Post by Bozur on Nov 24, 2005 1:59:09 GMT -5
Screening for Abnormal Embryos Offers Couples Hope After Heartbreak
By LAURIE TARKAN
Published: November 22, 2005
After enduring six miscarriages and undergoing six artificial inseminations and two in vitro fertilizations, Kelly Santos, at the age of 35, was dealt the final blow.
Aaron Houston for The New York Times
SCREENING Olivia Santos was born healthy after a genetic procedure.
Genetic Testing of Embryos
"My doctor told me that I would never have a biological child," said Ms. Santos, who lives in Gillette, N.J. The diagnosis was a chromosomal translocation, a mix-up in the arrangement of a few genetic pieces that leads to a high proportion of abnormal embryos and a 90 percent rate of miscarriage.
"It was depressing having all those miscarriages, but when they told me it was over, I wanted to kill myself," she said.
By chance, she heard about a procedure called preimplantation genetic diagnosis, a test that can screen out the abnormal embryos that cause miscarriages. A year later, using the technique, she gave birth to a healthy girl, Olivia.
Preimplantation genetic diagnosis, referred to as P.G.D., is an increasingly popular way to ensure a healthy pregnancy for women who have had multiple miscarriages, those having I.V.F. treatment and couples that are carriers of a genetic disorder.
Only healthy, disease-free embryos are implanted into the uterus, increasing the odds of having a successful pregnancy and a healthy child.
The test is no guarantee that a miscarriage can be avoided because many factors can interrupt the normal course of a pregnancy.
P.G.D. has also been used by parents who want to have a child who is a tissue match for a sibling with a devastating disease. These so-called save-your-siblings can provide umbilical cord cells to the other child, in some cases saving the sibling's life.
And a study published in Nature's online edition last month reported that P.G.D. is also being used to develop embryonic stem cell lines without destroying the embryo.
Amid the excitement, some experts urge caution, because of a lack of research on the procedure's success rate, error rate and potential risks.
Ethicists worry about a procedure that can also allow couples to choose the sex of their child and may one day be used to select embryos for traits like intelligence and physical strength.
There are some failures, and they can be devastating. Doreen Flynn, 29, of Lewiston, Me., had one daughter with Fanconi anemia, a disease that leads to bone marrow failure and a high risk of leukemia and other cancers at a young age.
Ms. Flynn and her husband had P.G.D. to create a tissue-matched baby to provide cells to save their daughter.
Ms. Flynn said she had two tissue-matched embryos transferred, both of which she expected to be disease-free based on medical information she had received. She opted out of the amniocentesis because of the small risk of miscarriage.
Two months after the babies were born, they were tested for Fanconi and both girls had the disease.
"You feel so guilty because you're trying to help one daughter and you end up hurting two other children," Ms. Flynn said. "Now we understand that it's not an exact science and there's room for error."
Still, those who have been helped by P.G.D. describe it as nothing short of miraculous. According to a 2004 survey by the Genetics and Public Policy Center at Johns Hopkins University, about two-thirds of the respondents approved of the use of P.G.D. to prevent a fatal childhood disease and for tissue matching to save a sibling, said Kathy Hudson, the center's director.
The procedure was first successfully performed in humans in 1989 in London, after years of animal testing. It is currently performed in about 10 percent of I.V.F. procedures annually in the United States. (Some 100,000 I.V.F. cycles were performed as of 2002, the most recent year to have complete statistics.) The test adds an estimated $2,000 or more to the already high cost of in vitro fertilization, which can range from $7,000 to $10,000 for each attempt. A majority of women turning to P.G.D. are those who have had more than three miscarriages due to a translocation. Second on the list are I.V.F. patients who are over 35 and have a high risk of having offspring with chromosomal abnormalities, like Down syndrome.
Without P.G.D., many women over 35 get an amniocentesis around the 15th week of pregnancy to test for disabling genetic diseases. If a disease is found, the couple then faces the choice of having an abortion or bearing the child.
Andrew R. LaBarbera, scientific director of the American Society of Reproductive Medicine, said, "That's very distasteful for many people who don't have a problem undergoing P.G.D. to avoid this situation."
Also using the procedure are couples who are carriers of single-gene disorders like cystic fibrosis, fragile X and Tay-Sachs disease. These couples have an extremely high risk of passing the disease on to their children and may have already given birth to a child with the disease. Tests can be given for more than 100 single-gene disorders.
P.G.D. is performed when an embryo has only six to eight cells, called blastomeres. The zona pellicuda, the outer shell of the embryo, is opened with a micro needle, and a single blastomere is removed by gentle suction and sent to a P.G.D. lab for analysis.
This does not kill the embryo because at this stage, each blastomere is capable of developing into a complete organism, or totipotent.
It is not until the embryo passes the 16-cell stage that it begins to differentiate and give rise to stem cells. Yuri Verlinsky, director of Reproductive Genetics Institute, a leading P.G.D. lab based in Chicago, projects that in the next couple of years, P.G.D. "is going to be done for every I.V.F. case, because it definitely improves results."
But Dr. Hudson said there was not enough data on the risks and benefits of P.G.D. and on the long-term health risks to the child.
Numbers coming out of the leading labs show that P.G.D. leads to sharply lower rates of miscarriage and abnormalities, but the data have been reported in different forms by the labs themselves, not by independent researchers.
Santiago Munne, director of Reprogenetics in West Orange, N.J., another leading center, published his miscarriage rates in the August issue of the journal Fertility and Sterility. He reported doing the test for 58 women with recurrent miscarriages.
They had experienced an average of 3.9 previous pregnancies, of which 87 percent were lost. After P.G.D., the miscarriage rate was only 16.7 percent.
At Reproductive Genetics, Dr. Verlinsky reported that of the 4,000 P.G.D. tests his lab has performed, there were 900 pregnancies and 700 live births.
Some experts are concerned about the rate of misdiagnosis.
There is a phenomenon called mosaicism, which occurs when the eight cells that make up the early embryo are not identical.
Mosaicism occurs in about 30 percent of embryos. So a biopsied cell could be abnormal while neighboring cells are normal.
During growth, the normal cells could dominate, producing a completely healthy embryo. But with P.G.D., those embryos would likely be discarded.
On the other hand, if the biopsied cell is normal but the other cells are abnormal, the result may be a diseased embryo.
"About 4 percent of P.G.D. will be misdiagnosed because of mosaicism and maybe 1 percent more are misdiagnosed due to technical error," said Dr. Munne, drawing from his own data on chromosomal abnormalities. Most of these abnormal embryos, though, will not implant or survive, he said.
Dr. Munne said his own rate of clinical error, when a defective embryo does implant and thrive, is 6 in 5,000 cases.
Of these six, all but one spontaneously miscarried; the other pregnancy was terminated.
Dr. Verlinsky reported rates of error for single-gene testing. Of 250 babies, 5 were misdiagnosed; 2 were missed because of technical errors and 3 were because of human error - transferring the wrong embryos.
But error rates vary among centers, and Dr. Munne recommends asking for these figures before getting P.G.D.
Some experts worry that couples may not appreciate the risks. In one survey, Dr. Hudson interviewed P.G.D. patients to see if they understood the potential risks. "We got the impression that while the information had been transmitted, it was not received," she said.
Many couples having P.G.D. see the procedure as foolproof and choose not to have amniocentesis once pregnant because of the small risk involved, said Dr. Serena H. Chen, director of the division of reproductive endocrine and infertility at St. Barnabas Medical Center in Livingston, N.J.
There are other ethical questions about creating one child to save another. The most pressing, Dr. LaBarbera said, is what happens when the cord blood transplant does not work and the parents decide to put the child through a bone marrow transplant?
"That's a very painful procedure, but when you ask parents, they will do anything to save a child they have," Dr. LaBarbera said.
There is no solid research on long-term effects on P.G.D. children, but the potential risk of the procedure should be weighed against the reason a family is getting it, Dr. Hudson said.
"In the case of a family who's facing a one in four or a one in two chance of having a child with a fatal genetic disease," she said, "the context is quite different from those who want to pick the sex of a kid," she said.
By LAURIE TARKAN
Published: November 22, 2005
After enduring six miscarriages and undergoing six artificial inseminations and two in vitro fertilizations, Kelly Santos, at the age of 35, was dealt the final blow.
Aaron Houston for The New York Times
SCREENING Olivia Santos was born healthy after a genetic procedure.
Genetic Testing of Embryos
"My doctor told me that I would never have a biological child," said Ms. Santos, who lives in Gillette, N.J. The diagnosis was a chromosomal translocation, a mix-up in the arrangement of a few genetic pieces that leads to a high proportion of abnormal embryos and a 90 percent rate of miscarriage.
"It was depressing having all those miscarriages, but when they told me it was over, I wanted to kill myself," she said.
By chance, she heard about a procedure called preimplantation genetic diagnosis, a test that can screen out the abnormal embryos that cause miscarriages. A year later, using the technique, she gave birth to a healthy girl, Olivia.
Preimplantation genetic diagnosis, referred to as P.G.D., is an increasingly popular way to ensure a healthy pregnancy for women who have had multiple miscarriages, those having I.V.F. treatment and couples that are carriers of a genetic disorder.
Only healthy, disease-free embryos are implanted into the uterus, increasing the odds of having a successful pregnancy and a healthy child.
The test is no guarantee that a miscarriage can be avoided because many factors can interrupt the normal course of a pregnancy.
P.G.D. has also been used by parents who want to have a child who is a tissue match for a sibling with a devastating disease. These so-called save-your-siblings can provide umbilical cord cells to the other child, in some cases saving the sibling's life.
And a study published in Nature's online edition last month reported that P.G.D. is also being used to develop embryonic stem cell lines without destroying the embryo.
Amid the excitement, some experts urge caution, because of a lack of research on the procedure's success rate, error rate and potential risks.
Ethicists worry about a procedure that can also allow couples to choose the sex of their child and may one day be used to select embryos for traits like intelligence and physical strength.
There are some failures, and they can be devastating. Doreen Flynn, 29, of Lewiston, Me., had one daughter with Fanconi anemia, a disease that leads to bone marrow failure and a high risk of leukemia and other cancers at a young age.
Ms. Flynn and her husband had P.G.D. to create a tissue-matched baby to provide cells to save their daughter.
Ms. Flynn said she had two tissue-matched embryos transferred, both of which she expected to be disease-free based on medical information she had received. She opted out of the amniocentesis because of the small risk of miscarriage.
Two months after the babies were born, they were tested for Fanconi and both girls had the disease.
"You feel so guilty because you're trying to help one daughter and you end up hurting two other children," Ms. Flynn said. "Now we understand that it's not an exact science and there's room for error."
Still, those who have been helped by P.G.D. describe it as nothing short of miraculous. According to a 2004 survey by the Genetics and Public Policy Center at Johns Hopkins University, about two-thirds of the respondents approved of the use of P.G.D. to prevent a fatal childhood disease and for tissue matching to save a sibling, said Kathy Hudson, the center's director.
The procedure was first successfully performed in humans in 1989 in London, after years of animal testing. It is currently performed in about 10 percent of I.V.F. procedures annually in the United States. (Some 100,000 I.V.F. cycles were performed as of 2002, the most recent year to have complete statistics.) The test adds an estimated $2,000 or more to the already high cost of in vitro fertilization, which can range from $7,000 to $10,000 for each attempt. A majority of women turning to P.G.D. are those who have had more than three miscarriages due to a translocation. Second on the list are I.V.F. patients who are over 35 and have a high risk of having offspring with chromosomal abnormalities, like Down syndrome.
Without P.G.D., many women over 35 get an amniocentesis around the 15th week of pregnancy to test for disabling genetic diseases. If a disease is found, the couple then faces the choice of having an abortion or bearing the child.
Andrew R. LaBarbera, scientific director of the American Society of Reproductive Medicine, said, "That's very distasteful for many people who don't have a problem undergoing P.G.D. to avoid this situation."
Also using the procedure are couples who are carriers of single-gene disorders like cystic fibrosis, fragile X and Tay-Sachs disease. These couples have an extremely high risk of passing the disease on to their children and may have already given birth to a child with the disease. Tests can be given for more than 100 single-gene disorders.
P.G.D. is performed when an embryo has only six to eight cells, called blastomeres. The zona pellicuda, the outer shell of the embryo, is opened with a micro needle, and a single blastomere is removed by gentle suction and sent to a P.G.D. lab for analysis.
This does not kill the embryo because at this stage, each blastomere is capable of developing into a complete organism, or totipotent.
It is not until the embryo passes the 16-cell stage that it begins to differentiate and give rise to stem cells. Yuri Verlinsky, director of Reproductive Genetics Institute, a leading P.G.D. lab based in Chicago, projects that in the next couple of years, P.G.D. "is going to be done for every I.V.F. case, because it definitely improves results."
But Dr. Hudson said there was not enough data on the risks and benefits of P.G.D. and on the long-term health risks to the child.
Numbers coming out of the leading labs show that P.G.D. leads to sharply lower rates of miscarriage and abnormalities, but the data have been reported in different forms by the labs themselves, not by independent researchers.
Santiago Munne, director of Reprogenetics in West Orange, N.J., another leading center, published his miscarriage rates in the August issue of the journal Fertility and Sterility. He reported doing the test for 58 women with recurrent miscarriages.
They had experienced an average of 3.9 previous pregnancies, of which 87 percent were lost. After P.G.D., the miscarriage rate was only 16.7 percent.
At Reproductive Genetics, Dr. Verlinsky reported that of the 4,000 P.G.D. tests his lab has performed, there were 900 pregnancies and 700 live births.
Some experts are concerned about the rate of misdiagnosis.
There is a phenomenon called mosaicism, which occurs when the eight cells that make up the early embryo are not identical.
Mosaicism occurs in about 30 percent of embryos. So a biopsied cell could be abnormal while neighboring cells are normal.
During growth, the normal cells could dominate, producing a completely healthy embryo. But with P.G.D., those embryos would likely be discarded.
On the other hand, if the biopsied cell is normal but the other cells are abnormal, the result may be a diseased embryo.
"About 4 percent of P.G.D. will be misdiagnosed because of mosaicism and maybe 1 percent more are misdiagnosed due to technical error," said Dr. Munne, drawing from his own data on chromosomal abnormalities. Most of these abnormal embryos, though, will not implant or survive, he said.
Dr. Munne said his own rate of clinical error, when a defective embryo does implant and thrive, is 6 in 5,000 cases.
Of these six, all but one spontaneously miscarried; the other pregnancy was terminated.
Dr. Verlinsky reported rates of error for single-gene testing. Of 250 babies, 5 were misdiagnosed; 2 were missed because of technical errors and 3 were because of human error - transferring the wrong embryos.
But error rates vary among centers, and Dr. Munne recommends asking for these figures before getting P.G.D.
Some experts worry that couples may not appreciate the risks. In one survey, Dr. Hudson interviewed P.G.D. patients to see if they understood the potential risks. "We got the impression that while the information had been transmitted, it was not received," she said.
Many couples having P.G.D. see the procedure as foolproof and choose not to have amniocentesis once pregnant because of the small risk involved, said Dr. Serena H. Chen, director of the division of reproductive endocrine and infertility at St. Barnabas Medical Center in Livingston, N.J.
There are other ethical questions about creating one child to save another. The most pressing, Dr. LaBarbera said, is what happens when the cord blood transplant does not work and the parents decide to put the child through a bone marrow transplant?
"That's a very painful procedure, but when you ask parents, they will do anything to save a child they have," Dr. LaBarbera said.
There is no solid research on long-term effects on P.G.D. children, but the potential risk of the procedure should be weighed against the reason a family is getting it, Dr. Hudson said.
"In the case of a family who's facing a one in four or a one in two chance of having a child with a fatal genetic disease," she said, "the context is quite different from those who want to pick the sex of a kid," she said.