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ICSI – Is It Really Safe?

A study that appeared in the May 2012 New England Journal of Medicine explored the risk of birth defects when using reproductive technology. That story had the media and infertility circles buzzing, and lots of my clients asking questions.  Is IVF safe? Is ICSI safe?  Since ICSI is used as a standard by many clinics for all IVF treatments unless a patient requests otherwise, I decided to do a bit more research and ask an expert for her opinion.

Although the media focused on the higher rates of birth defects with ICSI, the study itself indicated (in my own words here) that there was no clear correlation between the ICSI procedure and birth defects vs. the possibility that increased birth defects were the result of the underlying issues that necessitated IVF and ICSI.  I have read other experts who have suggested that perhaps because the study was over such a long period of time, that the techniques have also improved in that time.  Thus, ICSI has become commonplace in IVF and is used by many clinics in all IVF cycles.  Often, it is used almost as insurance for good fertilization – the technqiue is employed even when there is no clear evidence of sperm issues that would necessitate its use.

So, I went to Mgr. Hana Krásna, one of the embryologists at the IVF clinic ReproGenesis in the Czech Republic and was fortunate that she was willing to take the time to provide her thoughts and analysis.  I asked for her to address the study and article as well as the overall safety and effectiveness of ICSI. The text that follows are her comments (reprinted with her permission):

The conclusion of the article was the following: A significantly higher probability of birth defects occurrence was found in patients who underwent ICSI treatment.

This assertion can be on the either logically explained based on real causes which influence the final percentage of birth defects, or it is possible to question the assessment of the results which is challenging the assisted reproduction per se.

Male factor in the thesis:

The article pays only marginal attention to the age of the male patients; the age was evaluated as statistically unimportant based on previous research. This assertion is based on the fact that men produce significantly more reproductive cells than women, and furthermore, they do so naturally without the need of hormonal intervention. Sperm cells (that numerically average 100 – 1,000 cells per fertilization dish) can be more effectively selected according to their morphology and motility directly while performing assisted reproduction, i.e. ICSI or PICSI. On the contrary, the number of oocytes harvested during oocyte retrieval is on average 10 and their selection is much more complicated. The truth is that sperm quality definitely declines with age, even though this fact is unimportant from the point of view of statistics.

Notwithstanding the fact that the statistics solely focuses on numbers, which does allow us to view a problem objectively; however, at the same time this view provides often only average values. The statistical adjustment automatically removes extreme values on both ends; therefore an individual case does not necessarily have to be in compliance with the statistics.

Another important fact which was not mentioned in the article at all is the patient’s diagnosis. ICSI and PICSI are methods of reproductive medicine used when trying to help couples who have demonstrable difficulties conceiving in a natural way. One of the most important reasons for choosing this method is a situation when the sperm analysis results (spermiogram) are below normal values. The reproductive system (and consequently the sperm analysis values) is the most sensitive part of a human body. It reacts to unfavorable conditions and situations defensively, demonstrating that something is wrong. Often this defense is only aimed against the person’s life style, the outside environment or against permanent stress. It is quite certain that these factors will be of importance for the evaluation of the physiological and genetic potential for future generations. The body can detect such problems, and it naturally initiates its defense in order to prevent the spreading of this “defect” into next generations. Although serious defects are only a fraction among all other causes of infertility and sterility, they can be the source of the difference in the number of birth defects from spontaneous pregnancies versus when using the methods of assisted reproduction.

Female factor in the thesis:

From the point of view of the female patient, it is important to consider the initial diagnosis of the patient before her infertility treatment. These patients are coming to a center of assisted reproduction for treatment. Already this fact makes them a higher risk group when considering the possibility of carrying a healthy fetus to term, compared
to patients with no physiological problems which would be in a way of spontaneous conception. As opposed to the male patient, the body of the female patient is exposed to a direct hormonal intervention and hormonal changes in order to induce superovulation. Consequently, the female patient has to go through another stressful situation, the egg retrieval, which is related to additional risks. Let me quote a sentence from the article which addresses the possible impact of the stress factors described above: “The risks of birth defects associated with other forms of minimal treatment (e.g., timed intercourse, semen tests, or low- dose hormonal stimulation) were not significantly different from the risk with spontaneous conception.”(p.1810). This assertion sees the problem of a higher number of birth defects as a problem related to the stimulation. This can also be proven by statistical analysis of children born from FET treatment, where no significant difference in the number of birth defects was found when compared to spontaneously conceived children. Could the statistical difference be caused by a disruption of the physiological balance of the female patient, or does a coaction of multiple factors during the treatment, such as stress and other factors, play a role? We do not know the answer.

To conclude, I see the article as a statistical analysis of two different groups of population; i.e. a group which has undergone ICSI treatment and a group which has not. The statistical result is negative for the former group. In no way does the article state or lead to a conclusion that there would be a direct connection between a higher number of birth defects and the ICSI method.

The methods of processing of the collected data

The article assesses several aspects independently as part of the thesis analysis, however, it does not separate the female patients into groups based on the fact whether they underwent their own stimulation, or whether they were recipients of oocytes and thus were not hormonally stimulated to achieve hyperovulation. I assume from the above stated, that the latter group was not included in the research since this information is missing in the text. Therefore we are missing an important piece to the puzzle which could have supported or disproved the assertion related to a non-existing difference between FET cycles and spontaneous conception.

It is stated in the method description that the period of data collection was 1986-2002. This time period casts shadows over the research and brings about some doubts, for two reasons: During the 16 years of data collection, major progress has been achieved in the methods of assisted reproduction, be it regarding directly the medication and stimulation, or the laboratory work related to assisted reproduction.  The second reason is a question about the relevance of this research: why are the results of this analysis published 10 years after the last data collection, when assisted reproduction has made
another step ahead in that time?

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