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Clinical guidelines for IVF with PGD for HLA matching
ARTICLE IN PRESS Reproductive BioMedicine Online (2014) ■■, ■■–■■
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COMMENTARY
Clinical guidelines for IVF with PGD for HLA matching Ilan Tur-Kaspa a,b,*, Roohi Jeelani a,c a
Institute for Human Reproduction (IHR), 409 West Huron Street, Suite 500, Chicago, IL, United States; b Department of Obstetrics and Gynecology, The University of Chicago, 5841 S. Maryland Ave-MC2050, Chicago, IL, United States; c Department of Obstetrics and Gynecology, Wayne State University/DMC, 3980 John St, Detroit, MI, United States * Corresponding author.
E-mail address: [email protected] (I Tur-Kaspa).
Preimplantation genetic diagnosis (PGD) for human leukocyte antigen (HLA) typing is an established procedure for conceiving a child who may donate cord blood or haematopoietic stem cells for transplantation to save an ill sibling. Haematopoietic stem cell transplantation (HSCT) from related matched donors improves overall survival compared with unrelated or non-matched donors. Since HSCT from related matched-donors is unavailable for 70% of patients, IVF for PGD-HLA is a relevant clinical option. Recent success of HSCT after PGD–HLA, and excellent health and family support of the children born, suggests that debate over this kind of ‘designer baby’ and ‘gift of life’ should subside. Discussions about IVF for PGD–HLA should be held with families when a related matched-donor is unavailable, when HSCT can wait at least 9–12 months, within weeks of diagnosis irrespective of prognosis, and when the mother is of reproductive age. Related half-matched egg donors may also be considered. National and international collaborations should be established, and couples choosing this modality should be referred to experienced IVF and PGD centres. Clinical guidelines will improve physician and patient awareness of IVF for PGD-HLA and its role in advancing the clinical care of children in need of HSCT. Abstract
© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: bone marrow transplant, cord blood, hematopoietic stem cell transplantation, human leukocyte antigen matching, inherited and acquired hematological disorders, PGD
The gift of life Conceiving a child just to provide a match bone marrow to cure a living sick child? The world was shaken in 1990 when the Ayala family from California did just that in order to save their daughter who was suffering from leukaemia. As the chance to conceive a matched child is 1:4, they felt blessed to spontaneously conceive with a matched baby. In spite of the controversy on ‘baby farming’, the sisters and their parents had an amazing journey of hope, survival and happiness (Alby, 1992; Quigley, 2011). The story of such a unique ‘gift of life’ had a major turn in 2000, when Adam Nash was born unaffected for Fanconi anaemia and human leukocyte antigen (HLA) matched to his
6-year old sister, after IVF with preimplantation genetic diagnosis (PGD) for the mutation and HLA typing (Verlinsky et al., 2001). This was done so that a related healthy sibling could be matched for a girl suffering from bone marrow failure secondary to Fanconi anaemia. Therefore, PGD was used to identify the embryos that were unaffected from Fanconi anaemia to avoid another affected child, and, out of the unaffected ones, HLA typing was used to select the embryo/s that matched the sick child. These matched unaffected embryos were transferred and a healthy boy was born. Cord blood of the girl’s healthy matched brother was used for haematopoietic stem cell transplant (HSCT), which was successful and the girl was cured (Grewal et al., 2004). This first case of this new application of PGD, published by Verlinsky
http://dx.doi.org/10.1016/j.rbmo.2014.10.007 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ilan Tur-Kaspa, Roohi Jeelani, Clinical guidelines for IVF with PGD for HLA matching, Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.10.007
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et al. (2001), instigated a worldwide debate on the issue of ‘saviour siblings’ (Ingerslev and Hindkjaer, 2012; Madanamoothoo, 2011; Shenfield et al., 2005; Soini et al., 2006). Although the debate is still ongoing in some countries, it has subsided significantly worldwide. In some countries, the treatment has been approved and is routinely offered to families in need (Fernandez et al., 2014; Harper et al., 2012; Kahraman et al., 2011; Kuliev et al., 2005a, 2005b; Rechitsky et al., 2006; Samuel et al., 2009; Tur-Kaspa, 2012; Van de Velde et al., 2009). More than 10 years after the first ‘saviour baby’, still less than 35% of parents of children with Fanconi anaemia are offered PGD by any healthcare professional, and only 70% are aware of PGD for HLA as a reproductive option (Zierhut et al., 2013). The study published by Kahraman et al. (2014) describing 44 out of 48 successful HSCTs (92%) after PGD for HLA to cure, save an ill sibling, or both, and previously published cases, may serve as a proof of concept. Although outcome of HSCT from mixed non-matched donors has improved dramatically recently, related-matched donor for HSCT, and thus IVF for PGD-HLA, is here to stay. Clinical guidelines on the role and usage of PGD for HLA will assist in incorporating it into routine clinical care and will help parents in their reproductive decision-making process.
PGD for HLA Preimplantation genetic diagnosis is the genetic testing of embryos obtained by IVF before transferring them into the uterus to achieve conception with a healthy child, and has been established worldwide as a clinical service. The American Society for Reproductive Medicine, the European Society for Human Reproduction and Embryology, the European Society of Human Genetics, and the Preimplantation Genetics Diagnosis International Society, support PGD as an option for couples at risk of having children with heritable and debilitating genetic diseases who wish to avoid the difficult dilemma of possibly terminating the pregnancy with an affected fetus or delivering a sick child (Preimplantation Genetic Diagnosis International Society (PGDIS), 2008, Practice Committee of Society for Assisted Reproductive Technology and Practice Committee of American Society for Reproductive Medicine, 2008, Soini et al., 2006; Harper et al., 2012). In 2000, PGD for HLA was added to the expanding indications of PGD. As it is considered ethically and clinically justified to test children for HLA typing for possible HSCT to save their siblings (Policy Statement, 2013), we argue that the same rule may apply for embryos before implantation. Kahraman et al. (2011, 2014) summarized their experience with 242 couples who underwent 461 IVF cycles for PGD with HLA typing. Their data may assist physicians in consulting such couples. A total of 3973 embryos were biopsied, of which 90% were diagnosed successfully. For HLA matching plus mutation testing, 12% of analysed embryos were found as both disease-free and HLA compatible (versus 19% expected). For the HLA-only testing group, 17.0% of analysed embryos were found as HLA-compatible and transferrable (versus 25% expected). In 60% of cycles, at least one suitable embryo could be transferred, resulting in an ongoing pregnancy rate of 30% per transfer. Ninety healthy and HLA compatible children were already born. One HLA non-identical baby was born as a result
of a misdiagnosis out of 91 babies (1.1%). Forty-four sick children have already been cured by HSCT from these HLA matched born siblings. Graft failure occurred in four additional children with beta-thalassemia where a second HSCT was planned (92% success rate). Although such results clearly support the clinical use of PGD for HLA, its limitations should be properly communicated to families before starting treatment. They should have realistic expectations for the overall success of this approach, and should be informed on the possible risks and complications of IVF, intracytoplasmic sperm injection, PGD, PGD error rate and pregnancy outcome. They should also receive information on the experience and IVF success rates of their particular clinic, with or without PGD, the chance of have a matched embryo (as described above) and the fact that even if an HLA matched embryo is available, the transfer might not necessarily result in pregnancy, and further IVF-PGD cycles may be needed. Additional aneuploidy testing may further decrease the percentage of available embryos for embryo transfer, but the pregnancy rate per embryo transfer may improve (Rechitsky et al., 2006; Tur-Kaspa, 2012). As indicated by Kahraman et al. (2014), stem-cell dose obtained from umbilical cord blood was frequently insufficient, and extra time was needed for the child to gain sufficient weight to be able to donate his or her bone marrow cells. All of these limitations might increase the time it will take for the ill sibling to undergo the transplant, other than the fact that 9 months are required for delivery of a successfully implanted embryo. When the chance to conceive with a matched child and the number of oocytes to be retrieved are very low because of diminished ovarian reserve, advanced maternal age, or both, egg donation from a half-matched relative of the mother may be considered (Tur-Kaspa et al., unpublished data). To justify PGD for HLA, related HSCT must result in a significantly better clinical outcome over unrelated or nonmatched HSCT (Samuel et al., 2009). About 70% of patients who need a transplant do not have a suitable donor in their family. When there is no related HLA matched donor, matched unrelated donors might be identified in national or international donor registries. The Center for International Blood and Marrow Transplant Research showed a superior overall survival when using an HLA-identical sibling donor compared with an unrelated matched donor for leukaemia as well as for non-malignant conditions (Horan et al., 2012; Pasquini and Wang, 2013). The overall benefits of related-matched HSCT compared with matched unrelated HSCT are as follows: decreased risk of graft versus host disease, improved longterm disease-free survival in malignant conditions, superior overall survival, decreased post-transplant morbidity and decreased risk of treatment failure (Horan et al., 2012; Pasquini and Wang, 2013; Samuel et al., 2009). If unrelated HSCT in conjunction with a novel transplant protocol demonstrates long-term similar outcomes to related-matched transplant for all diseases, then PGD for HLA may no longer be needed (Li et al., 2012).
To whom PGD-HLA should be offered? PGD–HLA should be offered to anyone with a condition that requires matched-related HSCT. Creating an HLA-matched child to an existing sick sibling in case the sibling needs
Please cite this article in press as: Ilan Tur-Kaspa, Roohi Jeelani, Clinical guidelines for IVF with PGD for HLA matching, Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.10.007
ARTICLE IN PRESS Clinical guidelines for IVF with PGD for HLA transplantation in the future because of lack of response to treatment for leukaemia or aplastic anaemia or a later relapse have also been attempted. Such treatments have been carried out in our clinic after proper consultation with the couple and the transplant team as well as with the IVF–PGD team. Couples see this treatment as the best medical insurance they can offer their sick child and also the best way to avoid the adverse effect of age on the IVF success rate, if unfortunately their sick child will need HSCT later. Should matched embryos be transferred in such cases, or kept cryopreserved, remains for the couple to decide. Although PGD-HLA is now an established clinical procedure with documented positive outcomes, the question is whether this option is presented to families in need by their healthcare provider in a timely fashion. Unfortunately, it has been our personal experience that this is not the case for many families. Lack of knowledge or ethical concerns by the healthcare providers of this treatment modality significantly delays the initiation of PGD–HLA (Tur-Kaspa, 2012; Zierhut et al., 2013). Kahraman et al. (2014) found that, for patients with leukaemia, the average time from diagnosis to first consultation with the IVF–PGD centre was 1.5 years. Sadly, such a delay may contribute to the fact that five children with acute forms of leukaemia died while awaiting HSCT, either before or immediately after their HLA-matched sibling was born. The fact that many patients who may benefit from PGD for HLA are not aware of it, corroborates our clinical experience with dozens of families in need of PGD–HLA for HSCT. These clinical situations, along with the two presented below, prompted us to search for a tool that can facilitate a faster delivery of this unique healthcare option to these families. We have identified a need for practice guidelines on when and how PGD for HLA should be discussed with families that are in need for related-matched HSCT, and by whom.
Clinical scenarios Case 1 Parents of a 7-year-old girl who suffered from aplastic anaemia for 1.5 years contacted us from Asia after hearing about a recent case that had a successful PGD for HLA treatment at our centre on an international news bulletin. She was in need of HSCT because of the severity of her disease, and no matched donor was found. Within 8 weeks, we were able to complete genetic set up for PGD and to start ovarian stimulation in collaboration with a local IVF centre. One matched embryo was identified by PGD-HLA and was transferred, and the mother conceived a healthy matched child. Unfortunately, their daughter passed away 3 months before delivery. When they confronted the treating haematologist and paediatrician on why PGD for HLA was not discussed with them earlier, the physicians’ response was that they still considered it an experimental procedure, that it was not available in their country and that it was an expensive procedure. The parents told the physicians that they had ‘proved them wrong on all these points’. This case demonstrates the possible adverse outcome of not informing parents about PGD for HLA in time, and the need for international collaboration.
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Case 2 A 45-year-old woman consulted us about PGD for HLA. Her son was diagnosed with leukaemia when she was 39 years old and had been in remission. No one had discussed the option of PGD with them at that time. When her son’s leukaemia (ALL) relapsed, a transplant was recommended, and no HLA matched donor was found. The woman was informed that, at the age of 45 years, her chances of having an HLA-matched baby by IVF–PGD was practically zero. Sadly, their son passed away a few months later. This exemplifies the importance of maternal age in IVF outcome, and that the PGD–HLA option should be discussed at the time of diagnosis, regardless of the prognosis of the disease.
The role of practice guidelines in healthcare delivery Clinical practice guidelines have demonstrated improved health outcomes, have helped to standardize care and have diminished variations in local care. Once guidelines had been set by haemato-oncologists on offering the possibility of fertility preservation before starting cancer treatment, awareness and use of such services by men and women of reproductive age significantly increased (American Society of Clinical Oncology, 2006; Levine et al., 2010). Our group (Tur-Kaspa, 2012; Tur-Kaspa et al., 2014), as well as others (Samuel et al., 2009), have identified a need for guidelines in the case of IVF for PGD–HLA. Data were analysed to determine when and to whom IVF with PGD for HLA should be offered, and what measures can be taken when this procedure is not available locally or nationally. The draft practice guidelines were presented to members of American Society for Reproductive Medicine and Preimplantation Genetics Diagnosis International Society, as a group of experts and interested individuals and organizations, for review and consultation (Tur-Kaspa and Jeelani, 2010a, 2010b). The next step, to benefit all families in need, is to involve multidisciplinary medical societies and the public for consultations and guideline dissemination (Tur-Kaspa, 2012).
Suggested practice guidelines for IVF for PGD–HLA After gathering relevant data, the following clinical guidelines for PGD for HLA have been suggested: (i) it should be offered to families when a related matched donor is not available; (ii) when HSCT is not urgent and can wait for at least 9–12 months (it will take at least 2–3 months for the IVFPGD process and then to carry the pregnancy and deliver; therefore, at least 1 year is needed before possible HSCT); (iii) the mother is of reproductive age or has a half-match related egg donor; (iv) it should be offered to all families within weeks of diagnosis, even for diseases with very good prognosis; and (v) if PGD for HLA is not available locally or nationally, then collaboration with another centre should be established to make this treatment available. Families should be informed about this option of PGD for HLA sooner rather than later to allow them ample time for consideration,
Please cite this article in press as: Ilan Tur-Kaspa, Roohi Jeelani, Clinical guidelines for IVF with PGD for HLA matching, Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.10.007
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especially as women’s age is a major factor in assisted reproduction techniques success. The procedure should be performed at an assisted reproduction tecniques centre with experience with such cases.
Conclusions When PGD for HLA was not available, parents had to conceive naturally in the hope that their offspring will be a matched donor for their sick child. It is now possible to use PGD to HLA match an embryo, and also to avoid the underlying genetic disease as well as to screen for 24 chromosomes. Although this option is readily available in many IVF centres, no set guidelines have been established, and most healthcare providers are still unaware of such options or how to introduce them to patients. To help facilitate families in need of PGD-HLA, clinical guidelines should be implemented outwith the reproductive professional societies. Over the past decade, considerable progress has been made towards improving the outcome of related and unrelated donor transplants. Advances have been made in HLA typing, particularly in allelic matching, transplant conditioning, graftversus-host disease prophylaxis and supportive care, allowing for recipients of all various HSCT to be more likely to survive than in previous years. Still, at this time, related-matched HSCT shows superior outcomes, especially for non-malignant diseases. Once significant advances lead to improved outcomes of unrelated transplants compared with related HSCT, this rationale should be revised. It is important that families are informed about the option of PGD for HLA in a timely manner. They need time to discuss procedures, possible risks and PGD error rate, limitations, cost, fears, questions, to gain reassurance, and, most of all, to be aware of all the available options from the beginning. When a related-matched donor is needed for a sick child, PGD-HLA is at this time a realistic option. Conceiving a healthy child that is HLA matched to their sibling gives parents an opportunity to act independently to save their sick child, and at the same time they can be assured that their next child will be free of a genetic disorder. If the appropriate health authorities advocate these guidelines, it will allow most families to consider the option of PGD-HLA in a timely fashion. This will increase awareness, prevent future unfortunate outcomes, and improve patient care. These practice guidelines need to be adapted by health authorities, national and international medical societies, or both, at a multi-disciplinary level (i.e. paediatrics, oncology, haematology and obstetrics and gynaecology) to benefit patients who are in need of such treatments worldwide. If conducted within an appropriate time-frame, IVF with PGD for HLA typing could help save lives.
Acknowledgement The authors thank Adi Tur-Kaspa for her excellent editorial assistance.
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ARTICLE IN PRESS Clinical guidelines for IVF with PGD for HLA Medicine, 2008. Preimplantation genetic testing: a Practice Committee opinion. Fertil. Steril. 90, S136–S143. Preimplantation Genetic Diagnosis International Society (PGDIS), 2008. Guidelines for good practice in PGD: programme requirements and laboratory quality assurance. Reprod. Biomed. Online 16, 134– 147. Quigley, R., 2011. Born to save her sisters life: Anissa was concieved simply to save her cancer stricken sister. . .and said she has never looked back. (accessed 02.08.14.). Rechitsky, S., Kuliev, A., Sharapova, T., Laziuk, K., Ozen, S., Barsky, I., Verlinsky, O., Tur-Kaspa, I., Verlinsky, Y., 2006. Preimplantation HLA typing with aneuploidy testing. Reprod. Biomed. Online 12, 89–100. Samuel, G.N., Strong, K.A., Kerridge, I., Jordens, C.F., Ankeny, R.A., Shaw, P.J., 2009. Establishing the role of pre-implantation genetic diagnosis with human leucocyte antigen typing: what place do “saviour siblings” have in paediatric transplantation? Arch. Dis. Child. 94, 317–320. Shenfield, F., Pennings, G., Cohen, J., Devroey, P., Tarlatzis, B., 2005. Taskforce 9: the application of preimplantation genetic diagnosis for human leukocyte antigen typing of embryos. Hum. Reprod. 20, 845–847. Soini, S., Ibarreta, D., Anastasiadou, V., Ayme, S., Braga, S., Cornel, M., Coviello, D.A., Evers-Kiebooms, G., Geraedts, J., Gianaroli, L., Harper, J., Kosztolanyi, G., Lundin, K., Rodrigues-Cerezo, E., Sermon, K., Sequeiros, J., Tranebjaerg, L., Kaariainen, H., 2006.
5 The interface between assisted reproductive technologies and genetics: technical, social, ethical and legal issues. Eur. J. Hum. Genet. 14, 588–645. Tur-Kaspa, I., 2012. Clinical management of in vitro fertilization with preimplantation genetic diagnosis. Semin. Reprod. Med. 30, 309–322. Tur-Kaspa, I., Jeelani, R., 2010a. The 10th International Conference on Preimplantation Genetic Diagnosis (PGD), Montpellier, France. When to offer PGD for HLA typing to parents of a sick child: suggested clinical guidelines. Reprod. Biomed. Online 20, S38. Tur-Kaspa, I., Jeelani, R., 2010b. PGD for HLA typing: suggested clinical guidelines on when, where and to whom it should be offered. Fertil. Steril. 94, S43. Tur-Kaspa, I., Jeelani, R., Doraiswamy, P.M., 2014. Preimplantation genetic diagnosis for inherited neurological disorders. Nat. Rev. Neurol. 10, 417–424. Van de Velde, H., De Rycke, M., De Man, C., De Hauwere, K., Fiorentino, F., Kahraman, S., Pennings, G., Verpoest, W., Devroey, P., Liebaers, I., 2009. The experience of two European preimplantation genetic diagnosis centres on human leukocyte antigen typing. Hum. Reprod. 24, 732–740. Verlinsky, Y., Rechitsky, S., Schoolcraft, W., Strom, C., Kuliev, A., 2001. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA 285, 3130–3133. Zierhut, H., MacMillan, M.L., Wagner, J.E., Bartels, D.M., 2013. More than 10 years after the first ‘savior siblings’: parental experiences surrounding preimplantation genetic diagnosis. J. Genet. Couns. 22, 594–602.
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w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
COMMENTARY
Clinical guidelines for IVF with PGD for HLA matching Ilan Tur-Kaspa a,b,*, Roohi Jeelani a,c a
Institute for Human Reproduction (IHR), 409 West Huron Street, Suite 500, Chicago, IL, United States; b Department of Obstetrics and Gynecology, The University of Chicago, 5841 S. Maryland Ave-MC2050, Chicago, IL, United States; c Department of Obstetrics and Gynecology, Wayne State University/DMC, 3980 John St, Detroit, MI, United States * Corresponding author.
E-mail address: [email protected] (I Tur-Kaspa).
Preimplantation genetic diagnosis (PGD) for human leukocyte antigen (HLA) typing is an established procedure for conceiving a child who may donate cord blood or haematopoietic stem cells for transplantation to save an ill sibling. Haematopoietic stem cell transplantation (HSCT) from related matched donors improves overall survival compared with unrelated or non-matched donors. Since HSCT from related matched-donors is unavailable for 70% of patients, IVF for PGD-HLA is a relevant clinical option. Recent success of HSCT after PGD–HLA, and excellent health and family support of the children born, suggests that debate over this kind of ‘designer baby’ and ‘gift of life’ should subside. Discussions about IVF for PGD–HLA should be held with families when a related matched-donor is unavailable, when HSCT can wait at least 9–12 months, within weeks of diagnosis irrespective of prognosis, and when the mother is of reproductive age. Related half-matched egg donors may also be considered. National and international collaborations should be established, and couples choosing this modality should be referred to experienced IVF and PGD centres. Clinical guidelines will improve physician and patient awareness of IVF for PGD-HLA and its role in advancing the clinical care of children in need of HSCT. Abstract
© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: bone marrow transplant, cord blood, hematopoietic stem cell transplantation, human leukocyte antigen matching, inherited and acquired hematological disorders, PGD
The gift of life Conceiving a child just to provide a match bone marrow to cure a living sick child? The world was shaken in 1990 when the Ayala family from California did just that in order to save their daughter who was suffering from leukaemia. As the chance to conceive a matched child is 1:4, they felt blessed to spontaneously conceive with a matched baby. In spite of the controversy on ‘baby farming’, the sisters and their parents had an amazing journey of hope, survival and happiness (Alby, 1992; Quigley, 2011). The story of such a unique ‘gift of life’ had a major turn in 2000, when Adam Nash was born unaffected for Fanconi anaemia and human leukocyte antigen (HLA) matched to his
6-year old sister, after IVF with preimplantation genetic diagnosis (PGD) for the mutation and HLA typing (Verlinsky et al., 2001). This was done so that a related healthy sibling could be matched for a girl suffering from bone marrow failure secondary to Fanconi anaemia. Therefore, PGD was used to identify the embryos that were unaffected from Fanconi anaemia to avoid another affected child, and, out of the unaffected ones, HLA typing was used to select the embryo/s that matched the sick child. These matched unaffected embryos were transferred and a healthy boy was born. Cord blood of the girl’s healthy matched brother was used for haematopoietic stem cell transplant (HSCT), which was successful and the girl was cured (Grewal et al., 2004). This first case of this new application of PGD, published by Verlinsky
http://dx.doi.org/10.1016/j.rbmo.2014.10.007 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ilan Tur-Kaspa, Roohi Jeelani, Clinical guidelines for IVF with PGD for HLA matching, Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.10.007
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et al. (2001), instigated a worldwide debate on the issue of ‘saviour siblings’ (Ingerslev and Hindkjaer, 2012; Madanamoothoo, 2011; Shenfield et al., 2005; Soini et al., 2006). Although the debate is still ongoing in some countries, it has subsided significantly worldwide. In some countries, the treatment has been approved and is routinely offered to families in need (Fernandez et al., 2014; Harper et al., 2012; Kahraman et al., 2011; Kuliev et al., 2005a, 2005b; Rechitsky et al., 2006; Samuel et al., 2009; Tur-Kaspa, 2012; Van de Velde et al., 2009). More than 10 years after the first ‘saviour baby’, still less than 35% of parents of children with Fanconi anaemia are offered PGD by any healthcare professional, and only 70% are aware of PGD for HLA as a reproductive option (Zierhut et al., 2013). The study published by Kahraman et al. (2014) describing 44 out of 48 successful HSCTs (92%) after PGD for HLA to cure, save an ill sibling, or both, and previously published cases, may serve as a proof of concept. Although outcome of HSCT from mixed non-matched donors has improved dramatically recently, related-matched donor for HSCT, and thus IVF for PGD-HLA, is here to stay. Clinical guidelines on the role and usage of PGD for HLA will assist in incorporating it into routine clinical care and will help parents in their reproductive decision-making process.
PGD for HLA Preimplantation genetic diagnosis is the genetic testing of embryos obtained by IVF before transferring them into the uterus to achieve conception with a healthy child, and has been established worldwide as a clinical service. The American Society for Reproductive Medicine, the European Society for Human Reproduction and Embryology, the European Society of Human Genetics, and the Preimplantation Genetics Diagnosis International Society, support PGD as an option for couples at risk of having children with heritable and debilitating genetic diseases who wish to avoid the difficult dilemma of possibly terminating the pregnancy with an affected fetus or delivering a sick child (Preimplantation Genetic Diagnosis International Society (PGDIS), 2008, Practice Committee of Society for Assisted Reproductive Technology and Practice Committee of American Society for Reproductive Medicine, 2008, Soini et al., 2006; Harper et al., 2012). In 2000, PGD for HLA was added to the expanding indications of PGD. As it is considered ethically and clinically justified to test children for HLA typing for possible HSCT to save their siblings (Policy Statement, 2013), we argue that the same rule may apply for embryos before implantation. Kahraman et al. (2011, 2014) summarized their experience with 242 couples who underwent 461 IVF cycles for PGD with HLA typing. Their data may assist physicians in consulting such couples. A total of 3973 embryos were biopsied, of which 90% were diagnosed successfully. For HLA matching plus mutation testing, 12% of analysed embryos were found as both disease-free and HLA compatible (versus 19% expected). For the HLA-only testing group, 17.0% of analysed embryos were found as HLA-compatible and transferrable (versus 25% expected). In 60% of cycles, at least one suitable embryo could be transferred, resulting in an ongoing pregnancy rate of 30% per transfer. Ninety healthy and HLA compatible children were already born. One HLA non-identical baby was born as a result
of a misdiagnosis out of 91 babies (1.1%). Forty-four sick children have already been cured by HSCT from these HLA matched born siblings. Graft failure occurred in four additional children with beta-thalassemia where a second HSCT was planned (92% success rate). Although such results clearly support the clinical use of PGD for HLA, its limitations should be properly communicated to families before starting treatment. They should have realistic expectations for the overall success of this approach, and should be informed on the possible risks and complications of IVF, intracytoplasmic sperm injection, PGD, PGD error rate and pregnancy outcome. They should also receive information on the experience and IVF success rates of their particular clinic, with or without PGD, the chance of have a matched embryo (as described above) and the fact that even if an HLA matched embryo is available, the transfer might not necessarily result in pregnancy, and further IVF-PGD cycles may be needed. Additional aneuploidy testing may further decrease the percentage of available embryos for embryo transfer, but the pregnancy rate per embryo transfer may improve (Rechitsky et al., 2006; Tur-Kaspa, 2012). As indicated by Kahraman et al. (2014), stem-cell dose obtained from umbilical cord blood was frequently insufficient, and extra time was needed for the child to gain sufficient weight to be able to donate his or her bone marrow cells. All of these limitations might increase the time it will take for the ill sibling to undergo the transplant, other than the fact that 9 months are required for delivery of a successfully implanted embryo. When the chance to conceive with a matched child and the number of oocytes to be retrieved are very low because of diminished ovarian reserve, advanced maternal age, or both, egg donation from a half-matched relative of the mother may be considered (Tur-Kaspa et al., unpublished data). To justify PGD for HLA, related HSCT must result in a significantly better clinical outcome over unrelated or nonmatched HSCT (Samuel et al., 2009). About 70% of patients who need a transplant do not have a suitable donor in their family. When there is no related HLA matched donor, matched unrelated donors might be identified in national or international donor registries. The Center for International Blood and Marrow Transplant Research showed a superior overall survival when using an HLA-identical sibling donor compared with an unrelated matched donor for leukaemia as well as for non-malignant conditions (Horan et al., 2012; Pasquini and Wang, 2013). The overall benefits of related-matched HSCT compared with matched unrelated HSCT are as follows: decreased risk of graft versus host disease, improved longterm disease-free survival in malignant conditions, superior overall survival, decreased post-transplant morbidity and decreased risk of treatment failure (Horan et al., 2012; Pasquini and Wang, 2013; Samuel et al., 2009). If unrelated HSCT in conjunction with a novel transplant protocol demonstrates long-term similar outcomes to related-matched transplant for all diseases, then PGD for HLA may no longer be needed (Li et al., 2012).
To whom PGD-HLA should be offered? PGD–HLA should be offered to anyone with a condition that requires matched-related HSCT. Creating an HLA-matched child to an existing sick sibling in case the sibling needs
Please cite this article in press as: Ilan Tur-Kaspa, Roohi Jeelani, Clinical guidelines for IVF with PGD for HLA matching, Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.10.007
ARTICLE IN PRESS Clinical guidelines for IVF with PGD for HLA transplantation in the future because of lack of response to treatment for leukaemia or aplastic anaemia or a later relapse have also been attempted. Such treatments have been carried out in our clinic after proper consultation with the couple and the transplant team as well as with the IVF–PGD team. Couples see this treatment as the best medical insurance they can offer their sick child and also the best way to avoid the adverse effect of age on the IVF success rate, if unfortunately their sick child will need HSCT later. Should matched embryos be transferred in such cases, or kept cryopreserved, remains for the couple to decide. Although PGD-HLA is now an established clinical procedure with documented positive outcomes, the question is whether this option is presented to families in need by their healthcare provider in a timely fashion. Unfortunately, it has been our personal experience that this is not the case for many families. Lack of knowledge or ethical concerns by the healthcare providers of this treatment modality significantly delays the initiation of PGD–HLA (Tur-Kaspa, 2012; Zierhut et al., 2013). Kahraman et al. (2014) found that, for patients with leukaemia, the average time from diagnosis to first consultation with the IVF–PGD centre was 1.5 years. Sadly, such a delay may contribute to the fact that five children with acute forms of leukaemia died while awaiting HSCT, either before or immediately after their HLA-matched sibling was born. The fact that many patients who may benefit from PGD for HLA are not aware of it, corroborates our clinical experience with dozens of families in need of PGD–HLA for HSCT. These clinical situations, along with the two presented below, prompted us to search for a tool that can facilitate a faster delivery of this unique healthcare option to these families. We have identified a need for practice guidelines on when and how PGD for HLA should be discussed with families that are in need for related-matched HSCT, and by whom.
Clinical scenarios Case 1 Parents of a 7-year-old girl who suffered from aplastic anaemia for 1.5 years contacted us from Asia after hearing about a recent case that had a successful PGD for HLA treatment at our centre on an international news bulletin. She was in need of HSCT because of the severity of her disease, and no matched donor was found. Within 8 weeks, we were able to complete genetic set up for PGD and to start ovarian stimulation in collaboration with a local IVF centre. One matched embryo was identified by PGD-HLA and was transferred, and the mother conceived a healthy matched child. Unfortunately, their daughter passed away 3 months before delivery. When they confronted the treating haematologist and paediatrician on why PGD for HLA was not discussed with them earlier, the physicians’ response was that they still considered it an experimental procedure, that it was not available in their country and that it was an expensive procedure. The parents told the physicians that they had ‘proved them wrong on all these points’. This case demonstrates the possible adverse outcome of not informing parents about PGD for HLA in time, and the need for international collaboration.
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Case 2 A 45-year-old woman consulted us about PGD for HLA. Her son was diagnosed with leukaemia when she was 39 years old and had been in remission. No one had discussed the option of PGD with them at that time. When her son’s leukaemia (ALL) relapsed, a transplant was recommended, and no HLA matched donor was found. The woman was informed that, at the age of 45 years, her chances of having an HLA-matched baby by IVF–PGD was practically zero. Sadly, their son passed away a few months later. This exemplifies the importance of maternal age in IVF outcome, and that the PGD–HLA option should be discussed at the time of diagnosis, regardless of the prognosis of the disease.
The role of practice guidelines in healthcare delivery Clinical practice guidelines have demonstrated improved health outcomes, have helped to standardize care and have diminished variations in local care. Once guidelines had been set by haemato-oncologists on offering the possibility of fertility preservation before starting cancer treatment, awareness and use of such services by men and women of reproductive age significantly increased (American Society of Clinical Oncology, 2006; Levine et al., 2010). Our group (Tur-Kaspa, 2012; Tur-Kaspa et al., 2014), as well as others (Samuel et al., 2009), have identified a need for guidelines in the case of IVF for PGD–HLA. Data were analysed to determine when and to whom IVF with PGD for HLA should be offered, and what measures can be taken when this procedure is not available locally or nationally. The draft practice guidelines were presented to members of American Society for Reproductive Medicine and Preimplantation Genetics Diagnosis International Society, as a group of experts and interested individuals and organizations, for review and consultation (Tur-Kaspa and Jeelani, 2010a, 2010b). The next step, to benefit all families in need, is to involve multidisciplinary medical societies and the public for consultations and guideline dissemination (Tur-Kaspa, 2012).
Suggested practice guidelines for IVF for PGD–HLA After gathering relevant data, the following clinical guidelines for PGD for HLA have been suggested: (i) it should be offered to families when a related matched donor is not available; (ii) when HSCT is not urgent and can wait for at least 9–12 months (it will take at least 2–3 months for the IVFPGD process and then to carry the pregnancy and deliver; therefore, at least 1 year is needed before possible HSCT); (iii) the mother is of reproductive age or has a half-match related egg donor; (iv) it should be offered to all families within weeks of diagnosis, even for diseases with very good prognosis; and (v) if PGD for HLA is not available locally or nationally, then collaboration with another centre should be established to make this treatment available. Families should be informed about this option of PGD for HLA sooner rather than later to allow them ample time for consideration,
Please cite this article in press as: Ilan Tur-Kaspa, Roohi Jeelani, Clinical guidelines for IVF with PGD for HLA matching, Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.10.007
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especially as women’s age is a major factor in assisted reproduction techniques success. The procedure should be performed at an assisted reproduction tecniques centre with experience with such cases.
Conclusions When PGD for HLA was not available, parents had to conceive naturally in the hope that their offspring will be a matched donor for their sick child. It is now possible to use PGD to HLA match an embryo, and also to avoid the underlying genetic disease as well as to screen for 24 chromosomes. Although this option is readily available in many IVF centres, no set guidelines have been established, and most healthcare providers are still unaware of such options or how to introduce them to patients. To help facilitate families in need of PGD-HLA, clinical guidelines should be implemented outwith the reproductive professional societies. Over the past decade, considerable progress has been made towards improving the outcome of related and unrelated donor transplants. Advances have been made in HLA typing, particularly in allelic matching, transplant conditioning, graftversus-host disease prophylaxis and supportive care, allowing for recipients of all various HSCT to be more likely to survive than in previous years. Still, at this time, related-matched HSCT shows superior outcomes, especially for non-malignant diseases. Once significant advances lead to improved outcomes of unrelated transplants compared with related HSCT, this rationale should be revised. It is important that families are informed about the option of PGD for HLA in a timely manner. They need time to discuss procedures, possible risks and PGD error rate, limitations, cost, fears, questions, to gain reassurance, and, most of all, to be aware of all the available options from the beginning. When a related-matched donor is needed for a sick child, PGD-HLA is at this time a realistic option. Conceiving a healthy child that is HLA matched to their sibling gives parents an opportunity to act independently to save their sick child, and at the same time they can be assured that their next child will be free of a genetic disorder. If the appropriate health authorities advocate these guidelines, it will allow most families to consider the option of PGD-HLA in a timely fashion. This will increase awareness, prevent future unfortunate outcomes, and improve patient care. These practice guidelines need to be adapted by health authorities, national and international medical societies, or both, at a multi-disciplinary level (i.e. paediatrics, oncology, haematology and obstetrics and gynaecology) to benefit patients who are in need of such treatments worldwide. If conducted within an appropriate time-frame, IVF with PGD for HLA typing could help save lives.
Acknowledgement The authors thank Adi Tur-Kaspa for her excellent editorial assistance.
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Please cite this article in press as: Ilan Tur-Kaspa, Roohi Jeelani, Clinical guidelines for IVF with PGD for HLA matching, Reproductive BioMedicine Online (2014), doi: 10.1016/j.rbmo.2014.10.007