Maybe it’s just the 24/7 political news cycle in an election year making me cranky, but the current drive to repeal women’s rights on various issues and reproductive rights specifically makes me want more protective regulation for infertility patients, not less. The US Healthcare system is one of the most contentious areas of debate in this election year. I can’t speak to the whole healthcare system but there is plenty to improve on in the way we deliver reproductive services, particularly infertility services.

Because there are (apparently) a lot of citizens out there who are aghast at the thought of helping people get pregnant on some shared healthcare dollar, we have a system that is largely market driven, with little of the safety features that are built in for patients seeking other kinds of health services. This market-driven approach is particularly corrosive when applied to fertility services because there are so few patient protections. Put another way, what keeps us safe from healthcare cowboys? You have heard of these bad actors, they make the papers when something goes terribly wrong. These docs who promise patients anything –for a price.  The marketing is slick and patients expectations are “well-managed”- which sometimes means that even when the doc screws up, the patient believes they are at fault so they don’t sue.

I am actually strongly in favor of tort reform because the current system tends to create an adversarial relationship between patients and doctors from the get-go which does not promote transparency and good medical care. But in exchange for tort reform, there must be a better system in place to curtail extreme medical practices.

In the non-infertility healthcare market, most  services are covered by insurance and insurance companies are notoriously conservative in what they will cover. If it hasn’t been in use and proven, they typically call it research and don’t cover it. So what happens?- docs don’t offer the crazy out-there stuff, it has to be somewhat proven if they want to get paid. That’s the patient’s first layer of protection. Don’t get me wrong, I am all for clinical research  to advance the field and try new things but it has to be called research and the protections afforded to human research subjects have to apply. The protections for research subjects are expected to be even higher than for routine medical care offered to patients.

The history of IVF is a series of unproven clinical procedures (in science, we call this experimentation) on patients. To this day, there is no tax payer-funded US research on infertility procedures. The original IVF pioneers breathed a sigh of relief when Louise Brown, the first IVF baby,  was born with the requisite number of toes and fingers and only one head. They really didn’t know what they were doing. They breathed another sign of relief when the first IVF kids proved they could be fertile and have kids. The same goes for intracytoplasmic sperm injection (ICSI). In clinical use since 1993, and rapidly becoming the primary, if not only, insemination method for many clinics, it skipped over being experimental and studied and went right to clinical use. We (or should I say other non-US countries who can use tax dollars ) are still collecting long-term outcome data on these children. That means the oldest ICSI baby is just of age and we are still debating the long-term effects, if any, of being conceived via ICSI.

Medical licensing is the other way the extremes of medical practice are controlled. The bar may be high to initially obtain the medical license but the bar to lose that license is still higher. One of my professional colleagues, a malpractice attorney, wryly remarked that unless a physician sleeps with his patients (and they complain about it) or until patient corpses are so prevalent they can be stacked like cord wood, there typically isn’t sufficient actionable evidence to revoke a medical license. There is generally a lot of good will and presumed good effort that is attributed to licensed physicians. Most of them hold up their end of the bargain but there are some real stinkers out there and the current system does little to reign them in. There is a lot of latitude in what is considered the standard of medical care, arguably because it is a medical art, not pure science.  Still, you would hope scientific evidence of efficacy should precede most, if not all, medical intervention.

Reproductive clinics are not licensed in the US, as they are in other countries, so there are no required medical standards that must be adhered to for a clinic to stay in operation. The facility may be duly inspected for building safety, but no one is empowered to close the clinic because they aren’t following some (to be determined)  standard of care for provision of ART services.  One problem in the ART medical field is there is no universal agreement on standards of care. Resistance to universal standards is promoted by a vocal subset of physicians who apparently believe that they alone have the “secret sauce” to cure infertility and their rates will go down if they do IVF according to some universal standard. There is no “secret sauce”.  Good programs are built on non-secret science-driven medicine carried out by dedicated professionals who put patients, not money, first.  The closest thing to universal medical standards in the US are the voluntary Practice Guidelines published by professional societies such as the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technologies (SART).

Unfortunately, clinic accreditation is also no guarantee of quality. In order to achieve voluntary accreditation, programs may elect to be inspected by Joint Commission or the College of American Pathologists (CAP), to validate that their standards are being followed.  In my experience, inspectors are not omniscient and some are not competent so achieving accreditation based on passing inspection doesn’t entirely assure patients can that their program is following the highest standards. Some physicians don’t truly endorse these standards and consider inspections  (and compliance) as an interference in both their professional license-given right to practice medicine and their business goals in a market-driven arena of healthcare.

In twenty years of working in the IVF field, I have encountered very good physicians doing very good work and unfortunately,  some that shocked me with their callous disregard for their patients and exceptional high regard for themselves and their own financial self-interest. Below are some of the jaw-dropping comments I have heard over the years which reflect a less than compliant attitude toward regulation and standards, paraphrased of course.

• Don’t worry about compliance with standards, the next inspection isn’t for two years.
• Regarding donor eligibility screening required by the FDA: The FDA can’t tell me what to do; they are interfering with my right to practice medicine as I think is best based on my license and my experience.
• Yes, we know the previous lab director lied to the inspector about having written protocols for everything we do in the lab, but we don’t think writing protocols up is a priority, we won’t be inspected again for two years.
• We don’t need written protocols for training or a training program;  “see one, do one”  has always worked for us.
• If this lab error happens again, don’t tell me about it.
• Techs creating false medical records??- we call that a clerical error.

So, if I had super powers, I would give inspection agencies that inspect ART clinics real teeth to enforce standards. I would want physicians to develop and abide by professional standards and CLIA regulated standards in order to stay in business, not just for voluntary accreditation. I think licensing clinics would additionally protect patients and should be required. If infertility services were covered by insurance plans, this  layer of oversight would also reign in outlier practices. I would use tax-payer dollars to fund prospective research on ART outcomes. None of these initiatives would interfere with the good work done by good physicians because they are already doing the right things for the right reason, but it may reign in or eliminate the bad apples.  In short, I would stack the deck in the patient’s favor since if we can’t guarantee a “cure” for infertility, at least we should do no harm, right?

Today I had this  question from a patient,  “How much info should you expect to get in terms of follow-up from your RE and lab after a failed cycle?”  She was expressing her frustration that all the follow-up she had was that they would try ICSI next time because she had zero percent fertilization in her IVF cycle. She was extremely frustrated that her doctor gave her no possible explanation or suggestions as to why there was zero fertilization in this cycle. She had a history of 5 previous IVF cycles with fertilization.

Her question is more difficult than it might seem at first. Every case is different. Sometimes there is no obvious reason or next steps. In her case, part of the problem was indeed communication. Specifically, that after multiple failed IVFs with diminishing returns, her physicians at two different clinics  never discussed the most obvious reason for her failed cycles. She was over 40 years old.

Now, I obviously wasn’t in the room so maybe they tried to tell her and she wasn’t ready to hear it. That would be  perfectly common and understandable human response. We have all been there. But if they simply never brought it up, I think they should be ashamed of themselves. Yes, there is obviously great risk with full disclosure, even if it is done diplomatically. Telling a woman that her age may be her biggest obstacle in achieving pregnancy is a message no patient wants to hear and she may well leave and never return. Many years ago, a doctor once said to me regarding a similar situation with another patient, “Well, if I don’t do the cycle someone else will. She will go ahead and do it somewhere else. Why shouldn’t I do it?” Why indeed. For me, turning away a patient seems a more ethical option than providing a service with little hope of success. Or worse, not fully disclosing all possible risks , benefits and ALTERNATIVES. That’s that pesky informed consent thing you hear mentioned (I imagine)  in medical school.

The American Society for Reproductive Medicine actually published an ethics committee opinion piece called ” Fertility treatment when the diagnosis is very poor or futile” that you can download from here.  They define “futile”  as less than 1% probability of a live birth and poor prognosis as between 1- 5% chance of a live birth. At 44, your chance of a live birth is under 3% and finally meets the ASRM ethics committee criteria for poor prognosis! Really? I would argue that you still should tell a 40 year old that all things being equal, her chance of a live birth is less than 20%–and if not futile- certainly a poor prognosis. How many of us would happily spend $12-20,000 out-of-pocket for a treatment that has a one-in-five chance of working? I think I’d want to know about that up front.

Here, copied from the ethics statement are the main points (bolded emphasis is mine):
1. For the purposes of this statement, ‘‘futility’’ refers to treatment that has a less than 1% chance of achieving a live birth;‘‘very poor prognosis’’ refers to treatment for which the odds of achieving a live birth are very low but not nonexistent(>1% to <5% per cycle).
2. Clinicians may refuse to initiate a treatment option they regard as futile or having a very poor prognosis. Referral information should be offered, if appropriate.
3. Decisions about treating or refusing to treat couples and/or individuals always should be patient-centered. Protecting fertility center success rates is not an ethical basis for refusing to treat couples and/or individuals with futile or very poor prognoses. Conversely, care should not be  provided solely for the financial benefit of the provider or center.
4. Upon request, clinicians may treat couples and/or individuals in cases of futility or very poor prognosis provided the clinician has assessed the risks and benefits and fully informed the couples and/or individuals of the low chance of success.
5. Thorough discussions are advisable at the beginning of the patient-physician interaction when couples and/or individuals have indicators of futility or very poor prognosis.
6. Fertility centers should develop evidence-based policies to guide decisions about treating couples and/or individuals with futile or very poor prognoses. In such cases the couples and/or individuals should be fully informed and offered information about referrals, especially if other clinics have had greater success with similar medical indications.
7. Decisions to refuse to initiate or continue infertility treatment should be made in cooperation with couples and/or individuals. Toward this end, it is advisable for clinicians periodically to revisit the treatment plan with couples and/or individuals.

Fertility and Sterility Vol. 92, No. 4, October 2009 0015-0282/09/$36.00

Assuming that your doctor has fully discussed the anticipated risks, benefits, alternatives and probability of success with you and the cycle still fails, what are some of the questions you can ask?

If fertilization is poor…what factors may have contributed to the poor outcome? Some factors could include egg maturity (related to stimulation protocol- what might we try different with the stimulation next time?) , sperm quality or quantity (are there medications or other factors that can be adjusted that might improve poor sperm quality?), lab factors (what is the normal fertilization rate you expect with conventional IVF?, with ICSI?

If embryo progression is poor and few if any embryos made it to transfer day with the expected cell number and low fragmentation rate, some questions you might ask include: What is your experience with embryo progression to day 3? to day 5? for patients like me? Are most of your transfers at day 3 or day 5? If day 3 transfers are the predominate type, that may be because the lab has had poor success with extended culture.

Ideally, these are questions you want to discuss up front. Do you do ICSI? How much ICSI do you do?- on all your patients? or a subset of patients if they meet criteria? What criteria do you use to decide whether ICSI is appropriate?

Unfortunately, sometimes there is no clear answer. Your team is as perplexed by an IVF failure as you are. They may not have all the answers but they should recognize that your questions are legitimate and should answer them thoughtfully and patiently. if they can’t or won’t, you can always find a more patient-centered clinic.

According to the Bionews report Frozen embryo ‘adoption’ scheme to lose US government funding,   the Department of Health and Human Services (HHS) will not request funding  for continued support of the Embryo Adoption Awareness Campaign and the program will be discontinued in 2013.  This Campaign was created in 2007 by Nightlight Christian Adoptions, a Pro-life group. The purpose of the campaign was to ” increase awareness regarding embryo donation and adoption as a family building option”, according to the Embryo Adoption Awareness Center’s website.  Last year, the center received 1.9 million dollars and a total of 23 million dollars since the first year of funding. According to their website, there have been 270 children born from embryo “adoptions” facilitated by the center, or about $85,000 per birth.

If this was the only avenue for couples seeking pregnancy via embryo adoption, it might just be worth it. But it is not.  Almost every fertility center has a program in place for embryo adoption within its patient population. Why? Because  every center has some patients with extra embryos that they would prefer to donate to infertility patients  rather than discard and some patients who would like to have an embryo transfer with donated embryos to become pregnant. So it’s a nice tidy ecosystem of supply and demand, if you want to be utilitarian about it.

Even Barbara Collura, the executive director of Resolve: The National Infertility Association, is shedding no tears over the loss of this funding. According to the Bionews article,  she thinks the money Congress already has spent on embryo adoption awareness has ‘done the trick’ and believes that more funding is needed for general education about infertility.  I would agree. Any benefit from this funding has been had.

I have to admit that I was always more than a little skeptical of the value of this program because my personal interactions with Snowflake facilitators on the behalf of patients has never been encouraging and sometimes downright disturbing.  One case in particular stuck in my mind for two reasons. First, these embryos had been donated and re-donated at least 3 times, traveling from clinic to clinic, trying to find a “home” , perhaps explaining their poor quality at thaw. Secondly, in order to receive these Snowflakes embryos,  the recipient patient told us that the Snowflakes organization required her to promise that she would to transfer all the thawed embryos, regardless of quality. Typically, because we can’t predict which of the embryos, if any , will prove to be viable after thaw, more than 1-2 are thawed and the best growing (or sometimes only growing ) 1-2 are transferred. The patient was worried that if we thawed them only 1-2 at a time, she wouldn’t have any good quality embryos for transfer and if we thawed all of them, there were too many to safely transfer. I believe in the end the patient’s physician was able to convince her that her medical safety came first, any obligations to the Snowflakes organization came second.

This possible demise of this program which was initially funded under the conservative presidency of George W. Bush during the great stem cell debate, is being decried by the religious right as though its demise will actually have any effect on the continuation of embryo adoption in the US. The political activists who are shedding tears over this program are ignorant (or pretending to be) regarding what really happens in fertility centers all over this country. Embryo adoption was a viable option prior to this program, funding this program had minimal effect on the number of embryos donated, and loss of this funding will likewise make zero difference in the options patients have. Why? Because most fertility centers are working to help their patients get pregnant, regardless of the patients religious or political views. If anything, the fertility industry is often more market than mission, so you can be sure if there is a way to help two patients with a problem (one with excess embryos and one who wants an embryo transfer), this medical need will be met.

The creation of this awareness campaign was politically motivated and its demise is no loss to the infertility community.

What annoys me is that infertility is so often used as a political football by political groups to advance their political agenda and not because they care (even a little) about solving the problems of infertility patients.  The Pope thinks IVF is a sin and so embryo donation has deeply troubling moral implications and arguably may not be moral because IVF embryos were created by immoral means. The Christian Snowflakes group thinks that women are required to thaw every single embryo they receive, transfer it to their uterus (even against medical advice)  and hope for the best. The embryo “uber alles”. What about the patient?

The oft-reported statistic that 400,000 embryos reside in storage in US fertility clinics is also very misleading because it is always implied that but for embryo donation, these would all be discarded. In fact, Snowflakes says  “we are trying to provide a loving option to the families of the over 600,000 (estimated) embryos frozen in clinics throughout the United States. “  Wrong, Wrong. Wrong. In fact the vast majority of these stored embryos are not  available for donation and will be “used”  by the patients who created them to start or enlarge their own families. It is only when their own family building efforts are complete and they still have embryos in storage, that disposition of these embryos  become an issue for the patient.  This group of patients with excess embryos is a minority in the IVF patient population. In my experience, perhaps only half of the patients had excess embryos to freeze after a fresh cycle. For most patients, any excess embryos were used in the next cycle (if the fresh cycle failed) or in two years time when they wanted another child. Very few patients had left over embryos after two cycles.

In most programs, patients with excess embryos are offered all the options for disposition (embryo adoption, donation to stem cell research, donation to the clinics to keep technical skills sharp or discard). And guess what, the patients made that choice!  Not the government. Not the clinic. Not political interest groups. So leggo my “eggo”.

A better use for this funding would be education about the preventable causes of (some kinds of)  infertility and all the options for family building (not just IVF) when infertility becomes an issue.  When patients are informed about all their options, they can make the best choices for themselves and their families based on their own (varied) personal beliefs and ethics. That seems fair to me.

Sometimes wisdom can be found in the oddest places. I came across this quote from Winne the Pooh.

“Promise me you will always remember: You are stronger than you seem, braver than you feel, and smarter than you think,” — Christopher Robin to Pooh.

This is the message I hope to pass on to all of you struggling with infertility. Infertility can take control of your life, darkening your spirits and making you question your  entire life, your choices and decisions, past and future. It can make you question everything, even your place in the world. Don’t let it. You will get through this. The ending may not be written the way you expect but you will find an answer for yourself. You will do the best you can with what you have. You are stronger than you seem.

Don’t give up hope that a better day lies ahead. No one can promise you a biological child. Even the best science can’t guarantee that. But you will get through this. There is a morning after infertility where you either face the brand new challenges of parenthood (one way or another)  or find another path to nurture the future, your way. You are braver than you feel.

Don’t let someone else push you to do something that  you don’t understand or that troubles you for some reason. Ask questions until you feel confident about your choices and can make the best decision for yourself and your family. If your  doctor can’t or won’t explain something, find another who will.  If something sounds too good to be true, it probably is. You are smarter than you think.

Promise me you will always remember: You are stronger than you seem, braver than you feel, and smarter than you think.

If we put the progress in IVF methods that have occurred since Louise Brown’s birth in 1978 in a time capsule to be opened 100 years from now in 2112,  what are some of the milestones in it? What would people think of it when they found it?

First a preview of the pre-IVF time capsule. The the late thirties, an editorial published in the New England Journal Of Medicine  (NEJM 1937, 21 October) commented on the description of IVF described in Aldous Huxley’s 1932 science fiction novel “Brave New World. Unbeknownst to Huxley, scientists Pincus and Enzemann from Harvard were doing embryo implantation studies around that time which involved the transfer of embryos from one rabbit to another. These words from the 1937 editorial in NEJM describe the evolving science of IVF and speculate about the future, “Conception in a watch glass: The ‘Brave New World’ of Aldous Huxley may be nearer realization. Pincus and Enzmann have started one step earlier with the rabbit, isolating an ovum, fertilizing it in a watch glass and reimplanting it in a doe other than the one which furnished the oocyte and have thus successfully inaugurated pregnancy in the unmated animal. If such an accomplishment with rabbits were to be duplicated in the human being, we should in the words of ‘flaming youth’ be ‘going places.’”

Many of the early “methods” in IVF were far from ideal and speak more to the robustness of life to “find a way” even in circumstances that were far less from ideal.  These early successes were clearly NOT based on a deep understanding of the female reproductive cycle. The first IVF cycles were natural, not stimulated, so the ability to control follicle growth and final maturation through exogenous hormones that are the basis of modern IVF did not exist. Although there was early recognition that Clomid might be helpful , the deliberate use of gonadotropins was not introduced until 1981 (Introduction of Clomiphene Citrate and hMG in the IVF treatment protocol (Trounson AO, Leeton JF, Wood C, Webb J, Wood J. Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science 1981 8;212:681-2).

In the early days, physicians made their best guess on when the eggs might be mature, without the benefit of follicular ultrasound monitoring. That came later when methods for evaluation of follicle growth and size by  first abdominal ultrasound and then later by vaginal ultrasounds were developed. Today, superovulation medication is given and adjusted depending on feedback from routine “checks” of the induced cycle via ultrasound evaluation of follicular growth and blood work looking at hormone levels (primarily E2). Spontaneous LH surges to induce ovulation could easily wreck an IVF cycle in the early days. Now hCG is routinely given to stimulate the final maturation process in the eggs and also to give physicians a definite known end point when ovulation will occur so they can schedule the egg retrieval before ovulation occurs. In addition, medications can be given to prevent spontaneous premature LH surges.

In the early days, eggs were retrieved using laporascopic egg retrieval via an incision in the abdomen (major surgery) which is now replaced with  transvaginal oocyte retrieval (an outpatient procedure).  The original vaginal ultrasound with a sharp needle attached to puncture the follicles looked more like a medieval torture instrument than modern medical device.

Embryo transfer catheters also have evolved over time. The early stiff catheters used in veterinary practice were eventually replaced by flexible softer tipped catheters when it was understood that minimizing or eliminating trauma to the cells lining the uterus helped improve implantation rates.

ICSI or sperm injection was wildly innovative in 1993 but now many programs perform almost 100% sperm injection to increase the odds that fertilization will occur. ICSI was preceded by partial zona dissection (PZD) and subzonal insemination (SUZI),   which opened up the zona for the placement of sperm beneath the zona but neither technique ensured that the sperm was able to penetrate the actual plasma membrane. PZD and SUZI are ancient tales of lore to new embryologists if they know about them at all.  IMSI is the newest modification of ICSI which may replace standard ICSI.  IMSI is a modification of ICSI sperm selection in which individual sperm are evaluated under much higher power using a modified microscope so that the shape of the sperm nuclei can be evaluated. It is too early to say whether this technique will replace ICSI or is just a fad.

Early culture medium was in no sense customized to the needs of gametes and then embryos as they grew in culture after fertilization. In fact, in the early days, eggs were fertilized and thrown back into the fallopian tubes (a procedure called zygote intrafallopian tube transfer or ZIFT) the next day because culture systems were so inferior to nature. Gamete intrafallopian tube transfer (GIFT) took it one step further and bypassed the IVF laboratory entirely by first collecting eggs and sperm and then dumping eggs and sperm back into the tubes (usually separated by a air bubble) preventing accidental mixing until the gametes were both in the Fallopian tubes. GIFT is the only technique which the Catholic doctrine found tolerable because fertilization occurred in the body, not in a dish. Except for religious reasons, GIFT is infrequently (if ever) performed in most modern programs. IVF has many advantages to GIFT and ZIFT including the ability of selection via extended culture of the most robust embryos, and limiting the  number of viable embryos that are available for implantation, minimizing multiple gestation pregnancies with their poor outcomes.

In the early days, culture to day 3 was as far as embryo could go without dying in culture so transfers had to happen on day 3, if not earlier. One well known clinic, as far as I know,  still transfers embryos on day 2 of culture.  Today, most clinics are culturing embryos for 5-6 days post-fertilization which allows them to reach the blastocyst stage, the appropriate stage for introduction into the uterus which may assist implantation through a better synchrony between embryo and uterus.

Embryo freezing methods were originally adopted from embryo freezing methods in cattle. These slow freezing methods are largely being replaced by vitrification, a sort of flash freezing of embryos. Vitrification was also first used routinely to freeze the embryos of other species, then slowly adopted for use in clinical IVF.

Assisted hatching methods have also evolved over time.  The first method were entirely mechanical, using sharp needles to cut away a piece of the zona. This method was replaced by using a fine stream of an acid solution (Acid Tyrodes) to dissolve a hole in the zona. This method is currently being replaced by even safer and easier methods employing laser technology.

Third party donation using sperm, eggs and embryos from donors and the use of surrogates are routine today. The earliest IVF was conducted only with married couples.

Genetic testing of cells biopsied from embryos is rapidly becoming routine. While selection of gender and other traits may be ethically problematic, the technical aspects are becoming easier every year. Biopsy for embryos to detect genetic disease is routine in many clinics. Earlier methods like polar body biopsy and single cell biopsy are largely being displaced by trophectoderm biopsy which provides more cells for testing and is therefore more likely to deliver accurate test results.

Since this evolution in reproductive medicine and IVF procedures occurred over a mere 34 years,  I can’t even predict how infertility methods will evolve in the next 100 years and how patients might react about these “time capsule” methods 100 years from now. Will it be considered quaint? primitive? or too radical?

In the future, will we be able to identify patients (via. advanced diagnostic tests) who are most likely to benefit from IVF?, thus sparing those who won’t benefit from needless expense and riding the hope-disappointment roller coaster without reward?  Will pre-implantation genetic testing be routine ?- or banned? Will the female ovary still be the limiting factor or will ovarian stem cell rejuvenation  (or donor transplantation) be routine? Will we need embryologists or will the entire process be programmed and managed by sophisticated robot incubators?

References:

IVF Worlwide Unit Directory IVF Timeline

American Experience: Timeline : The History of IVF

Hi Victoria,

You asked me:  Do previously cryopreserved embryos develop similarly to fresh embryos so that, if one is attempting an e-SET, growing them out is one way to determine the ‘best’ one or are they somehow more fragile?

How well thawed embryos grow out depend on several factors:

• method of freezing and thawing (Vitrification has the potential to completely preserve the integrity of the cells meaning no cells die, if performed properly compared to slow freeze protocols in which some loss of cell viability is expected)
• How well method was performed (Even vitrification, if done poorly, can kill some or all of the cells)
• Both the freezing and the thawing (thawing is termed  “warming” for vit) must be done expertly. A botched freeze can’t be saved by a perfect thaw  and vice versa.
• The culture method employed by the clinic (can they routinely grow fresh embryos to blastocyst stage- or is this problematic for them?- do they mostly transfer on day 3?), If day 5 culture is one of their strengths, go with it.
• Intrinsic properties of the embryo (genetic or metabolic) which determine if it will continue or die

If all these factors are in your favor, it is perfectly reasonable to grow thawed embryos out in culture to see which ones can make it to blastocyst stage because these are most likely to implant. Frozen embryos shouldn’t really be more fragile once they have recovered from the freeze/thaw process. The only other alternative is to thaw one for eSET and hope for the best (that it will progress appropriately and be transferred) which is more risky than thawing several and growing them out to select for one “best”.  Good luck for a positive pregnancy!!

Related posts:

Embryo stages, progression and pregnancy outcomes

Day 3 vs. Day 5 culture

I have written before on the topic of medical tourism, the practice of seeking medical care oversees because it is less expensive or because you can only get the services you want overseas and not in your home country. I blogged about this in two previous posts , Affordable IVF and Global Outsourcing of IVF. Recently I came across a debate on-line about the ethics of gender selection of IVF embryos to select the gender of the child.  There are numerous on-line communities that are supportive of gender selection using IVF. I am happy to provide “ask the Embryologist ” service to one of them  (Gender Dreaming ) so I am familiar with the topic. The patients whom I encounter at this site are not rabid “design a baby fanatics” portrayed by the media. Generally speaking, they have a lot of one gender and want one of the other. About half of them want that next baby to be a girl and the other half a boy so overall, it evens out.

My philosophy is pretty utilitarian regarding reproductive issues in general and gender selection of embryos before transfer in particular, namely that every child should be wanted and welcomed by his or her family and if selection of gender helps ensure that welcoming attitude before the child arrives, that seems pretty innocuous to me. Also, I have noted no preference for either males or females in the patient population I have served. Basically, if they have all boys, they want a girl and vice versa. Overall, it probably averages out.  I realize that not everyone shares this philosophy, especially when embryos may be produced that are not transferred. The American Society for Reproductive Medicine has published an Ethics Committee report on Preconception Gender Selection for Non-Medical reasons which you can download from their site here. which discusses the ethical PRO and CON viewpoints. In the end, they conclude that :”

“The Committee believes that reasonable persons might legitimately disagree over which view of gender discrimination best agrees with values of equal respect and concern for both genders. Until a more clearly persuasive ethical argument emerges, or there is stronger empirical evidence that most choices to select the gender of offspring would be harmful, policies to prohibit or condemn as unethical all use of nonmedically indicated preconception gender selection are not justified. Nor would it be unethical for parents to use or for physicians to provide safe and effective means of preconception gender selection to have a child of the gender opposite to that of an existing child or children. Similarly, it would not be unethical for parents to prefer that their firstborn or only child be of a particular gender because of the different meaning and companionship experiences that they expect to have.”

What did surprise me  was that many countries actually make gender selection for family balancing illegal.  Some countries will make an exception and allow gender selection, but only if there is a medical indication, for example, a medical condition that will be passed only to male offspring so those male embryos are not transferred. Gender selection for social reasons, also called “family balancing” is prohibited in these countries. Some (perhaps) surprising countries in which gender selection for family balancing is illegal is Canada, the United Kingdom and Australia.

Completely illegal without exception: Austria, New Zealand, South Korea, Switzerland, Vietnam
Permitted only for Medical Indication, not Family Balancing :Australia , Belgium, Bosnia & Herzegovina ,Bulgaria, Canada,China Croatia, Cyprus , Czech Republic , Denmark, Estonia, Finland, France, Germany ,Greece, Hungary, Iceland, India ,Israel, Italy Latvia,  Lithuania ,Netherlands, Norway Portugal, Singapore, Spain, Turkey, United Kingdom   (Source: Countries with laws or policies on sex selection, Marcy Darnovsky, Center for Genetics and Society, April 2009)

No restrictions on use of IVF for gender selection: USA, Russia

The BBC published an online piece  called Parents queue to select baby gender. Apparently British couples are traveling to Russia or the US to have gender selection, precisely because they can not find these services at home. The piece also cautions patients about some unethical programs that claim to provide gender selection like this IVF program , the Jinemed Center in Istanbul, which promised these services even though they are illegal in Turkey. After that investigative piece was published, that clinic came under investigation by Turkey authorities. Medical tourism requires the same, if not higher, vetting process before choosing a clinic.

Medical tourism, while it has its advantages may have a serious downside for US citizens who seek ART services overseas. Current US law requires that if US citizens want their overseas born,  ART conceived children to be US citizens, they must be able to prove that the eggs and sperm originated with the US couple and no foreign gametes were used. The article US CItizenship denied to IVF babies born overseas  describes the experience of Ellie Lavi, a dual US and Israeli citizen who learned that in order for her twins conceived by ART and born in Israel to become US citizens, she would have to prove the eggs used were hers and not that of a donor. The State Department has issued a travel warning for US citizens who seek infertility services abroad which clearly lays out the requirement to prove  biological link to at least one of the US parents. Using a surrogate overseas has the same perils.

This law seems particularly archaic since US citizens who adopt unrelated children from abroad generally have little difficulty acquiring US citizenship for their child. Furthermore, being born on US soil instantly confers citizenship regardless of parentage. So why put a special burden on children born overseas through ART?  Actually, many babies of ex-pats may face the same difficulty even conceived naturally. Ex-patriots of any country living as residents elsewhere may face problems with their child “inheriting” their home citizenship as described in Ex-pat Baby Limbo. In some cases the children may be declared citizens of a country different from both their ex-pat parents. Obviously, the law has not kept pace with emerging technologies and greater global living.

IVF frequently upends old law that existed before IVF was created. Original laws regarding who is eligible for social security survivor benefits may be a case in point. The 1939 Social Security Act states that Social Security survivor’s benefits go to any child of a covered deceased individual. To further complicate things, social security looks to individual state law to determine inheritance laws and further define child eligibility for benefits.

Enter IVF and the possibility of  posthumous conception.  What is disputed now in at least 100 cases pending in courts is whether a biological child (conceived by IVF  after the death of the covered individual) has the same rights to survivor benefits as a child conceived while the covered individual was still alive.

National Public Radio (NPR) reported on one of these social security cases that was heard on Monday in front of the US Supreme Court.

The Social Security Administration denied benefits to Karen Capato’s twin children who were conceived using frozen sperm from her husband Robert after he died from esophageal cancer. The couple’s previous child who had been conceived before his death was granted survivor benefits by Social Security Administration.

Robert and Karen were wed in 2000 and had one child. Robert was diagnosed with cancer only a few months after they were married. Because he was concerned that chemotherapy treatment would make him sterile, Robert cryopreserved semen before his chemotherapy began. Robert and Karen agreed that they wanted a sibling for their existing child and so before Robert’s death made plans for Karen to use the sperm with IVF to conceive a sibling child. Robert died in early 2002. Karen applied for social security survivor benefits for her existing child who was deemed eligible and provided the benefit.  In 2003, Karen used Robert’s cryopreserved sperm with IVF and conceived twins. This time, when she applied for survivor’s benefits on her twins behalf, she was denied.

The government does not disagree that the twins are also Robert’s biological children, but dispute the claim in part based on state inheritance law in Florida. In Florida,  children conceived after the death of a parent cannot inherit property, unless specifically provided for in a will. Since he died before the twins existed, he could not specifically provide for the twins in a will and therefor, his twins were deemed not eligible for the survivor benefit.

Karen’s lawyer argues that the 1939 Social Security Act simply states that survivors’s benefits are due to any biological offspring of a married couple. Her attorney argues further that the inheritance statutes only become applicable when biological parentage is disputed which is clearly not the case here. Furthermore,  even when children are biologically unrelated to the survivor,  state laws usually do not disqualify them.  For instance, adopted children, stepchildren, grandchildren or even step-grandchildren all  receive survivor’s benefits, making this exclusion of IVF children curious.

The government attorneys argue that IVF children conceived posthumously are different from these other eligible non-biological children because “they were brought into being by a surviving parent with the knowledge that the deceased biological parent will not be able to contribute wages for their support.”

It will be interesting to see what the US Supreme Court decides. Which factor will be considered dominant in determining eligibility for survivor social security benefits: biological paternity, intent to parent, or time of conception?

When is surrogacy not really surrogacy? The recent legal case of attorney Theresa Erickson sheds considerable light on at least one way to manipulate and defraud both intended parents and gestational carriers and redefine surrogacy as baby-selling for personal gain.

Most IVF programs in the US will produce embryos for couples (usually using their own gametes) and will transfer these embryos to a gestational carrier. The reasons patients require a gestational carrier are almost always medical. The intended mother no longer has a uterus or has other medical conditions that would make pregnancy a high-risk proposition. Typically, the gestational carrier has no genetic connection to the embryo because the carrier’s eggs are not used. This lack of genetic connection tends to clarify the maternal claims of the intended parents to the baby.

Most IVF programs don’t get involved in the legal arrangements between the intended parents and the surrogate although they may ask to see proof that such a legal arrangement exists prior to performing the medical procedures to create and transfer the embryos. In the state of California, the law requires that such a legal arrangement be in place before the embryos are created and transferred. California is progressive in that it not only recognizes surrogacy as legal but allows that if such a pre-surrogacy agreement is in place, the intended parents can have their name placed on the baby’s birth certificate at the time of the birth without filing for adoption.  Most state law does not even attempt to deal with these issues to support surrogacy. Some states ban surrogacy outright. Other states ban profiting from surrogacy. Some states don’t recognize surrogacy contracts as legally valid, thus discouraging surrogacy.

Some people saw this California law as an opportunity for illegal and unethical profit. Theresa Erickson who until last year was a highly respected  reproductive attorney specializing in surrogacy arrangements admitted to fraudulently submitting legal paperwork to the courts which claimed that pre-surrogacy agreements were in place which actually did not exist. What she admitted to doing was creating an inventory of pregnant surrogates which were then shopped around to prospective intended parents after the first trimester and whose babies were in effect auctioned off to the highest bidders.

How did Erickson and her co-conspirators manage to mislead both the surrogates and the intended parents? Surrogates were told that intended parents were waiting to adopt the children although they never met the parents in advance. This is a red flag. Ethical (and legal) surrogacy requires that parents and surrogates meet in advance and work out their legal obligations to each other in advance of any medical procedures. This did not happen in these (at least 12 admitted) fraudulent cases. Intended parents were told that the original intended parents (who did not exist) had backed out of the surrogacy agreement and they could now assume the initial surrogacy agreement for $150,000. Ironically, this ‘deal” was more than what they told the intended parents the original surrogacy agreement cost ($100,000).  Surrogates were told they would receive between  $38,000 and $45,000 to be surrogates but at least some of the surrogates were never paid.

The surrogates were sent overseas to an IVF lab (or labs?)  in the Ukraine where embryos were created from donor eggs and donor sperm. The resulting embryos transferred to the surrogates overseas and then the surrogates came home to have the babies. (Surrogates were required to give birth in California, to take advantage of  the supportive surrogacy laws). These overseas labs did not require any evidence of a surrogacy agreement before performing the medical procedures. No medical history is available on these Ukraine donors which is a great loss to the children who were created and their intended parents who will be responsible  for their medical needs going forward.

How did this scheme (allegedly in place since 2006) unravel? One surrogate was suspicious about the requirement to go overseas for the IVF procedure but since Theresa Erickson was so very well respected in the field, she did not question it further. When she was in her second trimester and had been told twice that the intended parents had backed out, she became suspicious again and contacted another attorney who contacted the FBI. The FBI investigated. Theresa Erickson,  Hilary Neiman, another attorney who operated an adoption/surrogacy agency in Maryland and Carla Chambers of Nevada, who served as the “surrogacy facilitator” were all convicted and sentenced to time (less than a year) in jail and under house arrest (also less than one year).

What actual fraud laws were violated?

From the legal blog  Financial Fraud Law, “According to court records, Erickson admitted to lying to the California Superior Court by fraudulently representing in court documents that these post-pregnancy agreements between the GC and IPs were legitimate surrogacies, which allowed Erickson and her co-conspirators to make over $400,000 in profit from the sale of parental rights. Specifically, Erickson admitted that she prepared and filed with the Superior Court of California, County of San Diego, declarations and pleadings that falsely represented that the unborn babies were the products of legitimate surrogacy arrangements—that is, ones that involved agreements between the IPs and the GCs prior to embryonic transfer. With these fraudulently obtained pre-birth orders, the IPs’ names would be placed on the babies’ birth certificates through a surrogacy and the conspirators would be able to profit from their sale of parental rights.”

The attorneys were convicted of wire fraud (payments were wired) and  and Chambers was charged with “monetary transactions in property derived from illegal activity.” There is no actual law against the scheme they used to basically, create an inventory of babies to sell to the highest bidder.

There is so much to be upset about regarding this story, it’s hard to know where to start. The only good news is that babies placed with intended parents by Erickson will stay with them because the intended parents are not guilty of any crimes in this scheme so those placements will stand.

One other victim of this scheme was trust between patients and their health care team. Melissa Ford in her blog Stirrup Queens, describes her own visceral reaction and feelings of betrayal when news came out that Erickson was found guilty in her post Theresa Erickson Sentenced. She felt especially betrayed by Erickson because she was well-respected in the infertility community and reached out to infertility patients through her blogs on surrogacy law. The feelings of intimacy created by the free exchange of personal stories and information on the internet make patients even more vulnerable to those who would exploit this intimacy for personal gain.

How can patients protect themselves? Be informed. Your doctor or your attorney should not be the only source of information regarding your medical options. You should find out all you can about your medical providers and your medical options from second opinions, other patients, friends, family, (yes, even the internet), the library and professional societies. You should use old tools like the Better Business Bureau and new tools like Angie’s List to evaluate medical business entities you might use.  Each of these sources will likely have some bias that, by themselves, might make them an unreliable source. But if your information comes from a variety of sources, I think you’ll be more able to pick out the voices that don’t ring true. The overly slick advertising. The overly practiced patient spiel. The special deals. The special protocol that you can only get at one place. If you are discouraged from asking questions or seeking other sources of information from a provider, walk away. We’d like to believe that our doctor or our attorney has only our best interests in mind and that the bad apple in the barrel is out there, not working for us. Unfortunately, in every field, in every trade, there are two kinds of people: those who have strong personal ethics which can withstand greedy impulses and those whose ethics and understanding of right from wrong are rather more “flexible”. To imagine otherwise, is to be both delusional and vulnerable to people like Erickson who looked so good on the outside and were so very rotten on the inside.

I get a lot of questions from you (Q from U) about assisted hatching so here is more on that topic.

What is assisted hatching (AH) ? Assisted hatching is a technique used by embryologists to produce an opening in the outer shell of the egg called the zona pellucida.  We talk about hatching in two contexts. Normal embryos, left to their own devices will hatch on their own as shown in the picture below.  The embryo must escape or hatch from the zona or it can’t implant into the endometrial lining of the uterus. Receptors on the embryo and on the maternal cells must be free to interact with each other and cause implantation to occur. If the embryo is trapped in the zona after transfer, that can’t happen.

So if the embryo will normally hatch on it’s own, why does an embryologist ever open the zona artificially? The procedure of assisted hatching was developed by a Dutch embryologist ,Jacques Cohen, PhD in the early 1990′s. Dr. Cohen moved to the US in the early days of IVF here and is one of the most highly respected pioneers in micromanipulation techniques (ICSI and AH).  Dr. Cohen writes about his early successes and concerns regarding assisted hatching in this review and this paper. He developed the AH technique because he noticed that some embryos grown in vitro had zonas which remained thick, instead of thinning naturally as the embryo grew and expanded. This natural thinning of the zona at the same time as the swelling growth (expansion) of the blastocyst work together to breach the zona and release the blastocyst. If the zona stays thick, the embryo may be trapped inside and fail to implant.

What methods exist for assisted hatching? The original methods involved making a mechanical slit in the zona with microneedles (also called partial zona dissection) or alternatively, the use of a chemical solution (acid Tyrodes solution) to dissolve the zona. A stream of acid Tyrodes is released onto the surface of the zona and the zona dissolves until the technician stops the stream and retracts the hatching pipette containing the acid solution. Both of these methods required very high levels of technical skill to avoid damaging the embryo and have largely been replaced in most programs by almost idiot-proof laser hatching (point and shoot) technology.  You can see a video of a laser in action on the Hamilton-Thorne manufacturer website and also below. Lasers are relatively expensive which is the only drawback of this relatively safe technology compared to older methods of assisted hatching.

Why is assisted hatching ordered? The most common indications for AH are maternal age (over 37 years of age), elevated FSH levels which can negatively impact egg quality, thick zona pellucida (the original indication), slow embryo progression, lots of fragmentation (fragments can sometimes be removed during the hatching procedure) , previous failed IVF cycles and cryopreserved embryos which may have hardened zonas from the freezing solutions used and the freezing process itself.

Other reasons for ordering assisted hatching is patient preference (e.g. they were successful several years ago using AH and want to do everything the same) and (cynically) there is a procedure code for hatching so labs can charge separately for it.

Is it always needed? No. Hatching was a much more useful technique in the bad old days of cell culture when we could only grow embryos for three days in culture and the medias were not optimized for embryo growth. There is evidence to suggest that zona hardening and failure to thin may have been an unintended consequence of these early culture methods. These concerns and the observations of persistently thick zonas in culture is what prompted Dr. Cohen to want to breach the zona for the embryo since it might not bbe able to breach a hardened zona through simple expansion. There is no evidence that the newer culture systems that support embryo growth to the blastocyst stage result in thick zonas. We routinely see embryos growing to relatively huge sizes with zonas strained to almost invisible thinness just prior to spontaneous hatching in vitro. Frankly, a bigger problem today may be that embryos hatch before we get them into the catheter and back into Mom.

Assisted hatching of thawed cryopreserved embryos may still be beneficial for implantation according to some studies. Cryopreservation by some methods may cause zona hardening and assisted hatching could theoretically bypass hatching difficulties for these embryo. Most programs would rather hatch “just in case” rather than having to try to explain to the patient why her frozen embryo transfer didn’t work, but her friend who had AH, did get pregnant.

Does AH make everyone (patients and doctors) feel like they have done everything they can to ensure hatching (and hopefully pregnancy) will occur? Yes. Because we can’t be sure that it is unnecessary, it is often done “just in case”. What’s the downside? The technician may not be skilled enough and damage the embryo. Or the hatching will work “too well” and the zona will be lost prior to transfer, making the embryo more “sticky” and possibly harder to move around and pick up with handling pipettes. Zona-free embryos may be more likely to be retained in the catheter and may be less protected from shear forces in the catheter during pick up and transfer. Some studies have suggested that the risk of monozygotic twins is higher in assisted hatched embryos, possibly because the inner cell mass is torn into two, causing twins. Twin pregnancies, especially if the placental structures are shared among twins (monoamniotic, monchorionic twins), tend to have more obstetrical complications and poorer outcomes than singleton pregnancies.

The good news is that AH is much easier for the technician (and therefore safer for the embryo) with the advent of laser technology. AH is probably used more than absolutely required because the only obvious indications it will be helpful (a big fat zona) is rarely seen. AH is more often done for “just in case” reasons, or if you will, as insurance against “failure to hatch”.