Why didn’t I get pregnant with genetically normal embryos?

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As an infertility nurse practitioner, I am asked this question often and it’s a valid one.

First, I want to say that I am so sorry. I understand how devastating this news is. By explaining the potential reasons why this treatment cycle didn’t result in a pregnancy I don’t mean, in any way, to diminish the sadness and frustration that you might be having, only to give you information that, in my experience, many people desire in your situation.

Let’s discuss what preimplantation genetic testing (PGT) is and does. An embryologist gently removes a few cells from the early placental portion of a blastocyst (a day 5-6 embryo that has hundreds of cells at this point), extracts the DNA and sends them to a special lab to be analyzed for the number of chromosomes. Humans have 23 chromosomes but get a copy of each one from both parents. Normal embryos are called euploid and contain 46XX if female or 46XY if male. Abnormal embryos, called aneuploid, would not have this normal complement of chromosomes. Any of the 23 human chromosomes can be abnormal in different ways and have one too many (called a trisomy) or one too few (called a monosomy). Some chromosomes are more commonly abnormal than others, but they can all commonly and randomly be abnormal in embryos. Aneuploidy is the by far the most common reason for miscarriages in humans. PGT allows us to identify these aneuploid, or abnormal, embryos before any are transferred back into your uterus. Since the most common reason for recurrent implantation failure and miscarriage in women >38 y/o is aneuploidy, the ability to use PGS prior to embryo transfer has improved clinical pregnancy rates tremendously in this age group.

It is completely normal that a percentage of every women’s eggs, and therefore embryos, will have chromosomal abnormalities, but the proportion of normal embryos goes down with age, and that of abnormal embryos goes up with age. Women with diminished ovarian reserve/egg quality may have a higher percentage that are abnormal, compared to women with normal ovarian reserve of similar ages.

Let’s assume that out of all the blastocysts analyzed in your cycle, there are some that were euploid (or had the normal number of chromosomes). Your reproductive endocrinologist (RE) transferred one of these into your ‘optimally primed’ uterus, supported by ‘perfect’ hormone levels. You behaved yourself, rested for a bit after transfer, didn’t sneeze too hard, stopped going to spin classes and didn’t drink your evening glass of wine. Now, it’s just waiting for implantation to occur. Why wouldn’t a pregnancy test be positive in this scenario?

Because implantation is a relationship. Like any relationship, there is an attraction, an investigation period, then, if all is a go, lots of energy and effort is required for it to continue. So, we have an embryo that should work (a person that ‘seems’ normal/’looks good on paper’) and a lining that should be receptive (both are ‘ready’ for a relationship). But, like every relationship, even with two strong prerequisites, there may not be a lasting connection or the timing may be ‘off’.

Although our technology has improved greatly over the last 5-10 years, and our diagnostic testing continues to be refined, even with ‘normal’ results, we can’t predict that that person will have a clinical pregnancy. For example, a normal semen analysis result tells us that there is enough motile sperm to fertilize an egg, but the real test is if fertilization takes place. The saline sonogram or hysterosalpingogram tells us that the uterus ‘should’ be able to carry a pregnancy. PGT testing tells us that we have a normal embryo that ‘should’ create a baby. On paper, we have all the building blocks necessary for a successful pregnancy.

But people aren’t pieces of paper. We are infinitely more complex and nuanced. There are important dynamics necessary for implantation that we are just learning to identify and can’t treat (yet) if they are lacking or abnormal.

Implantation is just the first step in a cascade of interrelated events necessary for a clinical pregnancy to take place. Earlier, we discussed chromosomes and genes. Although important concepts, when discussing them, we are only describing what happens in the nucleus of the cell. The other part of the cell (the body of the cell, if the nucleus is the brain, per se) is called the cytoplasm, and it is also important for cell division and reproduction. In the cytoplasm are many organelles, structures important for the functioning of that cell. For example, the mitochondria are located here, and they are responsible for providing the energy necessary for all of the processes for that cell. When the cell ages, the cytoplasm and the mitochondria age too. So, even though an embryo is euploid, the mitochondria may be suboptimal and not produce enough energy to fuel blastocyst development and differentiation. Early embryo development and differentiation are hard work (actually some of the most energy-requiring processes in the entire body). When the energy-producer (mitochondria) can’t meet this need, these processes themselves can suffer, which can lead to early pregnancy loss or failure to implant and grow.

Although this article is mostly about the embryo component of implantation, as we are well-aware there is a uterine component too. How do we determine that a woman’s uterine lining is receptive? The testing that we used to use (such as an ultrasound or endometrial biopsy where the cells are reviewed microscopically by a pathologist) has been shown to have poor predictive value. There is emerging research, though, that utilizes DNA analysis to reveal patterns that were too subtle to see using previous technology. These investigators can, then, attempt to pinpoint that particular woman’s window of implantation (as opposed to assuming that every woman has the same window). This technology, and others like it, is promising, but we still have much work to do to discover and improve the propensity for the embryo to attach to the uterine lining, or to help the body find the right ‘fit’ between the best embryo and the ideal spot in the uterus in which it should implant.

Does this mean that since the first cycle didn’t result in a healthy pregnancy, that subsequent cycles won’t either? The short answer is no. In my experience, there are many who do not get pregnant on their first try with PGT but do get pregnant on future cycles with a different euploid blastocyst. So even though the building blocks of a healthy pregnancy were present for both cycles, we don’t have an answer for why only the second one worked. Yet.

For some, having the facts can help them accept the current situation and maybe lessen any guilt or other negative emotions generated as a result of an unsuccessful treatment cycle, however we realize that information doesn’t detract from the pain or lesson the emotional toll that a failed cycle can trigger. We encourage you to continue your journey as you see fit and want to acknowledge how brave and resilient you already have been and will continue to be. How do we know this? Because we, as nurses, are witness to your courage and tenacity every day; because you are reading this blog; because you are asking questions; because you are making informed, rational decisions about a situation that is anything but rational, at times.

Because you are not allowing yourself to be hobbled by a difficult journey.
That is true strength.

The fact that someone else loves you doesn’t rescue you from the project of loving yourself

Sahaj Kohli.

A final thought: please offer yourself all the compassion and tenderness that you can muster during this vulnerable time.

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