This week, a reader contacted me regarding fragmentation in her embryos. She was told by her RE that things were looking “good” but then he also mentioned that some of the embryos on day 3 were showing some signs of fragmentation. Her question was how concerning was this observation that her embryos had some fragmentation?

The article , “Human embryo fragmentation in vitro and its implications for pregnancy and implantation”, published by Richard Scott MD, Jacques Cohen PhD and colleagues looked at the question of how much and what kind of embryo fragmentation was significant in terms of hampering further development. They found that very large fragments were more problematic than more smaller fragments. Jacques Cohen is one of the  pioneers in micromanipulation techniques and his team promoted the practice of fragment removal on day 3 of development. Their experience described in this paper suggested that embryos with a wide range of fragmentation (as low as 6% to as much as 35%) could experience equivalent implantation rates after fragment removal.

Mina Alikani, PhD, a member of the Scott/Cohen clinical research team published a comprehensive review of the implications of embryo fragmentation, entitled  “Pathogenesis, developmental consequences, and clinical correlations of human embryo fragmentation”, Fertility and Sterility Volume 95, Issue 4, Pages 1197-1204, 15 March 2011.

Summary of the main points of her paper:

Fragmentation is a cellular process that generates cell fragments that do not contain an nucleus during early embryo development. Fragmentation is inversely correlated with implantation; meaning that the more fragmentation you have, the worse the prognosis for implantation. Because of its potential significance for implantation, the percent of embryo fragmentation is a standard component of various embryo grading systems. Although it can be correlated with poor developmental potential, it is important to remember that fragmentation is commonly observed for a majority of human embryos in culture.

Based on time-lapse photography studies, fragmentation occurs during the process of cell division and fragment reincorporation into other cells has infrequently been observed, suggesting that in some cases, it may even be a normal part of cell division. However, it is also well established that moderate to extensive fragmentation is associated with chromosomal abnormalities and mosaicism. Chromosomal abnormalities in this context usually means the condition of an incorrect number of chromosomes after cell division, aka. aneuploidy.

Mosaicism refers to the situation in which different numbers of chromosomes are present in different cell lineages in the embryo. For instance, if one cell of eight on day 3 finds itself with an incorrect number of chromosomes, this abnormality may be passed on to all the future daughter cells it gives rise to with successive divisions, creating an embryo with a mix of normal and abnormal cell lines. Mosaicism has been an issue for determining whether an embryo is normal based on genetic testing of a single cell, because when mosaicism is present, the single cell tested may not be representative of the rest of the embryo, leading to a misdiagnosis.

Fragmentation reduces the total functional cell numbers in either the trophectoderm or inner cell mass of the embryo. Lower  numbers of cells in these vital compartments may reduce the embryo’s implantation potential. In addition, if fragments lay between the embryo and the zona pellucida, they have the potential to interfere with normal hatching of the embryo.

The following types of fragmentation patterns have been described in human embryos:

• Type 1: few small fragments typically associated with only one blastomere;
• Type 2: many small and localized fragments associated with one or more cells; may result in fewer cells overall
• Type 3: small and scattered fragments associated with multiple cells;
• Type 4: large and scattered fragments associated with several unevenly sized cells; may result in fewer cells overall

A localized pattern of fragmentation is more conducive to fragment removal by a technician trained in this micromanipulation technique. Fragments scattered among and in between other cells are impossible to remove and one paper suggests this pattern of scattered fragmentation may be associated with a higher incidence of chromosomal abnormalities.

There is a mix of inconclusive studies in the literature regarding what effect, if any, fragmentation has on clinical outcomes. Some published studies found an association with increased fragmentation and miscarriage, compelling the authors to recommend that patients who only have severely fragmented embryos (50% or greater) be counseled regarding their increased risk for miscarriage.

Some researchers have suggested that poor egg quality in regards to the egg’s nuclear and cytoplasmic competence for development may be a cause of increased fragmentation. Poor egg quality could result from inherent deficiencies in mitochondrial DNA content or suboptimal follicular environment at the level of the granulosa cells which are vital for guiding egg maturation. Some studies suggest that stimulation protocols may be a contributing factor to poor egg quality resulting in increased fragmentation but these studies are still inconclusive.

Cellular mechanisms for fragmentation are also poorly understood and several possible pathways have been suggested including programmed cell death (apoptosis), defects in the microtubule and cytoskelatal framework of the cell that orchestrates the mechanical movements that happen during cell division, reactive oxygen species involvement and faulty cholesterol metabolism. More research is needed.

The graphic summary  below (copied from Alikani et al, March 2011) summarizes the correlations between embryo fragmentation, developmental milestones and clinical outcomes. Which of these correlations are causative requires further investigation but the underlying message is clear: A little localized fragmentation is well tolerated by the embryo and may even be normal. A great deal of fragmentation can have severe developmental consequences and if it can be minimized by improved stimulation protocols or technical defragmentation, that is probably beneficial.

It might interest you to know that the founder of the modern Mother’s Day holiday was herself childless.  Two years after her own mother’s death, Anna Jarvis held a small celebration to honor her mother on  May 12, 1907, and 7 years later in 1914 succeeded in establishing a federal holiday when President Woodrow Wilson declared the second Sunday in May as Mother’s Day.

Anna’s mother Ann Jarvis, had  founded an organization called the Mothers’ Day Work Clubs in five cities in West Virginia  to help improve sanitary and health conditions for mothers and their children. The elder Ann also worked to clothe and feed soldiers from both sides of the Civil War.  Anna’s Mom, the  elder Ann Jarvis, was a tough act to follow.

Interestingly, daughter Anna quickly became disillusioned with the commercialism of the federal holiday she created and in 1923 crashed a confectioner’s convention to protest using the holiday to sell candy.  In 1925, she was actually arrested for disturbing the peace at an American War Mothers convention which also used Mother’s Day for fundraising. She objected to the use of the holiday to praise the institution of motherhood and to use the holiday as an excuse for driving sales of flowers, candies and greeting cards. She fought against the Mother’s Day holiday well into the 1940′s, spending her entire inheritance in the effort. In her eighties, she was penniless, suffering from dementia and ultimately died in a mental institution in Philadelphia.

Her vision for the holiday was an intimate celebration of every person’s own mother. A day to simply say thank you to the person who nurtured you. Anna advocated the writing of personal handwritten notes to say thank you and was dismayed by the use of commercial cards.

She was very outspoken in her irritation with what Mother’s Day had become and her New York Times Obituary quoted her as saying:

“A printed card means nothing except that you are too lazy to write to the woman who has done more for you than anyone in the world. And candy! You take a box to Mother—and then eat most of it yourself. A pretty sentiment.”

Ironically, her own mother’s vision of the holiday may have been more a universal salute to motherhood–or a not too subtle hint to her own daughter that she could use a little appreciation. The elder Ann was quoted as saying after a Sunday School  service:

“I hope that someone, sometime will found a memorial Mother’s Day commemorating her for the matchless service she renders humanity in every field of life. She is entitled to it.”

In fact there are some suggestions in the historical accounts that the relationship between Ann and Anna was not always idyllic and Anna the daughter may have lost her mother before she had a chance to reconcile with her after some angry words. Her work to achieve a Mother’s Day holiday may have been a kind of atonement for her unresolved issues with her own mother.

It may make Mother’s Day sting less if we remember that the creator of Mother’s Day had a simple vision of showing appreciation for the woman who nurtured her. Mother’s Day was not meant to be about having babies and becoming a mother. It was not meant to make women who don’t have children feel inferior to women who do have children.  The holiday was simply about thanking the woman (or women) who nurtured us in childhood and helped make us who we are as adults. Hopefully, all of us have at least one person like that in our lives so Mother’s Day is a holiday for all of us. Mother’s Day is as good a day as any to say “Thank You” to the women in our lives who mother us.

More articles on the origin of the Mother’s Day holiday:

Wikipedia Mother’s Day (US):

A 19th Century Lobbiest, An Arrest, And The Birth Of Mother’s Day

Mother’s Day’s Dark History

Like a forgetful spouse, I missed my two year  “blogaversary” last week on May 3rd, 2012. In the last two years, I have tried to answer as many questions as I can from patients both through my blog and as many of you know, through my contact email. In the two years, the most popular posts have been these five:

1. Embryo stages, progression and pregnancy outcomes | Fertility Lab Insider
2. Sperm Morphology: Kruger’s Strict vs. WHO criteria, what’s the difference? | Fertility Lab Insider
3. Understanding the Gardner blastocyst grading scale | Fertility Lab Insider
4. Egg Count Mathematics: Why the numbers change between retrieval and transfer. | Fertility Lab Insider
5. IVF Disasters: No Fertilization | Fertility Lab Insider

All five are focused on technical issues related to navigating ART treatment, so their popularity is not surprising. I hope I have answered some of the questions that come up in the car on the way home from the clinic or after you hang up the phone with your clinic doctor, nurse or embryologist. I hope that you have felt empowered through this blog to ask more questions of your doctor, your nurse and your embryologist. If they care about you as a patient, believe me they want you to ask questions that help clarify your understanding of your treatment plan. If they don’t, you should feel empowered to seek treatment elsewhere.

Ironically, the post that got the most page views and links back had nothing to do with technical expertise, but rather with the emotional challenges of infertility. Sometimes it takes hours for me to write a single post to get all the relevant informational links in and detangle my sometimes circuitous thoughts and grammar. This Winnie the Pooh inspired post was written in a blink of an eye from my heart..and received a record number of daily page views…

Stronger, braver, smarter….

My personal favorite posts are those that take up ethical, legal and  political issues related to ART- where I get my “activist on”. I have been especially concerned about embryo personhood laws that could potentially make ART illegal.

Colorado Amendment 62 pits embryo against mother    or Personhood Bills Threaten IVF  or  Embryo Personhood Laws

Two years ago, when insurance reform actually seemed possible, I wrote several posts on the need for and hope that infertility insurance coverage would become more widespread. With the Affordable Care Act under attack this election season, derisively known as ObamaCare by it’s opponents, progression on insurance for infertility treatments is waaaay on the back burner. Some past insurance posts include:

Could insurance be part of the basic insurance plan?

Understanding and negotiating your insurance benefit

New study on IVF insurance in the US

Somewhere around the middle of the two year stretch, I wrote the book Fertility Lab Insider , an IVF primer for patients navigating treatment. You can buy the e-book for less than a cup of coffee. Sales from the book pay the hosting expenses for the blog, so if you have gained $2.99 worth of information from the blog, consider buying the book to support the blog. I would appreciate it.

I recently started a “Q from U”  post series which answers some of the most common or most interesting questions I get from patients.

• Q from U: New Series: Biopsy
•  Q from U: US  Standards for embryologists and fertility labs
• Q from U: When the IVF cycle fails: Follow-up Questions
• Q from U: Growth potential of frozen vs. fresh embryos
• Q from U: Assisted Hatching

Still after two years, it’s not enough. Because no matter what I do to help inform patients, that’s only one part of the puzzle we need to put together to achieve the goal of high quality affordable health care for all patients who need ART for one reason or another.

The ART field, while mainstream, is still underdeveloped as a clinical practice. Embryologists need to consider what being a professional embryologist means. Does an embryologist need to have a deeper understanding of the life of the embryo or is cook book knowledge of technical skills enough? For the future of our professional field, I hope for the former. Can examination of best practices in the most successful programs inform us as to which technical procedures are most effective for which patients? Can we agree on terminology, grading systems for embryos and the most effective vitrification protocols? I am getting more actively involved in my embryologist community to try to see if we can answer some of these questions and because I am increasingly frustrated with the commercialism of ART. Is it really all about the money? I hope not.

Now I have a question for you: What issues are most significant to you?And perhaps most importantly, once you are through the intense fertility treatment phase, what can you do as a citizen or an ex-patient to improve the quality and accessibility of ART  to others that will follow in your foot steps? We all have a piece of this puzzle.

A while back, I wrote the article, Participatory medicine – the e-patient revolution which talked about e-patient Dave and the Society for Participatory Medicine.   There appears to be increasing momentum to encourage patients to become more involved in healthcare decisions. The very concept that patients don’t have to be bystanders in their health care is  liberating for patients who wanted to play a more active decision-making role in their health care. Well, I found another great patient advocacy blog written by a nurse, Barbara Bronson Gray, who has worked in hospitals, created a website for WEb MD, and advocates for patients in her blog   “BodBoss”

Although her blog has nothing specifically to do with ART, many of her observations about health care are highly relevant. I particularly liked her post “Long waits at the doctor’s office disrespects patients” that was recently featured on the (mostly) physician authored aggregated blog Kevin MD.  She makes a very important point which dovetails with what has been bugging me about financially successful IVF practices who run patients through the office like a herd of cattle. She points out that except for rare emergencies, long patient delays don’t have to happen if offices would schedule the patients with patient care in mind, instead of just their bottom line. In her own words:

“A practice that doesn’t make you wait has undoubtedly made a philosophical and financial decision that it’s not right to make patients sit very long in the waiting room. They respect your time as much as they respect their own. So they are careful to reserve a few slots every day in their schedule in case a patient’s visit takes longer than expected or there’s an emergency. They also create some “breathing time” in the schedule to help ensure the ebb and flow of people in and out won’t create a frustrating and tiring delay for their patients.  A practice that always makes you wait has a different perspective. They are typically maximizing revenue, over-booking multiple appointments to allow for some “no-shows,” and even encouraging extended patient visits and un-planned procedures because they increase the day’s revenue. Basically:

And lest you think that this is a problem with just family care generalists, specialists typically have longer wait times than the family doctor. Unfortunately, overbooking patients is a very common phenomenon in ART practices and totally avoidable. Offices make appointments every day and every day they gain real world experience on how long it takes their docs to see a certain kind of patient for a certain kind of procedure or test. So if they haven’t figured this out within their first month of business, they are making a decision to let you wait. Period.

Why does this overbooking happen? Again, because adding staff costs money and spreading patient appointments apart costs money. Ideally, patienst and their samples are spread out throughout the day when staffing levels are lean, but ironically this approach, though best for patient care may also displease patients who are asked to come at less popular times. Clinics know that patients want to come before work or at lunchtime or late afternoon on Friday to accommodate their busy lives and asking them to come at less popular times may displease patients. So clinics give everyone the time slot they want and patients think they are being well served, but if it increases the potential for a lab mistake, any perceived advantage is lost.  So stacking patients up ultimately benefits only  the bottom line for the clinic, not the patient. Consider that the next time you wait for the doctor for hours or have the same appointment time as one (or more) fellow patients for an IUI. Or better yet, get out your smart phone and start looking up their competition.

According to the  Yes!Weekly  blog and videotaped interview with the wife of  NC Senator Peter Brunstetter,  the North Carolina legislator who sponsored the latest marriage amendment on the May state primary ballot, his support for Amendment One was motivated in part by his concern that gay people can’t reproduce.

Amendment One would amend the NC constitution to explicitly define marriage as between one man and one women and also strip legal rights from all kinds of civil unions, even heterosexual ones. Gay marriage is already illegal under state law but amending the constitution would make it more impervious to reversal by “activist judges” , according to supporters of the amendment. In other states where these type of amendments have passed, unintended consequences included the loss of insurance benefits to partners in civil unions  and also the loss of protection orders against non-married partners in domestic violence cases, leaving their victims vulnerable to repeated abuse.

The Brunstetter kerfluffal  turns on an alleged conversation between poll workers and Jodie Brunstetter,  the wife of the senator which was then repeated to  Chad Nance, a Winston-Salem freelance journalist who is currently active in electoral campaigning. A poll worker working alongside Senator Brunstetter’s wife reported to Chad Nance  that the Senator’s wife explained that her husband promoted this bill to protect the Caucasian race. In effect, Caucasians weren’t reproducing enough and gay marriages further reduced this proliferative potential.  Specifically, she was reportedly overheard to say, “The reason my husband wrote Amendment 1 was because the Caucasian race is diminishing and we need to uh, reproduce.” When the Senator’s wife, Jodie Brunstetter, was questioned by Nance about her remarks in a videotaped interview, she had a lot of trouble defending her remarks  (perhaps in part because she obviously felt ambushed by “gotcha” journalism and perhaps due to possibly having heat stroke). I actually felt some sympathy for her after viewing this videotape, because my brain tends to go  stupid when anyone starts videotaping me, a clear sign that I am not cut out for politics. None the less, I heard her link her and her husband’s support for Amendment One with the idea that gay couples don’t produce children.

Nance’s transcript recaps  the conversation in part like this, copied from “Yes Weekly account and also audible in the much longer videotaped conversation:

NANCE: You didn’t tell that one lady that it was to preserve the Caucasian race because they were becoming a minority?

Jodie Brunsetter: No.

NANCE: She’s lying?

Jodie Brunsetter:  No. It’s just that same sex marriages are not having children.

Now I have no idea what Mrs. Brunstetter actually said to anyone regarding Caucasians but I clearly heard her say that same sex marriages don’t produce children. Leaving aside the racism issue, which if true, is just too stupid to address,  is outside of my expertise and is being thoroughly covered by everyone else,  I thought I would address the “gay marriages don’t produce children” issue which is casually used to support Amendment One. I would be happy to put Senator and Mrs. Brunstetter’s  mind at ease if they have any concern regarding the ability of gay people to reproduce. I would hate for a simple misconception (sic) to be the basis of their support for a discriminatory Amendment.

Actually, Senator Brunstetter, gay people reproduce very well with just a little help from assisted reproductive technology. Unlike our straight patients who usually have underlying issues with plumbing or ovarian reserve or perhaps underlying genetic issues, gay people are typically reproductively healthy so they are the easiest patients to treat with ART. Their reproductive systems are fine, we just need to provide gay patients with a little help uniting egg and sperm, and maybe finding a nice uterus to grow the embryo. In fact, many gay couples, with just a little help,  can easily have as many children as they like with relatively little difficulty. Their infertility is often based solely on social, not biological causes.

Ironic, isn’t it Senator Brunstetter?  If your concern regarding gay marriage is merely reproductive capacity, maybe you should direct your efforts to promoting reproductive rights and supporting equal and affordable ART treatments for everyone- gay and straight- and  then everyone could reproduce easily and affordably, even if they need a little medical help. With everyone’s procreative potential maximized, you no longer have to worry that there will be a future shortage of NC citizens.

Here are some of the options for gay couples who want to have children, just to further inform and ease your mind:

• Lesbian couples can avail themselves of donor sperm with intrauterine insemination and even take turns being the biological Mom.
• Lesbian couples can use a sperm donor with IVF and again take turns being the biological Mom.
• Gay men require a little more high tech help needing both an egg donor and a gestational surrogate but with ART and third party reproduction, all things are possible.
• Lesbian couples or gay men with a gestational carrier could “adopt” spare embryos from other couples who have excess embryos in storage. Of course, many of the embryo adoption agencies are Christian and not gay-adoption friendly so you might have to work to change those discriminatory attitudes if you want to make sure that gay couples have every option for reproduction available to them.

So, hopefully, this little bit of education regarding the reproductive capacity of gay couples will alleviate any concerns you have that same sex marriages don’t produce children. This should  allow you to pull your misguided support for Amendment One and instead support  the procreative efforts of all kinds of loving unions before any lasting damage is done to the many recognized and unrecognized families already here in North Carolina.

You might think that the infertility community has nothing in common with the ProChoice community, but you would be very wrong. Both groups risk access to reproductive health care if the numerous personhood bills pending in various states are actually passed.

If you haven’t already run across these personhood bills, they all have in common the goal of creating a new legal definition of personhood. namely, personhood would be defined as beginning at the moment of conception which means the zygote would have all the rights of a person. These personhood laws are designed to eliminate the rights granted by Roe vs. Wade to have lawful abortions. The side effect of these laws will be to eliminate any procedures which have the potential to harm an embryo.

The infertility advocacy and support group, Resolve,  states succinctly why the infertility community opposes personhood. From their website:

“Why the Infertility Community Opposes Personhood:

• Defining an embryo as a person will ultimately undermine access to safe and reliable infertility medical treatment, including IVF.
• Personhood legislation is anti-family as it restricts access to medically necessary assisted reproductive technologies for people diagnosed with infertility.
• Personhood legislation would eliminate access to medical treatments for cancer patients as a way to preserve their fertility.”

Interestingly, because the earliest versions of personhood bills have been defeated, the authors of these type of bills have become more crafty in their wording. In House Bill 1 in Virginia, the opening statement seemingly protects infertility treatments, reading as follows:

“Nothing in this section shall be interpreted as affecting lawful assisted conception.”

The sticking point is that adjective “lawful”. What is lawful?  Lawful is defined as treatments which have zero chance of damaging, destroying or losing an embryo. Well, Hello, welcome to the world of medicine because there are risks to every medical intervention that exists, now or in the future. In IVF, some percentage of all embryos created are accidentally damaged, destroyed or lost as an INEVITABLE consequence of techniques used EVERY DAY in EVERY IVF lab in the world. If your clinic tells you this never happens in their lab, they are big fat liars. It should happen rarely but it does happen, every day somewhere. Moving embryos from dish to dish is risky. Injecting eggs with sperm is risky. Loading embryos in catheters has a risk of loss. Freezing embryos is risky. Thawing embryos is risky. Storing embryos is risky.  Embryo biopsy is risky. The only way to be sure there is NO RISK is to never create an embryo in the lab. Voila, there it is, the end of IVF in whichever states pass these laws. Arguably, this would be boon for IVF in surrounding states but certainly a hardship for patients in that state.

How many  physician practices or hospitals would risk their business and possibly their freedom by offering IVF if the possible damage or demise of an embryo from  IVF treatments  would be an actual CRIME because damaging, losing or destroying an embryo would be damaging, losing or destroying a PERSON? IVF labs would close their doors so fast, it would make your head spin. REI’s could do non-IVF endocrinology and infertility treatments.  REI’s are often OBGyns so they could fall back on this specialty. Embryologists would be clamoring (most unsuccessfully) to find employment in animal labs. Patients would be most severely affected.

According to IVF Connections,  personhood bills have been put forward in these states: Colorado, Alabama,Arizona, Iowa, Georgia, Montana, Mississippi, Oklahoma, Texas and Virgina. Signatures are being collected for proposed ballot measures in Colorado ( although bills were defeated twice previously), Ohio, Montana and California. In Kansas, Virginia, Oklahoma, Wisconsin, Alabama and Georgia, bills are in the works that could also lead to personhood referendums. The anti-choice advocacy group Personhood USA has activists working in every state to pass personhood laws so no one should feel safe from these anti-IVF initiatives.  The bottom line is that if you want to protect access to IVF as a lawful fertility treatment in every state in the US, you need to vote against these personhood initiatives in every state.

In recognition of National Infertility Awareness week which ends Saturday, Resolve asks bloggers to blog on the topic of patient issues and start with the phrase “Don’t ignore….” Here are my thoughts on the topic.

Infertility treatments are complicated, expensive and emotionally distracting ….BUT  you will NOT spend your whole life in treatment. There is a life “after infertility treatment” for everyone. What that “after” looks like depends on in part, some luck but also your perspective. Everyone has a different perspective-  their big picture. What really drives you as you seek treatment for infertility? Is it having a biological child that looks like you? Is it raising a child? Is it carrying a child? Ideally, all those things come together with infertility treatments. If not, you might have to take the long view or the big picture view. If I must choose among those outcomes, which one really matters most to me?

If it’s a biological child that matters most to me and my own gametes or partner’s gametes aren’t cooperating, can we ask a sibling or other blood relative to donate?

If it’s having my own biological child but my uterus won’t cooperate, can we consider using a gestational surrogate to carry our embryo to term?

If  the biological experience of pregnancy is very important to us but isn’t happening with our gametes, can we “adopt” an embryo from another patient who is looking for a good home for their “spare” embryos? We could give birth to our “adopted” embryo.

If it is the experience of raising a child, perhaps adoption of an existing child will fill that need.

If it is because we want to share everything with our beloved partner and make a difference in the world, perhaps there are other passions we can share to make our world better and our lives more satisfying.

Sometimes we see patients so deep in the trenches fighting the infertility wars, that they lose sight of the big picture reasons for this battle. We see patients pursue apparently futile treatments until financial reserves wither away leaving patients deep in debt.  Relationships among loved ones and friends can be damaged or even destroyed by the stress of infertility treatments. Sometimes patients achieve pregnancy only to find themselves divorced a year or two later. Keeping your big picture in mind may save you from these unfortunate outcomes as you go through treatment.

Infertility is really hard. Don’t ignore your big picture as you work through the treatments. Make sure that your treatment choices serve your big picture, whatever that is.

Additional resources:

• http://www.resolve.org/infertility101  (Basic understanding of the disease of infertility.)
• http://www.resolve.org/national-infertility-awareness-week/about.html (About NIAW)

The other day I received this question (paraphrased)  from a reader of my blog: “What, if any, training and on-going education is required for embryologists in the US ?  And, what, if any, regulations are placed on a fertility  lab in terms of passing muster or maintaining some standard?”

Well, the answer to that simple question is somewhat complex but we can start with the Clinical Lab Improvement Amendments of 1988 or CLIA’88. This legislation was passed  in 1988 and periodically updated to establish the quality standards for all laboratory testing performed in the US  to” ensure the accuracy, reliability and timeliness of patient test results regardless of where the test was performed”. The Centers for Medicare and Medicaid Services (CMS) have the mandate to see that this legislation is followed and laboratories must be certified as CLIA compliant to receive Medicare or Medicaid payments. CLIA’88 defined levels of testing complexity and adjusted educational requirements for personnel according to the level of complexity. Some tests were classified as “waived” testing and so not all the standards applied. Other tests were considered moderate complexity or high complexity. Blood tests using chemical analyzers and semen analysis are examples of high complexity testing. Lab Directors must be board certified as High Complexity Lab Directors (HCLD) in order to direct laboratories  that provide high complexity testing. Board certification is in addition to advanced education (PhD, MD, or DO) and years of experience required to sit for the examination. In addition, board-certified individuals must demonstrate on-going education to keep their certification.  Several government approved testing boards including the American Board of Bioanalysis (ABB) perform this lab knowledge  certification testing and offer certification for supervisors, managers and consultants as well as lab directors.

Okay, so that sounds pretty intense, right? Well, actually not so much  because when the law was initially passed, the Society for Assisted Reproductive Technology (SART) successfully lobbied to exclude embryology labs  from CLIA’88 because there is no testing involved. Embryology procedures such as egg collection, insemination and on-going embryo culture are more procedural like research and not like testing so that point is valid. Unfortunately, that left a big gap in federal oversight for embryology labs.

In contrast, Andrology lab work clearly met the testing definition and was regulated by CLIA’88.  So in the early days of IVF,  the inspector from CAP or the Joint Commission would roar into the lab, check out our semen testing protocols and never step foot in the Embryology lab where arguably the more high risk patient activities were occurring. Even if embryology hadn’t been deliberately excluded from CLIA’88 oversight, one of the incentives for compliance with CLIA’88, namely,  receiving Medicare or Medicaid payments did not apply to embryology or IVF procedures because they weren’t covered.

In summary, Andrology labs are required to have a CLIA license for operation. Embryology labs are not required to have a CLIA license and are not required to comply with CLIA’88.

In spite of this spotty oversight, IVF labs did receive some trickle down regulation from CLIA ’88 because the same employees in the IVF lab often performed both Andrology and Embryology procedures so it was simpler to require all technicians to meet the educational and training standards expected for high complexity testing personnel, and having them work in either capacity (embryology or andrology) as needed.

The Society for Assisted Reproductive Technology (SART) issued two Professional Guidelines which use CLIA’88 as a backbone and then modify the regulations for IVF labs. The complete Guidelines can be downloaded from the ASRM website or click on the links below.  These Guidelines discuss expectations for personnel training and continuing education. The Guidelines also lay out recommendations for organizing and running an IVF lab. The only problem with these standards is that following them is voluntary. Still most programs adopt some, if not most, of the guidelines because they set patient expectations as well and clinics must compete for patients.

Revised Guidelines for Human Andrology and Embryology Laboratories (2008)

Revised Minimum Standards for Practices Offering Assisted Reproductive Technologies (2008)

To work as an embryology technician, SART/ASRM guidelines recommend that technicians should have a college education (bachelors or masters) in either a Medical Technician program or in one of the biological, clinical, physical or chemical sciences or reproductive laboratory science. In addition, technicians should have performed at least 30 ART procedures under the supervision of their lab director or lab supervisor before performing these procedures solo. On an on-going basis, they should have 12 hours of continuing medical education and perform at least 20 ART cases a year. In the beginning. all training was in the lab and there were no academic training programs for IVF techs. That has changed and there are educational training and hands-on workshops for technicians who want to get a specific IVF education. In the old days, most of us had an animal research background, then found ourselves applying what we learned from mice, hamsters or cattle to clinical IVF. The other track was the med tech track where techs were trained in medical quality control and patient issues  but then had to learn the technical piece in hands-on training in an IVF lab.

To become a lab director of an Andrology lab, you must have a PhD (or MD or DO) and must be board-certified as a high complexity lab director. The American Board of Bioanalysis (ABB) administers the board exams after determining that an individual has the education and experience requirements to sit for the exam. In contrast, to be  an Embryology lab director, the CLIA’88 regulations are not applicable, but the SART Guidelines suggest a Bachelors or Masters degree is preferable. Some individuals became ‘grandfathered” as lab directors if they had been functioning as a lab director before the CLIA’88 regulations were in place and the board certification requirement was slowly phased in so as not to dislocate individuals already working as lab directors. A separate board certification was created for those aspiring to be Embryology Lab Directors but these are independent of any CLIA’88 requirement.

There are two other federal government agencies that have a interest in specific aspects of IVF practice. The Food and Drug Administration (FDA) has oversight for the safety of donated human cells and tissues used for medical purposes. This includes tissues like corneas, skin, cartilage that is recovered from cadavers and used in living humans. Blood donation is also regulated by the FDA. Where these  FDA interests overlap  with IVF labs is when semen, egg, or embryos are donated from one individual and used by another. The screening of potential donors who donate these reproductive tissues is regulated by the FDA. ART facilities that  engage in various processes associated with the donation of tissue are required to be registered with the FDA and undergo periodic unannounced inspections.

The Centers for Disease Control (CDC) collect various kinds of data on the US health care system. The  Fertility Clinic Success Rate and Certification Act of 1992 (Pub. L. 102-493, 42 U.S.C. 263a-1 et seq.) required all operating ART facilities to annually report their pregnancy outcomes to the Centers for Disease Control (CDC). The CDC was then tasked with  summarizing the data into a National Report and also creating a website through which the public could look up the success rates for individual programs. What is the punishment for non-reporting? The facility gets placed on a non-reporting list which is not prominently displayed on the site so it is hardly a deterrent.

SART  quickly stepped in as a go-between the CDC and the clinics so that clinics could report their data to SART (for a fee) and then SART would display the summarized data on their site and also pass it on to the CDC.  SART members are highly encouraged to use SART to report their results to the CDC although there is no federal requirement to use SART. Clinics can report directly to CDC using a data entry tool maintained by Westat.  SART warns their membership that “Failure to report when obliged to do so will trigger the routine penalty for non-reporting in force at the time of required reporting.” Which is what? The only stick SART has for non-reporting is canceling the membership of the offending clinic.

So there is relatively little US federal oversight of infertility clinics, except specific areas of interest (third party reproduction and annual success rates). There is some carry-over in the CLIA’88 requirements for Andrology labs that affects the education and training requirements of embryology techs when both types of service (Andrology and Embryology) are offered in the same lab.

Market forces are the primary external force for compliance. In order to capture the greatest market share in their area, a program must be perceived to be in compliance with the highest possible expectations for patient care and deliver the highest possible pregnancy rates. So although the CDC does not rank clinics and cautions that pregnancy rates should not be compared between two clinics because underlying patient populations may be different, these rates are still used by patients to select clinics and indirectly used by clinics to market their success rates by providing links to SART or CDC where patients can view rates.

In my experience, lab inspectors vary widely in their training and ability to determine compliance. Good labs and non-compliant labs both pass inspection.  Labs that pass inspection use this milestone as a marketing tool to advertise their program. In fact, the agencies that inspect labs will also sell the labs posters and such to help advertise their successful inspection to their customers.

The major driving force within the clinic for compliance with standards and for ensuring a high quality lab is the professional integrity of the Medical Director and Lab Director. If these key personnel are motivated to do the right thing for the right reasons, there is lots of guidance to help them create an exceptional lab. If these key personnel are interested in making money primarily and see compliance as something that occurs only when the inspector is on-site every other year, federal oversight is too weak to to ensure high quality lab operations.

Other countries who are less in love with the free market handle this differently. For example, in the United Kingdom,  the Human Fertilization and Embryo Authority (HFEA),  licenses and inspects fertility clinics in the UK to ensure that UK IVF  personnel meet expected education and training standards. Programs must present evidence that they are capable of offering high quality services before they are given a license to offer those services. Of course, this regulation goes hand in hand with the federal health care system which pays for infertility medical services for its citizens so there is a federal interest in setting quality standards. So it’s a trade-off. Here in the US, the infertility industry it is a market-driven self-pay system which is largely unregulated by the federal government. That’s not the only way to provide health care but that’s (apparently) how we like it in the US.

Ever wonder what your physician is thinking? Well, in lieu of truth serum or ESP, you might find some answers at Kevin MD.com, a social media medical blog. The physician viewpoints expressed through his blog are especially timely because health care in the US is such a hot political topic. This aggregate medical blog, created by Kevin Pho, MD, is a combination of his own posts as well as guest posts from physician (and other health care providers) to voice their opinion and insights from their daily work in various fields and at various stages of their career.

Although, the topic  on Kevin, MD is rarely ART, I still find it very interesting, because of the insights it provides regarding physician opinions about the current health care system. Trained as a scientist and not a health care provider,  I have always been interested in how different people handle the (at least to me) awesome responsibility of treating sick and or hurting people. Even as a behind-the-scenes lab person, I felt the responsibility of every patient’s positive outcome resting often too heavily on my shoulders. Intellectually, you know that you can’t make it turn out positive for every patient, but you feel the failure personally when they don’t get pregnant. This perspective makes me particularly thankful for the very good physicians out there who handle this responsibility with grace and kindness and also conversely dismayed by other physicians who take this responsibility lightly or even worse abuse the responsibility our society (and the medical board) has given them.

On the Kevin.MD stage, you generally get a more progressive vision from the often, but not always, younger physicians who are more open to the concept of sharing health care decisions with their patients and who have not yet lost their enthusiasm for patient-centered (or partnered) care. For instance, here’s an intriguing post, “Is patient-centered care an out-moded concept?”  by Dr. Kevin Bear in which he praises the activist patient who is interested in being involved as a partner in their own care. Or as one commenter on the post said, “patients do not want to be in the driver’s seat…but neither do they want to be in back seat…or waiting for a bus!”

Other posts provide insights regarding hot button topics, such as tort reform.  For instance,  “Patients deserve a medical malpractice early offer”, written by Kevin Pho  supports  legislation to require “early offer ” malpractice compensation as a means of tort reform. The current malpractice system serves no one really well, not even the patient. A study published in the New England Journal Of Medicine in May 2006 (volume  354, pages 2024-2033) reviewed almost 1500 closed medical practice claims from five malpractice insurance companies from all over the US. Interestingly, only 56% of the claims received compensation, with the majority of the cases reviewed (85%) settled out of court. In fact, of cases that went to trial, only 21% resulted in the patients being awarded damages. The average financial award was $485,348 (median $206,400). As you might expect, the overhead costs for prevailing in court were much higher (on average $52,000) compared to settling out of court. The average length of time to settle the claim was 5 years.

The claims were also evaluated by physicians to determine whether the claims were medically valid in that medical errors were demonstrated or alternatively, if the claims were without merit. In their estimation, 73% of the claims were correctly decided. Of the remaining claims in which compensation and merit were discordant, errors were of three types. Patients received payment without evidence of documented injury in only 0.4% of all claims and payment in the absence of error was made in only 10% of the claims. In contrast, patients failed to receive any compensation even in the presence of error in 16% of the cases. So, bottom line, although the process got it right 3 out of 4 times, when it failed, patients who should have received compensation were not paid more often than those who shouldn’t have received compensation were paid. So patients really aren’t bringing many frivolous suits nor are they using the legal system as a cash cow.

One alternative to the slow and sometimes faulty current system for compensating patients for medical errors and harm is to offer patients an “early offer”  settlement out of court. These “early offer” financial compensation plans have been criticized by opponents as too low. In the case of Senate Bill 406, the highest possible award would be $117,4500 for major injury or death, less than half of what the average successful claim received in the New England Journal of Medicine study. But patients would receive that settlement within 90 days of the injury, instead of five years. Opponents of the measure also argue that patients who reject the early offer would face a higher standard of proof to prove their lawsuit in court. Interestingly, many states already limit the extent of allowable compensation. In Indiana, the ceiling was $250,000 that could be paid out per claim from the State insurance pool.

I believe that the current malpractice determination and compensation system is deeply flawed and creates a counterproductive adversarial relationship between physician and patient. Patients often feel they have no recourse but to sue when errors occur. Part of the problem is that some patients need to believe that their doctors are superpowers who can fix everything that ails them. Some docs do little to re-size this God-like impression. Setting expectations too high results in a great fall (and sometimes extreme patient anger) when physicians show that they are human too.

Both patients and doctors have to change their assumptions to create a more functional physician patient relationship. Patients have to recognize that their doctor is at best, an imperfect partner in their healthcare. Their doctor, no matter how smart or experienced won’t get it right every single time and will always need the patient’s cooperation, full involvement and honest communication to optimize treatment.  Doctors need to be more open to patient input and involvement in their care. The paternalistic “Doctor knows best” attitude no longer serves physician’s purposes either when almost every patient has access to medical information on the internet and wants to discuss this information with their doctor. Telling patients to avoid the internet just makes patients suspicious of their doctors, not the internet.

If expectations are right sized, there will be more tolerance by patients of human error on the part of physicians. When doctors make non-malicious mistakes, they need to be able to learn from the experience and move on without being crippled by a punitive process. Along with that forgiveness for human error,  there should be no mercy for doctors who prey on their patients or put profit ahead of patient safety. My hope is that physicians will police their own more effectively and develop more robust and effective systems for physician review and correction instead of ignoring or worse protecting colleagues who make mistakes with alarming frequency or callous disregard.

In the end, the daily human interactions between doctor and patient (or patient and everyone else) have a healing power of their own. I think you’ll enjoy this little story of the power of human kindness , The healing power of ice cream. Enjoy.

The on-line version of Fertility and Sterility published a review of 56 previous studies; “Birth defects in children Conceived by in vitro fertilization and intracytoplasmic sperm injection: a meta-analysis”on April 3, 2012, epub ahead of print. This study found an increased relative risk (RR) of congenital birth defects reported in children conceived with either IVF or ICSI compared to spontaneously conceived children. The study found no difference between the relative risk of birth defects between IVF and ICSI, but both IVF and ICSI techniques showed elevated birth defect risk compared to spontaneously conceived children.

Relative risk is a statistical term used to express the relative probabilities of an event occurring in two groups, usually a control and experimental group. If the relative risk is 1.0, than the probability of an event occurring is the same in both groups. If the RR is greater than 1.0 (eg, 1.37) as found in this study, the risk is elevated in one group relative to the other. What this means is that the probability of having a child with birth defects is elevated if that child was conceived using IVF or ICSI compared to spontaneous conception. Specifically, compared to spontaneous conception, use of ART increases the risk of birth defects by 37% over spontaneous conception. So if the probability of birth defects is (for example ) 3% in the spontaneously conceived population, the probability of birth defects in the IVF/ICSI population would be a little over one-third (37%) more or about 4%. It does not mean that the risk of birth defects is 37% if you use IVF or ICSI to conceive your child. More simplified explanations of odds ratios and risk ratios can be found here.

I am not a statistician but I suspect statisticians may take issue with this paper and argue that odds ratio might have been a better method to compare the two groups or that some studies were improperly excluded or included, but I can’t address any of that. What is sobering is that even if you quibble over the best way to have performed the meta-analysis, it still doesn’t fundamentally change the take-home message which is that in a review of 46 studies involving 124,465 children comparing the mechanisms of conception, most of the studies (n=38) showed elevated risk with the relative risk ratios varying from 1.03 to 5.53.

So what could this mean if the analysis is correct? There are at least three proposed explanations for this finding:

•  ART procedures themselves (ovarian stimulation or technical lab interventions) somehow increase the risk of birth defects.
• The reported rates for birth defects are higher in the ART population than the spontaneously conceived population because ART children are studied more closely from conception, thus falsely raising the apparent relative risk.
• There are more underlying genetic conditions in the ART conceived population than the spontaneously conceived population and these genetic conditions are revealed through birth defects when otherwise infertile patients conceive using ART. If this is true, the proper control group would be subfertile patients who conceived spontaneously after some time compared to subfertile patients who conceived using ART. Unfortunately birth outcome data on spontaneously conceiving subfertile population is not readily available.

Already, bioethicist Art Caplan has chimed in with his usual dire warnings about IVF , “Time to think of health costs to IVF babies, bioethicist says” in which by not explaining relative risk and characterizing this increased risk as “huge”, he implies that the 37% increased risk is an absolute, not increased relative risk, implying that using IVF gives you a greater than one-in-three chance of having a child afflicted with a birth defect.  While I disagree with Dr. Caplan’s sloppy use of statistics, I agree wholeheartedly  that we should all be cognizant of the possible implications of these findings and more long-term studies should be performed. I would even go further and suggest that professionals in the ART field should clamor for federal funding of longitudinal studies of children born using ART so that we can finally settle this question and be able to better advise patients of their actual risks depending on which scenario above (or alternative explanation) best explains these findings.