Course BASIC_Graduate level learning material about the challenges of human reproductive medicine in a changing Europe

SYLLABUS

7. Regulations of ART across Europe and their effect

(Basic level)

IVF began more than 40 years ago, and since that time it is estimated that more than 8 million people have been born from pairs who needed ART techniques to conceive. Originally ART was used as a therapeutic treatment for infertile couples with irreversible tubal factor infertility, but gradually it has been extended to other situations of infertility caused by  factors such as male factor, endometriosis, PCOS; or other types of unexplained infertility.
Moreover, impaired reproductive capacity of a people, such as single women, same-sex couples has been also addressed from ART.
Because of the many political, social, and sensitive ethical issues surrounding ART practice, it is not unexpected that different regulations exist in different countries. To date there are no consensus based regulatory measures in Europe. Regulations differ from country to country thus the availability of ART for individuals, the available methods, costs, possibility of preimplantation diagnostic, availability of counseling vary.
Many factors have been examined and recognized as contributing to these very important differences between countries. Some relate to financial issues such as affordability, cost of treatment, and user co-payments. Others relate to cultural and belief dimensions (religious patterns of the community or level of acceptance by society, the intention of the policy makers). Some differences root from long existing political traditions, which deeply influence policy making.

Slides 2-5
First let`s look into shortly the different methods of ART.

Assisted reproductive technologies (ART), by the American Center for Disease Control (CDC) definition, are any fertility-related treatments in which eggs or embryos are manipulated. Procedures where only sperm are manipulated, such as intrauterine inseminations, are not considered under this definition. Additionally, procedures in which ovarian stimulation is performed without a plan for egg retrieval are also excluded from the definition. Assisted reproductive technologies are most frequently performed secondary to infertility. In patients with tubal factor infertility, IVF directly bypasses the fallopian tubes. Other infertility etiologies in which IVF is employed include male factor infertility, diminished ovarian reserve, ovarian failure (with donor eggs), ovulatory dysfunction, and unexplained infertility. Preparation for ART procedures largely involves the evaluation and workup for etiologies of infertility. Infertility is defined as failure to achieve pregnancy after at least one year of unprotected intercourse. Infertility evaluation can also be initiated at six months of failure to achieve pregnancy in women over 35 or in cases where there are known possible barriers, such as known uterine or tubal disease or male infertility.[8] Initial comprehensive history taking includes menstrual history, pregnancy history, infertility duration, prior infertility treatments, past medical and surgical history, family history, and social and environmental exposures/habits. The physical exam includes evaluating

In vitro fertilization is the most commonly utilized assisted reproductive technology. It involves the collection of oocytes from the ovary, followed by fertilization in vitro, and is completed with transferring the resulting embryo into a uterus. It involves various steps outlined below, including controlled ovarian stimulation, oocyte retrieval, fertilization, embryo culture, and embryo transfer. Additionally, preimplantation genetic testing and intracytoplasmic sperm injection may also be included in the process. Cryopreservation with vitrification is then used to freeze excess embryos or for fertility preservation of eggs or embryos.   
 
Controlled Ovarian Hyperstimulation:
Injection of exogenous gonadotropins, like follicle-stimulating hormone (FSH) and luteinizing hormone (LH), is frequently used for controlled stimulation.

Gonadotropin-releasing hormone (GnRH) Antagonist cycles-
 Mixed gonadotropin medications are used through two types of injection, one with FSH activity (Recombinant FSH) and one which has both FSH and LH activity. The premature LH surge is protected from occurring by a GnRH antagonist. These cycles can be started with menses after normal baseline parameters are confirmed with ultrasound and normal hormonal levels of FSH and estradiol levels. On many occasions, the cycle starts after pretreatment with oral contraceptives for 2-4 weeks.  

GnRH Agonist cycles
- Mixed gonadotropins are also used through two types of injection, one with FSH activity (Recombinant FSH) and one with both FSH and LH activity. The premature LH surge is protected from occurring by a GnRH agonist. The GnRH agonist is started in the luteal phase of the cycle before the gonadotropins are started. When the gonadotropins are started, the dose of the GnRH agonist is customarily halved until a trigger is given for final maturation before egg retrieval. Pretreatment with oral contraceptives can also be used in these cycles.

Oocyte retrieval:  Trans- vaginal punction of each follicle and aspiration of the follicular fluid, which contains the oocyte using ultrasound guidance under general anesthesia or conscious sedation.

Fertilization:  1)IVF occurs in vitro by mixing oocytes obtained from retrieval with spermatozoa in a culture medium.  2)ICSI uses a single sperm that is injected directly into the cytoplasm of the oocyte based on morphologic parameters of the sperm .

Embryo culture and transfer: Embryos are incubated for either a day 3 (cleavage stage) or day 5 (blastocyst stage) transfer. Day 5 transfers are more common and have a higher chance of success.

 Preimplantation genetic testing (PGT) for aneuploidy (PGT-A) screens for whole chromosome abnormalities, whereas preimplantation genetic testing for monogenic disorders (PGT-M) screens for single-gene disorders in high-risk patients.

While PGT is classically used for selection against aneuploidies and genetic disorders, it can be used in more ethically controversial avenues such as in sex selection. Additionally, individuals in specific communities, such as the dwarf and deaf community, have been reported to request selection for dwarfism or genetic deafness. A shared decision-making model is recommended in such circumstances.

In vitro maturation (IVM) immature follicles are collected with minimized to no exposure to hormonal stimulation during the germinal vesicle to metaphase II stage. Typically, a short course of FSH administration is performed, with or without hCG administration for follicular priming.  Retrieval and culture is modified to mature the immature oocytes before fertilization.

For patients with uterine anomalies or difficult trans-cervical access, intrafallopian transfer via gamete intrafallopian transfer (GIFT) or zygote intrafallopian transfer (ZIFT) is a possible alternative laparoscopic transfer technique.

Following the embryo transfer, the luteal phase is typically supported with progesterone supplementation to promote implantation and pregnancy continuation.

Cryopreservation von embryos or oocytes through vitrification, a rapid freezing process possible.

Slide 6

A number of questions arise as a result of the aspects mentioned.

• Should there be a common policy in the EU for the use of ART?
• What forms of ART should be allowed?
• Who should get access to these technologies?
• Should  preimplantational genetic diagnostic (PGD) be unlimitedly allowed?
• What kind of information should be given to doctors, patients and allied professionals?
• What kind of psychological preparation is needed for people undergoing ART?

Slide 7

Legal framework
This section was written in 2023, and might be subject to rapid change.

Most countries reported having specific ART laws, in which various ART techniques are precisely regulated, but these laws differ from country to country.  ART methods include intrauterine insemination (IUI), in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS) as well as egg donation, sperm donation, embryo donation, surrogacy.
No regulating law exists in Albania, Bosnia and Herzegovina (Federation), Ireland, Romania and Ukraine.

But these laws also make a strict distinction as to who has access to these ART techniques.

Slide 7.-11

Access is restricted by law to heterosexual couples in 11 countries – Albania, Bosnia and Herzegovina, Czech Republic, France, Italy. Lithuania, Poland, Slovakia, Slovenia, Switzerland and Turkey. In five from this eleven countries, ART and IUI techniques are also allowed for single women and same-sex couples. Most countries fall somewhere between these two extremes, with a total of 30 where treatments are available for single women and 18 countries where treatments are also available for female couples.

IUI counts as an ART technique under the national laws of 35 countries.
The use of donated sperm in ART and IUI is legal in most countries except Bosnia and Herzegovina and Turkey. However, Croatia and Montenegro indicated that domestic donors are not available in their countries, which is why sperm can only be imported to Croatia from abroad.
Egg donation is not allowed in Bosnia and Herzegovina, Germany, Norway, Switzerland and Turkey. Although accepted in Croatia, Ireland, Italy and Montenegro, no local donations are made.
Simultaneous sperm and egg donation is not allowed in countries where egg donation is banned, such as Armenia, Croatia, France, Montenegro, Slovenia and Sweden.  14 countries do not allow embryo donation, including Austria, Armenia, Belarus, Bosnia and Herzegovina, Bulgaria, Denmark, Iceland, Italy, Kazakhstan, Norway, Slovenia, Sweden, Switzerland and Turkey.

Slide 12

In order to manage the growing data and information collected on ART, there is a need for a registry system that can provide accurate statistics about activities and outcomes and ensure quality control. ART aggregated data generated by national registries, clinics or professional societies have been gathered and analysed by the European IVF-monitoring Consortium (EIM) since 1997.
A good example for quality control is the data collected about multiple embryo transfers and the number of multiple pregnancies, which are iatrogen high risk pregnancies. Based on registry data most European countries and societies regulated the number of embryos to transfer thus the number of multiple pregnancies generated by ART also decreased.

 
 Long-term medical and psychological health of egg donors and children born from donated oocytes or sperm is still an urgent need to see the long-term consequences of these procedures.

Slide 13

Slide 14
In some countries there is also a difference in relation to certain techniques. This is the case for preimplantation genetic testing (PGT) for monogenic diseases/chromosomal structural changes (PGT-M/SR; formerly PGD), which is allowed in all countries except Bosnia and Herzegovina and Malta.
PGT for aneuploidy (PGT-A; formerly Preimplantation Genetic Screening) is not allowed in Bosnia and Herzegovina and Malta, as well as in Denmark, France, Germany, Hungary, Lithuania, Norway, Slovenia, Sweden and the Netherlands.
Surrogacy is legal in Albania, Armenia, Belarus, Belgium, Cyprus, Czech Republic, Georgia, Greece, Kazakhstan, Macedonia, Romania, Russia, Netherlands, United Kingdom and Ukraine.

Embryo sex selection (with the exception of PGT-M for sex-linked diseases) is not allowed in any of the 43 countries.

Legal limits for ART access

As previously mentioned, marital status and sexual orientation are often considered limitations on ART. However, 34 of the 43 countries also have legal age limits for candidates for ART. In 21 countries, men and women must be over 18 years of age. Belgium, Kazakhstan and Malta define a minimum age for women but have no such restriction for men. The maximum female age is also a legal limit in 18 countries, ranging from 45 years in Denmark and Belgium (in the latter this limit applies to egg retrieval, while embryo replacement and insemination are allowed up to 47 years) to 51 in Bulgaria. In Austria, "natural cycle available" is an undefined criterion for a maximum age until women reach menopause. The maximum age for men is 60 years in Portugal, while in Finland 60 years and in Sweden 56 years are recommended age limits for men. According to Swiss regulations, "the potential father should be able to live until the child is 18 years old". A particular case is France, where there is no definition of numerical age limits and it is the responsibility of the centers to define the legal notion of “normal reproductive age” in practice.
It is also interesting to mention that in Lithuania, for example, ART is not allowed if patients have medical contraindications listed in the specific ART law. According to the regulations in Germany, ART is not reimbursed after sterilizations such as vasectomy and tubal ligation.

Slide 13 Legal limits in third-party donations

Sperm donation is restricted to men over the age of 18 in 16 of the 41 countries where donation is legal. In other countries where the procedure is allowed, no minimum age is defined. 21 countries have maximum male ages for donors, ranging from 35 in Hungary, Kazakhstan, Russia and Slovakia to 55 in Slovenia. The most common maximum age is 40 years. In 30 countries there are some restrictions on the number of infants from the same donor, although in five countries this restriction is only a recommendation and not a legal obligation. This number ranges from 1 Cyprus to 25 in the Netherlands. In 7 of the 30 countries (Belgium, Denmark, Finland, Portugal, Slovenia, Sweden and United Kingdom) there is a maximum number of families/women who can have children from the same donor (from two for Slovenia to 12 for Denmark).

Egg donors must be over 18 in 15 of the 36 countries where donation takes place. 25 countries set a maximum age for donors, ranging from 34 in Serbia to 38 in France, with the vast majority of countries setting the limit at 35. Bulgaria and Denmark have less restrictions on the maximum age of the donor if the donors/relatives are known to each other. In Belarus, Bulgaria, Hungary and Ukraine, egg donors must have at least one child. This condition is considered desirable but not mandatory when selecting egg donors in Romania and Sweden. The maximum number of donations is set in 10 countries - from one (two in rare exceptions) in Slovenia to 20 in Belarus. The most common numbers are between 4 and 6. 25 countries have defined a maximum number of infants from the same donor, although in 3 of them it is only a recommendation and not a legal requirement. This value ranges from 2 in Montenegro to 10 in France, Greece, Kazakhstan and Italy. In 6 of the 25 countries (Belgium, Finland, Serbia, Slovenia, Sweden and the UK) there is a maximum number of families/women that can have children from the same egg donation (from 1 for Serbia to 10 for the UK). Which countries don’t have age limits

Embryo donations,

The anonymity issue
There are different approaches to anonymity of the donors across Europe.
Regarding gamete donation, four different scenarios were identified. Strict anonymity is the rule in 18 countries, although 5 of these countries allow disclosure of the donor's identity in the event of serious health problems of the child. A special situation is Lithuania, where the identity of a donor may be known after a court decision for other (unspecified) important reasons. In some countries (Estonia, Poland and Russia) general information about the donors (nationality, age, weight, height, education) is available for recipients and children. In a second group of countries, the recipients are anonymous, but the children born can have access to the donor's identity if they are over a certain age (Austria, Croatia, Finland, Malta, Portugal, United Kingdom). Which countries with non-a donations? A third scenario is gamete donation in a mixed system (anonymous and non-anonymous) as described in 13 countries. In Bulgaria, non-anonymity is an exception and affects donors who are relatives, while recipients in Germany and Switzerland can bring their own donor who will only donate to that couple. In Belgium, non-anonymous donation is only allowed if there is a formal agreement between the donor and the recipient. In Hungary, egg donors must be a relative of the recipient, but a sperm donor must be anonymous. In Romania, local donations do not have to be anonymous, but imported gametes can come from anonymous donors. Finally, non-anonymity is stated as the rule for gamete donations in Georgia and the Netherlands.

Embryo donation is allowed in 29 countries under one of three perspectives: strict anonymity, anonymity except for born children, and non-anonymity. No country has a mixed system of embryo donation. Five of the 13 countries with a mixed situation for gamete donation allow embryo donation under strict anonymity (Belgium, Germany, Hungary, Ireland and Ukraine). In Romania, embryo donation is only possible with non-anonymous donors. In the seven remaining countries, no embryo donation is carried out.

Preservation of fertility potential

Fertility protection, gamete cryopreservation for fertility-limiting diseases is allowed in all countries, although 17 of them have no specific legislation. The same applies to the cryopreservation of gonad tissue (with the exception of Bosnia and Herzegovina, where the technique is not performed). The cryopreservation of embryos for medical reasons is not permitted in Italy and Portugal, but is only possible in Germany in the two-nuclear stage and is carried out in all other countries. Non-medical egg freezing is not allowed in Austria, France, Hungary, Lithuania, Malta, Norway, Serbia and Slovenia, nor is it performed in Bosnia and Herzegovina and Moldova, although there are no laws prohibiting this technique. Non-medical egg freezing /social freezing (which countries allowed?)

Public Funding

The importance of public and private ART centers varies greatly from country to country.
In 29 of the 39 countries with public financial support for ART, access to public funding is subject to some limiting criteria, such as the age of the woman or man, the indication, the number of previous attempts, or the presence of previous children.
In order to contract with the public support system, centers in Austria, Bulgaria, Finland, Romania and the United Kingdom must have a minimum success rate. A special case is Hungary, where no minimum success rate is required, but public centers receive a special amount of money for each live birth resulting from ART.

The total number of cycles reimbursed also varies by country, with information on some countries requiring additional detail. In Austria, for example, the funded number of cycles per clinical pregnancy applies without a defined limit on the number of pregnancies.

In 19 countries, not all ART performed are eligible for public financial support. PGT is not promoted in Bulgaria, Greece and Italy. Russia and Spain (Spain is not supported only for repeated implantation failures). Expenditure related to donor cycles is not financially supported in Estonia, Montenegro and Russia. Cryopreservation of gametes and embryos is not publicly funded in the Czech Republic, Lithuania, Montenegro and Russia. In the case of premature ovarian failure, egg donation is not publicly supported in Spain for women over 36 years of age. Iceland and Ukraine indicated that only standard IVF/ICSI receive public funding, and the Czech Republic and Slovakia that ICSI does not receive public financial support. In Austria, Latvia and Turkey, "add-on" techniques are not included in the public funding. The Federation of Bosnia and Herzegovina, Macedonia and the United Kingdom indicated that not all techniques will be funded, but no details were given.

In Belarus, the Federation of Bosnia and Herzegovina, Estonia, Denmark, Germany, Italy, Kazakhstan, Norway, Russia, Spain and the UK, ART was considered to be unequally publicly funded across the country.

So there are lots of points to be debated

• should there be a homogeneous law in Europe?
• who are the decision makers? political, religious and specialists point of views, lack of a social consensus or compromise
• psychological aspects: effect on the couple, effect on the child born after autologous ART and donations.
• ethical arguments: autonomy of the infertile couple, bene and non maleficience, motivation of the donations, exploitation of donor/ surrogate, 

-> Difference in regulations lead to „Fertility Tourism“

Fertility Tourism
Over 97% of infertile couples are actively considering the concept of a fertility journey.
Cost does not appear to be the primary reason for all travelers, with the possible exception of younger patients who do not have comparable access to financial resources as their older counterparts.
Surprisingly, providing anonymous donors isn't the main determinant of the fertility traveler either — although it is important for some. It is much more the possibility of different treatments and feedback from patients who have returned from treatment.
Recently, more fertility clinics have opened in different places and the fertility tourists are overloaded with the number of choices. Countries that have traditionally done well in treating international patients continue to do so - Spain, Greece and Cyprus remain popular, but new markets such as the Czech Republic and Ukraine are becoming increasingly popular. At the moment the war in Ukraine forced fertility centers to reduce or stop their current activites.  
Efficient and reliable regulatory frameworks are also important drivers for patients and this is a reason for patients to seek treatment in countries like the United States and the United Kingdom. Visitors to treatment providers in these countries are not necessarily driven by price but by the reassurance and perception that they are receiving quality, regulated treatment that is performed professionally.

Yet there is no such thing as a general fertility tourist. Everyone has a different portfolio of needs, demands, expectations, doubts and fears and must be treated as an individual.
Nevertheless, the worries that torment patient couples,- be it the language barrier, travel arrangements or the legal framework- should not be ignored.

Europe moves towards complete statutory regulation of assisted reproduction. But large variations still exist in how the legislation is applied. So what are the real questions behind the legal regulation and practice of assisted reproductive technology?

• Issues of moral politics which are socially highly controversial
•  Discussion is about value conflicts,
• New and traditional family forms
• Forms of sexuality
• The status of the embryo
• The attitude towards disability
• Negative and positive eugenics
• New forms of exploitation of females
• Growing global inequality because of the costs of assisted reproductive technology.

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Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2020 Mar;113(3):533-535. https://www.ncbi.nlm.nih.gov/books/NBK576409/#article-136062.r8

https://ivf-worldwide.com/education/introduction/ivf-regulation-around-the-world/ivf-sex-selection.html

Zahmatkeshan M, Naghdi M, Farjam M, Mokhtaran M, Yazdani A, Mahmoudvand Z, Safdari R. ART Registries-Characteristics and experiences: A comparative study. J Family Med Prim Care. 2019 Feb;8(2):449-454. doi: 10.4103/jfmpc.jfmpc_453_18. PMID: 30984653; PMCID: PMC6436318.

European IVF Monitoring Consortium (EIM), for the European Society of Human Reproduction and Embryology (ESHRE); Wyns C, De Geyter C, Calhaz-Jorge C, Kupka MS, Motrenko T, Smeenk J, Bergh C, Tandler-Schneider A, Rugescu IA, Goossens V. ART in Europe, 2018: results generated from European registries by ESHRE. Hum Reprod Open. 2022 Jul 5;2022(3):hoac022. doi: 10.1093/hropen/hoac022. PMID: 35795850; PMCID: PMC9252765.