Implantation and Early Development - study group statement
Consensus views arising from the 48th Study Group: Implantation and Early Development
- The process of embryonic implantation is still something of a black box. A molecular definition of endometrial receptivity is needed. This would not only allow researchers to focus on a well-defined process but might also lead to the development of new therapeutic targets and diagnostic tools, and to the use of a multidisciplinary systems biology approach (involving clinicians, scientists and other stakeholders) to achieve a better understanding of implantation, placentation and early development. Understanding of this process should improve the treatment of disorders such as pre-eclampsia, miscarriage and infertility.
- Given the constraints on investigating early human pregnancy, there is a need to continue to take an enlightened approach to embryo research and the use of animal models for functional studies (within an appropriate ethical and legal framework and whilst pursuing a policy of reduction, refinement and replacement).
- Further basic studies should address the complexity of the endometrialva sculature, including the key ‘what, where and when’questions relating to factors that affect endothelial cells (including assessment of regional differences in vascular function within the uterus, and extension of the observations into early pregnancy using appropriate models).
- The multidisciplinary systems biology approach that is needed to assess endometrial receptivity should also be used to understand the reciprocal dialogue between the embryo and the decidualised endometrium. This will include a continued focus on human embryo research and the development of appropriate functional models of implantation that will allow the investigation of molecules mediating blastocyst–endometrial/decidual interaction. Ulti-mately, this should lead to novel targeted therapies to treat implantation defects
- Extrauterine (ectopic) pregnancy is a life-threatening event and is not uncommon in humans. The precise reason why implantation occurs in a site distant to the uterus is still unknown. Ectopic pregnancy could be considered as a model to study the failure or the absence of mechanisms that limit implantation. A molecular understanding of the aetiology of ectopic pregnancy could advance our knowledge of how implantation is regulated in normal pregnancy.
Gamete and embryo biology
- Further work is required to determine the link between oocyte quality and embryo development. Pivotal to this will be an understanding of the role of epi-genetic modification during the later phases of oocyte maturation. Experience with cell nuclear replacement has identified the key role of cytoplasmic and nuclear factors for normal embryonic development. A cautious approach should be adopted in relation to the clinical application of oocyte in vitromaturation(IVM) until the mechanisms governing epigenetic modification have been more clearly determined.
- More sophisticated tests are required to assess the contribution of the malegamete to fertility and embryo development. The conventional measurements of sperm concentration, motility and morphology only act as surrogate markers of fertility. These surrogate markers should be assessed in relation to more definitive outcomes, including population live birth data.
- The role of epigenetic modification in early embryo development needs to bemore clearly defined, again by the application of a multidisciplinary systems biology approach. We still need to understand what makes an ‘implantation-competent blastocyst’that will give rise to a normal baby. Furthermore, large-scale follow-up studies will be required to determine the impact of such epigenetic modification on long-term health and disease.
Early pregnancy failure
- There is a need for a national framework responsible for coordinating clinical trials assessing the efficacy of pharmacological interventions in patients with recurrent pregnancy failure.
- Women miscarrying one normal pregnancy should ideally be investigated for maternal causes for their loss. However, there is a need for a comprehensive economic and cost evaluation assessment to see whether such an approach would be feasible in practice.
- Further research is needed to establish the contribution that inherited thrombotic disorders make to reproductive failure.
- The number and activity of natural killer (NK) cells in peripheral blood show no correlation with reproductive success. There are no controlled data to support the current use of these tests in clinical practice.
- There is no scientific rationale for offering women with infertility or recurrent pregnancy loss treatment with steroids, white cell infusions or intravenous immunoglobulin. The use of these interventions cannot be recommended in normal healthy women because of the incidence of well-recognised and potentially severe adverse effects.
Translation into clinical practice
- More data from randomised trials are needed to demonstrate whether a single-embryo transfer policy would be effective, acceptable and financially viable in the UK.
- Parents of children born following embryo biopsy should be encouraged to take part in follow-up studies of the health and development of their children(including into adult life).
- Further work is needed to identify appropriate criteria for recommending pre-implantation genetic screening (PGS) and, through appropriately structured research, an assessment should be made of its efficacy per treatment cycle.
- New treatments should not be introduced into clinical practice until they have undergone rigorous evaluation and have been shown to be effective by adequately designed clinical trials.
Management of early pregnancy loss
- Antiphospholipid syndrome is an established cause of fetal loss. Treatment with aspirin and heparin during pregnancy significantly improves the live birth rate.
- There is no evidence to support the notion that couples should wait three months before trying to conceive again following early pregnancy loss.
- Pre-implantation genetic diagnosis (PGD) should be carried out by specialist centres that have a multidisciplinary genetic support infrastructure including genetic counselling, and CPA (Clinical Pathology Accreditation) qualified cyto-genetics and molecular genetics laboratories.
- Elective single-embryo transfer substantially reduces the risk of twins following in vitro fertilisation.
- There are no data to support the practice of endometrial biopsy as part of the pretreatment assessment for assisted conception.
- One to two per cent of children born in developed societies are now the result of assisted conception-related technologies. There is an urgent need to coordinate large-scale (national) follow-up studies of mothers and their children to audit the safety and long-term outcomes of these treatments.
- As outlined in the clinical practice section above, new treatments should only be introduced when they have undergone rigorous evaluation and have been shown to be effective by adequately designed clinical trials. For example, the possible risks of oocyte in vitromaturation (IVM) need to be further evaluated. Similarly, studies are required to assess the potential teratogenic effects of the high concentrations of cytotoxic chemicals employed during the process of vitrification.
- Funding of PGD should be considered outside the remit of normal infertility purchasing as the procedure is not aimed specifically at alleviating infertility but at preventing genetic disease. On the other hand (if appropriate), PGS might be considered as part of infertility service provision.
- Despite certain methodological limitations, epidemiological studies are useful for determining both genetic and environmental risk factors for reproductive health. There is a strong public heath argument for being able to link national databases (such as those held by the National Cancer Registry and the Human Fertilisation and Embryology Authority).
- Children born after assisted reproduction are usually healthy. However, multiple pregnancy is the single biggest cause of perinatal morbidity and mortality in pregnancies conceived following assisted conception treatments.
- Our understanding of developmental biology continues to proceed at a rapid rate. Regulators and policy-makers should therefore scan the horizon to be aware of possible future developments in assisted conception (such as in vitromaturation of gametes, germinal vesicle transfer or the creation of artificial gametes).