Embryo Screening

Preimplantation genetic diagnosis provides some answers but raises questions for IVF parents.

By Charlotte Huff featured image Juan Gaertner/ Science Photo Library

When Katie Cox and her husband, Chris, reached their decision that August day in 2014, the embryos were identified only as 9 and 11.

By that point, the 33-year-old suburban Dallas woman had undergone more than a month of daily injections to stimulate egg production, followed by enviably fertile results — 17 embryos that had survived to the third day, the earliest that they could be genetically tested. The Cox parents, who already had two sons, wanted to know which embryos carried the mutation for a serious genetic disorder called autosomal dominant polycystic kidney disease (ADPKD).

Katie’s mother has the adult-onset disease, in which fluid-filled cysts accumulate in the kidneys, causing progressive damage, even kidney failure. Patients may need dialysis. Katie herself was diagnosed a decade ago, at age 25. It wasn’t until she was pregnant with her second son that she first heard about preimplantation genetic diagnosis (PGD) at a medical conference. “I said to my husband, ‘You know, if we decide to have another child, knowing this information now, it would not be smart to do it without using preimplantation genetic diagnosis,’ ” she recalls.

The technique, which was first described in humans in study publications in the late 1980s, tests one or more embryonic cells within the first five or so days after conception. In the years since, its potential uses have significantly expanded, and these days PGD can screen for more than 200 genetically linked diseases, according to a 2014 piece published in Nature Reviews Neurology. Even though in most cases only a single known familial condition is being tested for, the genetic science opens the door to a host of related financial, logistical, and ethical conundrums for prospective parents to sort through.

Couples like Katie and Chris, who had no prior difficulty getting pregnant, have to commit to the rigors and costs — if they can afford it — of undergoing in vitro fertilization (IVF) prior to genetic testing. Plus, there are ethical issues that prospective parents, ethicists, and clinicians continue to struggle with, regarding when it’s appropriate to use this relatively new scientific option. While the testing was developed to target serious diseases diagnosed in childhood, such as sickle cell disease and cystic fibrosis, it’s also ethically permissible to use for adult conditions that are “serious” and for which “no safe, effective interventions are available,” according to a 2013 committee opinion from the American Society for Reproductive Medicine (ASRM).

But since there are no legal restrictions on PGD, the final decision falls on the prospective parents and their doctor, often in consultation with a genetic counselor, says Mark Sauer, professor of obstetrics and gynecology at New York City’s Columbia University and an ASRM ethics committee member. And more couples are facing these choices, as pre-conception genetic testing becomes more common and disease vulnerabilities are picked up that haven’t yet appeared in the family, he says. “PGD is being applied to people that are fertile, not infertile — this is where the field is moving, and rapidly.”

Katie vividly recalls sitting with her husband in the doctor’s office that August day, already prepped for the implantation procedure, waiting on the results from the cells, which had been shipped to a lab in Michigan. Of the 17 embryos, then five days old, they learned that seven carried the mutation for the kidney disease. Five more had insufficient genetic information from testing to make a conclusive determination, according to Rebecca Chilvers, Katie’s reproductive endocrinologist, who practices near Dallas.

Of the remaining five embryos, three were male and two were female. The Cox parents had opted to learn gender, a still controversial option in the PGD process. (In a 2015 committee opinion, the ASRM failed to reach a consensus, stating that selecting for gender for non-medical reasons was up to individual clinics and practitioners.) But with two boys already, Katie said she wanted to boost her odds of bringing home a daughter. The two female embryos, 9 and 11, were implanted and joined the family in spring 2015 as Elizabeth and Sarah.

The IVF process was far from enjoyable — there are much more fun ways to have a baby, Katie quips — and not cheap. Treatment costs approached nearly $20,000, she estimates, of which roughly $6,000 was related to the genetic testing. But, she counters, “it’s a lot cheaper than it’s going to be to have medicine and dialysis and a kidney transplant later. And so, it just seemed like the right thing to do.”

Detecting Mutations

Preimplantation genetic diagnosis is often combined with preimplantation genetic screening, but the two procedures are distinct. PGD checks for a variety of gene-linked mutations, including those that directly cause disease and others, such as the mutations for BRCA, which significantly increase a disease-related risk. Preimplantation genetic screening, also performed before the embryo is implanted in the uterus, looks for abnormalities in the number of chromosomes that can increase the chance of miscarriage or a disorder such as Down syndrome.

The spectrum of diseases and conditions that PGD can screen for is long and getting longer: Huntington’s disease, Duchenne muscular dystrophy, familial Alzheimer’s disease, and mitochondrial disorders, as well as cancer-susceptible mutations such as Lynch syndrome and BRCA, to name just a few. Some, such as cystic fibrosis, are classified as recessive disorders because two copies of the defective gene — one from each parent — must be inherited to cause the disease, which means any child has a 25 percent risk of being affected. With a dominant single gene disorder like the mutation for PKD, only one copy is required and the newborn’s risk is 50 percent.

With the Cox embryos, a single cell was extracted from each one at three days, when the embryos measure six to 10 cells, to be tested for the PKD mutations. That approach worked well because the testing was looking for only a single gene, and it allowed the embryos to be immediately transferred while fresh — rather than frozen for a later implantation procedure — which Katie preferred, according to Chilvers, her doctor.

Increasingly, though, the embryos are being tested once they reach the blastocyst stage, typically on day five, Sauer says. At that point, the embryo is larger, with roughly 100 cells, and has developed two distinct areas, one of which will ultimately become the baby’s placenta. Thus, a few cells can be removed from that area rather than the inner mass of cells that will become the fetus, he says.

Regardless of the approach, patients shouldn’t be guaranteed 100 percent accuracy or safety, Sauer says. To date, the testing hasn’t been linked to any fetal abnormalities, according to the 2013 committee opinion by the ASRM. But long-term safety data is not available and the possibility can’t be ruled out, the committee members wrote.

PGD is typically not covered by insurance, although there have been some exceptions, says Emily Mounts, director of genetic services at Oregon Reproductive Medicine, a clinic in Portland. Prior to starting the process, the test has to be customized to a family’s relevant mutations, a process that requires one to two months, but may take longer, Mounts says. In all, the PGD cost can range from $5,000 to more than $10,000, depending upon how many mutations are being screened and the number of embryos involved, among other factors, she says.

One significant challenge, Mounts says, is lack of awareness. One survey analysis published in 2013 involving 220 U.S. internists found that only 5 percent reported suggesting PGD to their patients. Another analysis, published in 2010 in Fertility and Sterility, focused on 210 couples with known genetic disorders who wanted to get pregnant. Of them, 42 percent had never heard of PGD.

Ethical quandaries

Among ethicists and clinicians, there’s been more debate about the use of PGD to screen for adult-onset conditions rather than for those that appear in childhood, says George Annas, author of Genomic Messages, who also directs the Center for Health Law, Ethics & Human Rights at the Boston University School of Public Health. Part of that debate stems from the medical uncertainty, Annas says. “You’re looking 40 to 50 years into the future and one might think there may be cures [for the adult-onset disease] by then. Depends upon how optimistic you are about medicine.”

The ASRM 2013 committee opinion states that PGD is ethically justified when the adult-onset condition is serious and “there are no known interventions” or the “available interventions are either inadequately effective or significantly burdensome.” The committee also opens the door to using the technique with less severe conditions, citing the right to reproductive autonomy, as long as worrisome risks aren’t one day identified.

Still, the severity of a particular disease or condition depends to a large extent on the perspective of the beholder, says Sauer, who helped to write the 2013 opinion. “This is an example of an ongoing debate that will probably continue about quality of life and whether or not these types of disabilities or disorders should alter someone’s being born.”

Sharon Goyette, a seventh-grade social studies teacher in Massachusetts, has faced such a genetic dilemma with both of her pregnancies. She tested positive for Lynch syndrome in her early 20s, shortly before her mother died at age 59 of colon cancer. She and her husband, Jesse, first learned about PGD when they were trying to get pregnant with their first child, now age 3, and met with a genetic counselor.

Her husband was opposed from the start. He pointed out that he couldn’t guarantee a mutation-free tree in his side of the family, Sharon says. Plus, they both knew that even if a child of theirs tested positive for a Lynch syndrome mutation, he or she wouldn’t necessarily later be diagnosed with colon cancer or one of the other associated malignancies.

Still vacillating, Sharon called her doctor at Dana-Farber Cancer Institute, where she gets her cancer screening. During that conversation, her doctor raised a question that Sharon hadn’t considered. “She talked to me about how if my mom had done PGD, I wouldn’t be here. And would I trade that in?”

As it happened, in vitro fertilization wasn’t needed. Sharon got pregnant with only the help of an egg-stimulating medication, and their son was born in 2012. But IVF was required the next time they tried to expand their family. Even though genetic testing would be much easier, because it simply could be added to the IVF process, the couple remained firm in their resolve not to go down that road.

Sharon notes another consideration: How could they screen for one child and not for the other? This thought further underscores the ethical complexity PGD introduces. On December 29, 2015, the 35-year-old delivered her daughter, Lydia.

Unforeseen conundrums

For prospective parents considering PGD, costs can also present a considerable hurdle, says Lisa Rubin, an associate professor in the psychology department at New York City’s New School for Social Research. Rubin interviewed nearly 40 BRCA mutation carriers who were contemplating whether to pursue PGD. She discussed her findings in a 2014 issue of the journal Human Fertility.

One woman, who needed IVF to get pregnant, decided not to add genetic testing because it would limit the number of IVF attempts she could afford, Rubin says. Another woman initially chose to test her embryos for Tay-Sachs — a rare child-onset disease that progressively destroys nerve and brain function — and then decided to add screening for the BRCA mutations.

But the process resulted in a limited number of viable embryos. During the second IVF attempt, two embryos were implanted that didn’t carry Tay-Sachs, but one of them did carry a BRCA mutation. The woman delivered a girl; her daughter’s BRCA status is unknown. In short, the logistics of going through IVF and PGD sometimes created a whole new set of ethical questions, says Rubin, as she reflects on the feedback she got from BRCA carriers.

“So, okay, I have very few embryos and they are all BRCA positive, or all of the good ones are BRCA positive. Now I just really want to get pregnant. Is it ethical to now implant a BRCA positive embryo?”

For her part, Sharon does wonder if her children will one day blame her if they test positive for Lynch. But she hopes that advances in science and aggressive screening will lessen their long-term risk of cancer.

Katie knows that there’s no guarantee, but she feels that the genetic testing provided her daughters their best shot at dodging the potentially life-threatening kidney disease. She and her husband have already discussed offering to pay for the testing for their sons, if one or both of them prove to be carriers and decide themselves to have children.

“To me, it’s kind of a cure,” Katie says. “It’s not 100 percent. But if you do cure a genetic disease by doing this — stop it in your family tree, then why wouldn’t you?”