Embryo selection and preimplantation diagnostics of embryos are now permitted by law in Switzerland. At the same time, there is a “back-to-nature” trend toward natural cycle IVF – an effective, often inexpensive and less stressful alternative to traditional in vitro fertilization.
Swiss reproductive medicine is currently undergoing a transformation. In September 2017, the new Reproductive Medicine Act came into force in Switzerland, allowing embryonic diagnosis of genetic diseases in addition to the possibility of embryo selection to reduce the risk of twins. In addition to the associated increasing mechanization of Swiss in vitro fertilization, however, there is also a trend towards “slimming down” reproductive medicine and largely dispensing with hormone stimulation (IVF in the natural cycle).
Embryo selection
The new law on reproductive medicine now makes it possible to keep embryos in culture for five days and then select those embryos for transfer (embryo selection) that have the best developmental potential. Since 50% of embryos naturally die from successful fertilization to the fifth day of culture, the surviving embryos have, on average, twice the developmental potential of the average embryos on the first day of culture. This makes it possible to transfer only one embryo per embryo transfer instead of two embryos, as was previously customary, with the same chance of pregnancy. This will significantly reduce the risk of twin births, which has been around 20% per IVF treatment in Switzerland.
In other European countries, this has led to a significant reduction in the twin rate. However, in other countries there is the possibility to link the reimbursement of IVF therapy to the condition that only one embryo is transferred. Since in Switzerland IVF is a purely self-paying service and many couples prefer to increase their chance of success rather than reduce their risk of twins, the next few years will show to what extent the rate of twins can also be reduced in Switzerland by embryo selection and the transfer of only one embryo.
Preimplantation Genetic Diagnosis
The new law on reproductive medicine now allows genetic diagnostics of embryos. Previously, only the diagnosis of oocytes was allowed. PGD refers to all procedures of genetic testing of oocytes or embryos before implantation, i.e. before implantation of the embryo into the endometrium (preimplantation genetic diagnosis, PGD). PGD is the generic term for any genetic analytical procedure performed on gametes and embryos prior to implantation. These include:
PGD, Preimplantation Genetic Diagnosis: PGD in the narrower sense refers to targeted genetic testing for a specific hereditary disease. Either the oocytes are analyzed by polar body diagnostics (PKD) or the embryos are analyzed by trophectoderm biopsy (TE) (Fig. 1). PGD allows reliable identification of the oocytes or embryos that do not have the genetic alteration sought and are therefore suitable for further use.
PIS, Preimplantation Screening: PIS is an untargeted genetic examination (screening) of oocytes or embryos and is primarily used to identify and exclude (aneuploidy screening) embryos with chromosomal abnormalities (aberrations) that have a limited developmental potential during IVF therapy. By excluding these aneuploid embryos, whose number increases significantly with the age of the woman (Fig. 2), the chance of pregnancy per transfer, but not per oocyte retrieval, can be increased.
In whom are PGD and PIS indicated and feasible?
PGD by embryo biopsy is allowed if the disease would probably develop before the age of 50 and if there is no appropriate therapy elsewhere. These criteria do not exist for the examination of oocytes, so that it is possible to examine oocytes for all hereditary diseases for which a mutation is known to be the cause.
PGD is usually only feasible in cases of familial chromosomal aberrations and especially in monogenic diseases. The most common disorders diagnosed by PGD include X-linked disorders such as fragile X syndrome, muscular dystrophy (Becker and Duchenne types) and hemophilia, autosomal dominant disorders such as Huntington’s disease, myotonic dystrophy type I and neurofibromatosis, as well as autosomal recessive disorders such as spinal muscular atrophy, cystic fibrosis, beta-thalassemia, and sickle cell syndrome.
In women with at least three consecutive idiopathic habitual abortions, PIS may be considered because the use of euploid embryos decreases the abortion rate. However, expensive and stressful IVF therapy is always required. Thus, this procedure is indicated only in the case of an exceptionally heavy burden of a large number of abortions.
PGD and PIS can only be performed effectively if the chance of success for IVF therapy is basically high. Accordingly, the woman should not be significantly older than 35 years and still have a good ovarian reserve of at least 1 ng/ml (7.14 pmol/ml), better 2 ng AMH i.S..
What is the cost of treatment?
A classic IVF costs at least about CHF 7000. The egg and embryo biopsy and genetic diagnostics cost an additional several thousand francs. If it is a rare mutation, all genetic diagnostics must be established individually before IVF, which means additional work. Thus, the total cost for a complete treatment cycle is likely to be over CHF 10,000 for accurate billing. So far, the costs are not covered by health insurance.
Where is PGD performed?
In principle, any fertility center may perform PGD and PIS. The diagnosis of genetic diseases requires a high degree of consultation and interdisciplinary cooperation with human genetic centers, so that PGD is more predestined for university centers. To ensure a high quality of treatment, the Swiss network of university centers (pid-schweiz.ch) was founded.
“Social freezing”
For some years now, the topic of “social freezing in women” has repeatedly dominated the media and is predominantly associated with the incompatibility of career and family. However, studies [1] now show that it is rather the lack of a partner that is the basis for the desire to preserve oocytes. The storage of oocytes is limited to ten years in Switzerland.
The success rate depends in particular on the individual number of oocytes to be harvested and the age of the woman. Although the question of expected success can be addressed with calculation models, the individual success rate is nevertheless difficult to calculate.
In Table 1, using IVF registry data and based on the study results of the research group led by Cobo et al. [2] calculated the success rate for two age groups. Accordingly, the probability of birth in women under 35 years of age – with an age-appropriate ovarian reserve – is approximately 50% per stimulation cycle (using all embryos to be transferred). For a woman aged 36-40, this is only about 20%.
In this context, the monetary aspect should not be disregarded, which does not allow all women to carry out “social freezing”. Thus, approximately CHF 5000 is incurred per stimulation attempt and follicle puncture. Cryopreservation of oocytes, including an annual storage fee, is additionally billed at approximately CHF 300-400.
The high costs and limited chances of success should be considered during counseling, as well as the obstetric risks and social aspects of late pregnancy and motherhood. However, despite all the controversial discussions, the possibility of “social freezing” reflects one aspect of the social change in the way we deal with reproduction and family planning. Although the cost-benefit ratio of “social freezing” and its usefulness can be questioned, it is a new technique that has become an accepted supplement to family planning in some strata of society and is also accepted by Swiss ethicists. It is therefore no longer appropriate to portray the desire for “social freezing” as a selfish course of action on the part of women who are concerned about reconciling work and motherhood with the right partner at the right time.
IVF in natural cycle
The first successful IVF pregnancy in the world was achieved after natural cycle IVF (NC-IVF), i.e. IVF without any hormones and with natural folliculogenesis. Shortly thereafter, gonadotropins were used to enable an increase in the pregnancy rate through polyfollicular stimulation and the associated transfer of multiple embryos (classical IVF).
The desire of many women to take as few hormones as possible, advances in the delivery of NC-IVF, and new evidence regarding the benefits of this treatment are leading to increasing interest among couples and increasing use of this therapy in designated centers.
Effectiveness of IVF in the natural cycle
What is meant by “effectiveness”? The pregnancy rate or birth rate per transfer, per month, per franc, per patient time, per stress unit? Reproductive physicians and couples often have different views on this. Thus, for some couples, the length of therapy plays a less important role, but avoiding hormone stimulation, avoiding egg and embryo selection by the laboratory, and avoiding cryopreservation and storage of surplus embryos do. These points show that “effectiveness” is more than just the birth rate per initiated IVF cycle. However, since these points are difficult to summarize, the success rate per IVF therapy will be discussed below.
Calculating the success rate per transfer, the most significant factor for the success of NC-IVF therapy is the age of the woman (Fig. 3). It holds true:
- The younger the woman, the higher the chance of success (Fig. 3)
- NC-IVF therapies are psychologically less stressful than classical IVF treatments [3].
- The time to generate a pregnancy is 30% longer with NC-IVF, but the cost per pregnancy achieved is 30% lower [4]
- The effort in terms of number of consultations is the same for three NC-IVF cycles as for classical IVF [4].
It should be noted that NC-IVF therapy is not suitable for every couple (overview 1) . Due to these characteristics, NC-IVF is preferred by many women. Since approximately one third to one half of all couples are well suited for this technique and many women prefer this treatment, NC-IVF is also increasingly performed in Switzerland. However, it requires special expertise and specialization, which only a few centers in Switzerland have so far. Some of these centers have joined the “IVF-Naturelle” competence network organized by the Fertility Center in Bern (ivf-naturelle.ch).
Take-Home Messages
- The new reproductive medicine law allows embryo selection to be performed, which can reduce the risk of twin pregnancies. It also allows preimplantation genetic diagnosis (PGD) of embryos to be performed. Thus, in the case of known severe genetic diseases, the occurrence of a pregnancy with a genetic defect can be avoided. PGD is a self-pay service and is mainly performed by university IVF centers (pid-schweiz.ch).
- The motivation for “social freezing” is usually a lack of a partner or the concern that one will not be found in time.
- IVF in the natural cycle, i.e. without gonadotropin stimulation, has become an effective, often inexpensive and less stressful alternative to classical IVF. It is further developed in Switzerland by the Fertility Center of the University Women’s Hospital in Bern and carried out at designated centers (ivf-naturelle.ch).
Literature:
- Woodtli N, et al: Attitude towards ovarian tissue and oocyte cryopreservation for non-medical reasons – a cross sectional study. Arch Gynecol Obstet [in press].
- Cobo A, et al: Oocyte vitrification as an efficient option for elective fertility preservation. Fertil Steril 2016; 105: 755-764.
- Haemmerli Keller K, et al: Treatment-related psychological stress in different IVF therapies with and without gonadotropin stimulation. Acta Obstet Gynecol Scand 2018; 97: 269-276.
- von Wolff M, et al: Modified natural cycle in vitro fertilization – an alternative IVF treatment with lower costs per achieved pregnancy but longer treatment time. J Reprod Med 2014; 59: 553-559.
- Franasiak JM, et al: The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril 2014; 101: 656-663.
- von Wolff M, et al: Only women’s age and the duration of infertility are prognostic factors for the success rate of Natural Cycle IVF. Front Endrinol [in press].
- Singer N, von Wolff M: Career or children? Guess what? Role of Social Freezing. Gynecologic Endocrinology [in press].
HAUSARZT PRAXIS 2018; 13(7): 16-19
