For women hemophilia carriers, the choice to add a child to the family goes far beyond the question: “Should we or shouldn’t we?” and deeply into the complex territory of reproductive technologies and ethical considerations.
Kate Grazely*, a 28-year-old newlywed from New York City, says she was shocked when she and her fiancé discovered she was a carrier for hemophilia just months before their wedding. “My brother has hemophilia, but my mother had been tested 30 years ago and found not to be a carrier. The disorder is nowhere else in the family, so we always assumed it was a new mutation and I was OK.”
Still, the couple never considered not having biological children—in part, Grazely says, because her brother has had a full life and his bleeding disorder is manageable. The couple spoke to a genetic counselor immediately after discovering her status and learned of their options for starting a family when the time came.
A pregnant woman who is a carrier for hemophilia A or B can expect one of several possible outcomes: A girl who is not a carrier, a girl who is a carrier, a boy without hemophilia or a boy with hemophilia. In rare cases, a girl may also be born with hemophilia. Faced with these possibilities, some couples choose not to have children or to adopt.
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“This [decision not to have children or to adopt] was something that happened more often with the previous generation of the ’50s and ’60s,” says Carol Kasper, MD, emerita professor of medicine at the University of Southern California. “Treatment for hemophilia was inadequate.” More recently, those who came of age during the AIDS crisis of the 1980s often decided not to have their own children, says Kasper, who counsels carriers in her role as hematologist at Orthopaedic Hospital’s hemophilia treatment center (HTC) in Los Angeles.
Today most carrier families do decide to have a biological child, understanding their odds of having an affected child and sometimes lowering those odds through testing and technology. Constance Gibb, a board-certified genetic counselor at Weill Cornell Medical Center in New York, notes that the majority of carriers she works with are looking for ways to reduce the likelihood of passing on the mutation.
“What is so interesting is that when people with a family history of the disorder come in, I can have no preconceptions about what they will choose,” remarks Gibb. “A woman may tell me about watching her brother with hemophilia suffer and will be determined to never have a child with the disorder. Another woman with the exact same history and experience will make a very different choice and feel just as strongly about it.”
Some couples opt to increase their chances of having a child without hemophilia by selecting for a female only. Sex selection can be attempted before pregnancy through a process called sperm sorting. The technology enables Y chromosome sperm to be separated and only X chromosome sperm used to fertilize an egg, either through artificial insemination or in vitro fertilization. The most common procedure is a patented process called Microsort®, developed by the Genetics and IVF Institute in Fairfax, Virginia. It involves adding a fluorescent dye to the sperm and placing the mixture into a device where a laser beam causes the dyed DNA to glow. Because a sperm cell with the X chromosome carries more DNA, it is likely to shine more brightly than a sperm cell with the Y chromosome. Microsort is available through infertility clinics nationwide and costs about $4,000.
The technique is considered safe, but Kasper is skeptical about the 90% success rate touted by the Genetics and IVF Institute. “I would give sperm separation a better than 50 - 50 chance, but nowhere near the 90% the institute claims,” she notes.
Gibb believes the lack of a 100% guarantee and the inability to prevent the birth of a female carrier is probably one reason more couples do not opt for this approach. “I have only had one client do this in the five years I have been here,” she says. The attempt was successful.
Genetic counselors often advise carriers who are already pregnant and want to have the embryo tested for hemophilia or carrier status. This can be accomplished early in pregnancy with chorionic villus sampling (CVS). It can be done as early as 11 to 12 weeks and involves inserting a needle into the womb and extracting a tiny piece of placental tissue containing fetal cells. The sample can then be analyzed for gender and for a hemophilia mutation—but only if the carrier’s specific mutation is known.
[Steps for Living: Family Planning for the Next Generation]
“There are more than 1,000 different mutations for hemophilia, so we have to know which one affects the family’s genetics,” says Kasper. Labs can only look for a specific mutation to determine if an embryo has the disease or is a carrier. “Fathers and brothers with the disease can be tested, but if there are no living relatives with hemophilia and we know the mother is a carrier, it can be done through her.”
Fetal cells may also be screened through amniocentesis at 15 to 20 weeks’ gestation. Amniotic fluid is drawn from the womb, fetal cells are cultured and the chromosomes are studied for the carrier’s hemophilia mutation. The risk of miscarriage from CVS or amniocentesis is small—1% or less, according to data published in the September 2006 issue of Obstetrics and Gynecology. However, some studies have linked CVS to infant limb deformities in rare cases, especially when the test is done before 10 weeks. CVS also slightly raises the risk of uterine infection.
A third, rarely performed, prenatal procedure is percutaneous umbilical blood sampling. It is more invasive and carries a slightly higher risk of miscarriage—about 3%. A needle is inserted into the abdomen to retrieve a sample of blood from the umbilical cord that can be tested for factor VIII or IX. The test is performed at 18 to 22 weeks’ gestation, usually on women whose family mutation could not be identified for some reason. “Testing this late in pregnancy is much tougher for the family psychologically, because they may be facing a second-trimester abortion,” says Kasper.
Personal experience can have a profound influence on choosing abortion. “Many carriers have a lot of feelings related to what they witnessed in their family as children and young adults. I do try to make sure that they are making their choices based on their understanding of what it means to have hemophilia today and not 30 or 40 years ago,” says Gibb.
Still, not all positive results from prenatal testing end in pregnancy termination. Many women use the prenatal results to plan for life with an affected child and to avoid childbirth and postnatal procedures that could trigger a bleeding episode. “We do a lot of liaison with obstetricians and pediatricians who will be caring for a newborn with hemophilia. They do want to know so everyone can be better prepared,” Gibb says. In these cases, obstetricians will attempt a gentle, natural delivery without using injections, forceps, suction or vaginal incisions (episiotomy), and the infant will not be circumcised.
Test Tube Testing
One of the most promising reproductive innovations for carriers is preimplantation genetic diagnosis (PGD). This option involves in vitro fertilization (IVF) and testing the resulting cells so that only an embryo without the mutation is implanted in the womb and carried to term. As with any IVF procedure, hormones are given to the mother to stimulate egg development in her ovaries; then a few are removed and fertilized with the father’s sperm. “Embryos can be diagnosed when they reach eight cells, when it’s safe to pluck off one cell and look at the DNA for the family mutation,” says Kasper.
This is the option Grazely and her husband chose when they were ready to have their first child early this year. “We didn’t want to be put in the position of terminating at 11 weeks [after CVS]. We were just not comfortable with that choice, knowing [hemophilia] is a disorder you can live a full life with. If it had been a horrible, destructive disease, we may have thought differently.”
Grazely’s PGD procedure occurred over about four months at Weill Cornell. It involved self-injections twice a day and going into the hospital almost every day until her eggs were harvested, fertilized, tested for the mutation and implanted. The couple decided to have two healthy embryos implanted, a male and a female. Still, the odds of conception weren’t much better than infertile couples experience, a fact that surprised Grazely. “The doctors told us not to expect me to get pregnant the first time, because it was such an imprecise process,” she says. “They wouldn’t give us exact numbers, but said the first-time success rate for IVF even in a fertile couple is just 30% to 50%.”
Fortunately for Grazely and her husband, one of the two embryos implanted successfully and is growing into a healthy boy without the mutation. Because the doctors told them PGD was not 100% accurate—closer to 95% to 97%—they opted for CVS at 11 weeks to confirm that their fetus is an unaffected son. They also have six frozen embryos waiting for them when they are ready for a second child—two unaffected males, an unaffected female and three female carriers.
Like the Grazelys, many couples store unused unaffected embryos for future pregnancies. Still, since PGD requires the destruction of affected or never-used embryos, the practice could create ethical concerns for those who believe that life begins at conception and should be preserved. It is important that couples understand what will become of unused fertilized embryos before they begin the IVF process. Some people may be open to the options of allowing unused embryos to be used in medical research or donating them to infertile couples.
Kasper estimates the cost for the procedure to be about $20,000 for the IVF, plus another $2,500 to $4,000 for the cell biopsy. “But here’s something interesting,” says Kasper. “Private insurance companies are starting to pay for [these procedures] for genetic disorders. The expense of having a baby with hemophilia under their coverage is huge.” Public insurance, like Medicaid and state insurance for people with hemophilia, hasn’t caught on to paying for genetic testing yet, though. “Sometimes you are better off with private insurance companies because they will listen to reason.”
Grazely estimates her own expenses at about $30,000, but her health insurance didn’t pay for any of it. “It was a huge struggle trying to get it covered, and it really was the most uncomfortable, unpleasant thing we had to deal with in the whole process,” she recalls. “We were lucky to be able to afford this option, and we are so excited about the future. It was all worth it.”
With so many options, carrier families considering their first or subsequent child benefit enormously from genetic counseling, available through most HTCs. The National Hemophilia Foundation’s Medical and Scientific Advisory Council recommends genome-based diagnosis for anyone with inherited coagulation factor deficiencies as part of an overall comprehensive care plan, thereby enhancing the medical management of carriers and their unborn children at risk. Armed with the results, highly trained counselors can help families get appropriate information to help them weigh all the options in an environment that allows them to explore their feelings about each one. For more information, read MASAC Guidelines #192 for Perinatal Management of Women with Bleeding Disorders and Carriers of Hemophilia A And B.
“Families really like to have the time and a safe place to talk,” says Liane Abrams, a board-certified genetic counselor and consultant with Children’s Hospital & Research Center in Oakland, California. Through the hospital’s bleeding disorders clinic, she conducts about a dozen sessions a year with families affected by hemophilia.
“With most medical procedures, people are given information about what it entails and that is the limit of their interaction,” Abrams says. “That’s what’s different about genetic counseling. Rather than simply being given facts and asked to make a decision, families have a chance to have their thoughts and emotional processes be part of the session. They can talk to someone who has an understanding of what this means to themselves and their families.”
To give the best advice, genetic counselors ask for test results before a session indicating the type of mutation affecting the family and whether that correlates with the mild, moderate or severe form of hemophilia. “We also need results of genetic testing on the carrier,” Abrams notes. “For example, if the father has a particular mutation, we assume the carrier has the same one, but there is always the possibility—though infrequent—that [the carrier’s] test results might be surprising.”
In a counseling session, which typically lasts an hour, a detailed family history is taken and a pedigree created. Then the discussion becomes more intimate, Abrams says. “I always like to have a sense of how hemophilia has affected these people’s lives, and in what ways it has been manageable—or not,” she says. “I want to learn how they view this condition in relation to themselves, their child and their family.”
Abrams also asks carriers if they have complications related to their condition, such as excess menstrual bleeding, to ensure they have no underlying problems managing their own disorder. “It’s helpful to know how they view themselves, health-wise.”
Then she will review the family’s reproductive options. Like all genetic counselors, she never makes recommendations but simply offers detailed information. “If [the carrier is] pregnant already, we will talk about prenatal diagnosis. If it is before nine weeks, we’ll discuss CVS. After 11 weeks we talk about amniocentesis.”
Many of Abrams’ clients are not pregnant, however. “Many have been recently diagnosed as carriers and want to talk about the “big picture” of their future. Others are ready to get pregnant and want to discuss specific plans,” she says.
Abrams points out that counseling may take on different tones depending on the setting. “My setting is unusual in that it is a specialty clinic in a pediatric hospital that does not offer prenatal tests or procedures,” she says. “They come to me because I am a specialist in bleeding disorders.” In a prenatal testing center, on the other hand, patients who seek counseling are more interested in learning about specific procedures they are considering, and how to care for themselves afterward.
Both settings embody an oasis where families can talk candidly about their situation, says Abrams. “As we talk, we go over how the results [of upcoming tests] will affect the family. How might they feel if it is a girl who is a carrier or boy with hemophilia?”
“Genetic counselors know how to put all the pieces together for the woman but will be nonjudgmental,” agrees Kasper. “I try very hard to do this. I will never push a woman into a decision.”
Still, these sessions sometimes produce unexpected results for clients. Kasper remembers one client who initially did not want to go through with her pregnancy. “She was a carrier of a very mild type, but told me her father [who had hemophilia] was always in the hospital. It turns out he [was an avid motorcycle enthusiast].” Once the client realized her worries were probably exaggerated, she saw things differently. “She is very happy with her baby now. Although we still don’t know if he inherited the motorcycle gene.”
* Name has been changed