JBRA Assist. Reprod. 2011;15(1):31-32
ARTIGO DE OPINIÃO
doi: 10.5935/1518-0557.2011.15.1.06
Stockholm, Sweden
ABSTRACT
It has recently been clearly demonstrated that some (but not all) of previously documented, additive risks for children born after IVF treatments can actually be avoided, just by changing clinical IVF policies. Using SET as the norm will significantly reduce multiple births, which in turn reduces prematurity, which leads to reductions of specific medical problems like pre-clampsia, perinatal death and cerebral palsy. National IVF outcome data has been a powerful instrument, in some countries, to achieve this clinical transition of policies, directly protecting IVF safety.However, further steps must now be taken to reduce other additive risks with IVF (not affected by multiple pregnancies). Causative factors behind birth defects and imprinting disorders and, eventually even more significant, intrauterine growth disturbances and thereby birth weight disturbances with possible consequences for health later in life, are now being discussed. Epi-genetic mechanisms are involved. A closer scientific look are now being taken at the IVF method(s) per se. Strong versus milder ovarian stimulation as well as laboratory factors like the composition of culture media and culture time are in focus.IVF is not totally safe, but currently safe enough to continue to be used, provided monitoring of safety and research on possible risk factors will continue. Strategies for further risk reductions should be explored and research in this direction is already under way.
Key words: IVF, safety.
RESUMO
Recentemente, foi demonstrado claramente que alguns (mas não todos) dos riscos adicionais documentados anteriormente para as crianças nascidas após tratamentos de fertilização in vitro podem realmente ser evitados, apenas mudando as políticas clínicas de fertilização in vitro. Utilizando-se SET (single embryo transfer) como norma resultará na redução significativa de nascimentos múltiplos, que por sua vez reduz a prematuridade, o que leva a uma redução de problemas médicos específicos, como pré-eclampsia, mortalidade perinatal e paralisia cerebral. Dados dos resultados nacionais de FIV tem sido um instrumento poderoso, em alguns países, para alcançar essa transição clínica de políticas, diretamente protegendo a segurança de FIV. No entanto, outras medidas devem agora ser tomadas para reduzir outros riscos adicionais à fertilização in vitro (não afetado pela gravidez múltipla). Assim, agora estão sendo discutidos fatores causais de doenças que estão por trás de defeitos congênitos ou problemas de imprinting e, eventualmente, ainda mais significativos, distúrbios do crescimento intra-uterin e distúrbios do peso ao nascimento, com possíveis conseqüências para a saúde. Mecanismos de Epigenéticos estão envolvidos. Um olhar científico mais atento está voltado para o método das FIVs per se. Estímulos oavrianos mais intensos versus suaves, bem como fatores laboratoriais, como a composição de meios de cultura e tempo de cultura estão em foco. A FIV não é totalmente segura, mas atualmente é suficientemente segura para continuar a ser utilizada, desde que a monitorização da segurança e da investigação sobre possíveis fatores de risco vá continuar. Estratégias para redução do risco ainda deve ser exploradas e pesquisas nesse sentido já estão em andamento.
Palavras-chave: FIV, segurança
The safety of IVF has always been an issue, even before it was introduced clinically. Preclinical research grants to Roberts Edwards and Patrick Steptoe, the IVF pioneers, were withheld in the U.K. for the (then only theoretical) fear of severe and non-acceptable safety risks. But focus has shifted over time. When the first IVF babies turned out to be quite healthy the worries subsided. Later, when Paul Lancaster in Australia 1987 first reported on an actually increased (additive) risk for birth defects (Lancaster), concerns were again voiced but the level of risk increase was judged to be not too alarming. Importantly, the IVF technique itself was not blamed.
Effectiveness was not very impressive at first. It was soon discovered, however, that it could be much improved by transferring several embryos at each procedure. The resulting sharp increase of multiple births was then not necessarily regarded as a drawback, rather even as a blessing. After a number of years data had accumulated (Bergh et al,1999), at least in some countries, to show that there was indeed a price to pay for the improvements in effectiveness. The balance between effectiveness and safety was show to be heavily affected. (It turned out, however, that in most settings stakeholders were willing to pay that price). The future children were not asked, of course, as they were not yet in utero and not even born at the time of the decision.
However, in the “trade-off” between effectiveness and safety, some settings/countries reacted to the “de-railed” balance and decided to try and protect safety by reducing the multiples. These countries are usually characterized by effective and valid monitoring systems for national data on safety and by generous reimbursement systems. “SET (single embryo transfer) as the norm” was introduced, and it turned out that effectiveness actually did not suffer much (Karlström & Bergh,2007).
It has recently been clearly demonstrated, from Sweden on a national basis (Källén et al,2010), that SET policies since 6 years back now have resulted not only in a reduction of multiples from 35% down to now only 5% duplex (no triplets), but consequently also to a reduction of prematurity from 40% to under 10%, leading to extra risks vanishing, e.g. for pre-eclampsia, perinatal deaths and cerebral palsy, CP.
Interpreting data on safety in a specific setting and deciding on treatment strategies is indeed complicated and difficult. Many factors are important and may be quite country specific: Safety levels: There is, of course, a basic level of risk for any pregnancy - with a very wide range between countries, much dependant of the level of maternal health care. For IVF patients, there are additive risks from their the sub-fertility, from the method per se, and for the way the techniques are used clinically. Safety data characteristics: Data come from relatively small investigations at the level of clinics or from much larger national data bases (Nygren et al, 2007). Ideally they come from your own country/setting but sometimes the only available data comes from elsewhere/other countries. Then the question to what extent foreign data are applicable comes to the surface. Risk validity: Risk estimates often progress from first being merely theoretical risks, (not yet investigated but potentially vey important), to risks under preliminary evaluation and further on to more validated risks estimates on established procedures, again country specific. Patient mix: Age, life style factors, infertility diagnosis etc. all differs over time and place. Technical developments and diversity: IVF is inclusive of a number of different technologies and they develop over time. Stakeholder´s interpretations: Not surprisingly, patients, doctors, industry, governments, the public at large may interpret data differently. Patient autonomy: In some countries patient autonomy is dominating in regulations and in practice. In other countries it is less so. Society: Law and regulations may be more or less permissive. Reimbursement policies may be more or less generous. Culture and religion are very important factors with a sometimes dramatically different impact in different countries.
Thus, no wonder that different settings may come to different conclusions. However, most countries seem to join in the transition to less embryos -being transferred, albeit on a different pace (Nygren, 2010, Nyboe et al, 2009).
Now that the safety problems with multiple pregnancies after IVF is well described and well documented most stakeholders seem to have come to the conclusion that SET as the norm may be the future of IVF transfer policies, especially now as benefits of such policies have been clearly demonstrated also for the final endpoint, specific health improvements for IVF children and their mothers. Therefore, and for the future, focus on IVF safety has now be directed towards, (as yet merely theoretical) risk factors with the IVF methodologies per se. Research is already now looking at the possible benefit for safety for mother and child and the clinical feasibility of milder forms of ovarian stimulation in conjunctions with IVF. For the risk of OHSS such an approach would obviously be very positive, but also for the children, through improved egg quality, improvements might be possible. Further, early investigations suggest that culture media composition may influence methylation patterns in epigenetic regulation (Dumoulin et al, 2010) and that culture timing may, possibly, influence embryo development. Different freezing techniques also have a significant impact on fetal growth. In conclusion, the safety of IVF is today estimated to be good enough to allow further utilisation. Some 4.5 million IVF children have been born so far and access to this treatment is increasing. Some of the risks with IVF have been clearly identified and can actually be prevented, as recently demonstrated, while other indentified (as for birth defects) or investigational (as for embryonic growth disturbances) risks need to be further investigated. IVF safety needs to be monitored and protected. Confidence in IVF needs to be maintained.
References
Bergh T, Ericson A, Hillensjö T, Nygren KG, Wennerholm UB. Lancet 1999, 6; 359 (9160), 1579-85.