DARTMOUTH-HITCHCOCK MEDICAL CENTER Lebanon, New Hampshire IN VITRO FERTILIZATION PROCEDURE DESCRIPTION

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1 DARTMOUTH-HITCHCOCK MEDICAL CENTER Lebanon, New Hampshire IN VITRO FERTILIZATION PROCEDURE DESCRIPTION I. INTRODUCTION A. The Assisted Reproductive Technology (ART) Program. The ART Program is operated jointly by the Mary Hitchcock Memorial Hospital and the Dartmouth-Hitchcock Clinic. The goal of the ART Program is the achievement of pregnancy by women who have not otherwise achieved pregnancy, through use of in vitro fertilization (IVF), or fertilization outside the womb (uterus). Before IVF is considered as a medical option, participants (both female and male) must undergo a medical evaluation including various diagnostic tests, such as semen analysis, endometrial biopsies (examination of tissues taken from the womb), hysterosalpingogram and/or sonohystogram (tests to study the condition of the female reproductive tract), laparoscopy (a surgical procedure which allows the physician to view the female reproductive organs internally), etc. These tests are designed to determine the appropriateness of IVF for the participants. IVF may be an appropriate treatment if these tests indicate that the woman has damaged fallopian tubes, or that the man's sperm is low in count or slow in movement, or in certain cases where there is endometriosis or unexplained infertility. In addition, the tests will determine the medical acceptability of the woman to undergo IVF, and the medical acceptability of the man as a sperm donor. Participants will also meet with a clinical social worker to review any psychosocial and ethical concerns that may need to be considered in managing their treatment. The ART Program uses a team approach to patient care. Information obtained regarding the participants' medical acceptability and psychological status may be shared within the team for IVF-related treatment purposes. Women who participate in the ART Program must be at least 21 years old. Any married person who participates in the Program must participate with his or her spouse. B. The IVF Procedure (Summary). Prior to the IVF Procedure, the woman is given medications to stimulate her ovaries to produce several ripened eggs. IVF itself involves three stages: (1) removing the mature eggs from the woman's ovaries with a suction needle in a surgical procedure, (2) uniting the eggs with sperm (previously obtained from the man) in a laboratory dish, and (3) transferring those normally fertilized eggs (embryos) which have begun cell division back to the woman's uterus (womb), where one or more may implant and continue to develop. Freezing of embryos (an optional procedure) makes possible the preservation of "excess" eggs to be used in a later transfer. See Section VIII below. Although the IVF procedure has been successful in allowing some women to achieve pregnancy, there is no guarantee that, even after repeated attempts, a pregnancy will result or 1 revised 11/05

2 that, if pregnancy is achieved, it will continue to full term and result in the birth of a normal, completely healthy child. Not all patients who participate in IVF programs achieve pregnancy. Success rates increase with repeated cycles, but pregnancy is never certain. C. Definitions. 1. Pronuclear embryo. As used throughout this Procedure Description, the term "pronuclear embryo" means a fertilized egg prior to the initial stages of cell division. A pronuclear embryo contains DNA, the genetic contribution, from both the egg and the sperm. This DNA is found within separate structures within the egg, DNA from the male and female have not yet combined as it will prior to the first cell division. 2. Embryo. As used throughout this Procedure Description, the term "embryo" means a fertilized egg from the pronuclear stage through the initial stages of cell division before the time of implantation. At this stage the embryo contains the material that will eventually become the fetus, the placenta and the amniotic fluid. Cells of an embryo are not differentiated, and any single cell can theoretically develop into a fetus. The embryo cannot survive indefinitely outside of the uterus without the use of artificial preservation techniques. 3. Participants. As used throughout this Procedure Description, the word "participants" means: (a) both members of the couple, in the case of couples who participate in the ART Program together; and (b) the woman alone, in the case of an unmarried woman who participates without a partner. II. THE PRE-IVF STAGE AND ITS POTENTIAL RISKS In the pre-ivf stage (ovulation induction), the woman is given injections of medications to stimulate her ovaries to ripen more than one egg. (Ordinarily, only one egg ripens in any given month.) Medications are used to help the developing eggs mature. They include Gonadotrophin-Releasing Hormone (GNRH), Menotropins (Follicle Stimulating Hormone, or FSH, and Luteinizing Hormone, or LH), Human Chorionic Gonadotrophin (HCG), Clomid and others. In order to anticipate ovulation and the collection of eggs appropriately, two monitoring techniques are used during this pre-procedure phase: ultrasound scans, which produce images of the follicles (round sacs within the ovary) in which the eggs develop, and blood tests which determine the woman's estrogen levels. Potential risks during ovulation induction include: 1. Allergic reactions to the medications. There are no data which suggest that this result is likely, but the possibility cannot be ruled out. 2 revised 11/05

3 2. Normal risks associated with any injection, including infections, bruising or nerve damage at the injection site, and blood clot formation. 3. Hyperstimulation syndrome. Although unlikely in connection with the in vitro fertilization process, a hyperstimulation syndrome associated with the injection of protein hormones could develop. The ovaries could become markedly enlarged. An ovary could twist on itself, requiring surgical removal. Fluids could also shift from the blood vessels into the abdomen, causing abdominal swelling as well as decreased urine output and an increased tendency for blood clot formation. Hyperstimulation syndrome may require extensive hospitalization. 4. Cycle cancellation due to poor response. Not every patient produces multiple eggs following stimulation with hormones. If the woman's ovary does not respond to the medication there may not be enough eggs for a retrieval to be performed. If this occurs your physician may decide to cancel the cycle before the harvest. 5. Cycle cancellation due to overstimulation. Occasionally estrogen levels are so high following stimulation with medications that a patient is in danger of developing severe hyperstimulation syndrome (see point 3). If this occurs the cycle may be stopped prior to retrieval or transfer. III. THE IVF PROCEDURE AND ITS POTENTIAL RISKS Stage 1 - Harvesting the Eggs. Just before ovulation (the release of the eggs from the follicles in which they are contained), the eggs are removed from the woman's body. This is done under ultrasound guidance, often by passing an aspirating (suction) needle through the woman's vagina directly to the ovaries. Alternatively, the aspirating needle may be passed through the abdomen and bladder (which has been distended by injecting culture media through a catheter) into the ovaries. Ultrasound scanning, which produces images of the follicles, aids in guiding the needle to those eggs that are ready for harvesting. The woman remains awake during this procedure; at her choice, either i.v. sedation, or possibly spinal anesthesia are administered. In the case of egg donation: ONCE A DONOR'S EGGS HAVE BEEN REMOVED, ALL DECISIONS ABOUT THE EGGS WILL BE MADE SOLELY BY THE RECIPIENT, HER PARTNER, IF ANY, AND/OR THE ART PROGRAM, AS FURTHER DESCRIBED BELOW. DONORS MUST UNDERSTAND THAT, FROM THIS TIME FORWARD, THEY HAVE NO CONTROL OVER THE USE OR DISPOSITION OF THEIR EGGS OR THE RESULTING EMBRYOS, EXCEPT THAT THE EGGS OR EMBRYOS WILL BE USED IN ACCORDANCE WITH THIS PROCEDURE DESCRIPTION. Potential risks of the egg harvesting phase include: 3 revised 11/05

4 1. Possible damage to the ovaries caused by the aspirating needle, including bleeding or infection and possibly requiring removal of the ovaries. There are no data to suggest this is likely, but the possibility cannot be ruled out. 2. Reaction to the anesthetics which will be reviewed with you by the anesthesiologist. 3. Inflammation of the bladder due to the Foley catheter, if used, which could result in infection. Although not likely, the possibility cannot be ruled out. 4. Bleeding, inflammation of the vein, bruising, or infection at the intravenous injection site or the aspirating needle skin site, as with any injection. 5. Bleeding into the bladder due to needle puncture of the bladder during a transabdominal puncture, which occurs in about 10% of patients. This is rare or unknown when the transvaginal approach is used. 6. Accidental puncturing of the bowels or of an abdominal blood vessel by the aspirating needle, which could lead to internal hemorrhage or infection (peritonitis). 7. Failure to harvest the eggs due to such factors as premature ovulation or unforeseeable technical reasons. 8. Harvest of eggs that are immature or not fully mature and thus cannot be used. In rare cases all of the eggs will be of this type and none will fertilize. 9. As with any invasive surgical procedure, there is always the possibility of serious bleeding or infection. At the outside possibility, this could theoretically result in permanent injury or death. Stage 2 - Insemination and Development Outside the Womb. The harvested eggs are placed in a solution that will support their growth and development in the laboratory. Then, in a petri dish, eggs are combined with sperm that has been collected from a semen sample provided by either the male partner in the couple, or a donor. Semen from a male partner may be fresh or frozen. Semen from a donor must be frozen and quarantined. Because there are fewer moving (motile) sperm in frozen vs. fresh semen, the use of fresh semen is preferred. However, the ART Program recommends that a semen sample be collected and frozen prior to the day of egg transfer, for use as a back-up in the event that a fresh sample cannot be produced. The number of eggs that will be combined with sperm is an issue that will be discussed with participants prior to egg harvesting; it depends on the number of embryos to be transferred to the woman and the participants' decision regarding disposition of any excess embryos that develop. It is ART Program policy to limit the number of embryos transferred in any one cycle. Transfer of more than the recommended number of embryos increases the risk of multiple 4 revised 11/05

5 pregnancy without increasing the likelihood of a successful outcome. The number of embryos transferred will depend on the age of the female participant and the condition of the embryos on the day of transfer and will be discussed with participants individually. Prior to egg harvesting participants will be asked whether they would like the ART Program staff to freeze excess embryos that develop as a result of fertilization (see Section VIII below) or to allow excess embryos to die. If they are unwilling to allow any fertilized eggs to die, then the ART Program staff will take measures to limit the number of eggs that will be combined with sperm. The participants should understand, however, that the fertilization rate is generally not 100% and could be as low as 10-20% in some cases. Therefore, a decision to combine fewer eggs with sperm could decrease the likelihood of obtaining embryos for transfer and makes the likelihood of having none to transfer that much greater. Transfer of fewer than the recommended number of embryos has been correlated with lower pregnancy rates in some patients. On the other hand, transfer of one embryo does not guarantee against multiple pregnancy (i.e., identical twins). If fertilization occurs, the fertilized eggs (embryos) continue their development in the laboratory for two to four days. Eggs, sperm and embryos are kept under the best possible conditions of temperature, atmosphere and nourishment. In order to successfully implant in the uterus and establish a pregnancy, embryos must hatch out of the protective coating (zona pellucida) that surrounds them during early development. In some patients this hatching is not accomplished efficiently and the embryos do not implant. A laboratory procedure called Assisted Hatching can help embryos to implant in the uterus by weakening the zona pellucida which surrounds them. The Assisted Hatching procedure involves making a small hole in the zona pellucida with a weakly acidic solution prior to embryo transfer. Your physician will discuss with you the applicability of Assisted Hatching to your IVF treatment. In general, situations which warrant Assisted Hatching include a history of multiple non-conception IVF cycles, or unusually thickened zona pellucidae. Although this stage holds no immediate risk to participants in the ART Program, damage to the egg(s) or embryo(s) is a possibility. Potential risks include: 1. Failure to inseminate the egg(s) due to (a) failure to obtain an appropriate semen sample from the man; (b) loss of movement (motility) of sperm due to freezing; or (c) uncertainty as to the donor of the semen sample. (It is the responsibility of the man to be certain that the semen sample is properly labeled and left with the appropriate personnel.) If there is any question as to the identity of the semen, the laboratory personnel will not inseminate the egg(s). 2. Failure to achieve a successful fertilization. 3. Abnormal fertilization. This includes fertilization by more than one sperm or activation of the egg without penetration by a sperm. 4. Accidental damage to or rupture of the egg(s) or embryo(s) during handling in the laboratory, or due to mechanical failure of laboratory facilities (e.g., incubators necessary for egg growth, microscopes used for detection and transfer of eggs and embryos, water 5 revised 11/05

6 purification systems). This could result in failure to achieve fertilization, possible damage to eggs or embryos leading to birth defects, or loss of fertilized eggs. 5. Loss of the egg(s) or embryo(s) due to viral or bacterial infection. 6. Fertilization of an egg by more than one sperm, resulting in an abnormal embryo and possible birth defects. See Section V below. It is not always possible to detect when fertilization by more than one sperm has taken place; however, those eggs that are known to have been fertilized by more than one sperm will be allowed to die rather than being transferred back to the womb. 7. Unless the participants have chosen to have extra embryos frozen or allowed to die, the only eggs that will have sperm added to them will be those that will be transferred. All additional eggs will be cremated. This decision may result in sperm being added to no more than 2 eggs and it is possible that neither of these will fertilize and continue to develop. Note that, regardless of the precautions taken, IVF may at times result in discard, destruction or loss of embryos despite efforts to prevent this from happening. 8. If Assisted Hatching is used there is a small chance that embryos may be damaged by the acid used to break the zona pellucida leading to the death of the hatched embryo. There have also been reports of a slightly increased chance of identical twinning as a result of the Assisted Hatching procedure. Stage 3 - Embryo Transfer. After fertilization, embryos normally undergo cell division. In the third stage of the IVF procedure, embryos that have begun to divide normally as of the time that is deemed appropriate for embryo transfer (typically day 3 or day 5 after oocyte retrieval) will be transferred back to the woman. If the participants have chosen to have excess embryos frozen (see Section VIII below), then of embryos left unfrozen on day of transfer, the best will be transferred to the woman and the rest will be allowed to die or frozen on d5 if they reach the blastocyst stage. If freezing was not chosen, the decided upon number of embryos will be transferred to the woman and any remaining ones will be allowed to die. The transfer is made by drawing the embryos into a transfer catheter, inserting the catheter through the vagina and cervix to the uterus (womb), and gently flushing the embryos into the uterus. Anesthesia is generally not required for this procedure. One or more of the embryos may implant in the lining of the uterus and continue to develop. Potential risks of this stage include: 1. Failure to transfer embryos. Failure to transfer embryos could occur among other reasons because of problems related to the position of the uterus (womb), difficulty negotiating the cervical opening, or problems related to cervical mucus or cervical bleeding. 2. Bacterial or viral infection of the woman or the embryo(s), possibly resulting in birth defects. See Section V. 6 revised 11/05

7 3. Accidental destruction of the embryo(s) or loss by spillage in the course of transfer. 4. Puncture of the uterus, which could result in hemorrhaging in the woman and, in some cases, could result in loss of the uterus and/or ovaries. While the risk is perhaps greater with endometrial biopsy or D & C, the possibility with transfer cannot be ruled out. 5. If donated sperm, eggs or embryos are used, there is a risk that the woman will contract a sexually transmitted disease including, but not limited to, gonorrhea, syphilis, herpes, hepatitis and acquired immune deficiency syndrome (AIDS). Some of these diseases, including herpes and AIDS, cannot be cured, and AIDS may be fatal. While donors are screened for these diseases, we cannot absolutely guarantee that such diseases will not be present. Furthermore, if the woman were to contract herpes, AIDS, or other disease from the donated sperm, egg or embryo, the child and the woman's sexual partner may also be infected. 6. Failure of any embryos to implant. 7. Possible twins, triplets or other multiple gestations due to the transfer and implantation of more than one embryo. With IVF there is a 30-40% chance of multiple gestations. For example, a transfer of up to four embryos can lead to the development of four or more fetuses. (More than four fetuses may develop from four embryos in those instances when a single embryo divides after implantation resulting in identical twinning.) 8. Implantation of the embryo(s) in the woman's fallopian tube(s), which connect the ovaries with the uterus, resulting in a non-viable, ectopic pregnancy (pregnancy outside the womb); there is a 3-5% chance of ectopic pregnancy. 9. With IVF there is always the potential for an embryo to be destroyed, lost or allowed to die despite the best efforts of the ART Program staff. For those participants choosing to fertilize only those eggs intended for transfer we also cannot assure that there will never be times when embryos will be destroyed or allowed to die. Post-Procedure Care A pregnancy test ordered by the ART Program staff two to three weeks after the embryo transfer will determine whether there is a pregnancy. Although no special prenatal care is recommended for IVF patients, routine obstetrical care and regularly taking folic acid are strongly recommended. The risk of spontaneous miscarriage is higher in women who become pregnant using IVF than in the general population. Of women using IVF, 20-25% will miscarry in the first twelve weeks of pregnancy, while in the general population 10-20% will miscarry during that period. See Section VIII.B.5. below regarding the effect of embryo freezing on the risk of miscarriage. 7 revised 11/05

8 As noted earlier, 30-40% of women who become pregnant through IVF have multiple births (twins, triplets, etc.). Like all women who have multiple births, these women face an increased risk of pre-term delivery, high infant mortality, and toxemia (eclampsia). Except as noted in the previous two paragraphs, the usual risks inherent in any pregnancy and delivery do not appear to be increased or reduced by IVF. See Section VIII.B.6 below regarding potential unknown risks of embryo freezing. IV. THE SUCCESS RATE ART Program staff will share current statistics on IVF pregnancy rates with you before you decide to undergo treatment. Current national statistics indicate an IVF live birth rate of about 20-25% per stimulated cycle. Statistics indicate a greater overall chance of success after repeated attempts, however, it must be emphasized that pregnancy cannot be guaranteed for any specific participant even if the participant undergoes multiple treatment cycles. Of those participants who do become pregnant, 65-75% will give birth % will suffer spontaneous miscarriage in the first twelve weeks; 3-5% will experience non-viable pregnancies (such as ectopic pregnancies); 3-4% will suffer miscarriage after the first twelve weeks or deliver a stillborn baby. Roughly 10% will have pre-term infants. National statistics indicate that approximately 70% of pregnancies result in the delivery of one or more live, term infants. See Section VIII.B.5. below regarding the success rate when embryo freezing is used. V. BIRTH DEFECTS In the general population, there is a 3-5% risk of having a child with a birth defect (3-5 in 100 births). Findings published in 2002 suggested the risk of birth defects to be doubled in births associated with IVF. However, other studies of IVF over the last years have not shown an increased risk of having an infant with birth defects as a result of IVF. Participants should be prepared emotionally and psychologically for the statistical possibility of giving birth to a defective child after any pregnancy, including IVF pregnancies. Such defects might be fatal to the child within a short time after birth or might not be fatal but might result in permanent abnormality or deformity, possibly requiring sustained and costly medical care. Birth defects could range from minor abnormalities to serious deformities, including mental or psychological impairment, missing organs, malformed limbs or spine, or major changes in facial appearance. If donated sperm, eggs, or embryos are used, there is a risk that donors will carry genetic or family disorders that could be passed along to the child. For example, certain deformities, such as cleft palates and spina bifida, can have a genetic origin, as can diseases such as muscular dystrophy, cystic fibrosis, epilepsy, alcoholism and psychosis. There are many other disorders and diseases that can be inherited; we have not listed them all here but further information can be obtained from your physicians. Although donors will be screened for genetic disorders, we cannot guarantee that all donors are free of such genetic disorders. 8 revised 11/05

9 used. See Section VIII.B.3. below regarding the risk of birth defects when embryo freezing is VI. PSYCHOLOGICAL RISKS We have described, in earlier sections of this Procedure Description, the potential medical risks involved in the specific procedures that are used in the ART Program. It is important to consider as well the psychological consequences of participation in the Program. As is discussed above, there is a significant risk that, despite participation in the Program, a fullterm pregnancy will not result. See Section IV. Participants are advised to consider potential psychological consequences of investing time, money and hopes in the IVF procedure should the procedure, in the end, be unsuccessful. In addition, participants should consider in advance their feelings about creating embryos that, for one reason or another, may be allowed to die. If they choose to request freezing of embryos, they should consider the psychological consequences of having frozen embryos held in storage under the conditions described in the Procedure Description. For participants who have a multiple pregnancy after IVF there are issues related to carrying such pregnancies to term or undergoing multifetal reduction. Because these and other issues potentially raised by participation in the ART Program can be troubling to individuals, we strongly recommend that participants seek counseling to explore their feelings and the likely psychological consequences of such participation. VII. ETHICS With each new advance in reproductive technology, new ethical questions are raised and need to be addressed through an ongoing process. These questions are presented to and discussed with the Mary Hitchcock Memorial Hospital Ethics Advisory Committee, and its deliberations may well result in changes in the IVF protocol. Participants who have ethical questions about IVF or embryo freezing are encouraged to discuss them with the ART Program staff and/or their own family counselors. VIII. EMBRYO FREEZING PROCEDURE (OPTIONAL) The following is a description of the Embryo Freezing Procedure. Participants may choose to use this procedure or they may choose not to do so, without affecting in any way their status as patients in the ART Program. A. Description of Process and its Benefits. Following oocyte retrieval and insemination of oocytes, there are often multiple embryos available to develop into embryos to be transferred back to the womb leading to possible gestation. It has been found that transferring more than three or four embryos carries a 9 revised 11/05

10 significant risk of multiple pregnancy while it does not proportionately increase (and may possibly decrease) the chance of giving birth to a child. Embryo freezing allows participant(s) to save some of these fertilized eggs for use in a subsequent menstrual cycle. The procedure is used because of the "extra" embryos created by limitations placed on the numbers of embryos transferred. The limitations arise out of concern for the risk of multiple pregnancy. "Extra" embryos that are preserved through freezing may be transferred during one or more subsequent menstrual cycles, if the initial IVF procedure does not result in pregnancy, or following delivery if a pregnancy is achieved. By transferring previously frozen embryos, we avoid the need to use the ultrasound harvest procedure to collect new eggs for each embryo transfer, thus reducing the woman's exposure to the risks that accompany harvest (see Section III, Stage 1) and reducing the expense of the subsequent IVF attempts. In addition, by freezing embryos, we can save fresh embryos and make them available for later transfer to the woman when unforeseen circumstances, such as the woman's illness, make a transfer at a particular time less than optimal. In many cases embryos will be frozen in the pronuclear stage. Pronuclear embryos will be frozen on the day following oocyte retrieval. At this time we can determine the number of oocytes that have fertilized in vitro but we cannot be certain that all of these pronuclear embryos will continue to divide to become embryos or that all of the embryos will be in optimal condition at the time of transfer. When a participant(s) elects embryo freezing, we will freeze pronuclear embryos only if an appropriate number of eggs have fertilized. Depending on the number of embryos intended for transfer, 2 or more of the pronuclear embryos will be kept unfrozen and we will freeze only those pronuclear embryos in excess of these numbers. Sometimes, at the discretion of the program staff freezing will take place only if 2 or more are available to be frozen. Excess pronuclear embryos are kept unfrozen to increase the chances that there will be enough "good quality" embryos to transfer in the fresh cycle. Of the unfrozen embryos we will choose the requisite number to transfer. The extra embryos will be allowed to die. In this way we increase the likelihood of success in both the fresh and the frozen cycles. Embryo freezing is accomplished by placing the embryos in a special cryopreservative medium and freezing them in a series of technical steps. At the end of the cryopreservation procedure the embryos will be stored in liquid nitrogen at -196 Centigrade. At a future date, these frozen embryos can be thawed (in several steps over several hours) and transferred. Transfers of previously frozen embryos take place in a subsequent menstrual cycle. If a natural menstrual cycle is used, it is important to pinpoint the time of ovulation in these cycles and we may use various monitoring techniques, such as those that are used in the Pre-Procedure Stage before ovulation induction. (See Section II above.) Alternatively, a series of medications may be given to prepare the woman's uterus for implantation. Once the uterine lining is prepared for implantation, the time of embryo thawing and transfer is established. Transfer of previously frozen embryos takes place in the same way as transfer of embryos that have not undergone freezing. (See Section III, Stage 3 above.) B. Risks of Embryo Freezing. Potential risks of embryo freezing include: 10 revised 11/05

11 1. Medication risk: Normal risks associated with any injection, when blood tests are taken to establish the time of ovulation (See Section II.3. above.) or when medications are given to prepare the uterus. 2. Embryo death: The freezing and thawing processes are likely to destroy some, and may destroy all, of the embryos. Current statistics on survival rate will be given to you by program staff prior to the decision to have embryos frozen. Rates are in the range of 50-70% survival. In any particular case some, or even all, of the embryos may be destroyed. 3. Equipment malfunction: The freezing and thawing processes and the storage of the frozen embryos require mechanical and electrical support systems. As with any technical process, a failure of equipment could occur, leading to the loss or damage of some or all embryos. 4. Abnormalities: The freezing and thawing processes may damage some or all of the embryos, leading to birth defects in children born as a result of the transfer of damaged embryos. (See discussion of birth defects in Section V above) Human embryo freezing over the past 10 years has not demonstrated an increased risk of birth defects in children born after IVF using frozen embryos, as compared with children born as a result of natural conception or IVF using embryos that have not undergone freezing. However, there are no long term data yet available to indicate with certainty whether freezing and thawing increase the risk of developmental defects or other risks to the growing child. 5. Failure to achieve pregnancy: Statistics from the 2000 report of the registry of the Society for Assisted Reproductive Technology indicate that the rates of implantation and pregnancy for frozen thawed embryos are slightly lower than those for IVF. Rates of miscarriage do not seem to be significantly higher.(see Section IV above) It is possible that the freezing and thawing processes will have the effect of reducing the likelihood of success. 6. Unknown risks: As is true with the IVF procedure, the embryo freezing procedure is new and experience with it is limited. Thus, it is possible that there are additional risks inherent in the freezing and thawing of embryos and that we simply do not have sufficient data to know what those risks are. C. Conditions of Use and Disposition of Embryos. 1. Acceptable Uses. The ART Program will store frozen embryos no longer than 5 years. If pregnancy is not achieved we expect the embryos to be used within one year. In agreeing to store frozen embryos, the ART Program acknowledges that, in general, decisions regarding the use and disposition of any such frozen embryos remain with the participants provided that, where there are two participants, both must consent to any action that is taken, and that their choice is limited to the following options: 11 revised 11/05

12 (a) Embryo transfer: Upon the request of the participants, the embryo(s) may be transferred to the woman if and when such transfer is deemed medically advisable by the ART Program staff; (b) Discard: Upon the written request of the participants, the embryo(s) may be thawed and allowed to die; (c) Transfer to another facility: The participants may request that the ART Program permit another physician, hospital, clinic or other health care facility (the "Transferee") to assume responsibility for their embryos and to transport the embryos from the ART Program's storage facility to its own facility. However, participants should understand that the process of removing the embryos from the storage equipment and transporting them to another facility is delicate and carries a risk of damage to or destruction of the embryos. The ART Program will comply with a request to allow another entity to assume responsibility for the participants' frozen embryos only if: (i) the ART Program staff approves of the proposed use of the embryos by the Transferee; (ii) in the opinion of the ART Program staff, the Transferee has the medical and technical capacity to maintain proper conditions to preserve the embryos or, if transfer of the embryos to the woman or a donee is anticipated, to perform the transfer properly; (iii) the participants or the Transferee will assume responsibility for the embryos from the moment they are removed from the storage equipment by ART Program staff; and (iv) the participants sign a written statement requesting that the removal be permitted and releasing the Dartmouth-Hitchcock Medical Center, its component institutions, the ART Program and its physicians and staff from any and all responsibility for the care and disposition of the embryos. (d) Donation to another couple: Upon the written request of the participants, frozen embryos may be donated to other patients who are unable to produce their own embryos. Some donations may be anonymous, other donations are made to a particular designated individual or couple. The ART Program staff will agree to offer the participants' frozen embryo(s) to another patient only if the participants have both signed a written consent and screened negative for infectious disease in compliance with current FDA regulations. The ART Program staff may refuse to comply with a request to donate embryos if, in their opinion, such donation would be inadvisable for any reason. Under FDA regulations, participants in donor egg cycles or donor sperm cycles will not be able to donate embryos unless they are screened for infectious diseases at the time of 12 revised 11/05

13 retrieval, and in the case of donor egg cycles, unless the sexually intimate partner's sperm has been frozen and quarantined prior to use in ART. Participants in the ART Program may wish to seek the advice of an attorney knowledgeable in the field of reproductive technology before deciding whether to donate embryos, in order to receive current information regarding any potential legal risks that may be involved in such donation. Participants who have a strong desire either to have or not to have embryos donated in the event that they cannot make such a decision for themselves should present such information to the ART Program staff in writing prior to having the embryos frozen. To ensure that they can donate, they may also wish to be tested for infectious disease at the time of egg retrieval. (e) Donation for Research: Upon written request and agreement to sign a consent to donate form, participants may donate their embryos for research. Research embryos will at no time be transferred to recipients for use in establishing a pregnancy. 2. Required Consents or Approvals Before Frozen Embryos are Used for any Purpose. As a general rule, the ART Program staff will not offer a frozen embryo to a donee, release it to another physician or facility or intentionally thaw it and allow it to die without obtaining the prior written consent of the participants. However, the ART Program staff may take action with respect to an embryo (including removing it from storage and allowing it to die), without having first obtained the consent of the participants in situations where the embryo has been "abandoned." Abandonment will be considered to have occurred in the following circumstances: (a) the embryo has been stored at DHMC for a total of 5 years and the participants have been unable or unwilling to make arrangements to transfer the embryos to a long term storage facility; (b) the embryo has been frozen for one year or more and the participants have not responded within 30 days to a certified letter sent to the last address known to the ART Program requesting their consent to a disposition of the embryo. Note: The time frame for storage of over one year must be confirmed in writing by the participants. Storage times may be extended up to 5 years for conditions such as a pregnancy established in the original transfer or a medical condition which temporarily prevents pregnancy; (c) non-payment of storage fees or other hospital bills. Failure to pay storage fees or failure to make appropriate arrangements with the Business Office to pay preexisting bills, may result in discard of stored embryos. 13 revised 11/05

14 Additionally, after receiving the recommendation of the Mary Hitchcock Memorial Hospital Ethics Advisory Committee (hereafter known as the Ethics Committee), the ART Program staff may take action with respect to an embryo without having first obtained the consent of the participants under the following circumstances: (i) One participant has requested a particular disposition and the other can not or will not consent for any reason including, but not limited to, the death, mental incapacity or absence (by virtue of divorce, separation or abandonment) of the other; failure of the other to respond within 30 days to a notice sent to him or her by the ART Program; or the fact that the other participant desires that a different disposition of the embryo(s) be made; or (ii) The participants would like to take action with respect to their frozen embryos that the ART Program staff does not agree with. For example, the participants insist upon the donation of their frozen embryo(s) but, in the opinion of the ART Program staff, such a donation is inadvisable. Before the Ethics Committee makes any recommendation regarding the disposition of any embryos (unless otherwise required by law), it will send notice to the participants, at the last address known to the ART Program, informing them that the matter has been referred to the Ethics Committee and offering them an opportunity to express their opinions to the Ethics Committee. The Ethics Committee will make a recommendation to the ART Program staff and will also forward the recommendation to the participants. After considering the Ethics Committee's recommendation, the ART Program staff will make a decision about disposition of the embryo(s) and will promptly send notice of the decision to the participants. Unless otherwise required by law or court order, no action will be taken with respect to the embryo(s) until at least 30 days after such notification has been sent. While the ART Program staff will give consideration to the Ethics Committee's recommendations, it is not obligated to follow them. It is anticipated that, under some circumstances, the ART Program staff will decide to take action with respect to frozen embryos to which the participants have not consented. For instance, the ART Program staff might decide to thaw certain embryos and allow them to die even though the participant(s) have asked the ART Program staff to continue to store the frozen embryos. The ART Program staff retains discretion to take any action it chooses within the guidelines set forth herein unless ordered otherwise by a court of competent jurisdiction. Such action may include thawing the embryos and allowing them to die. It would not include donating the embryos for use by another couple or for embryo research. Finally, it is possible that the ART Program may be required by law or court order to make a disposition of embryos without first obtaining the consent of the participants or following the other procedures set forth herein. In this event, the ART Program will attempt to notify the participants in advance of taking the action, unless to do so would be impossible or unreasonable under the circumstances. 14 revised 11/05

15 Each participant is responsible for notifying the ART Program, in writing, of any change in his or her address. Any notices required to be given to the participants by the Ethics Committee or the ART Program will be deemed to have been given upon mailing to the last address(es) so provided to the ART Program. 15 revised 11/05