Best Practice Recommendations for Infertility Management.

O VERVIEW This guideline offers recommendations on the importance of assisted reproductive technologies in treating infertility. It also covers resolution on ethical issues encountered while providing ART benefits to respective patients. 1. Introduction 1.1 ART in Infertility Infertility cases are increasing day by day throughout the world and create social and mental trouble to the suffering couple. The success ratios of pharmacological treat ments in improving the infertility problems are not up to the mark hence require an alternative. Assisted reproductive technology (ART) majorly utilizing in vitro fertilization (IVF) technique for treating infertility has raised hopes for several couples throughout the world. Most ARTs are recommended because these do not treat the biological problems that give rise to infertility but circumvent them and offer ways to have children despite underlying fertility problems Infertility cases are increasing day by day throughout the world and create social and mental trouble to the suffering couple. The success ratios of pharmacological treat ments in improving the infertility problems are not up to the mark hence require an alternative. Assisted reproductive technology (ART) majorly utilizing in vitro fertilization (IVF) technique for treating infertility has raised hopes for several couples throughout the world. Most ARTs are recommended because these do not treat the biological problems that give rise to infertility but circumvent them and offer ways to have children despite underlying fertility problems 1.2 Necessity of ethical issues and regulation Specific clinical setup is required to provide such techniques for which regulatory guidelines has to be followed Regulatory interference is mandatory as it is accompanied by ethical and societal concerns. The majority of new techniques, which provide infertility solutions, require gamete (spermatozoa or the oocytes) handling outside the body. This may result in unethical practices affecting the recipient of the treatment, medically, socially, and legally Ethical issues which may arise during the use of ART are: » Bypassing the natural method of conception » Creating life in laboratory » Fertilizing more embryos than will be needed » Discarding excess embryos » Expensive technology, not affordable for common man » Creating embryos, freezing them, and storing » Destroying embryos for research » Selective selection of embryos for transfer Currently, ART is recommended throughout the world for the treatment of infertility and therefore, the chances of ethical misconduct at the same time are also high. In such scenario, it is recommended to create certain regulatory policies for use of ART to protect he medical, social and legal rights of women and the unborn child These regulations may advise in providing couples with the best possible management of their problems, while at the same time ensuring that there are no unnecessary risks or ineffective treatments Specific clinical setup is required to provide such techniques for which regulatory guidelines has to be followed Regulatory interference is mandatory as it is accompanied by ethical and societal concerns. The majority of new techniques, which provide infertility solutions, require gamete (spermatozoa or the oocytes) handling outside the body. This may result in unethical practices affecting the recipient of the treatment, medically, socially, and legally Ethical issues which may arise during the use of ART are: Bypassing the natural method of conception Creating life in laboratory Fertilizing more embryos than will be needed Discarding excess embryos Expensive technology, not affordable for common man Creating embryos, freezing them, and storing Destroying embryos for research Selective selection of embryos for transfer Currently, ART is recommended throughout the world for the treatment of infertility and therefore, the chances of ethical misconduct at the same time are also high. In such scenario, it is recommended to create certain regulatory policies for use of ART to protect he medical, social and legal rights of women and the unborn child These regulations may advise in providing couples with the best possible management of their problems, while at the same time ensuring that there are no unnecessary risks or ineffective treatments 2. Best practice recommendations 2.1 Clinical facility registration Register all ART clinics with central registration authority and provide all necessary details of techniques and procedures of ART practiced at clinics » Clinics performing IUI should also register » Only clinics that meet certain physical infrastructure requirements and have prescribed technical expertise are allowed to enroll in the registry Monitor quality and quantity of all assisted reproduction procedures. It is recommended to submit annual reports of all treatment cycles and their outcome to central database Monitor ART procedures data at individual clinics and with central registry to understand the improvement in efficacy, safety and success rates of the fertility treatments Register all ART clinics with central registration authority and provide all necessary details of techniques and procedures of ART practiced at clinics Clinics performing IUI should also register Only clinics that meet certain physical infrastructure requirements and have prescribed technical expertise are allowed to enroll in the registry Monitor quality and quantity of all assisted reproduction procedures. It is recommended to submit annual reports of all treatment cycles and their outcome to central database Monitor ART procedures data at individual clinics and with central registry to understand the improvement in efficacy, safety and success rates of the fertility treatments 2.2 Age, eligibility criteria, and ART treatments Make ART treatments available to each needy person accordingly to the law of the land Do not offer ART to women with age above 45 years and Men above 50 years Do not suggest ART for the women with age below 21 years and men below 23 years ART should be offered to the couple keeping in mind the best interests of a particular patient or their potential offspring to proceed with IVF because of Associated safety issues Older women are more prone to develop chronic disorders like diabetes which may affect off springs Chances of chromosomal abnormalities particularly after 35 years of maternal age Make ART treatments available to each needy person accordingly to the law of the land Do not offer ART to women with age above 45 years and Men above 50 years Do not suggest ART for the women with age below 21 years and men below 23 years ART should be offered to the couple keeping in mind the best interests of a particular patient or their potential offspring to proceed with IVF because of Associated safety issues Older women are more prone to develop chronic disorders like diabetes which may affect off springs Chances of chromosomal abnormalities particularly after 35 years of maternal age 2.3 Counseling during ART Offer professional counseling to all patients undergoing fertility treatments Explain various treatment alternatives available with reason for recommendation of particular treatment to arrive at informed decision Counsel patients regarding the implications and chances of success of ART procedures in India and internationally from the available reference data being updated regularly (6–12 months) Counsel patients about merits and demerits of ART procedures, side effects of drugs used during procedures, risks including the complications of multiple pregnancy, and ovarian hyperstimulation syndrome (OHSS) Inform patients about the costs of proposed and alternative treatments. Do not hide any charges to be applied for treatment Counsel patients about the associated benefits and loss of continuing treatment after a certain number of attempts Discuss the possibility of adoption with patients whenever required Counsel couples or individual about their rights of a child born through the use of ART Provide clear, precise and honest information (in the form of pamphlets) about the procedures to patients in local language and English The counseling should help the patient/s in taking an informed decision Offer professional counseling to all patients undergoing fertility treatments Explain various treatment alternatives available with reason for recommendation of particular treatment to arrive at informed decision Counsel patients regarding the implications and chances of success of ART procedures in India and internationally from the available reference data being updated regularly (6–12 months) Counsel patients about merits and demerits of ART procedures, side effects of drugs used during procedures, risks including the complications of multiple pregnancy, and ovarian hyperstimulation syndrome (OHSS) Inform patients about the costs of proposed and alternative treatments. Do not hide any charges to be applied for treatment Counsel patients about the associated benefits and loss of continuing treatment after a certain number of attempts Discuss the possibility of adoption with patients whenever required Counsel couples or individual about their rights of a child born through the use of ART Provide clear, precise and honest information (in the form of pamphlets) about the procedures to patients in local language and English The counseling should help the patient/s in taking an informed decision 2.4 Documentation, record keeping, and consenting Obtain written informed consent from all individuals/ couples before initiating any ART treatment or procedures Start freezing procedures of embryo only after obtaining informed consent from all individual seeking ART and also discuss about the management of frozen gametes or embryos in case of death or incapacity of any of the parties Allow individual seeking ART to withdraw consent any time before embryos or the gametes are transferred to the woman’s uterus Maintain detailed records of all procedures performed at clinic. These records should be maintained for a period of 10 years at least This data will automatically get transferred to national ART registry to be set up by the Department of Health Research at the Headquarters of the ICMR As may be prescribed by ICMR of all IUI and ART cycles Sperm, oocytes or embryos used The manner and technique of their use The individual or couple or surrogate mother in respect of whom it was used Of all donor oocyte and embryo cycles Maintain the clinic’s data of all infertility and ART procedures including adverse outcomes Record details of all the gametes or embryos received, used and stored Maintain proper records along with its identification during and after storage of gametes and embryos. Security of the stored gametes and embryos should also be provided Provide discharge certificate with details of ART performed Maintain confidentiality of all the patients who have undergone ART procedures Inform about legal right of born child and parents » In case of married couples, the child born to them through ART is considered legitimate child of couple » In case of a single woman the child should be considered as the legitimate child of the woman » In case a married couple separates or gets divorced, after both parties consented to the ART treatment but before the child is born, the child shall be the legitimate child of the couple » A child born to a woman artificially inseminated with the stored sperm of her dead husband with prior consent should be considered as the legitimate child of the couple Unused embroyos can be used for research with approval of the couple Mixing of sperms or oocytes from more than one person is not allowed Obtain written informed consent from all individuals/ couples before initiating any ART treatment or procedures Start freezing procedures of embryo only after obtaining informed consent from all individual seeking ART and also discuss about the management of frozen gametes or embryos in case of death or incapacity of any of the parties Allow individual seeking ART to withdraw consent any time before embryos or the gametes are transferred to the woman’s uterus Maintain detailed records of all procedures performed at clinic. These records should be maintained for a period of 10 years at least This data will automatically get transferred to national ART registry to be set up by the Department of Health Research at the Headquarters of the ICMR As may be prescribed by ICMR of all IUI and ART cycles Sperm, oocytes or embryos used The manner and technique of their use The individual or couple or surrogate mother in respect of whom it was used Of all donor oocyte and embryo cycles Maintain the clinic’s data of all infertility and ART procedures including adverse outcomes Record details of all the gametes or embryos received, used and stored Maintain proper records along with its identification during and after storage of gametes and embryos. Security of the stored gametes and embryos should also be provided Provide discharge certificate with details of ART performed Maintain confidentiality of all the patients who have undergone ART procedures Inform about legal right of born child and parents In case of married couples, the child born to them through ART is considered legitimate child of couple In case of a single woman the child should be considered as the legitimate child of the woman In case a married couple separates or gets divorced, after both parties consented to the ART treatment but before the child is born, the child shall be the legitimate child of the couple A child born to a woman artificially inseminated with the stored sperm of her dead husband with prior consent should be considered as the legitimate child of the couple Unused embroyos can be used for research with approval of the couple Mixing of sperms or oocytes from more than one person is not allowed 2.5 Gender selection in ART Do not offer the facility to identify/predetermination of sex of child before birth to recipient of ART Do not provide, prescribe or administer anything that would ensure or increase the probability that an embryo shall be of a particular sex except to diagnose a sex–linked disorder or disease Do not perform any procedure to separate, or yield fractions enriched in sperm of X or Y variations Human reproductive cloning is not allowed Do not offer the facility to identify/predetermination of sex of child before birth to recipient of ART Do not provide, prescribe or administer anything that would ensure or increase the probability that an embryo shall be of a particular sex except to diagnose a sex–linked disorder or disease Do not perform any procedure to separate, or yield fractions enriched in sperm of X or Y variations Human reproductive cloning is not allowed 2.6 HIV and ART ART cannot be refused to a HIV discordant couples however it is recommended to have facilities available to prevent horizontal and vertical spread of HIV Prevalence of HIV infected people is increasing day by day where majority of the infected patients are of reproductive age group. In such cases, couple should be counseled not opt for natural conception process because of associated risk to offspring ART procedures are recommended for HIV positive couples because » When male partner is sero-positive, modified density–gradient centrifugation and swim–up method for sperm preparation coupled with either inseminations or in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) can be used as these techniques have proven to be highly effective in avoiding seroconversion of uninfected women and offspring » When female partner is seropositive, a healthy conception can be achieved with help of antiretroviral treatment followed by intrauterine insemination or IVF Consider the preexposure prophylaxis of antiretroviral drugs before commencing fertility treatments, which may further reduce the susceptibility of the uninfected female partner and child. Research has shown that, once pregnant, the use of antiretroviral therapy and avoidance of breastfeeding in HIV infected women may reduce chance of newborn infection to approximately 2% Ensure safety through evaluation of clinical part of the program (oocyte retrieval) and of the laboratory conditions during IVF cycle Consider having separate tanks for storage of infected material ART cannot be refused to a HIV discordant couples however it is recommended to have facilities available to prevent horizontal and vertical spread of HIV Prevalence of HIV infected people is increasing day by day where majority of the infected patients are of reproductive age group. In such cases, couple should be counseled not opt for natural conception process because of associated risk to offspring ART procedures are recommended for HIV positive couples because When male partner is sero-positive, modified density–gradient centrifugation and swim–up method for sperm preparation coupled with either inseminations or in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) can be used as these techniques have proven to be highly effective in avoiding seroconversion of uninfected women and offspring When female partner is seropositive, a healthy conception can be achieved with help of antiretroviral treatment followed by intrauterine insemination or IVF Consider the preexposure prophylaxis of antiretroviral drugs before commencing fertility treatments, which may further reduce the susceptibility of the uninfected female partner and child. Research has shown that, once pregnant, the use of antiretroviral therapy and avoidance of breastfeeding in HIV infected women may reduce chance of newborn infection to approximately 2% Ensure safety through evaluation of clinical part of the program (oocyte retrieval) and of the laboratory conditions during IVF cycle Consider having separate tanks for storage of infected material 2.7 Multiple pregnancy and ART The incidence of multiple pregnancies is higher in ART, hence it recommended to not transfer more than 2 embroyos in young women and note more than 3 in older women and in recurrent implantation failure The incidence of multiple pregnancies is higher in ART, hence it recommended to not transfer more than 2 embroyos in young women and note more than 3 in older women and in recurrent implantation failure 2.8 ART and welfare of the unborn child Consider the medical risks, family environment, and social environment before initiating ART procedures Consider the best interest of unborn child before proceeding for ART Consider the medical risks, family environment, and social environment before initiating ART procedures Consider the best interest of unborn child before proceeding for ART 2.9 ART and preimplantation genetic diagnosis Inform and counsel couple undergoing (IVF/ICSI) preimplantation genetic diagnosis (PGD) cycle about its complexities and uncertainties, including possible dilemmas and conflicts regarding embryo transfer after PGD Offer PGD only to screen the embryo for known, preexisting, heritable or genetic diseases. PGD in order to select for handicap/disability is morally unacceptable Aneuploidy screening should be done in high risk patients Inform and counsel couple undergoing (IVF/ICSI) preimplantation genetic diagnosis (PGD) cycle about its complexities and uncertainties, including possible dilemmas and conflicts regarding embryo transfer after PGD Offer PGD only to screen the embryo for known, preexisting, heritable or genetic diseases. PGD in order to select for handicap/disability is morally unacceptable Aneuploidy screening should be done in high risk patients 2.10 Ethical aspect of gamete donation: Gamete donors should be free of all communicable diseases, sexually transmitted diseases, and identifiable genetic disorders Semen donors should be between 21 to 45 years (both inclusive). Donor sperm should be cryopreserved for at least six months (quarantine period) before being used and, at the expiry of such period, the ART bank shall not supply the sperm to any assisted reproductive technology clinic unless the sperm donor is tested for such diseases, sexually transmitted disease or otherwise, as may be prescribed Single donor sample can be used for 25 times One sample of semen supplied by an ART bank shall be used by the assisted reproductive technology clinic only once on only one recipient Oocyte donors should be between 23 to 35 years (both inclusive) Oocyte donor can donate oocytes for maximum of one time in her lifetime Eggs from one donor can be shared between two recipients only, provided that at least seven oocytes are available for each recipient All unused oocytes would be either appropriately preserved by the assisted reproductive technology clinic for use on the same recipient(s), or given for research to a bonafide organization An ART bank shall obtain all necessary information in respect of a sperm or oocyte donor, including the name, identity and address of such donor or surrogate, and shall undertake in writing to the donor to keep such information confidential No ART bank shall divulge the name, identity, or address of any sperm or oocyte donor to any person or assisted reproductive technology clinic except in pursuance of an order or decree of a court of competent jurisdiction Any person or ART bank who divulges the name, identity or address of a sperm donor shall be guilty of an offence The collection of gametes from a person whose death is imminent shall only be permissible if such person’s spouse intends to avail assisted reproductive technology to have a child Gamete donors should be free of all communicable diseases, sexually transmitted diseases, and identifiable genetic disorders Semen donors should be between 21 to 45 years (both inclusive). Donor sperm should be cryopreserved for at least six months (quarantine period) before being used and, at the expiry of such period, the ART bank shall not supply the sperm to any assisted reproductive technology clinic unless the sperm donor is tested for such diseases, sexually transmitted disease or otherwise, as may be prescribed Single donor sample can be used for 25 times One sample of semen supplied by an ART bank shall be used by the assisted reproductive technology clinic only once on only one recipient Oocyte donors should be between 23 to 35 years (both inclusive) Oocyte donor can donate oocytes for maximum of one time in her lifetime Eggs from one donor can be shared between two recipients only, provided that at least seven oocytes are available for each recipient All unused oocytes would be either appropriately preserved by the assisted reproductive technology clinic for use on the same recipient(s), or given for research to a bonafide organization An ART bank shall obtain all necessary information in respect of a sperm or oocyte donor, including the name, identity and address of such donor or surrogate, and shall undertake in writing to the donor to keep such information confidential No ART bank shall divulge the name, identity, or address of any sperm or oocyte donor to any person or assisted reproductive technology clinic except in pursuance of an order or decree of a court of competent jurisdiction Any person or ART bank who divulges the name, identity or address of a sperm donor shall be guilty of an offence The collection of gametes from a person whose death is imminent shall only be permissible if such person’s spouse intends to avail assisted reproductive technology to have a child 2.11 Research & ART Only those gametes and embryos donated for research purpose Maintain prior regulatory approval (Department of Health Research) before conducting any research studies Only those gametes and embryos donated for research purpose Maintain prior regulatory approval (Department of Health Research) before conducting any research studies 2.12 Code of practice Code of Practice deals with all aspects of the treatment provided and the research done at registered clinics. Any information about clients and donors must be kept confidential, except with the consent of the person to whom the information relates, or in a medical emergency or a court order All relevant information must be given to the patient before a treatment is given No treatment should be given without the written consent of the couple A standard consent form recommended by the accreditation authority should be used by all ART clinics Specific consent must be obtained from couples who have their gametes or embryos frozen, in regard to what should be done with them if he/she dies or becomes incapable of varying or revoking his or her consent People seeking registered treatment must be given a suitable opportunity to receive proper counseling about the various implications of the treatment Code of Practice deals with all aspects of the treatment provided and the research done at registered clinics. Any information about clients and donors must be kept confidential, except with the consent of the person to whom the information relates, or in a medical emergency or a court order All relevant information must be given to the patient before a treatment is given No treatment should be given without the written consent of the couple A standard consent form recommended by the accreditation authority should be used by all ART clinics Specific consent must be obtained from couples who have their gametes or embryos frozen, in regard to what should be done with them if he/she dies or becomes incapable of varying or revoking his or her consent People seeking registered treatment must be given a suitable opportunity to receive proper counseling about the various implications of the treatment Summary of recommendations ICMR reference not added References Human immunodeficiency virus (HIV) and infertility treatment: a committee opinion. Ethics Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama. Fertil Steril 2015. Guidelines for infertility counselling in different countries: Is there an emerging trend? Eric Blyth, Human Reproduction, Volume 27, Issue 7, July 2012, Pages 2046–2057. National Draft Guidelines for Accreditation, Supervision & Regulation of ART Clinics in India - Indian Council of Medical Research (ICMR) at www.icmr.nic.ins Human immunodeficiency virus (HIV) and infertility treatment: a committee opinion. Ethics Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama. Fertil Steril 2015. Guidelines for infertility counselling in different countries: Is there an emerging trend? Eric Blyth, Human Reproduction, Volume 27, Issue 7, July 2012, Pages 2046–2057. National Draft Guidelines for Accreditation, Supervision & Regulation of ART Clinics in India - Indian Council of Medical Research (ICMR) at www.icmr.nic.ins