[Corrected 2/12/14, see below] Was it that airline flight? The vitamin supplements? The hair dye?
Women who have miscarried may comb their memories for reasons, and the grieving process can last more than a decade, says Barbara Pettersen, clinical director for San Carlos, CA-based diagnostics company Natera.
Most of the time, miscarriages are the result of natural processes and no one is to blame, Pettersen says. “Up to 25 percent of all conceptions will result in a miscarriage,” she says. “Most people don’t know that.”
But when genetic factors cause a miscarriage, knowing the details can help hopeful parents plan for their next pregnancy, Pettersen says.
Natera, best known for its prenatal testing products, also makes a genetic test designed to identify reasons for the loss of a pregnancy. The answer often lies in the chromosomes of the fetus, says Pettersen (pictured above right). Working with a tissue sample from the miscarriage, Natera searches 317,000 sites along the fetal DNA to look for variations that could have caused the trouble.
A large fraction of pregnancy losses are due to genetic abnormalities in the fetus that arise by chance in the early steps that lead to the development of a fertilized egg, Pettersen says. These spontaneous errors are not inherited from either of the parents. But that still leaves aspiring parents with the question, “Will it happen again?”
In some cases, miscarriages do stem from genetic variations handed down from the mother or father. Analyses of chromosomes from both parents may be needed to figure this out. The answer may make a significant difference to the odds that the next pregnancy will be successful.
Couples who have suffered more than one miscarriage are particularly interested in knowing the reasons. So are those who have lost a pregnancy created through in vitro fertilization, Pettersen says.
“If they miscarry, they want to know the cause before they go through another IVF cycle,” she says.
It was working with that population of IVF clients that first got Natera interested in creating its test for the causes of miscarriage, Pettersen says. Natera was already making genetic screening tests that help clients of in vitro fertilization clinics to decide which of the early-stage embryos created through IVF should be implanted in the womb. The company’s preimplantation genetic diagnosis test identifies embryos with chromosomal abnormalities that could prevent implantation of the embryo in the uterus, cause a miscarriage, or result in birth defects in the child.
“We just basically modified that test to look at fetal tissue from a miscarriage,” Pettersen says. Natera began marketing the test in 2010.
Natera is part of an increasingly competitive group of genomics companies offering tests related to reproduction. Natera launched a genetics-based prenatal test, Panorama, in February of 2013, as an alternative to amniocentesis and CVS. These two traditional tests are accurate but invasive, and carry a small risk of miscarriage. The Natera prenatal test requires only a blood sample from the mother—like rival prenatal tests fielded by companies including San Diego, CA-based Sequenom, San Jose, CA-based Ariosa Diagnostics, and genomics heavyweight Illumina of San Diego.
In the area of miscarriage testing, also known as products of conception testing, Natera faces competitors including Irvine, CA-based CombiMatrix, Livingston, NJ-based Reprogenetics, and Integrated Genetics, a unit of Burlington, NC-based testing giant LabCorp.
Natera’s miscarriage test delves further than a longstanding scan called a karyotype that doctors have traditionally ordered for women who have miscarried more than once. The karyotype is a stained preparation of the chromosomes in tissue collected from the miscarriage, which are visually inspected through a microscope and photographed.
The karyotype can show whether the fetus has the normal number of chromosomes—a pair of each of the 23 different types of chromosomes for a total of 46. The test can reveal whether a chromosome is missing from one of the 23 pairs, or if there’s an extra copy of a chromosome. For example, Down Syndrome results when the cells have three copies of chromosome number 21. This is also called Trisomy 21, and it often results in a miscarriage—as do certain other fetal chromosome abnormalities.
Karyotypes have limitations. Technicians must grow the sample cells in a lab culture for several weeks, and some cultures fail due to contamination or other snags. Cells from the mother may be mixed in with the fetal tissue sample, so the karyotype may actually display the mother’s chromosomes instead of the fetus’s. The results of the test are then useless.
Natera’s test can sort out the fetal DNA from the mother’s, Pettersen says. Rather than relying on the physical appearance of the chromosomes, Natera uses a microarray or “gene chip” to identify variations in specific sequences of DNA, both from the fetal sample and another from the mother for comparison.
The Natera test can detect not only entire missing chromosomes or extra copies, but can also find abnormalities within the fetal chromosomes. For example, there might be missing or duplicated sections in a chromosome. The results can help women plan for their next attempt to conceive.
“If we know the chromosomal abnormality, we can give her risk factors for the future,” Pettersen says. Natera has a staff of 16 genetic counselors available to discuss the results of all its tests and their implications with both patients and their doctors, she says.
Identifying a genetic cause for a miscarriage can also help rule out other reasons for the pregnancy loss, including the shape of the uterus, maternal hormonal imbalances, antibody reactions, and clotting, Pettersen says. This can spare the woman from an extensive series of further tests, as well as save money for the healthcare system, she says.
For a young woman who has had a single miscarriage caused by a non-inherited chromosomal abnormality, the risk of another miscarriage may be only slightly higher, Pettersen says. During the woman’s next pregnancy, she could opt for prenatal tests to find out if the fetus again has genetic problems that could prevent a successful pregnancy or cause birth defects.
The risk of fetal chromosomal abnormalities is higher in older mothers—who may consider choosing in vitro fertilization after a first miscarriage.
Parents who have had multiple miscarriages may be able to trace back the causes with the Natera test if the tissues containing fetal DNA have been properly preserved, Pettersen says. The doctors most likely to order collection of tissue from a miscarriage are IVF specialists and physicians treating women who have lost more than one pregnancy, she says. (Women can collect the sample themselves if they miscarry at home, and know they are interested in having the test. Natera instructs women to place the sample in a sterile container such as a new Ziploc bag and refrigerate it. If the woman’s doctor then orders the test, Natera ships a collection kit to the woman for transport of the sample to the company for analysis.)
Although many miscarriages come from random genetic abnormalities that may never recur, the Natera test can detect problems that may pose continuing challenges in pregnancy.
For example, some couples have a 50-50 chance of miscarriage or a baby with birth defects if one parent has a “balanced chromosome rearrangement,” a condition that affects one out of 500 people in the healthy population, Pettersen says. This can occur when chromosomes “swap” sections with each other.
All the genes are retained in such balanced re-arrangements, and the parent is usually healthy. But when the chromosomes of the parent and partner are re-shuffled and combined in the process of conception, the chromosomes of the fetus may end up with missing parts. The Natera test can reveal that the fetus ended up with missing chromosome sections. Further testing might be needed to determine which of the parents has the balanced chromosome rearrangement.
“They don’t know they have it,” Pettersen says.
Another genetic accident of conception—a rare one—may have a profound impact on the mother’s health. Called “uniparental disomy,” this is a situation in which both copies of each of the 23 chromosomes in the fetus come from either the father alone or the mother alone, Pettersen says. If the father is the sole source of the fetal chromosomes, this can lead to a form of uterine cancer called choriocarcinoma, which is often curable when doctors diagnose it early. The Natera test can detect the chromosomal abnormality in the fetal tissue.
Natera has not conducted clinical trials on its miscarriage test, but the company in 2012 published a joint paper with the Stanford Fertility & Reproductive Medicine Center. In the study analyzing tissue from 30 miscarriages, the results of the Natera test agreed with traditional karyotype results in 93 percent of all findings of chromosomal abnormalities that were relevant to clinical treatment decisions. At the time, the Natera test didn’t detect certain rare genetic abnormalities, the authors pointed out. But they noted advantages of the Natera test: its quicker turnaround time; its elimination of the cell culture process needed for karyotyping; its ability to distinguish maternal from fetal chromosomes; and its identification of uniparental disomy.
Natera continously reviews the scientific literature for new insights on the impact of chromosomal variations on miscarriage and the health of the fetus, Pettersen says. The company has not changed the 317,000 locations called single nucleotide polymorphisms, or SNPs, that it tests across the chromosomes. But it has updated its bioinformatic algorithms to pick up smaller changes in DNA sequences that are now seen as significant, she says.
As a private company, Natera doesn’t disclose revenues for its products. But the company views miscarriage testing as a good business bet. For one thing, home pregnancy tests are making more women aware about a pregnancy early, Pettersen says. They are therefore more likely to realize that they are having a miscarriage if they begin bleeding, she says. In the past, an early miscarriage might have been mistaken for a heavy period.
Health plans are often willing to cover the cost of a miscarriage test for women who have had more than one miscarriage, for IVF clients, and for older women, Pettersen says. But younger women are increasingly eager to know the cause of a miscarriage—even when it’s their first, Pettersen says. Aside from the insights they may gain about planning another pregnancy, women may benefit from knowing the miscarriage was just a fairly common “accident of nature,” she says.
“There’s nothing they did to cause that,” Pettersen says. “That can help them.”
[Corrected 2/12/14. Due to a typographical error on Natera’s website, a previous version of this story misspelled Barbara Pettersen’s surname. It is Pettersen, not Petterson.]
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