic. Factors that may influence the type of stimulation protocol selected include the patient’s age, her day 3 hormone levels, her follicle antral count as determined by ultrasound, and her previous responses to any other attempts at ovarian stimulation.

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Question 57. I was told I need assisted hatching. What is this, and why is it done?

Families are funny things. Some families are filled with artists and actors. Some are filled with athletes. Some are filled with engineers. Some are beyond simple description.

I grew up in a medical family and I am a 3rd generation physician. My nephew, Andrew, is currently a medical student at Tufts and he represents the first (maybe not the last) of the 4th generation Gordon to be a physician. My older brother Mike (on the far right in the photo) is a general surgeon in Sanford, NC. I don't think that he has gotten a full night's sleep in 25 years as he is regarded as the best surgeon at his hospital and is the most likely to be called when the ER needs a surgeon at 2 am!

My brother Steve was never interested in being a doctor. He is an outstanding hospital sdministrator. We talk several times a week which is incredible to me considering how much we fought as kids (so parents don't give up hope that your kids will someday get along!). But when we fought it was epic. He teased. He tortured. He told me I had been hatched!

But as you will see from today's Question of the Day, we actually all really do hatch! Steve just didn't realize it at the time....In IVF we sometimes recommend Assisted Hatching and let's take a look at what that means and who needs it..




57. I was told I need assisted hatching. What is this, and why is it done?

Dr. Gordon’s older brother Steven used to tease him by claiming that he was hatched and not born, but actually all of us do “hatch” in early embryonic life. The human embryo hatches out of the eggshell (zona pellucida) at the blastocyst stage of development. Assisted hatching involves weakening the zona to facilitate the emergence of the embryo following its transfer into the uterus after IVF. Proponents of assisted hatching suggest that it increases implantation and pregnancy rates.

Assisted hatching can be performed chemically or more recently using a laser. In the chemical technique, a dilute acid solution is used to dissolve the external eggshell. Some clinics still perform mechanical hatching, in which a slit is made in the eggshell. Along with many other clinics, we have moved to laser-assisted hatching, in which a laser is used to thin the zona sparing the embryo from any exposure to the chemicals used in hatching. (See Figure 5).

There is some controversy regarding which patients benefit most from assisted hatching, and the indications for assisted hatching remain somewhat unclear. Most clinics recommend this procedure in cases where the female partner is older than age 37, has diminished ovarian reserve with increased levels of FSH, or is undergoing a frozen embryo transfer (FET) with previously cryopreserved embryos. Patients who have previously failed IVF following replacement of good-quality embryos may also benefit from assisted embryo hatching.

The risks of assisted hatching are believed to be quite low. There have been reports of increased rates of identical twinning following mechanical hatching (but not after chemical or laser assisted hatching). There is no evidence that assisted hatching harms the embryo or causes any increased rate of birth defects in children.

Carol comments:
After my first IVF attempt failed for no obvious reason, the RE suggested that we utilize assisted hatching during our second attempt. We immediately moved into a second fresh cycle and employed assisted hatching. From my perspective, there was no difference. The procedure happened after the egg retrieval, so I was not involved. I did get pregnant during the second cycle, and in theory, the assisted hatching was the primary variable that was different.

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Question 56. What is the Sperm Chromatin Structure Assay (SCSA), and should my husband have it done?

The Holy Grail of Reproductive Endocrinology is the test that definitively tells us whether a patient has a good egg or a good sperm. This is not to be confused with the Holy Grail of Monty Python which is one of the finest films ever made and won the Oscar for "Best Movie Ever" the year after Highlander won that very same award. If you don't get these jokes then don't worry as it probably demonstrates that you are a lot more normal than me and explains why I spent every Saturday night in high school watching the Love Boat....

Back to fertility. So the million dollar question remains is there a good egg and a good sperm that can make a baby? The answer is we don't know until you actually deliver a healthy baby and then the answer is "yes" (obviously).

There have been tests proposed to answer this question. But do not be misguided into thinking that a woman's FSH, estradiol, AMH and antral follicle count answer that question...they do NOT.

Similarly, tests on sperm have been proposed to answer this question for men. I don't think that we have an answer but the SCSA has been proposed as a predictive test. Personally, I have not used this test as my understanding is that there is no level of sperm DNA fragmentation that precludes pregnancy. So let's go to the book and see what Dr D and yours truly had to offer on this subject.

56. What is the Sperm Chromatin Structure Assay (SCSA), and should my husband have it done?


The Sperm Chromatin Structure Assay (SCSA) has been proposed as a means to predict the likelihood of pregnancy in cases of male factor infertility. This test analyzes the degree of DNA fragmentation present in a representative sample of sperm. Increased levels of DNA fragmentation seem to be associated with reduced pregnancy rates, including poorer treatment outcomes with IVF and ICSI. There is no level of fragmentation above which pregnancy is completely ruled out, however, so the SCSA cannot ultimately provide a means to absolutely recommend the use of donor sperm over the sperm from the male partner. If a couple is making a choice between the use of donor sperm compared with partner sperm, then the SCSA may provide a relative indication to use the donor sperm option. At this time, most experts consider this test to be experimental.

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Question 55. My husband and I were told by one RE that we needed ICSI, but another RE says that we don’t. What should we do?

So if you have read the survey results you are aware that most readers like the clinical vignettes that I post to illustrate points of interest. ICSI really is an amazing procedure. It really should not work and yet we have hundreds of thousands of babies born after IVF/ICSI and some clinics do only ICSI and never do just plain IVF....

This year I had a returning patient. She and her husband had been successful with Natural Cycle IVF with ICSI. We did ICSI because they had unexplained infertility and his sperm parameters were slightly abnormal. Since they delivered a healthy baby after the second NC IVF, we thought that this should be a no-brainer.

However, that is not how it worked out. We kept getting tripped up. Almost all possible outcomes were experienced from no fert to embryo arrest. But the couple had absolutely no desire to try regular IVF. They were uncomfortable with many aspects of stimulated IVF and only wanted to try NC IVF.

Finally, on the 6th NC IVF since delivering I suggested that we try no ICSI as sperm quality looked OK. Guess what? Beautiful egg, normal fert, beautiful blast and now an ongoing pregnancy.

So was it doing IVF and not ICSI that made the difference or was it just time for them to have success....who knows.

This case demonstrates the difficulties we face in advising patients. Sometimes the decisions are clear cut but sometimes logic seems to depart. Patients want clear cut decisions and advice but as physicians we should be careful to reconsider all options if success is eluding us...

So as we keep working our way through all 100 Questions here is today's Question of the Day:

55. My husband and I were told by one RE that we needed ICSI, but another RE says that we don’t. What should we do?

ICSI is accepted as a standard treatment option for infertile couples with severe male factor infertility. In most clinics, approximately 50% to 90% of the eggs that are injected with sperm using ICSI will fertilize normally. Some eggs do not survive after injection with the sperm and subsequently degenerate.

The criteria regarding what constitutes severe male factor infertility, however, vary from clinic to clinic. One the one hand, some clinics use ICSI for all (or nearly all) patients based on the theory that assisted fertilization is better than no fertilization at all. Most clinics employ ICSI based upon specific sperm parameters. In general, ICSI is employed in cases where the semen analysis reveals abnormalities related to sperm count (less than 20 million/mL), sperm motility (less than 50% are motile), or sperm morphology (less than 30% have a normal shape). ICSI should also be considered in couples with no previous evidence of fertilization or a history of failed fertilization with a prior IVF attempt. ICSI must be used in cases of sperm obtained from the testicle or epididymis in men with azoospermia. Some clinics use ICSI in all cases of IVF with frozen donor sperm.

Not all cases are clear-cut, for example, in our clinic we often perform an IVF/ICSI split if sperm parameters are normal but the couple have no previous pregnancies. That is, the eggs that are collected during the oocyte retrieval phase are divided between normal fertilization and ICSI. If some component of male factor infertility is present, splitting the eggs between ICSI and IVF may reveal whether the sperm can actually fertilize an egg. If the eggs fail to fertilize with IVF but fertilize normally with ICSI, then the logical conclusion would be that the sperm is incapable of fertilizing the egg with IVF alone. Couples with unexplained fertilization failure with IVF may have a problem with the sperm, the egg, or both. In such cases a repeat cycle of IVF using ICSI will usually yield good fertilization results and, ideally, a pregnancy.

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Summer's Over Now Back to Work

Wow, no blogs in August 2011.....how did I manage to miss an entire month. I suppose I could blame it on the Earthquake that we had here in Northern Virginia....or Hurricane Irene...but the truth is that I was really enjoying summer and was just too tired and busy to post. Mea culpa.

Yesterday in the Wall Street Journal there was an entire article about the Post Labor Day Blues and apparently there is a recognized clinical syndrome called Post Vacation Syndrome. I know it well. Towards the end of my week at the beach on the Outer Banks I started to get a wicked toothache (note my clear Bostonian roots....just like seeing the movie The Town). I started myself on antibiotics and then on the Monday that I returned to work I found myself in the dentist chair in Arlington at 7 am. The news was not good...I needed an urgent root canal. Great. What a way to come back to work! So I got 2 recommendations from my general dentist and off I went at 11 am for my journey into the world of endodontics.

The doctor I saw was outstanding. He was amazingly skilled and I could tell from watching his hands that he was confident and precise in his approach to my procedure. The root canal took about 45 minutes and the next day I was 100% pain free. Amazing.

Out of curiosity I went online to check him out after the fact. Guess what? He had only a 60% positive rating. The reason seemed to be that he didn't spend enough time discussing the various options with some of the patients who posted. Another patient complained that he worked too fast !?! Let me tell you something, I have no knowledge of the ins and outs of endodontics. I have no desire to understand the ins and outs of endodontics. I wanted a skilled professional to do the right thing for me and I am very pleased with the result. That's why I am the patient and he is the dentist...

So as I prepare to get back into the swing of things I would like to share the results of the patient survey that I posted on Survey Monkey. Although nearly 10,000 individuals participated in the survey I have provided 49 of the best responses. Actually, truth be told those were the only responses. None of these are from my Mom.

If you want to see the summary of the survey then click HERE.

This month I have a lot of interesting stories to share and I will try to be a good Doc and post more frequently.

Goodbye Summer 2011.....you will be missed!

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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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Question 49. Are the children born after IVF normal?

The goal of all of our patients is to have a normal, healthy child. However, there are risks in life that none of us can eliminate and unfortunately any child can be born with a birth defect. So the real question is whether IVF derived pregnancies result in more complications and birth defects than non-IVF pregnancies. But here's the problem...patients who undergo IVF have a problem....INFERTILITY.

So really what we need to compare are the outcomes of pregnancies in infertile couples that conceived on their own and those that conceived with IVF...otherwise we are truly comparing apples and oranges. One very revealing study looked at pregnancies in gestational carriers (who have proven fertility which is why they were chosen to be gestational carriers in the first place!) and compared these to IVF pregnancies where patients carried themselves. Guess what? All the issues of bleeding, prematurity, low birth weight etc completely went away! So since most infertile patients do not use a gestational carrier, we need to realize that there may not be an easy way to separate out the cause and effect in terms of outcomes as the issue may be related to the patient needing infertility treatment and not necessarily the treatment itself. Twins are the clear exception as twins (at least non-identical twins) can be prevented by sticking with single embryo transfer.

I am proud to report that we have the highest percentage of single embryo transfers in the country. I know that this is true because we perform so much Natural Cycle IVF and 99% of these cycles result in only a single egg and therefore only a single embryo available for transfer.

So after that introduction, let's look at today's Question of the Day. I have included supplemental information that is in the stimulated cycle IVF consent form that we use here at Dominion. This consent form was produced by SART and provided to all US fertility clinics.

Question 49. Are the children born after IVF normal?


The question of the health of children born after advanced fertility treatments is one that has great importance both to patients and fertility physicians alike. In general, the data regarding the outcomes for children born after IVF, either with or without the use of ICSI, have been extremely reassuring.

The problem with these studies is the identification of an appropriate control group with which to compare the rate of problems found in the children conceived with advanced fertility techniques. Overall, most studies suggest a background risk of birth defects in naturally conceived children of approximately 4% to 5%. However, these couples tend to be younger than the couples undergoing IVF and, by definition, do not suffer from infertility. Although the vast majority of studies suggest no increased risk of anomalies in children conceived after IVF, few of these studies have looked at the rate of congenital anomalies in children conceived naturally but born to parents who suffered infertility that spontaneously resolved without treatment. This group of patients clearly represents a more appropriate control group with which to compare with patients who seek out advanced fertility treatments. The few studies that have looked at this question have noted that although patients who suffered from infertility have a higher rate of anomalies and pregnancy related complications, the means by which these couples eventually conceived (spontaneously or with IVF) did not influence the rate of these problems. Therefore it may not be the IVF process per se that is the issue here but rather the underlying infertility that matters.

The following is from the SART stimulated cycle IVF consent form.....

1. Overall risks.

Since the first birth of an IVF baby in 1978, more than 4 million children have been born worldwide following IVF treatments. Numerous studies have been conducted to assess the overall health of IVF children and the majority of studies on the safety of IVF have been reassuring. As more time has passed and the dataset has enlarged, some studies have raised doubts about the equivalence of risks for IVF babies as compared to naturally conceived babies.

A major problem in interpreting the data arises from the fact that comparing a group of infertile couples to a group of normally fertile couples is not the proper comparison to make if one wants to assess the risk that IVF technology engenders. Infertile couples, by definition, do not have normal reproductive function and might be expected to have babies with more abnormalities than a group of normally fertile couples. This said, even if the studies suggesting an increased risk to babies born after IVF prove to be true, the absolute risk of any abnormal outcome appears to be small. Singletons conceived with IVF tend to be born slightly earlier than naturally conceived babies (39.1 weeks as compared to 39.5 weeks). IVF twins are not born earlier or later than naturally conceived twins. The risk of a singleton IVF conceived baby being born with a birth weight under 5 pounds nine ounces (2500 grams) is 12.5% vs. 7% in naturally conceived singletons.

2. Birth Defects.

The risk of birth defects in the normal population is 2-3 %. In IVF babies the birth defect rate may be 2.6-3.9%. The difference is seen predominately in singleton males. Studies to date have not been large enough to prove a link between IVF treatment and specific types of birth defects.

Imprinting Disorders. These are rare disorders having to do with whether a maternal or paternal gene is inappropriately expressed. In two studies approximately 4% of children with the imprinting disorder called Beckwith-Weidemann Syndrome were born after IVF, which is more than expected. A large Danish study however found no increased risk of imprinting disorders in children conceived with the assistance of IVF. Since the incidence of this syndrome in the general population is 1/15,000, even if there is a 2 to 5-fold increase to 2-5/15,000, this absolute risk is very low.

Childhood cancers. Most studies have not reported an increased risk with the exception of retinoblastoma: In one study in the Netherlands, five cases were reported after IVF treatment which is 5 to 7 times more than expected.

Infant Development. In general, studies of long-term developmental outcomes have been reassuring so far; most children are doing well. However, these studies are difficult to do and suffer from limitations. A more recent study with better methodology reports an increased risk of cerebral palsy (3.7 fold) and developmental delay (4 fold), but most of this stemmed from the prematurity and low birth weight that was a consequence of multiple pregnancy.

Potential Risks in Singleton IVF Pregnancies




In this table, the Absolute risk is the percent of IVF Pregnancies in which the risk occurred. The Relative Risk is the risk in IVF versus the risk in non-IVF pregnancies; for example, a relative risk of 2.0 indicates that twice as many IVF pregnancies experience this risk as compared to non-IVF pregnancies. The numbers in parentheses (called the “Confidence Interval”) indicate the range in which the actual Relative Risk lies.

3. Risks of a Multiple Pregnancy

The most important maternal complications associated with multiple gestation are preterm labor and delivery, pre-eclampsia, and gestational diabetes (see prior section on Risks to Woman). Others include gall bladder problems, skin problems, excess weight gain, anemia, excessive nausea and vomiting, and exacerbation of pregnancy-associated gastrointestinal symptoms including reflux and constipation. Chronic back pain, intermittent heartburn, postpartum laxity of the abdominal wall, and umbilical hernias also can occur. Triplets and above increase the risk to the mother of more significant complications including post-partum hemorrhage and transfusion.

Prematurity accounts for most of the excess perinatal morbidity and mortality associated with multiple gestations. Moreover, IVF pregnancies are associated with an increased risk of prematurity, independent of maternal age and fetal numbers. Fetal growth problems and discordant growth among the fetuses also result in perinatal morbidity and mortality. Multifetal pregnancy reduction (where one or more fetuses are selectively terminated) reduces, but does not eliminate, the risk of these complications.

Fetal death rates for singleton, twin, and triplet pregnancies are 4.3 per 1,000, 15.5 per 1,000, and 21 per 1,000, respectively. The death of one or more fetuses in a multiple gestation (vanishing twin) is more common in the first trimester and may be observed in up to 25% of pregnancies after IVF. Loss of a fetus in the first trimester is unlikely to adversely affect the surviving fetus or mother. No excess perinatal or maternal morbidity has been described resulting from a “vanishing” embryo.

Demise of a single fetus in a twin pregnancy after the first trimester is more common when they share a placenta, ranging in incidence from 0.5% to 6.8%, and may cause harm to the remaining fetus. Multiple fetuses (including twins) that share the same placenta have additional risks. Twin-twin transfusion syndrome in which there is an imbalance of circulation between the fetuses may occur in up to 20% of twins sharing a placenta. Excess or insufficient amniotic fluid may result from twin-to-twin transfusion syndrome. Twins sharing the same placenta have a higher frequency of birth defects compared to pregnancies having two placentas. Twins sharing the same placenta appear to occur more frequently after blastocyst transfer.

Placenta previa and vasa previa are more common complications in multiple gestations. Abruptio placenta also is more common and postpartum hemorrhage may complicate 12% of multifetal deliveries. Consequences of multiple gestations include the major sequelae of prematurity (cerebral palsy, retinopathy of prematurity, and chronic lung disease) as well as those of fetal growth restriction (polycythemia, hypoglycemia, necrotizing enterocolitis). It is unclear to what extent multiple gestations themselves affect neuro-behavioral development in the absence of these complications. Rearing of twins and high-order multiples may generate physical, emotional, and financial stresses, and the incidence of maternal depression and anxiety is increased in women raising multiples. At midchildhood, prematurely born offspring from multiple gestations have lower IQ scores, and multiple birth children have an increase in behavioral problems compared with singletons. It is not clear to what extent these risks are affected by IVF per se.

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Question 48. How successful is IVF?

Different physicians have different styles. I have always attempted to involve my patient's in the decision making process so that they look upon the treatment plan as their plan not my plan. Not all patients want this responsibility. Some look to the physician to run the show with little to no input. I always try to make my recommendation clear but I think that there are often alternative pathways.

For the past 4 years we have been promoting Natural Cycle IVF as an alternative pathway to traditional IVF. I believe that many clinics are unable to offer this approach effectively because of cost limitations and volume concerns. However, it certainly represents more of a finesse approach than that of stimulated cycle IVF. On the other hand, no arguing that stimulated cycle IVF has a higher pregnancy rate per initiated cycle and a low cancellation rate. On the other other hand, some patients are willing to trade off the cancellation rate in order to avoid taking fertility drugs....and so on...

So here is today's Question of the Day from the 2nd Edition of 100 Questions and Answers about Infertility. We are almost halfway there!


48. How successful is IVF?

Overall, the success rates for IVF have improved markedly since 1978 (when Louise Brown was conceived), but success rates vary widely depending on the couple’s infertility factors and the clinic performing the IVF procedure. Success rates for U.S. IVF clinics are published on the CDC’s website (www.cdc.gov/ART/index.htm). The standardization of clinic success rates evolved from 1994 passage of the Fertility Clinic Success Rate and Certification Act (the so-called Wyden law), which seeks to protect U.S. consumers from inflated IVF success rates.

Importantly, many subtleties influence clinic-specific IVF pregnancy rates, including patient selection bias (that is, some clinics tend to treat tougher cases, so their success rates might be lower than those of clinics that take only routine cases). The paucity of clinics that offer Natural Cycle IVF is likely related to this reporting requirement. Natural cycle IVF can be an effective fertility treatment but the pregnancy rate will be less than for stimulated cycle IVF and the number of cancelled cycles will also be higher as patients may ovulate before egg collection, or fail to fertilize or fail to have a viable embryo to transfer.

Unfortunately, at the present time all IVF cycles are reported the same way with the CDC failing to segregate results from Natural Cycle IVF from stimulated cycle IVF. Needless to say, this reporting method does not encourage clinics to offer Natural Cycle IVF as the apparent IVF success rate will be reduced by the inclusion of Natural Cycle IVF in the calculations.

Table A: Factors influencing IVF success rates

1. Patient’s age
2. Type of infertility diagnosis
3. Duration of infertility (Best prognosis if <5yrs)
4. Experience/expertise of the clinic
5. Number of embryos transferred
6. Type of IVF performed: Stimulated vs. Natural Cycle IVF

For women younger than 34 years of age, most will achieve pregnancy within one to three treatment cycles; indeed, many succeed in their first attempt. For women older than 35 years, the success rates tend to decrease simply because the aging process affects the quality of these women’s eggs. For a detailed discussion of IVF success rates, couples should visit the website for the clinic where they are considering treatment. They should also discuss their specific likelihood of success with their reproductive endocrinologist. IVF pregnancy rates do vary by clinic, so patients should carefully scrutinize their chances for success at the particular clinic rendering treatment.

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Question 47. How do I know if I need IVF?

Although there are many paths to reproductive success, IVF is usually the fastest road to success. However, not all patients are thrilled about taking that road as the use of stimulation drugs can be intimidating to say the least. Our extensive experience in Natural Cycle IVF has been so encouraging that it makes one reassess how to counsel patients who are considering other options such as clomid/IUI or gonadotropin/IUI treatment cycles. Although our initial inclination was to encourage Natural Cycle IVF mainly in patients < 35 years old with well-defined fertility issues, our results suggest that success can be obtained in older patients and in those with unexplained infertility. Clearly pregnancy rates will be higher in patients < 40 years old but our current record holder was 47 years old with 4 failed stimulated cycle IVF attempts prior to achieving an ongoing pregnancy with Natural Cycle IVF. Go figure.

I spent over an hour on the phone with a reporter from NPR recently. She was very interested in Natural Cycle IVF and was considering running a piece on the topic. However, after speaking with some other local REs who were totally dismissive of Natural Cycle IVF she stopped answering my emails. Sad but true....good news doesn't sell papers or get listeners to stick with one radio station....and we believe that Natural Cycle IVF is very good news indeed!

So although the smug answer to the Question of the Day is that everyone needs IVF...they just don't know it yet.....here is a more balanced view.

47. How do I know if I need IVF?

Not all patients need IVF or are good candidates for IVF. Thus the answer to this question can be determined only after you undergo a comprehensive infertility evaluation by your reproductive endocrinologist. Nevertheless, some situations clearly require the use of IVF. For example, women with absent or severely damaged fallopian tubes should be treated immediately with IVF. Likewise, IVF should be performed first if the male partner has very poor sperm quality. For other patients, the use of IVF may be less clear-cut, especially given that many different treatment options exist. In such cases, the doctor should discuss with the couple the pros and cons of each option, and then all parties should jointly decide on a treatment plan.

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Question 46: What is IVF, and how is it performed?

Sometimes the first step is really the hardest in the entire journey. There is no doubt that IVF can be a roller coaster ride...physically, emotionally and psychologically. As physicians the best we can do is try to educate our patients so they can handle the ups and downs. Personally, I am really wimpy when it comes to riding roller coasters. At Universal Islands of Adventure my knees went weak at the site of the Hulk roller coaster and you can just forget any of the other big kid coasters. The best I can do is the little kid roller coaster as seen in this video. Those little girls thought it was so funny that I looked petrified but it's not my fault....it's my parents' fault for never taking me to Paragon Park in Nantasket Beach back in my formative years....



So as you consider the potential roller coaster ride of infertility treatment here is an overview of the IVF process from 100 Questions and Answers about Infertility, 2nd Edition.


46. What is IVF, and how is it performed?

In vitro fertilization (IVF) was first successfully performed in Oldham, England, in 1978, resulting in the birth of Louise Brown who was conceived using Natural Cycle IVF (NC-IVF). Since then, more than 4 million children have been born using IVF. The introduction of this technique completely changed—and greatly improved—our ability to treat even the most difficult cases of infertility, many of which were previously untreatable. Although it is clearly not a “cure-all” for infertility, IVF has revolutionized our approach to, and understanding of, the disease called infertility.

IVF literally means “the fertilization of eggs with sperm in glass” which translates to fertilization outside of the body in the laboratory. There are two types of IVF: 1) stimulated cycle IVF and 2) Natural Cycle IVF (NC IVF). We will focus on stimulated cycle IVF in this question but for more information on NC IVF please refer to many of the previous blog posts listed). An IVF cycle consists of several discrete phases, as detailed in the sections that follow.

Phase 1: Ovarian Stimulation
A woman’s ovaries contain thousands of fluid-filled sacs called follicles. Inside each follicle is an egg (or ovum). In a normal reproductive cycle, only a single follicle (and egg) reaches maturity. Louise Brown (the world’s first IVF baby) was produced in a natural cycle from a single follicle (NC IVF). Although a few clinics in the US (including our own) remain enthusisastic about NC IVF, most IVF in the USA is performed in a stimulated cycle using injectible fertility medications. The introduction of the medications (called gonadotropins) enabled physicians to increase the efficiency of IVF through the production of multiple mature follicles. Two forms of these medications are used: (1) drugs containing equal parts of the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH) [Menopur] or (2) drugs containing only FSH (Bravelle, Gonal-F, Follistim) or LH (Luveris). Both kinds of medications induce the growth of multiple ovarian follicles, so it is important to monitor the woman’s response to them carefully with ultrasound and blood hormone testing.

Estrogen is produced within each of the developing follicles and induces the growth of the lining of the uterus (endometrium). Unfortunately, the rise in estrogen can also induce the pituitary gland to prematurely trigger ovulation, resulting in the cancellation of an IVF cycle. Two other classes of drugs are used to reduce the chance of this problem occurring during an IVF stimulation: (1) GnRH agonists (such as Lupron and Synarel) and (2) GnRH antagonists (such as Centrotide and Antagon) . Lupron (or Synarel) is usually started 1 week prior to the woman’s anticipated next menstrual cycle. Given that a patient may have spontaneously conceived during this cycle, all women beginning Lupron are recommended to use a barrier form of contraception.

Approximately 1 week after starting Lupron, a woman should experience a normal menstrual period. An ultrasound exam is performed at the start of this menstrual cycle to examine the ovaries and measure any existing cysts. In some cases, empty follicles from a previous cycle will persist and may influence the response to FSH. If the baseline ultrasound and blood tests are normal, then the patient receives instructions that afternoon as to when and what dose of medication she should take and when she should report back to the office for repeat ultrasound and blood tests.

Patients remain on Lupron to prevent the premature release of the eggs until the end of the stimulation phase. During a typical treatment cycle, they take daily injections for 9 to 12 days before the follicles reach maturity based on ultrasound results and blood hormone levels. Once the follicles reach a 20- to 24-mm diameter, the woman receives an injection of human chorionic gonadotropin (HCG; Pregnyl, Profasi, Novaryl) at a precise time. This hormone serves as a trigger to incite the final maturation and release of the egg (ovulation). Ovulation typically occurs about 40 hours after this shot, so the egg collection procedure is scheduled for 34–36 hours after the HCG injection. Failure to take the hCG will result in an egg collection with apparently empty follicles as the eggs will not be ready for aspiration or eggs that are retrieved will be immature. Clearly, taking the hCG is absolutely critical which is why we check a blood test for hCG the morning after the shot to ensure that it was given correctly.

Cycles using GnRH antagonists are somewhat different. GnRH antagonists are started several days following the start of ovarian stimulation with gonadotropins. Most clinics add the GnRH antagonist once the largest follicle reaches a diameter of 14 mm. This medication effectively prevents the release of LH from the pituitary within hours of administration. Although many clinics have used GnRH antagonists successfully as part of their IVF stimulation protocols, some studies have demonstrated a trend towards decreased implantation rates in IVF cycles using this class of medications. Some physicians use GnRH agonists (Lupron) instead of hCG to induce follicular maturation. This approach only works in patients who have not already been taking Lupron as part of their stimulation protocol.


Phase 2: Oocyte Retrieval
Many physicians perform IVF as an office-based procedure, whereas others utilize a free-standing surgery center. Some programs are located within a hospital. There are advantages and disadvantages to each of these. We prefer to perform egg collections at our office in a special procedure room, as the location and staff are familiar to the patients undergoing the IVF process. We also find that the location of the IVF lab within the office encourages continuous communication between patient, physician, and embryology staff. However, clearly many successful programs utilize a surgery center or a hospital. The use of a hospital setting may allow patients with significant medical conditions (cardiac disease, severe pulmonary disease) to undergo IVF, whereas such patients would be considered an anesthesia risk in the office setting.

Although many patients are nervous about the oocyte retrieval, in fact the vast majority of women find it to be less uncomfortable than some of the screening tests leading up to IVF. The egg collection is performed under light conscious intravenous sedation using a vaginal ultrasound probe with a special needle guide adapter. The needle passes through the side of the vagina into the ovary, and the follicles are easily aspirated. The fluid containing the eggs is then inspected by the embryologist using a microscope. Both the eggs and the sperm are then placed together in small plastic dishes containing media and incubated for the next 3 to 5 days. If there is a significant male factor, then ICSI is performed several hours after the egg collection.

Phase 3: Embryo Culture
On the day following the egg collection, patients learn how many eggs were fertilized. Remember that although your RE measures all of the follicles during stimulation, mature eggs are usually found only in follicles with a diameter of more than 17 mm. In general, about 70% of the mature eggs will fertilize. Unfortunately, some attrition occurs at each point in an IVF cycle so the total number of healthy embryos is often much less than the original number of follicles or eggs.

Three days after the egg collection procedure, the embryos selected for embryo transfer will be identified. Allowing the embryos to grow for an additional 2-3 days in the laboratory may allow for enhanced embryo selection as some excellent appearing day 3 embryos will fail to continue to grow. Thus, implantation rates are usually higher for day 5-6 transfers because of this improved ability to select the best embryos. Additionally, there is some evidence that suggests waiting until day 5-6 may provide for improved synchronization of embryo and endometrium given that in nature the embryo usually doesn’t arrive in the uterus until day 5-6 after ovulation. On the day of embryo transfer your RE should review the quantity and quality of the embryos with the embryologist and then discuss with you his or her recommendations regarding the number of embryos to transfer.

Embryos that are not selected for transfer may still be of excellent quality, so they may be candidates for cryopreservation (freezing) with liquid nitrogen. These frozen embryos can then be replaced into the uterus during a future cycle, eliminating the need for the woman to undergo the entire IVF process of ovarian stimulation and egg collection. There is little benefit to freezing poor-quality embryos, however, because they are unlikely to result in a pregnancy and may not even survive the thawing process.


Phase 4: Embryo Transfer
Embryo transfer is one of the most critical aspects of an IVF cycle. During this phase, the embryos are transferred into the uterus by a procedure similar to an IUI. At our office, we perform our embryo transfers under abdominal ultrasound guidance to ensure the accurate placement of the embryos into the uterus. On the day of embryo transfer, patients are asked to drink 48 ounces of water and keep a full bladder to enable us to visualize the transfer of the embryos. No anesthesia is usually required for an embryo transfer and this step usually takes only 1-2 minutes to complete.

Phase 5: Post-Transfer and Pregnancy
During the 2 weeks after the embryo transfer, patients take supplemental progesterone (shots and/or suppositories). If a patient’s estrogen level drops significantly during the 2 weeks following embryo transfer, her physician may add supplemental estrogen as well.

Two weeks after the transfer, the woman typically undergoes a blood pregnancy test. Once a pregnancy test is positive, the physician may repeat the test every 2 days until the beta HCG level is high enough to visualize the pregnancy sac on transvaginal ultrasound (the beta HCG level should be more than 2000 IU around 3 to 4 weeks following embryo transfer). A follow-up ultrasound is then performed to confirm fetal cardiac activity. At this point, patients are usually referred back to their obstetrician/gynecologist for prenatal care.

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Question 45. How would I know when to pursue more advanced fertility treatments?

In the Kenny Rogers song the gambler there is a very famous line "you gotta know when to hold them, know when to fold them, know when to walk away, know when to run...." Sometimes I think about that line when counseling patients, but fortunately for them I never break out into song during a consultation. Deciding when to move onto more advanced treatments is a common concern among most fertility patients. Even those that start with IVF have to consider moving to donor egg/embryo if success is eluding us. I wish that I had that crystal ball to provide a glimpse into the future. That way I could advise patients "Don't worry, I know the 3rd IUI will work or the second clomid cycle or the first IVF or the FET or whatever.....But I don't have that ability...and if I did I would have used it to play the Powerball lottery and then it would be "see-ya later."

In general, most successful treatments will occur in the first 3-4 cycles of whatever treatment has been chosen. It can be hard to hold my tongue when a patient describes 18 months of continuous clomiphene or 9 clomid / IUI cycles or 7 FSH /IUI cycles etc etc.

No one wants to be a professional fertility patient....there just isn't any money in it. But seriously, most couples/individuals can only take so much disappointment before they throw in the towel and consider alternative paths to parenting. So if you don't have a Magic Eight Ball handy....how do you know when to "fold 'em" and move on.....well that is the Question of the Day from the 2nd Edition of 100 Questions and Answers about Infertility.

P.S. Princeton lost to Kentucky by 2 points.....oh well.


45. How would I know when to pursue more advanced fertility treatments?

The decision to seek out more advanced fertility treatments is a complex question, and multiple factors must be considered when making it. For most couples undergoing treatment with IUI (either alone or with fertility drugs), the best chances for success usually occur within the first four treatment cycles. After that, the likelihood for pregnancy decreases. In many of our patients, we recommend only one or two IUI treatments. If these efforts are unsuccessful, we suggest that the couple proceed with other more aggressive treatments including both Natural Cycle IVF and traditional IVF using injectible fertility medications.

For some patients, IUI should rarely be utilized. For example, those couples with severe tubal disease, severe endometriosis, pelvic adhesions, or severe male factor infertility may do best by directly proceeding with IVF as their first treatment option. If an age factor is present or if the couple has prolonged infertility (infertility lasting more than 5 years), we often recommend IVF first, as well. Remember that IVF is the only treatment for which even a failed treatment cycle provides some insight into a couple’s fertility potential. IVF does allow us to make some assessment of egg quality, fertilization and embryo development. A failed IUI cycle yields no such information as we only know that the cycle failed but learn nothing about fertilization, embryo growth or embryo quality.

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Princeton Beats Hahvahd (WARNING: This Post Has NOTHING to do with Infertility

I know that world events have been so depressing lately.....from the unrest in the Middle East to the terrible earthquake and tsunami in Japan. It is hard to find something to cheer about and for a moment forget all the troubles and suffering that confront us on a daily basis. And then something completely meaningless (in the cosmic sense) and really quite silly can lift your spirits and make you grin from ear to ear.

Last Saturday afternoon I had just such an experience as I watched the Princeton Men's Basketball team battle Hahvahd in a one-game playoff to determine which team would go to the NCAA Tournament. Princeton battled back from a half-time deficit to finally pull even in the last few minutes. The teams traded baskets and then Princeton had the ball with 2.8 seconds on the clock under the Hahvahd basket but trailing by 1 point.

Here is the YouTube video of what happened next.





For those few moments I was transfixed watching the joy of the players and fans as they swarmed onto the court.

GO PRINCETON! BEAT KENTUCKY!

DrG
Princeton Class of 1985

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Question 44. What complications can occur after IUI?

Years ago in Long Island I had a patient experience an allergic reactions to an IUI. She got very bad hives and even began to have a bit of laryngospasm (throat tightening). She was taken to the ER and did fine with a dose of epinephrine and some steroids. Such reactions are really really rare but it was so surprising given the number of IUIs that I have done over years without any weird reactions. Clearly the more concerning complications after IUI are those of multiple pregnancy and OHSS. Both have plagued our specialty for years. However, the risk of both can be somewhat mitigated (but not eliminated) through judicious use of fertility medications.

First of all, no one ends up with a litter without seeing it coming. A patient does not have one follicle on Monday and 14 on Tuesday. Secondly, if there are more than 2 follicles > 15-16 mm at trigger then there can be more than 2 babies. It may be too risky to try an IUI when so many follicles can ovulate so often we discuss 3 major options to try to prevent the patient from having to deal with a pregnancy with > 3 babies or having to make a decision about performing a selective reduction. I do not view Jon and Kate plus 8 as a good outcome....

1. Cycle cancellation: stop the medications and let the follicles all regress and avoid intercourse for 2 weeks.

2. Follicle reduction: perform an IVF like egg collection but then just discard the extra eggs and go forward with the IUI leaving behind only 2-3 follicles. This option can be effective and egg collection would be scheduled like we do for IVF using an HCG trigger. I like to have the embryologists at least look at the fluid to tell be how many eggs I retrieved. If the eggs have already ovulated then this option will not be helpful as the "horse is out of the barn."

3. Convert to IVF: simply go for egg collection as if this had been the plan all along. Patients may experience an LH surge before HCG trigger so consideration can be given to using a GnRH antagonist as soon as the decision is made to convert to IVF. Personally, I have not had any patients surge in this setting but the chance of an LH surge is probably 20% so I may just have been lucky so far!

In spite of impeccable logic: "But Dr. Gordon I have a history of recurrent miscarriage and I am 37 years old and I failed IVF....so how is there any chance that I would end up with triplets???" I have ended up with just that in such cases.....Oh well. It's biology and not engineering.....So good luck and as I tell all my patients in these settings: "remember I don't babysit so let's not have any multiples!"

With that introduction, here is today's Question of the Day from 100 Questions and Answers about Infertility.

44. What complications can occur after IUI?


Complications related to the actual IUI procedure are very rare. IUI is a simple, in-office, nonsurgical procedure, usually performed by nurses. Occasionally patients may experience mild to moderate uterine cramps as the catheter is passed through the cervix into their uterus. These cramps usually last 10 to 15 minutes. Infection rarely occurs (its incidence is less than 1%). Many infertility specialists routinely obtain cervical cultures prior to initiating an IUI cycle, and the culture media used to prepare the IUI specimen commonly contains antibiotics. Occasionally, patients may note some light spotting after placement of the IUI catheter, but this is not an indication of a complication or a problem. Multiple pregnancy can occur in any situation when two or more mature follicles are present at the time of HCG. Your physician should discuss with you the risk of multiple pregnancy in cycles using fertility medication to induce the growth of multiple follicles. Similarly, patients with an excessive response to fertility medication can also be at risk for ovarian hyperstimulation synderome (OHSS). However, both multiple gestation and OHSS can result from the stimultion of the ovary with hormones regardless of whether an IUI is performed or not.

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