The big news item yesterday was the announcement that Shoukhrat Mitalipov, a reproductive biology specialist at the Oregon Health and Science University and his colleagues produced embryonic stem cells from a human clone they produced. Their study, Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer, was published in Cell.

How they made a human clone:

1. Remove the nucleus (which contains  the DNA) from a human donated egg. The de-nucleated egg is now a sac filled with cytoplasm but no DNA. ( I expect there may be mitochondrial DNA from the egg donor but this is present as less than 1% of the DNA.)

2. Remove nucleus from another cell (in this case, a fibroblast type cell) obtained  from another person. Fibroblasts are a somatic cell type that gives rise to skin, for example.  For therapeutic cloning, the DNA for the clone comes from a patient who needs stem cell therapy. The clone that is produced is therefore a clone of the patient and has the patient’s DNA.

3. Transfer the DNA nucleus from the patient’s somatic cell (the fibroblast) to the  empty (no nucleus) donor egg using electrofusion, injection or other procedure.  The name for this procedure is Somatic Cell Nuclear Transfer, abbreviated SCNT in photo above.

4. The resulting embryo is cultured to the blastocyst stage. At this stage, in theory, it could be transferred to a human uterus to produce a human child, with DNA identical to the person who donated the fibroblast DNA.  That would be reproductive cloning.

5. For therapeutic cloning, the cloned embryo is dissected and the inner cell mass is removed, disaggregated and cultured further to produce stem cell lines (NT-ESC , Nuclear transfer – Embryonic stem cells) for all the cell types in the body. The cell type that needs repair (in the original donor) patient can be put to use to treat the patient. Because the new stem cells are made from the patient’s own DNA, tissue rejection is not an issue.

So what’s not to love with this approach? Patients get custom stem cells made for them to repair their hearts, their livers, or whatever organ is gone or going, and no human embryo produced in an IVF clinic (and otherwise meant to be a baby) was harmed.

But of course, it’s never that easy. Here are some of the concerns raised to date:

1. Slippery slope argument: Now that human cloning is technically feasible, it will be used for reproductive cloning, not just therapeutic cloning. First, reproductive cloning is illegal in most countries and most US states. Federal research dollars can’t be used to do reproductive cloning, so there are several barriers already in place to inhibit reproductive cloning. Some are calling for more restrictions. The other thing is that we don’t know how safe reproductive cloning is for the children produced. Since the early genetic imprinting is not through the normal pathways after fertilization, does this set the child up for health problems, possibly even cancer, down the road? There’s a lot we’d want to know first but whether anyone could ever legally (or ethically) do the research is questionable. The lead author of the paper, Masahito Tachibana, has stated that the next paper will explain why their approach will not work for reproductive cloning.

Some of the same concerns exist for therapeutic cloning. Can we be sure that the embryonic stem cells produced from a clone are normal enough not to give rise to health problems (even cancer) after they are injected into the patient?

2. Baby selling argument: Eggs are purchased from donors. We already pay donors for sperm and compensate egg donors for their time and trouble so it is not unprecedented. Also, eggs are not embryos and so egg selling. in my opinion,  is not akin to baby selling.

3. Pro-life argument: Any human embryo produced should only be used to make a baby (every embryo is sacred) and should not be destroyed/used for any other purpose. Human embryos should never be used as “parts” for therapy. The purpose or value of human embryos is what is at debate here. I can value human embryos and still believe it is okay to use them for an “alternative higher purpose” such as stem cell research or therapy. Others do not see this as an ethical option. The debate continues.

References and other articles about this scientific advance:

Cloning, Stem Cells Long Mired In Legislative Gridlock (NPR)

Cloning Is Used to Create Embryonic Stem Cells (New York Times) 

Patient-Specific Human Embryonic Stem Cells Created by Cloning (Scientific American)

Cloning FAQs page, National Genomic Research Institute

Original Paper: Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer (Cell)

If you are one of the one -in -six or one-in-eight couples who want to be parents, but it’s not working for you, it’s time to get mad. There are two kinds of infertility, medical fertility – which is very treatable– and financial infertility which is a much more difficult problem.

If you have a medical problem and can’t get pregnant, your odds of pregnancy become excellent if you can go to a high quality IVF program and avail yourself of a diagnostic work up followed up by one or more of these: superovulation with intercourse or insemination, IVF with or without ICSI, donor egg, donor sperm, donor embryo, or use of a gestational surrogate. Some combination of the above will solve pretty much everyone’s infertility depending on how far you are willing to go with technical interventions. It’s perfectly fine to draw the line at some point and say, Okay, that’s enough for me. I don’t feel comfortable with “fill in the blank”. That’s not unfair or unreasonable. What is unfair and unreasonable is when technical interventions you want are not available to you because you can’t afford them. That’s financial infertility. My international readers can tune out here because many of them have national healthcare that includes infertility treatment. Most of the people in the US don’t have an infertility insurance.

So what are you going to do about that? Nothing? How’s that working out for you?

Last Wednesday was Resolve’s National Advocacy Day, and lots of people affected by infertility went to DC to encourage our legislators to consider working on legislation to make infertility treatment accessible to everyone.  You can follow Tweets from Advocacy Day. There was a lot of excitement and Resolve advocates were able to encourage Rep. John Lewis (GA) to reintroduce the Family Act into the US House as bill HR 1851. From Resolve, here is a description of the Bill:

“The Family Act (S 881/HR 1851) creates a tax credit for individuals who have been diagnosed as infertile by a licensed physician and undergo in-vitro fertilization (IVF).  This bill will cover medical procedures, prescription medications, professional charges, the transfer of embryo and other necessary costs when a taxpayer undergoes in-vitro fertilization treatments. The Family Act also covers the out-of-pocket costs of fertility preservation if the woman or man has cancer or another disease that will render them sterile.”

There’s already a tax credit for adoption. This offers a tax credit for infertility treatments too which again, seems only fair. A tax credit is much less than a covered benefit but it is a start. Of course, if you can’t afford to pay the fees upfront, a tax credit on your expenses doesn’t help you at all.

I know times are hard and the drum beat of reducing government spending goes on. But here is the bottom line. THE GOVERNMENT WILL SPEND OUR TAX DOLLARS. THE ISSUE IS NOT WILL MONEY BE SPENT, THE ISSUE IS HOW WILL THE MONEY BE SPENT ? The government will fund its priorities. It’s your job as the people to let the government know what YOUR priorities are.

If you are still listening, here are some of the things you can do:

Resolve’s Take Action Page shows pending legislation and steps to get your legislators’ attention.

Ever wonder where your state ranked as far as being Infertility Friendly? Check it out here on this Fertility Scorecard on the map of the US.

Go to the Fertility Within Reach Advocacy Page to Empower Yourself  and “cure” yourself of financial infertility.HFind step by step advice on how to talk to your HR department about including infertility as a benefit in your insurance plan, how to talk to your legislator or your insurance provider. There’s even advice on how to talk to your doctor about a better deal. Your doctor may offer payment plans or discounts you don’t know about.

Your local Resolve Chapter support group may be organizing for action. If not, you can suggest ways to get moving in that chapter or start a new chapter.

Once you decide to get involved, there are lots of resources and groups to join with to advocate. But deciding that you are finally mad enough to get involved is the first step.

So today (May 3, 2013) marks 3 years since my first post  and the beginning of Fertility Lab Insider- my 3 year Blogaversary if you will   My blog started out slowly–I didn’t advertise or promote it– and for the longest time, I was sure that I was blogging only for myself. But at the 3 year mark, nearly 180,000 visitors from all over have stopped by and read the site. WOW! Thank you!!! Many of you have left comments, or asked me questions here or via info- which is fabulous!!! The first time I got a comment or question, I was shocked to realize that someone was actually reading my posts!

The blog started as an accident. I started Fertility Lab Insider in the months after I was “downsized” out of a job and replaced with a cheaper off-site consultant. I was devastated because I loved the people I worked with. At the time, I didn’t feel I could uproot my family yet again to move across the country and find another position. There aren’t a lot of IVF lab director jobs in any one city so moving or changing fields is often the choice a lab director has to make.  Reaching out to patients through the blog and explaining the work I did and loved as an embryologist was balm to my soul and helped me keep doing what I loved- although in a different way.

Over time, I gave more thought to effective communication because I realized from reader’s comments/questions that I wasn’t always clear. How can I communicate more effectively through my blog?  Some posts are better than others. Some posts are simply too long or too technical to be effective. I am still a work in progress on that front. Usually my Mom lets me know if I am too technical. My husband lets me know if my blog is too long- “split that post into 3 parts!”  

I think effective patient education is so very important because I think it leads directly to patient empowerment which leads directly to better outcomes. But effective communication is hard.  It is not easy to communicate clearly with patients, particularly when they are struggling with infertility -which is not only physically but emotionally difficult.  As embryologists (or nurses or doctors) , we need to remember that although we have said the same clinical message a thousand times before, each patient is hearing the message for the first time. It’s never old for them. It is a good thing for me to improve my communication as a blogger- but it is critically important in the clinic and can make the difference between cycle success and failure.

So, how can health care providers in the clinic (doctor, nurse and embryologists) do a better job of communicating with patients?

I’d like you to help me answer that question. You are experts at what good communication (or poor) communication looks like because you are at the receiving end. I need your help on a research project I am doing. To celebrate my blogaversary, I decided to look at the three years of data for Fertility Lab Insider based on Word Press statistics and also use Google Analytics data to try to understand which lab topics elicit the most comments or questions. I have done that and found some interesting trends in top landing pages and so forth. But I think it would be especially valuable to ask you directly about your healthcare communication experience with your IVF doctor, your clinic or your embryologist. So here’s your chance to give your feedback about what communication methods/styles worked for you and what didn’t.

As always, I welcome feedback on the blog- good or bad -and feel free to comment on this too  because I’d want to make the blog better.  But hopefully- your healthcare provider is your primary source of medical information for your case and so that is where good communication is most important- and that is a more important topic for research.

So here are some of the things I’d like to know about your experience with health care communication and how it helped or hurt your treatment outcome. Please don’t identify anyone by name.  Comment anonymously or with a pseudonym. If I include your actual comment in a presentation of the responses, I will not use your name.

Here are some questions to consider regarding effective communication methods– but feel free to comment outside of these questions. Part of the problem with effective communication is also understanding what questions someone else may have. (I am currently teaching my teenager to drive and I have found that understanding what they don’t know is a critical first step!! I think that may apply here too so if these questions are poor or irrelevant- substitute your own).  Answer one or more of these or just put in your two cents. Use the comment box or email me privately. I am listening.

• What lab topics are of most interest to you?
• Who was your primary communicator for lab info?- your doctor, your nurse, or lab staff?
• Was there anything about your clinic’s communication with you that was exceptionally good- or exceptionally bad?
• Did you feel that you had all your lab questions answered?
• Was your health care provider pleased/annoyed/disappointed when you asked for more information about lab topics?
• Did you want more or less lab information than you received- give an example.
• Why do you end up looking for more information on this blog? Was it to get primary info, to add to what you get from the clinic, or to verify the info from the clinic?

I hope that you will ALL participate. Everyone has experiences here that could help others.  I will summarize the comments and blog stats in a future post. Thanks!!!

What a week it has been.  This last week (beginning on April 15) we saw horrible events at the Boston Marathon, tearing apart the lives of many families. I am exhausted by the violence and carnage we must, it seems, expect in the modern world, but within the mayhem, I see hope. Each time we experience these tragedies, what makes it bearable, is realizing how reliably helpful most of our fellow humans are. Many who could have run away from the marathon mayhem ran back to render aid  or ran forward to donate blood. They dragged down the fences, they applied tourniquets from pieces of clothing, they wheeled the injured away to ambulances, even as they themselves shook and trembled as their fight-or-flight instinct struggled with their other human instinct – to help.

So what does this have to do with National Infertility Awareness Week? Nothing and everything. At times like this, we tend to reevaluate what is important to us –since life is shorter than we think- maybe much shorter than we think. We automatically hug our kids, our lovers, our parents, our siblings and friends tighter. The fragile emotional bonds between us make our lives rich with meaning.

If you want children and can’t have them for medical reasons, that creates a hole in the fabric of your life, precisely because these bonds are so precious. Now, I am not saying that these bonds can’t be just as precious between ourselves and other people who are critically important to us–but if you want children and can’t have them- that is a big deal. It is not just a social choice, it is a medical right to have access to infertility treatments.

I have been researching the barriers that infertility patients encounter to gain access to infertility treatments and the results have been illuminating.  Financial and social issues are the two biggest barriers and they are linked. Various studies have shown that there exists a social bias against single women, older women, lesbian women and women with disabilities, who are deemed somehow less deserving of extraordinary measures to become pregnant. Women in minority groups, particularly if they are poor are also more likely not to have access to infertility treatments. They may not even be offered treatment because IVF is considered too expensive for them. Under the current system, it often is. If you are in one of these groups- or simply don’t have the cash to pay for IVF- you are less likely to have access to infertility treatments. In some cases, it is because physicians elect not to provide care to these groups because of personal “values” about who should be a mother. In other cases, it is because insurance companies have decided to exclude certain groups (gay, single or older women) from their policies.

Society has done a poor job of supporting infertile people. The knee jerk reaction is often “Just Adopt’! which is bad advice for several reasons. First, adoption is not a good choice for everyone who wants to have a family. Second, adoption is hard to qualify for and expensive. The same groups of people who are excluded from infertility treatments (older, single, LGBT etc. ) are likewise often excluded from adoption due to discriminatory adoption agencies policies. Finally, it is pretty nervy to assign this problem of homeless kids solely to infertile people to solve. Unless you have already adopted a child, refrain from telling someone else to “Just Adopt”.  It just makes you look stupid.

So what does this mean? It means, currently, with the exception of a few islands of help,  you are on your own in figuring out how to get access to high quality infertility treatments. This could change if public perception of the infertility problem becomes more realistic (with less Octomom tabloid coverage and more education about causes and treatments). This could change if insurance policies and even  health initiatives like the Affordable Care Act would redefine infertility care as an essential medical benefit- like cancer treatment or setting a bone. Studies have shown that the emotional and psychological toll of infertility diagnosis and treatments can be as devastating as the diagnosis and treatments for cancer. The fact that infertility is not trivial is not fully appreciated. Education can change that. Advocacy can change that.

So about those islands of help… One of those islands is a small but growing non-profit, called Fertility Within Reach, (incidentally, located  in the Boston area), whose mission is to help people help themselves to get the infertility treatments they need. Sometimes you just have to know how to ask for something to get the help you need from your doctor, from your HR department, from your insurance plan or from your legislator. Fertility Within Reach has created patient toolkits to help you advocate more successfully  for yourself. You can download action checklists from the site. You can read about patient success stories on their site. Hopefully, you will come away feeling empowered.

I am working to find dollars to pay for the educational outreach that Fertility Within Reach offers in the form of  free tool kits that are available on their website. We are planning a webinar series in the Fall if we can find funding. If desired, Fertility Within Reach also offers one-on-one coaching for patients to guide them through navigating insurance etc. As I apply for grants from foundations that support women’s health issues,  I am running into the same problem with multiple foundations that you would think–based on their websites– would support infertility access as part of the bigger picture of women’s health. They say that they support women’s health and reproductive health initiatives but that does not mean they are sympathetic to or willing to support people with infertility. They will support contraception and abortion but not infertility. I still haven’t figured out how to extend their empathy (and dollars) toward programs to help infertility patients get access to care. So I am working on communicating better with these agencies.

So foundations, insurers and government programs aren’t yet rushing to pull down the fences to provide access to infertility treatments for people that need it.  But we can. Fertility Within Reach has partnered with See your Impact.org, to raise funds to support their programs during National Infertility Awareness Week which is next week (April 21-27). I have asked my colleagues, friends and family to support this initiative. Now I am extending this request to you to help other members of the infertility community. If you can give even $5 or $10, you can make a difference.

Next week for National Infertility Awareness Week, please check out Fertility Within Reach and if you can, send them a donation at my See Your Impact fundraiser page. I am hopeful for better days next week. Peace.

In the most current issue of Reproductive Biomedicine Online, IVF researchers in Europe (S. Palini, L. Galluzzi, S. De Stefani, M. Bianchi, D. Wells, M. Magnani, C. Bulletti) have reported  in their paper “Genomic DNA in human blastocoele fluid”,(DOI: 10.1016/j.rbmo.2013.02.01) that:

1) they were able to recover embryo DNA from the fluid-filled center (the blastocoel) of blastocyst stage embryos and

2) they were able to amplify the DNA sample to determine the gender of the embryo and in some cases whether the embryo had abnormal chromosome numbers (aneuploidy).

This is exciting because it’s the first time that the blastocoel fluid has been found to contain at least fragments of DNA–which might be a good source of DNA for genetic analysis for preimplantation genetic screening (PGS) or preimplantation genetic diagnosis (PGD). PGS is a method for testing embryos for chromosome number abnormalities and for determining gender. PGD is a method for testing embryos for genetic sequence abnormalities (mutations) giving rise to genetic diseases or conditions. When abnormal embryo are determined, they can be preferentially excluded from transfer.

Currently, technicians perform embryo biopsy on each embryo to be tested. Technicians need to carefully remove one or more cells from the embryo to recover DNA for testing, which is tricky and if done poorly, can damage the embryo. In a day 3 eight cell embryo, taking 1-2 cells may result in slightly slowed progression as the embryo has very few cells to begin with and is at a delicate stage of development. It is technically simpler, quicker and perhaps more kind to the embryo to insert an ICSI needle into the middle of a blastocyst and remove some fluid, compared to carefully pulling off a small number of cells.

Basically, this needle stick into the blastocoel is a routine measure done currently to temporarily deflate or collapse the blastocyst before vtrification for optimal freezing results. It would  take relatively less skill and only a little training beyond that needed for ICSI for most technicians to become proficient at this technique. If it were this easy to get good DNA for genetic testing, that would definitely improve the technique for sampling. But is the quality of DNA what is required to get good reliable test results?

There are a lot of questions yet to be answered.  Jacques Cohen, master of micromanipulation techniques and his colleagues (Gedis Grudzinskas, Martin H. Johnson), do a good job of outlining the questions that still need to be answered before we all get too excited about this possible replacement for biopsy in this article-in-press editorial, “Embryonic DNA sampling without biopsy: the beginnings of non-invasive PGD?” This editorial can be accessed from the RBO site for free; the actual research findings paper -in the same issue -requires payment to read more than the abstract.

Here are the main challenges to be overcome as put forth by Jacques Cohen and colleagues,  (copied below):

1. “Does the procedure sample DNA that is representative of the embryo? Control samples were obtained from the culture droplets, but it is known that human DNA is often present in embryo-free droplets of protein-supplemented culture medium. A follow-up trophectoderm biopsy was not performed, but this is an obvious second series of experiments to compare cell-free DNA results with those from biopsies.
2.  Could the DNA have been released from abnormal or degenerate cells that are often excluded from the embryo? If so, the DNA may not always be representative of intact cells from the embryo.
3. Is the procedure truly non-invasive? Whereas the procedure may not extract cells, damage may occur during the manipulation process possibly affecting the viability of the blastocyst.
4. Can it be proven that the piercing of the trophectoderm and suction of fluid does not inadvertently release cellular material from the blastocyst, which is then aspirated and analyzed? The authors exclude this alternative explanation theoretically, and they may well be correct, yet the assumption needs to be proven.
5. If DNA is dislodged into the blastocoel, can it also be released through the pores in the zona pellucida into the immediate environment?
6. If affirmative, can the procedure be implemented by culturing blastocysts in minimal volumes to sample the products externally without micromanipulation? Can such sampling be done before blastocyst formation?”

In any case, it is an interesting initial finding and if further validated may refine and make safer current DNA sampling methods for PGD or PGS.

Recently, I received this question from a blog reader, ” I want to ask you about testicular stem cell transplantation– is it true or hoax?”. The short answer is, “No, it is not a hoax, but it is not a clinical treatment yet either”.  I found this review article, “Restoring Fertility in Sterile Childhood Cancer Survivors by Autotransplanting Spermatogonial Stem Cells: Are We There Yet?“,  which does a very nice job of explaining why anyone would first, be interested in transplanting testicular stem cells and two, what hurdles stand in the way of this clinical treatment.

To understand this, it is important to consider the problem of childhood cancers. We are getting better at curing childhood cancers so that the life expectancy for some survivors of childhood cancers is well into adulthood and even old age. This increasing longevity makes one of the possible side-effects of life saving chemo and radiation therapies-namely, sterility–a quality of life issue. Although some cancer survivors can recover some or most of their sperm production ability, other male survivors are irreversibly sterile after treatment. It is not possible to exactly predict in which category a person may find themselves in the future. The type of cancer and intensity of the treatment used both affect the probability of becoming sterile.  For teenage boys who have gone through puberty and adult men, it is possible to collect one or more ejaculates before cancer treatment, and freeze and store these samples for future use, as a sort of “insurance policy”  against sterility.  For pre-pubertal boys, this is not an option because they aren’t producing sperm yet.

But pre-pubertal boys have lots of testicular stem cells called spermatagonial stem cells (SSC) which could in theory, be likewise recovered and saved  before cancer treatment and returned to the testicles later to repopulate the testicular tissue with sperm-producing cells.

SSC are the renewing stem cells whose job is to replicate themselves so that there is a continual stem cell supply (see Type Ad Spermatogonium (the blue cells) in a renewal cycle below). Not all stem cells replicate themselves. Some commit themselves to a differentiation pathway that ultimately results in the mature sperm cell (right handed pathway- with multi-colored cells). 

There are multiple steps after the secondary spermatocyte stage. The spermatocyte cell loses its round cell shape and begins to look like a sperm  in a process called spermiogenesis.  The cell elongates, gets a tail, puts it mitochondria behind the sperm head, loses excess cytoplasm, encapsulates the DNA in a proper sperm head etc. At puberty, some of the stem cells spring into action and start making sperm. A helper cell in the testis called the Sertoli cell (shown as the pinkish cells studded with blue spermatocytes- the smaller figure above) serves as a sort of docking station through which the spermatocytes pass as they morph into a proper sperm cell.

So how would gonadal cell stem cell transplantation work?

Step One: Under anesthesia, take a testicular biopsy. Freeze the biopsy and store for future use.

Step Two: Thaw tissue sample when the patient is in remission and is ready to start a family.

Step Three:  Inject a suspension of thawed testicular cells containing stem cells into the rete testis of the patient, where hopefully the stem cells will seed and re-activate to produce more of themselves and then many, many sperm cells.

Other proposed fertility preservation options using stem cells which one day may have clinical applications include:

• Grafting testicular tissue back into the testis. Tissue could be derived from frozen/thawed specimen or possibly donor tissue.
• Putting testicular stem cells in culture and growing out sperm cells from these stem cells in a dish. The number of sperm produced would likely be enough only for IVF or ICSI, not uterine insemination.
• Make more stem cells-and then sperm- from non-gonadal cells, by reverse engineering the pathway from more differentiated to less differentiated (stem cell)  and then committing the stem cell to make a more differentiated (sperm cell). Sperm was produced from embryonic stem cells (and in another experiment, fibroblast cells) in the mouse by first making induced testicular stem cells and then making those newly derived stem cells into sperm. These sperm were used to make mouse pups.

Hurdles to these approaches are not insignificant.

• We do not presently have a good method to propagate or amplify the rare stem cell recovered from a patient’s testis into significantly more stem cells in vitro. We also want to be certain that when these cells divide in culture that they remain”true” to the original copy and aren’t introducing genetic mutations because they are more unstable than “wild type” cells. We need to understand stem cells better.
• There is always a possibility when removing cells from a cancer patient, that you recover some contaminating cancer cells along with the normal healthy cells, even if the cancer is not in the testicle. If it is in the blood, there is some theoretical risk of transplanting the cancer. This would obviously be a catastrophe. We must figure out ways to minimize this risk but we are not there yet.
• If all the technical barriers were overcome, and it works, and we have babies born from these stem-cell transplant procedures, what assurances could we have that children born from these procedures will be as healthy as children in the rest of the population? Obviously, at the very least, we would want to do many generations of studies in animals first.

So although there is a long way to go, stem cell transplantation is a real area of research, not a hoax. Someday, it may even be a standard clinical procedure for fertility preservation in the pre-pubertal male who is at risk of sterility due to cancer treatment.

One of the biggest, if not the biggest, pioneer in IVF died today. Sir Robert Edwards died in his sleep today after a long illness. He was 87 years old. Here is a BBC article announcing his death.  This article about his early academic life which led, ultimately, to the clinical offering of IVF and the birth of the first “test-tube baby” Louise Brown in 1978 is a fascinating account compiled by Martin H. Johnson in collaboration with the Edward’s family. What I take away from this article is that the path to clinical IVF was a rocky one with frequent setbacks. Although many view IVF as a widely accepted clinical procedure today, it wasn’t always so.

Highlights of IVF as viewed through the career of Robert Edwards (summarized from the paper by Martin H Johnson, entitled Robert Edwards: the path towards IVF)

1925: Born in Yorkshire, England to a working class family. Passed special exam to attend Manchester Central Boy’s High School.

1945: Began university education but was interrupted by WWII

1951: Continued at University College of North Wales at Bangor, initially for agriculture, but then switched to more appealing Zoology. Surprisingly, he graduated with only a pass, without honors, which was very personally upsetting at the time.

1951: Was accepted at Edinburgh in a post-grad Diploma course in Animal Genetics; began intra-disciplinary research in Developmental Biology in the mouse model. Published 14 papers here, largely on sperm-related topics. Egg biology was more difficult to research due to lack of research material- namely mouse eggs. He mastered superovulation of the mouse in order to get sufficient eggs for his research. Superovulation with gonadotropins is critical to  IVF so this basic work was one of the stepping stones to human IVF.  During his time at Edinburgh, the work he did resulted in 38 papers, so many that some were not even published until 1963.

1957-1958: Worked at the California Institute of Technology in the US studying sperm-egg interactions. He became interested in reproductive immunology, particularly how the mother’s uterus was able to accept rather than reject an embryo that was half foreign (due to 50% paternal contribution).  Although he considered this time a “holiday” of sort, he published 23 papers from work he did in this area.

1958: Returned to the UK to work on the science of immuno-contraception, but was ultimately more interested in the mysteries of the egg, egg maturation and fertilization. He was interested how the egg could have problems during meiosis called non-disjunction events or lagging chromosomes which could result in an abnormal number of chromosomes (aneuploidy). Aneuploidy is a significant issue for older women and interferes with successful IVF outcomes.

1960-1962:  Edwards worked with a gynecologist to get ovarian biopsy tissue, recovered eggs for the tissue and noted that they seemed to spontaneously mature in vitro when released from the follicle. This phenomenon of spontaneous maturation, although encouraged by administration of hCG a few days before retrieval,  allows eggs to be combined with sperm after only a few hours post-retrieval.  Although encouraging, his work on human IVF using human eggs from ovarian tissue was banned by the director of the Institute, abruptly ending his progress toward clinical IVF for a time.

1965-1966: He published papers in which he showed that he could derive embryonic stem cells(ESC)  from rabbit embryos by dissecting the intercellular cell mass and growing the cells in vitro. This work was largely ignored for the better part of 20 years until two other researchers (Evans and Kaufman) demonstrated that ESC’s could be derived from mouse embryos in 1981. Edwards was a little too advanced in his ESC production and so his seminal ESC work failed to be appreciated for over twenty years.

1963: Moved to Cambridge as a Ford Foundation Research Fellow. For the next several years, he continued his efforts to understand egg maturation and the kinetics of chromosomal sorting that occur during meiosis. Mishaps with chromosomal sorting result in aneuploidy. He developed the “production line theory” of egg maturation to explain the increased occurrence of aneuploidy with increasing maternal age. In 1965, he reached out to Howard and Georgeanna Jones, IVF pioneers who opened the first US IVF Clinic and who provided him with sufficient human eggs to confirm his egg maturation theories in the human. This also started a long-lasting collaboration between Edwards and the Jones’s.

In this interesting interview with the now-deceased Howard Jones, he discusses his belief that he and Edwards may have actually fertilized a human egg in 1965 while Howard was still at John Hopkins, but they weren’t sure because they could not detect a sperm tail, just two pronuclei. Today we know that two nuclei is considered ample evidence of fertilization in humans. An intact sperm tail is rarely observed. (In 1979, a year after Louise Brown’s birth in England, Georgeanna and Howard Jones “retired” from John Hopkins and opened up the first US IVF clinic, the Jones Institute at Eastern Virginia Medical School.)

Wednesday 28 February 1968: Robert Edwards met Edward Steptoe, who had been a Consultant Obstetrician with a specialty in surgical laparoscopy at Oldham General Hospital since 1951. Steptoe’s interest in human IVF was treated with hostility by his colleagues and Edward’s was initially “warned off” contacting Steptoe. The earliest IVF egg retrievals were performed not with minimal invasive ultrasound-guided needle aspiration as is used today  but by opening up the abdomen. It was this surgical skill for egg removal for IVF that interested Edwards. Likewise, Steptoe found in Edwards, a life-long colleague, who shared his interest in human IVF. Together they would achieve the birth of the first IVF baby, Louise Brown, born in 1978,  ten years after this first meeting.

Another scientific problem holding back Edwards and Steptoe’s ambitions for human IVF was the problem of sperm capacitation. Sperm need to be exposed to the female reproductive tract fluids to become “capacitated”, the final step in sperm maturation so they are capable of fertilizing an egg. This sperm capacitation problem was solved when Robert Edwards encountered the work of Barry Bavister, who had just solved the problem of in-vitro capacitation in hamster sperm, by showing he could increase sperm fertilizing ability, simply by increasing the pH of the media.

December 1968:  Edwards, Bavister and Steptoe, submitted their landmark paper to the journal Nature, describing human IVF for the first time.  Previous papers by others had claimed success but this Nature paper was definitive.

1971: His 1968 IVF success was met with public distrust due to hostile media coverage of human IVF in Britain and his request for research funding was denied in the UK. Perhaps this was the first, but certainly not the last time that IVF research would be killed due to societal backlash, both in the UK and the US.

Edwards battled negative public perception of IVF and professional hostility from his colleagues for the better part of a decade. Some of his  colleagues considered human IVF a form of human experimentation, without merit. Treatment of infertility was not considered a societal good because human overpopulation was considered the overriding social ill and research to develop better population control was considered more worthy scientific work.

July 25, 1978: Louise Brown was born, and the social tide against human IVF began to turn. It is hard to deny the joy of new parents who have overcome infertility through the intervention of IVF. It was a long hard road for Edwards to see his life’s work culminate in joy for that first IVF patient. He was awarded the nobel prize in 2010 for his IVF work.

Robert Edward’s scientific work left a lasting mark on the world- for the better. Thank you, Sir Edwards.

The FDA appears to be getting more serious about IVF program compliance with their regulations, specifically regarding whether a person is medically eligible to donate gametes. Used to be, you never or rarely found a warning letter to an IVF clinic but fairly recently, there were two issued, for a clinic in Florida  and one in New York . Click on the link to see the actual warning letter. Warning letters and Cease Operation letters are issued only after violations have been identified by the FDA and program attempts to explain or correct the deficiencies are deemed insufficient by the FDA.

Below is an explanation about what the FDA regulates, copied from the FDA website. Although written with sperm donors in mind, egg donors are also included though some aspects of the regulations are modified (eg. testing interval before egg retrieval):

“What You Should Know – Reproductive Tissue Donation

11/5/10

Did you know that FDA regulates human reproductive tissue, which include donated eggs (oocytes) and sperm (semen)?  Below is information that you may want to know before becoming a recipient of donated sperm.

1) Is the establishment registered with the Food and Drug Administration (FDA)?

Donated reproductive tissue (eggs or sperm) are regulated as human cells, tissues, and cellular and tissue-based products (HCT/Ps).  Any establishment that performs one or more manufacturing steps for HCT/Ps (recovery, processing, storage, labeling, packaging or distribution of products) must register with FDA and list their HCT/Ps in accordance with Title 21 Code of Federal Regulations (CFR) Part 1271.

You can access information on registered HCT/P establishments by visiting our website.  The site includes the names of registered establishments, the products that they manufacture, and the manufacturing steps they perform. 

2) Are reproductive HCT/P donors required to be screened for risk factors that may increase the chances of transmitting a communicable disease?

Yes.  Donor screening consists of reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases.  These records include a current donor medical history interview to determine medical history and relevant social behavior, a current physical examination, and treatments related to medical conditions that may suggest the donor is at increased risk for a relevant communicable disease.

3) Are reproductive HCT/P donors required to be tested for infectious diseases?

Specimens from reproductive tissue donors must be tested for the following infectious diseases (referred to as “relevant communicable disease agents and diseases” in the regulations):

1. Human Immunodeficiency Virus (HIV), types 1 and 2 
2. Hepatitis B Virus (HBV) 
3. Hepatitis C Virus (HCV) 
4. Treponema pallidum (i.e. syphilis)
5. Chlamydia trachomatis
6. Neisseria gonorrhea

In addition to those listed above, sperm donors must also be tested for:

1. Human T-lymphotropic virus (HTLV), types I and II
2. Cytomegalovirus (CMV)

4) Are reproductive HCT/P establishments inspected by FDA?

Yes.  Various factors can determine the frequency of inspection, including any objectionable conditions found on a prior inspection and/or if FDA received Information regarding an establishment indicating there is a potential violation of FDA regulations. 

5) Where can I get more information?

Related information about the regulation HCT/Ps can be found on FDA’s website at:
http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/default.htm.”

Your IVF program, if they do IVF with donated gametes, must be able to prove that a donor was properly vetted and is eligible to donate.  It makes no difference if the program does one egg donor cycle a year or hundreds. They have to produce proof that they followed FDA regulations. Commercial sperm banks do the same for sperm they sell. It’s good for patients to know what the FDA expects and these public warning letters are useful for patients to recognize non-compliant clinics.

If you like to think (and perhaps debate) about ethical issues in assisted reproduction, you’ll  want to listen to this video debate. It’s put on by a foundation called Intelligence Quotient Squared (IQ2) in front of a live audience which votes before and after the debate on the question at hand. The question is “Should society prohibit genetically engineered babies?”

The debate for me is somewhat premature, in the sense that genetic engineering of babies to insert specific genes is not currently possible (with one possible exception– depending on your definition of engineering) and is not offered clinically. There is some debate  and confusion about the definition of ” genetic engineering”. Currently, through pre-implantation genetic diagnosis (PGD), we can identify embryos with genetic problems and decide not to transfer them. PGD or PGS to screen for healthy embryos is fundamentally different than inserting actual genes but some people are fundamentally uncomfortable with diagnosis and then discard of non-transferred embryos and do consider this a form of genetic engineering.

The closest thing to genetic engineering that has been performed in the ART clinic – in my opinion- are procedures in which successful pregnancies were produced by recovering egg cytoplasm from a  younger women and injecting this cytoplasm into the older patient’s egg. Thus the patient’s genome is  exposed to the benefits of younger more energetic mitochondria. This technique, although effective,  was shut down by the FDA in the US because it created babies with technically three genetic parents, even though the mitochondrial contribution is a miniscule part of the genome (less than 2% of the DNA and accounts for less than 1% of expressed genes).

Ovascience has developed a procedure to  inject mitochondria harvested (and amplified) from a patient’s own egg stem cells to “rejuvenate” the patient’s own egg to improve the chance of pregnancy, thus bypassing the “three parents” genetic issue. I believe this produce, called Augment, is in the clinical trial stage. This protocol can also be used to treat mitochondrial disease.

Leigh’s disease is one example of a dread mitochondrial disease. Most individuals with this disease don’t live past childhood and frequently spend many years in a near vegetative state. It is a truly horrible disease without a cure. Mitochondria are passed on through the mother’s egg. If a mother has a sufficient percentage of abnormal or non-functioning mitochondria, these passed on to her children can cause the condition in her children.  If these defective mitochondrial genes could be replaced with normal mitochondria, these women could have normal, healthy children.  Germ line therapy  for mitochondrial disease is in the research stage currently. It is not clear when these treatments might be clinically available or routine.

Anyway, the debate is very interesting and asks the following questions and many others not listed:

• What is genetic engineering?
• Where is the line between acceptable and non-acceptable parental interventions to give children a better life?
• Do we have a right to improve our children or just prevent disease?
• Prohibition of new technology vs. transparent oversight of new technology?
• Would government funding, instead of private or commercial funding, of new ART procedures ensure better oversight and transparency?
• Do we have a right to do things to people (not yet born children) who have no ability to give informed consent?

Enjoy listening to this video, then debate here in the comments or elsewhere with your friends.  Have a great weekend.

Here’s the thing. As an infertility patient, you have one thing going for you that other patients don’t have. Infertility clinics are required, by US law, to report their annual pregnancy outcomes to the CDC, either directly or via an intermediary, namely the Society for Assisted Reproductive Technology (SART). What troubles me is that–at least based on the emails I get– not all patients take advantage of this tool to find good IVF providers.  Instead, they rely on advertising or word of mouth to find a clinic. Those can lead you to a good clinic but they can as easily lead you to a mediocre or even terrible clinic. Sometimes patients confuse friendliness with quality. Good “bedside” manner is fine but that  doesn’t get you pregnant. There are support groups for sympathy, empathy and emotional support. I want my doctor to get results for me. Period. If he is a grump about it, that’s fine. I won’t see him much past the first few pregnancy tests anyway.

I wrote on this topic a long time ago in two previous posts Finding a good fertility doctor..part one and part two but it is probably time to revisit this topic.

Question: How do you evaluate an IVF clinic to determine if it is a good one?

Answer A. Accreditation? Nope. Accreditation is like getting your driver’s license. It is a minimal requirement to drive but doesn’t prove you are a good driver. Except unlike a driver’s license, labs aren’t even required to be accredited to operate. If a lab isn’t accredited (or hasn’t applied for accreditation) , that means they can’t even be bothered to do the minimum. That is not a good sign. Almost every lab achieves accreditation.  Accreditation, however, does not guarantee quality. One lab passed accreditation with flying colors, and then bragged about it in their advertising. So what?  The punchline is that they didn’t even have a written lab manual-the most minimal requirement for ensuring consistent high quality outcomes. They substituted another IVF lab’s manual for show and tell for the inspector and their deceit worked. Apparently, the inspector had some questions and concerns because what they were doing didn’t seem to match up exactly with the manual they presented but in the end gave them the benefit of the doubt and accreditation. In another unrelated case, a well-respected ART professional who performs inspections told me that they had been asked by the inspection agency to back off on their on-site inspections and stop being so picky. Is either of these incidents evidence of a widespread problem? I have no idea but I think that in a voluntary accreditation system where labs pay inspection agencies for the privilege of applying for accreditation,  this relationship can become more of  a customer relationship–where the customer is always right– rather than an oversight relationship. So I have become rather cynical about the value of accreditation as a sign of high quality. It is a minimal bar, that’s all.

Answer B. The best labs are the biggest most high-volume labs whose advertisements are heard on radio and TV. Nope, big labs have the biggest advertising budget and that’s all. Size is only significant at the extremes. Really low volume labs can have statistically unreliably good or poor rates because even a few negatives or positives can magnify the rate so it looks better or worse than what would be seen over the longer term. Also small labs may be just at the beginning of their business life with less-experienced staff or even insufficient staff. Extremely large programs with very high volumes (thousands of cycles a year) have greater challenges with maintaining quality over such a large system– often employing a dozen or more embryologists–each of which need to be consistently well-trained and high achieving.  CCRM in Colorado is arguably one of the best labs in the country with consistently high rates, reporting a 67% live birth rate per transfer in 2011 for its youngest age group.  It is a medium sized clinic, reporting 394 cycles in 2011.

Answer C. The best way to evaluate a lab is to first, compare live birth rates for your age group to the national average and secondly,  interview the clinic to get more up-to-date clinic data for recent pregnancy outcomes (not yet reported to CDC) and their experience with new services. C is the correct answer.

Question: How do I investigate the live birth outcomes for clinics in my area?

Answer: The CDC maintains a website for the public to evaluate outcomes. All reporting programs can be found here. You can also find a list of non-reporters who failed to comply with the law here. More information about the history of ART surveillance in the US and  the law that required reporting of outcomes in the US (called the  Fertility Clinic Success Rate and Certification Act ) can also be found on the CDC site.

You can also read about some factors to keep in mind when comparing rates here.  I actually disagree with the CDC regarding one point on this page. They suggest that rates aren’t an absolute indicator because some programs take in more “hard” patients than other clinics. Every clinic I have every heard about or worked with feels that they get more than their share of “hard” patients from time to time. I think this is a weak excuse for poor outcomes. Even if patients are “harder”,  their outcomes can be good with an appropriate treatment plan.

Part of what a good physician does is carefully analyzes a particular patient’s situation and recommends the “most-likely-to succeed” treatment plan based on their experience. Sometimes the right answer  for the patient is that IVF is unlikely to work for you and the first, or the second or the third cycle doesn’t get ordered. This may be hard for patients to accept but it is kinder to them then processing them through cycle after failed IVF cycle. Hard patients may be the ones that will benefit from donor egg, donor sperm or surrogacy. We didn’t advertise at all for patients in our Indiana clinic so we got a mixture of patients, harder and easier. Sometimes, we got patients who’d failed everywhere else and heard of us last. We had exceptional rates because the lab was good and- just as important- the doctors were good at ordering the most likely to succeed plan for the patient. Sometimes it was IUI. Sometimes IVF. Sometimes donor gametes were suggested. Every patient’s road map was individualized.

The only time a clinic’s rates get really low–and yet is not reflective of low lab quality — is when you have too many patients put into IVF cycles that are unlikely to benefit from them. This is a diagnosis failure if it occurs often enough to affect the rates. So why do it? Well, cynically, most clinics get paid just as much for failed cycles as successful cycles. But this “push to IVF” may recruit more patients on the front end, it invariably will bite the clinic in the back end when the clinic’s stats start to decline because they are using the wrong procedure for these patients.

Companies like Univfy are working to devise better predictive tools based on individual patient statistics for guiding patients and their doctors to the most effective treatments so hopefully, with time and better patient counseling,  this weak argument of  poor stats due to too many “hard” patients doing IVF will finally be kicked to the curb where it belongs.

I also like this site called  Fertility Success Rates for comparing clinics. It is simple to use and shows you side-by-side comparisons using the same data reported to the CDC. Top clinics are reported here in a list. The top clinics list is simply based on highest rates. Keep in mind that a clinic with 30 cycles and a 70% pregnancy rate may not be as good as a clinic with 300 cycles and a 50% pregnancy rate because the low volume clinic’s high rates may be a statistical anomaly and not reflect longer term outcomes. You can read some of the caveats about interpreting success rate reporting here.

To investigate fertility clinic outcomes, you can also go to the SART site, it’s easy to use and includes almost all IVF clinics.  SART also acts as a vendor for members who report their data to CDC. Most programs in the US are SART members so you can find almost all program results through the SART website. The SART site may be easier for patients to use than the CDC site, although the CDC has made great improvements in their site since its inception.

SART members are required as a condition of membership not to compare their rates to other clinic’s rates or the national average. That is most likely part of the facade of  “we are just one big happy family of IVF providers”, all of which pay SART handsomely for the privilege of membership. Read about this somewhat controversial SART membership requirement  –which some consider censorship– here.

You will find a map of the US on the SART site. Click on your state and a list of SART member clinics in your state will pop up. Click on each one that interests you. You will find a short summary of demographic info on each clinic. At the bottom of this clinic -specific pop-up window, you will find a link to that clinic’s specific stats for the most current year. 2011 stats are the most current at this time. You can print off the one-page report and compare clinics side-by-side. Pay special attention to your age group. The youngest age group typically sports the highest rates. If you are older than that, look to your age group for your chances, which will likely be lower.

What is a good success rate? Well, it is easy enough to find the National Summary Report on any of these reporting sites. The National Summary Report is a one page report summarizing the success rate for all US clinics for a particular year. The 2011 report can be seen from this link:  2011 SART Clinic Summary Report for US Clinics. Below, I have copied some of the report. This is for fresh IVF cycles using the patients own oocytes. There is also a section on the report for thawed embryo cycles and fresh egg donor cycles if you are having these procedures instead.

You’ll note that the AVERAGE live birth rate for US women who used IVF and were less than 35 years of age was 42.9% per retrieved IVF cycle  and 46.3% in cycles that had embryos transferred. I wouldn’t go to a worse than average clinic.  Would you?  If your clinic reports poorer results, ask for their own more recent in-house results. Maybe they have improved. Make sure that you are comparing apples with apples. Ask for the outcomes for women your age using the procedure you are considering. If the clinic doesn’t answer your questions or is vague about results for different age groups, maybe it is time to interview another clinic.

Fresh Embryos From Non-Donor Oocytes

Use this data from mandated reporting as a tool for advocating for your best possible health care. It’s more info than other types of patients get about their providers before they undergo medical treatment. It’s a shame not to use it.