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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