STEPS TO
PREGNANCYOne of the more disturbing pieces of information BMT patients may hear prior to their transplant is that their ability to achieve a pregnancy post-BMT will be impaired. For persons who have not yet begun or wish to expand their family, this news can be devastating.
It's not the BMT itself but the high-dose chemotherapy and/or radiation administered prior to the BMT that often damages reproductive cells. Most chemotherapy agents and radiation are incapable of distinguishing between normal and diseased cells and may damage delicate reproductive cells while eradicating the disease.
Not all patients undergoing a BMT experience infertility. The likelihood of infertility varies according to the patient's age, gender, sexual maturity, the type and amount of chemotherapy and/or radiation administered, and preventive steps taken during treatment. Thus, many patients with leukemia or Hodgkin's disease often are infertile before a BMT, as a result of prior chemotherapy.
Since post-transplant infertility is not a life-threatening condition, little medical attention has focused on the problem to date. As the survival rates for BMT patients continue to improve, however, "quality of life" issues like fertility are becoming a major concern for BMT survivors.
Fortunately, there are options available to couples who wish to have children post-transplant. Besides adoption, medically assisted reproduction techniques such as sperm-banking, cryogenic preservation (freezing) of embryos, artificial insemination, in-vitro fertilization, and sperm and embryo donation provide hope for patients who are infertile following their BMT. Religious, ethical, medical and financial concerns may temper the range of options an individual is willing to consider. However, understanding the options in advance of your BMT treatment will enable you to better plan for children post-transplant, and relieve some of the stress associated with the prospect of infertility.
STEPS TO
PREGNANCYAchieving a pregnancy is a delicately timed, intricate process. Normally, both partners must have functioning reproductive organs that enable the woman to produce a mature egg that can be fertilized by healthy male sperm. The fertilized egg must then migrate to the woman's uterus and implant in the lining (endometrium) where it will begin to mature into a fetus.
Eggs are produced in the ovaries. At the beginning of each menstrual cycle, follicle stimulating hormone (FSH) is released by the pituitary gland located near the brain. FSH causes immature eggs (oocytes) contained in fluid filled sacs (follicles) inside the ovaries to begin to mature-one egg per follicle. Although 100150 oocytes may begin to mature each cycle, only one egg in one ovary will usually reach full maturity around the 12th to 14th day of the cycle.
The developing eggs release a hormone into the bloodstream called estrogen. Estrogen, among other things, causes the lining of the uterus to thicken in preparation to receive an embryo. The estrogen level will peak when the single egg destined to mature that cycle is fully developed, stimulating the pituitary gland to produce "luteinizing hormone" (LH).
LH triggers the release of the mature egg into the fallopian tube. The enveloping outer layer of the follicle (after ovulation, called the corpus luteum) remains in the ovary and produces progesterone. Progesterone and other hormones secreted by the corpus luteum fortify the uterine lining so that it can receive and nurture the embryo.
The fallopian tubes connect the ovaries to the uterus. At the junction of the ovaries and fallopian tubes are small fingerlike "fimbria" that pick up the mature egg and move it into the fallopian tube where fertilization occurs. Since the egg must be fertilized within 24 hours of entering the fallopian tube, there is a very small "window of opportunity" for sperm to enter the woman's uterus via the vagina, migrate to the fal- lopian tube, and fuse with the egg to create an embryo. Although as many as W million sperm may be ejaculated during sexual intercourse, only a few hundred will successfully reach the fallopian tubes.
Once the sperm fertilizes the egg, the resulting single cell embryo begins to divide and multiply. By the 4th or 5th day, when it enters the uterus, it's composed of more than 100 cells. The embryo must implant in the uterine lining in order to continue growing. This usually occurs five to seven days after fertilization and is the beginning of a pregnancy. If implantation occurs, the embryo will discharge a hormone called "human chorionic gonadotropin" (HCG) that signals the ovaries to continue producing estrogen and progesterone to support the uterine lining. (Early pregnancy tests measure the level of HCG in the blood.) If the embryo fails to implant, it degenerates and is destroyed by the immune system.
Sperm are manufactured in microscopic threadlike tubes in the testicles called "seminiferous tubules." The same hormones that stimulate the production of eggs in women's ovaries-FSH and LH-stimulate production of sperm in men.
The cells on the inside walls of the seminiferous tubules generate millions of new immature sperm cells (spermatocytes) daily. A spermatocyte divides twice as it migrates to the center of the seminiferous tubule, where the resulting four "spermatids" mature into tadpole shaped sperm. The heads of the sperm contain the genetic information that will fuse with the woman's egg, as well as chemicles that enable the sperm to penetrate the outer shell of the egg.
The sperm leave the testicles and move through a long coiled tube called the "epididymis" where they mature and are stored. Upon ejaculation, the sperm move to pouches behind the bladder called "seminal vesicles" where fluid from the seminal vesicles and the prostate gland is added to create semen (98 percent fluid, 2 percent sperm). The fluid provides nutrients to sustain and protect the sperm. The semen then passes through the "urethra" a tube in the penis connecting both the bladder and the seminal vesicles to outside the body.
During sexual intercourse, sperm are ejaculated into a woman's vagina near the "cervix" or the entrance to the uterus. The sperm must navigate through the cervix and uterus into the fallopian tubes where fertilization of an egg can occur. Upon meeting the egg, one sperm will use the chemicals stored in its head to penetrate the shell of the egg and drill to the center where its genetic material (DNA) will fuse with that of the egg, creating an embryo.
Chemotherapy, especially combination chemotherapy, can damage or destroy the cells in testes and ovaries from which sperm and eggs evolve. Radiation causes similar problems, and can damage the uterine lining or fallopian tubes as well.
Infertility caused by chemotherapy and/or radiation may be temporary or permanent, and may occur at low doses as well as the higher doses administered pre-BMT. Patients who have undergone standard chemotherapy and/or radiation treatment for their disease prior to considering a BMT are often already infertile at the time of their BMT.
A class of chemotherapy drugs called "alkylating agents" is especially toxic to reproductive cells. They include cydophosphamide (Cytoxan), ifosfamide, melphalan (l-Pam), mechlorethamine hydrodchloride (nitrogen mustard), thiotepa, and busulfan (Myleran). Other chemotherapy drugs such as carmustine (BCNU), chlorambucil, cytosine arabinoside (cytarabine) (ARA-C), cisplatin (CDDP), doxorubicin (Adriamycin), procarbazine, and vinblastine (Velban) can also cause infertility.
In general, younger patients are less likely than older patients to develop permanent infertility as a result of standard chemotherapy treatment. This is particularly true of pre-pubertal patients and women. Infertility is often related to the type and dosage of chemotherapy administered, with higher cumulative dosages being more toxic to reproductive cells than lower dosages.
Patients with early-stage Hodgkin's disease can sometimes be treated with ABVD (Adriamycin, bleomycin, vinblastine, and DTIC or dacarbazine), which is equally efficacious, but less toxic to reproductive cells than another chemotherapy regimen used to treat the disease called
MOPP (nitrogen mustard, Oncovin, procarbazine and prednisone). This less toxic therapy is not an option, however, when the disease has progressed to the stage where a BMT is required.
Researchers have theorized that administering hormones in conjunction with chemotherapy to suppress reproductive organ functions during treatment may reduce the incidence of permanent infertility. This theory, however, has yet to be confirmed by large clinical trials.
Most of the information known about the effect of chemotherapy on reproductive cells has been drawn from studies of patients receiving lower doses of chemotherapy than typically administered to BMT patients. In the one study conducted on BMT patients (with aplastic anemia) who received high-dose chemotherapy pre-transplant (200 mg/kg of cyclophosphamide without total body irradiation), all females under the age of 26 regained fertility post-transplant, while only one-third of females over the age of 25, and two-thirds of all males regained fertility post-BMT. (These results should not be extrapolated to patients undergoing different high-dose chemotherapy regimens pre-BMT for different diseases.)
DRUGS THAT CAN CAUSE INFERTILITY
Use of radiation in combination with chemotherapy increases the risk of infertility, even in younger patients. Patient age, sex, stage of sexual maturity and total cumulative dosage affect the likelihood of infertility after radiation therapy. Few patients who receive total body irradiation pre-BMT remain fertile post-transplant.
Although data on pregnancies post-BMT are not systematically gathered and centrally reported, at least 64 pregnancies by BMT patients are known to have occurred.
Couples who wish to bear children post-transplant may benefit by recent advances in medically assisted reproduction technology. While not always successful, assisted reproduction provides men with the opportunity to contribute to the genetic make-up of their child and allows women to be the biological (and sometimes genetic) mother of the child.
For men undergoing chemotherapy and a BMT, sperm-banking is the best way to preserve their ability to be a biological father in the future. Artificial insemination is a procedure in which male sperm are injected into a woman's vagina at the point in her monthly cycle when the mature egg is most likely to have been released into the fallopian tube. Since it can be difficult to precisely predict when the egg will reach the fallopian tube, artificial insemination is often repeated over two consecutive days to maximize the likelihood of success. If the sperm fertilizes the egg, and the resulting embryo migrates to the uterus and implants in the lining, a pregnancy begins.
Frozen sperm have been successfully used in artificial insemination. Thus men facing the possibility of infertility post-transplant may wish to "bank" some of their sperm prior to the BMT to enable fertilization of their partner's egg at some later date.
Sperm banking is a relatively simple procedure. Typically, several ejaculates of sperm are collected over a one to three week period and frozen or "cryopreserved" in sterile containers. On average, six vials of Sperm are obtained per ejaculate. (One or two vials are needed for each
artificial insemination cycle.) Although the sperm count and motility (ability of sperm to propel themselves forward) of ejaculates from pre-BMT patients are sometimes lower than values typically required by a sperm bank for cryopreservation, they nonetheless can usually be frozen and later used successfully in artificial insemination cycles.
Charges for sperm banking include a fee to process the semen sam- ple ($100-$500 per ejaculate), an annual storage fee ($150-$400 per patient), and packing and shipping charges. Charges for the artificial insemination procedure itself include a fee to thaw and prepare the sperm ($100-$200 per vial) and the physician's fee. Health insurance plans may cover all, some or none of these charges.
If a patient's sperm is not frozen prior to the BMT, it is still possible to achieve a pregnancy via artificial insemination using donor sperm. The sperm may be provided by a donor known to the couple, or obtained anonymously from a sperm bank.
Some sperm banks that supply anonymous donor sperm samples will provide non-identifying information about the donor e.g. age, race, hair and eye color, religion, occupation, hobbies, etc. It's recommended that anonymous donor sperm be frozen for at least six months prior to use so that comprehensive testing for HIV (the AIDS virus) can be con- ducted. The cost of donor sperm varies from $25 to $125 per vial, depending on the sperm bank.
According to a 1988 study prepared by the U.S. Office of Technology Assessment, 65,000 infants are born annually through artificial insemination. Individual clinics report that 50 to 90 percent of women who undergo artificial insemination for a 12-month period using fresh sperm, or an 18-month period using frozen sperm, become pregnant.
A successful artificial insemination program requires a physician who's skilled in determining when a woman will ovulate so that the timing of the insemination maximizes the likelihood that the sperm will fertilize the ovum. Handling frozen sperm requires more physician and laboratory skill than working with fresh sperm since techniques and temperatures used in thawing, cleaning and incubating the sperm sample affect the number of sperm that survive the thawing process. Fifty to 75 percent of sperm in a cryopreserved sample typically survive the thawing.
In addition to a viable sperm sample, artificial insemination requires normal reproductive functions on the part of the woman to be inseminated. If she has difficulty producing a healthy egg, if her uterus is not properly prepared during the reproductive cycle to receive and nurture the embryo, if there is scarring in her fallopian tubes or if she is over the age of 39, succesful artificial insemination may not be possible without further medical intervention.
Although it's possible to freeze male sperm, it's very difficult to successfully freeze unfertilized eggs. No live births have yet been reported using eggs that were frozen prior to fertilization. An option analogous to sperm-banking, therefore, is not now available to women facing post- BMT infertility. It is, however, possible for women with post-BMT ovarian failure to attempt in-vitro fertilization (IVF) with donor eggs.
In IVF several mature eggs provided by a woman are combined in a laboratory dish with male sperm, where fertilization occurs. The resulting embryos are then transferred to the woman's uterus. If an embryo implants in the uterine lining a pregnancy begins.
Initially IVF was used to help women whose ovaries were functional (were capable of producing eggs) but who nonetheless had difficulty conceiving a child. More recently, women with ovarian failure, women of advanced age, and women who have concerns about the integrity of their eggs following chemotherapy or radiation treatment have used IVF with donor eggs to achieve pregnancy. Although IVF with donor eggs does not enable a woman to contribute to the genetic make-up of the child, she does provide the nurturing womb during the nine months of pregnancy required for successful childbirth, and is the biological (as distinguished from genetic) mother of the child.
Donors in IVF programs may either be someone known to the couple or anonymous. Some IVF donor programs require couples to provide their own egg donors, others strictly use anonymous donors, and still others will work with either.
To secure the necessary eggs, the donor is injected with drugs such as human menopausal gonadatropin (Pergonal), FSH (Metrodin), HCG, or leuprolide (Lupron) over a 10 to 21 day period to stimulate several eggs to mature in the ovaries. The patient into whose uterus the fertilized eggs will be transferred is put on a daily regimen of oral estrogen and progesterone injections to prepare the uterus to receive and nurture the embryos.
When the donor's eggs have matured, they are "harvested" through a minor surgical procedure called ultrasound guided needle aspiration, or through another surgical procedure requiring general anesthesia called laparoscopy. The eggs are combined with male sperm in a labora- tory dish and incubated for 18-24 hours. The resulting embryos are transferred to the recipient's uterus using a thin catheter with a syringe on the end. Typically three to five embryos are transferred during this five to 10 minute non-surgical procedure.
Two variations on IVF are "GIFT" (gamet intrafallopian tube transfer) and "ZIFT" (zygote intrafallopian tube transfer). In GIFT, male sperm and donor eggs are combined after retrieval and immediately injected into the fallopian tubes so that fertilization can occur in its normal environment rather than in the laboratory. In ZIFT, the eggs are fertilized by sperm in the laboratory and then transferred to the fallopian tubes rather than the uterus as in IVF. While some clinics report higher success rates with GIFT and ZIFT than with IVF, many experts argue these results are biased by patient selection, and do not control for the skill of the laboratory personnel who handle the fertilization process during IVF.
Charges for a single IVF, GIFT or ZIFT cycle range from $6,000 to $12,000 depending on the clinic involved, financial arrangements with the donor, and travel/lodging costs. All, some or none of these charges may be covered by your health insurance. Follow-up expenses (e.g. pregnancy tests, prenatal care, etc.) are usually covered by insurance in the same way that standard pregnancies are covered.
Although it is not currently feasible to freeze unfertilized female eggs, it is possible to freeze fertilized eggs or embryos. In most IVF programs, any embryos in excess of those needed for transfer to the uterus that cycle are frozen for later use.
At least one clinic, Center for Reproductive Medicine & Infertility at Cornell Medical College, New York City, has initiated an experimental program that affords women who are about to undergo chemotherapy and/or radiation the opportunity to freeze their own fertilized eggs prior to treatment. Eight women have participated in the program to date. Although fertilized eggs have been successfully frozen, none of the patients has sufficiently recovered from her disease thus far to attempt an IVF transfer with the frozen embryos.
According to figures released by the US IVF Registry, 48 clinics performed IVF with donor eggs on 328 women in 1989. Of the 377 IVF- donor embryo transfer cycles attempted, 21 percent resulted in live births. Success rates for IVF embryo transfer cycles using frozen embryos were lower (8 percent), with 10 of the 110 reporting clinics accounting for 54 percent of all live births.
Several factors influence IVF-donor embryo transfer success rates, and great care should be exercised in interpreting and comparing statistics from individual clinics. In addition to the skill of the physician and laboratory personnel, the age of the woman undergoing IVF, the age and responsiveness of the donor to ovary-stimulating drugs, and male sperm factor problems all influence an IVF success rate.
Finding a competent assisted reproduction program that suits your needs requires research, careful analysis, and guidance from an informed gynecologist or infertility specialist. You may need to travel out of state to find a program appropriate for you.
The Society for Assisted Reproductive Technology (SART) sets minimum standards that member programs must follow regarding cryopreservation of sperm and embryos, artificial insemination and in-vitro fertilization. SART also requires member programs to meet certain criteria regarding training and experience of physicians and laboratory personnel working in the program, and to publicaly release data on their clinic's success rates. The American Fertility Society (AFS) can provide you with a copy of these standards, a list of SART members, clinic-specific success rates for IVF (data does not include IVF cycles using donor eggs) and can identify those members with IVF-donor egg programs.
When selecting a fertility program, ask how many artificial insemination or IVF-donor egg cycle have been attempted by the clinic, and how many live births have resulted. When evaluating individual programs, it's helpful to focus on their success rate with couples whose specific fertility problems, medical history, and age mirror your own, as well as the program's overall success rate. Be wary of established programs that provide only national success rates or data on other clinics' experiences rather than their own.
If you're considering IVF with donor eggs and are unable to supply your own donor, ask whether the fertility clinic provides donors. If the answer is yes, find out how many active donors are currently available and how long you must wait before being matched. Some programs say they have donors available, but in fact are still trying to locate some. Others have numerous donors on call who can be matched with you in a reasonably short period of time. Ask how donors are recruited, what medical and other evaluations are conducted, and what you can specify about the donor with whom you're to be matched.
Fertility programs also differ in the level of emotional support and psychological counseling they provide. At some clinics, psychologists and social workers are an integral part of the program, while at others no such support services exist. Medically assisted reproduction can be a trying experience and you may find such support services important.
Before deciding to attempt medically assisted reproduction, couples need to consider the BMT patient's prognosis for long-term survival, whether the healthy partner is prepared to handle single-parenting (either temporarily or long-term) if relapse or death occurs, and the impact of a relapse or death on the child. Patients should also discuss with their physician whether pregnancy could exacerbate their medical condition.
As with BMTs, medically assisted reproduction offers no guarentee just a chance of pregnancy. It may take several tries before pregnancy is achieved and some couples may never be successful. Moreover, if pregnancy is achieved, the usual possibilities of miscarriage and fetal abnormalities exist. Couples should be prepared for disappointment as well as success.
Programs involving donor eggs or sperm can create additional dilemmas. Will the couple be more comfortable with a known donor or an anonymous donor? Should relatives and friends be told if a donor is used? What will the child want to know about the donor who helped make conception possible?
For couples who choose to produce and freeze embryos for future use, the question of what to do with the embryos if one partner dies or if the marriage is dissolved must be addressed. Should the embryos be destroyed? Should they be donated to another infertile couple? Should one partner in a divorce be awarded custody rights? These are emotionally charged legal and ethical questions that couples may find very difficult to address, particularly if the decisions must be made at the same time a BMT or other cancer therapy is being considered.
Successful adoption requires a major commitment of time, resources, and emotional energy. There are two adoption strategies to consider: agency-assisted adoption and private adoption.
Several agencies facilitate adoptions in the U.S. They vary greatly in the number of children available for placement, fees, and requirements for adoptive parents.
"Traditional" agencies (e.g., Catholic Charities, Jewish Children's Bureau, and several non-denominational agencies) are the least costly way to adopt a child, but facilitate the fewest adoptions annually. They have the most restrictive requirements for adoptive parents regarding religion, marital status, marital time, age, employment status, proof of infertility, the number of other children in the home, and health status. "Non-traditional agencies are more expensive but have more children available for placement and are more flexible in the type of adoptive parent with whom they're willing to work.
Some agencies specialize in out-of-state adoptions, international adoptions, or adoption of "waiting children" e.g., minority or biracial children, older children, children with special physical or emotional needs, and children who are part of a sibling group. Persons willing to adopt "waiting children" can often locate a child more quickly than those with stricter age, ethnic or health requirements.
Most agencies offer adoptive parents the security of knowing that birth mothers have been screened for medical fitness, history of drug/alcohol abuse, etc. and have been counseled in and assisted with prenatal care. Agencies also usually counsel birth mothers regarding their decision to place the child with adoptive parents and discuss with them all other options in an effort to ensure that the mother is making an informed decision.
In most states a replacement "home study" to license the adoptive parents is required for any agency-assisted, out-of-state, or international adoption. Adoptive parents must provide written proof of medical fitness as part of the home study. Former BMT patients may find it difficult or impossible to satisfy the medical requirements of a home study and may therefore need to pursue "private adoption. However some states require a home study for private adoption as well).
It's very common and usually much faster for adoptive parents to locate a birth mother on their own rather than rely on agencies. In most states, there are attorneys and/or adoption consultants who specialize in counseling adoptive parents on how to search for birth mothers and how to screen and work with prospective birth mothers during the pre-natal period. The consultants also provide guidance on legal issues such as the level of financial assistance (if any) allowed by the state to be paid to the birth mother during the prenatal period, custody rights of the birth mother and father, and the proper procedure for legally finalizing the adoption after birth.
Great care is advised when selecting an attorney to assist with a private adoption. Most states have strict laws against "baby brokering" that limit the level of attorney involvement in finding babies for adoptive parents. Attorneys who seek out birth mothers and pressure them into placing their child in an adoptive home, who make illegal payments to birth mothers to secure children, or who mishandle legal notices and filings required to finalize the adoption process place adoptive parents at risk of losing the child if the birth mother (or father) later seeks reversal of the adoption.
The cost of adoption can range from as little as $8,000 to $30,000, with most falling in the range of $10,000 to $15,000. Factors influencing the price include whether you use an agency or adopt privately, whether the adoption is in-state, out-of-state or international, the extent to which the birth mother's medical and personal expenses must be (and can legally be) financed by the adop ve parents during the prenatal period, and whether or not your insurance or employee benefit plan covers some adoption-related expenses.
Finding a baby to adopt can be a lengthy and frustrating process. It may take many months to locate a birth mother willing to place her child in your custody. Moreover in many states, birthmothers (and sometimes fathers) can, for a period of time after the child has been placed in an adoptive home, rescind their decision to allow the child to be adopted. These legal challenges can be very traumatic for everyone involved.
"Open" adoptions in which the birth parents and adoptive parents meet and/or learn something about each other are now quite common. Some birth mothers may want ongoing contact with the child after birth as a condition of adoption. Adoptive parents need to assess the level of "openness" (if any) with which they and the adoptive child will be most comfortable.
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