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In women under 35 four in ten embryos are expected to be genetically abnormal. After that age, gradually, more and more embryos are genetically abnormal reaching to nearly all at the age of 45

The most significant single major factor that substantially influences IVF success is maternal/oocyte age. This has been evident from long time ago, as natural pregnancy rates decline with increasing maternal age. In IVF, success rates also begin to decline after maternal age of 35 years. This is followed by a steep decline after its 40s and approaches to a low single digit around 45 years. Miscarriages also increase sharply after 40s. Emphatically, in egg donation the success rate is constantly high across maternal ages since the oocytes come from young, under 35 year old donors.

Such clear clinical evidence is supported by preimplantation genetic screening (PGS). The evolution of molecular techniques has made it feasible to determine embryo cell euploidy before embryo transfer. One or two cells (blastomers) are surgically removed from a day 3 embryo or a small number of cells of a day 5 embryo (blastocyst) and are sent for chromosomal copy number determination. Recent techniques can detect all 24 chromosomal copy numbers making genetic screening more accurate.

In 2016, Z.P .Demco, et al.  published an important scientific paper on PGS where they reported screening on 37711 embryos from different IVF centers. The mean percentage of embryos with normal chromosome numbers (euploid) was about 60 %, steady from 25 to 35 years of maternal age. But after 35 years there was a steep decline of the percentage of euploid embryos, reaching a small single digit number and frequently zero at the age of 45. These are very important numbers to remember when we run an IVF cycle. Objectively, the IVF success rate will inevitably be in proximity of these numbers for certain maternal/oocyte ages.

This is a so-called genetic bottleneck that restricts, by default, IVF results

We can otherwise say that in women under 35 four in ten embryos are expected to be genetically abnormal. After that age, gradually, more and more embryos are genetically abnormal reaching to nearly all at the age of 45. Normally even more, unknown numbers, embryos may have additional minor genetic problems. All these embryos cannot end up in live births. This is a so-called “genetic bottleneck” that restricts, by default, IVF results. This bottleneck is common and inevitable to all humans. We must take this into consideration when we explain IVF failures and discuss treatment expectations. Therefore the best approaches is to acknowledge and accept it and plan the whole infertility therapy and IVF process accordingly

From an evolutionary and theological point of view, humans cannot influence the rules of DNA rearrangement, which are random and chaotic

The pivotal event in either human natural conception or in IVF is the fusion of oocyte and sperm followed by mixing and rearrangements of maternal and paternal chromosomes. DNA rearrangement has no rules and is absolutely random and chaotic. Nature expects that the new cell will properly divide, implant into the endometrium/uterus and finally result in a live birth.

It can be said that the miracle of fertilization is a trial and failure procedure

From an evolutionary and theological point of view, humans cannot influence the rules of DNA rearrangement, which are random and chaotic and the final purpose of nature is to achieve offspring that will be better than their parents. However, this trial is frequently unsuccessful, which means that the new fertilized egg carries few or many genetic mistakes and mismatches that drive to a slow embryo growth, or inability to implant or even implant but with a final miscarriage. It can be said that the miracle of fertilization is a trial and failure procedure.

Therefore, fertilization is a genetic recombination that we cannot influence. We must just accept the outcome of randomness. In case of failure we must retry a new course of fertilization hoping that randomness and chaos eventually will reward us a new, genetically normal, human cell. We might have the feeling that there is a resemblance of shooting dice. To get sixes we must shoot the dice again and again. Then new issues that evolve: Is this well understood from people with infertility? How can we describe it to couples undergoing IVF? What is the implication in IVF planning and treatment? People tend to condemn those that handle their infertility problem and rarely like to acknowledge contribution of nature. Human beings get very stunned and feel insecure when facing the reality of randomness.

Human beings get very stunned and feel insecure when facing the reality of randomness

How should we describe this chaotic effect in fertilization? Our inability to provide a simple, earthy explanation after IVF failure makes people nervous, suspicious and finally vulnerable to any tangible cosmotheory, medical theory, mostly without any scientific evidence, but easy to vilify for the failure. I believe that this mental and sentimental background is why theories, such as immunological factors, thrombophilia and others are easily suggested as an explanation to IVF failure. Even if such theories are gradually rejected from evidence-based medical literature as irrelevant concerning IVF failure, patients and medical practitioners are still very reluctant to abandon them. It seems that the human brain is wired to easily accept a simple and measured cause and explanation for a failure against to nature randomness and chaos.

Couples must ask about numerators and denominators and certainly the maternal age when they evaluate programs and methods and prepare to manage their sentiments, plans and expectations.

Going through infertility and IVF literature we come across a lot of statistical data with attention to success rates. We must take into consideration that IVF, from initiation of ovarian stimulation to a live birth, is a series of steps that is either continued or stopped at some point. In addition, couples going through IVF have very different problems and causes of infertility at different ages. How can we find compass to navigate us through this ocean of parameters? These success rates are necessary to evaluate our work, compare methods and IVF clinics and offer some kind of prediction, so that couples can shape their expectation and planning.

Information is very helpful to offer clarification. Many descriptive studies and large IVF database results show that the causes of infertility are not major factors and may contribute little in success rates variations. Yet, the single major factor is maternal age. So the best way to report IVF rates is to group cases according to woman’s age. Any IVF events and rates must be referred for similar maternal age groups and disregard other details about underlying causes of infertility.

Other data commonly overlooked are statistical rates, which have a numerator (incidence of the event) and a denominator (the specific group that the numerator referred).  We must primarily pay detailed attention specifically to the denominator because it defines the value of the rates. Using steps in an IVF procedure I will attempt to show a paradigm of how easily a single number can misguide an IVF event.

Any IVF events and rates must be referred for similar maternal age groups

Lets start schematically with 100 couples, of a certain maternal age, that finally decide and start ovarian stimulation. Most, but not all of them, lets say 95, will reach the stage of egg retrieval. Lets assume that we get mature eggs from 92, and after the fertilization stage, 85 of them having divided embryos and finally undergo an embryo transfer. Later, 50 have positive and rising hCG serum levels, 45 have positive heart beats and in the end 35 couples return back home with a baby. The most frequent question asked among the community with infertility problems is; what is the pregnancy rate?

According to our example pregnancy rate can be any combination with numerator positive hCG or heart beats or live births and denominator number of women: initiated ovarian stimulation or successful egg retrieval or those that underwent embryo transfer. And the rates in our paradigm can span from 35% live births per women that initiated cycle to 59% positive hCG per embryo transfer. Remember, those numbers must be obligatory referred to a certain maternal age group. So numbers from 35 to 59 can describe the same event. All are legal, but give very different impressions and can easily misguide patients and drive to inaccurate decisions and expectations.

I hope that this paradigm will help couples ask about numerators an denominators and certainly the maternal age group when they evaluate programs and methods and prepare to manage their sentiments, plans and expectations.

Are we really offering our patients a significant, strong and positive intervention or are we just playing with biological randomness?

Clinical medicine is an array of decision-making. We can assume the approach is similar for IVF. In order to decide, a medical question must be precisely formulated. Then, in order to provide an answer we can either resort to personal and empirical information from observations that seem to have worked, the so-called “personal and empirical medicine”, or to data from the “evidence-based medicine”. The later, derivative of randomized controlled trials (CRTs), is the pure scientific approach.

What are those CRTs? Scientists/doctors select large numbers of patients with a certain medical question/problem.. To “tame” biological randomness they divide these patients randomly in 2 groups. In one group they blindly apply the technique or treatment in question, and in the other group they make no interventions. An independent researcher measures and edits the outcomes. In the end they report, whether the technique/treatment statistically significantly improved or compromised the measured outcome, or it made no difference at all. Statistical significance means that the outcome was truly affected by our intervention and was not a result of randomness. Our treatments really matter. CRT studies must be well designed and have the proper number of patients in each group to have the power to reveal a meaningful difference. A technique/treatment that has been verified by CRTs can therefore be utilized.  In other words, are we really offering our patients a significant, strong and positive intervention or are we just playing with biological randomness?

Interventions that are not evidence-based effective ultimately do not change the outcome

If we cannot beat randomness, it is much better not to do anything, but to explain to our patients all aspects, saving them time, money, treatment side effects, expectations and negative emotions. Interventions that are not evidence-based effective ultimately do not change the outcome. Whatever changes are observed are a random effect.

An ethical or even legal question might be raised. Is it ethical or legal for the patient to pay for a non-evidenced-based technique/treatment? Is it better to educate our patients, properly explaining that we have no truly effective interventions and in turn either not do anything or consent to a personal and empirical approach?
To discuss an example; Aiming for higher success rates in IVF, an endometrial injury or “scratch” has been proposed. Many studies and metanalyses of poor and moderate quality showed conflicting results. However, a lot of fertility clinicians perform endometrial “scratches” which is a relatively invasive procedure and charge for it. In January 2019, S Lensen et al., in the New England Journal of Medicine, published a CRT of endometrial scratching performed before IVF. They showed that endometrial scratching did not result in a higher rate of live birth even in cases of repeated IVF failures. It was a large, well-designed study that had the power to detect differences as of 7%. Having such data it is very difficult to justify this intervention before IVF even for those with repeated failure in implantation.

Is it ethical or legal for
the patient to pay for a
non-evidenced-based
treatment?

Unfortunately, we not always have proper CRTs to support clinical decisions. In such cases, we may resort to empirical medicine techniques/treatments, but we must be very cautious about possible side effects and expectations, and we must inform patients in detail and ask for their understanding and consent.

People undergoing IVF are very vulnerable. They should not be exploited. When we have the privilege and opportunity to apply evidence-based medicine, we must apply it.