Alive, but Well?
Science created IVF babies and now wonders about their long-term health
Every year in this country, 60,000 babies are born who would not be here had nature been left to its own devices.
They are babies conceived as a result of in vitro fertilization (IVF). The procedure was introduced just a little more than three decades ago,
with the first successful “test tube” baby born in 1978. Worldwide, there are now some 3 million people alive as a result of science’s intervention in the fertilization process.
But are they well?
“For many the answer is ‘yes,’” says Maurizio Macaluso, MD, DPH, epidemiologist and Director of the Division of Biostatistics and Epidemiology at Cincinnati Children’s. “But infertility treatments like IVF are also associated with increased risk of adverse health outcomes, both for the mother and for the infants.”
Federal law mandates that all clinics that perform IVF send data to the Centers for Disease Control and Prevention (CDC), which in turn publishes an annual report with summary statistics for each program. “The national data collected so far for IVF focus on whether it resulted in a live birth,” Macaluso (right) says. “That’s the measure most people want to see.”
“Most people” in this case are the hopeful, determined couples who are unable to conceive naturally. They put body and soul through a roller coaster ride of hormone treatments, clinic appointments and agonizing wait-and-sees in their drive to become parents.
For tens of thousands of families each year, the rigors of IVF pay off with the birth of a baby — often, more than one baby — which seems a happy ending. But it is not the end of the story, says Macaluso.
A growing body of research, including the surveillance data collected by the CDC, indicates that IVF-conceived individuals are at increased risk of health problems, and he wants to understand why.
Infertility is common, affecting 10 to 15 percent of couples during their reproductive years, and many of these couples use fertility drugs and intrauterine insemination to conceive. But IVF and other forms of assisted reproductive technology (ART), which are based on extracting the eggs from a woman’s body before fertilization, have higher success rates. Some 150,000 IVF procedures are performed every year in the U.S. to bring about those 60,000 babies, Macaluso says. In 2006, about 3,300 ART procedures were performed for Ohio residents, with 1,500 live-born children.
Macaluso is familiar with the numbers because before coming to Cincinnati Children’s in spring 2011, he directed the Women’s Health and Fertility Branch of the CDC, and one of his responsibilities was to oversee the data collection from the nearly 500 centers around the country that perform IVF and contribute to the CDC reports.
Time for a better look
Although the national focus is mostly on the effectiveness of IVF technology and whether the procedure results in live births, it has limited use for looking at safety. Macaluso thinks it is time to dig deeper into IVF’s outcomes. He wants to understand how assisted reproduction affects the long-term health of people born as a result.
It is already known that IVF results in a higher number of multiple pregnancies. Whereas the chance of a natural multiple pregnancy is around 1 to 3 percent, in IVF pregnancies the rate runs between 20 and 40 percent.
Macaluso says a multiple pregnancy can cause complications for the mother and puts the babies at risk of preterm delivery, low birthweight and more. “There is increasing evidence that multiple births are associated with longer-term adverse outcomes for the infant – developmental disabilities and birth defects.”
Armed with this evidence, the American Society for Reproductive Medicine, the Society for Assisted Reproductive Technology and the CDC are promoting the use of single embryo transfers in IVF.
But this has not yet translated into practice in the nation’s fertility clinics. Only 7 percent of women under 35 choose to use single embryos when they have IVF.
The risks of upping the odds
For most couples, the reason is financial. Infertility treatments are covered by insurance in only 15 states currently, Macaluso explains. And it is costly – anywhere from$12,000 to $20,000 per procedure. Most young couples can afford only one try – which means they want as many embryos transferred as possible.
“The more embryos transferred, the more likely it will lead to a live birth,” Macaluso says, “but the advantages are offset by the increased risk of multiple pregnancy.”
And by the health risks that extend beyond infancy. Research now indicates that people who were low birthweight babies are more likely to be obese, to have diabetes and to suffer hypertension by the time they reach age 50. Because the oldest of those born from IVF are still in their early thirties, there is no way yet to predict whether this same health pattern will emerge for these individuals.
Changes in DNA
Scientists have also discovered differences in the DNA expression of people born via IVF, which may put them at higher risk for conditions like cancer or diabetes later in life. In a study published last year in Human Molecular Genetics, researchers found epigenetic differences in the DNA of children conceived by IVF compared with those conceived naturally. Further complicating the picture is the fact that IVF and assisted reproductive technologies are the only forms of infertility treatment for which clinics are required to report outcomes, Macaluso says.
“Drugs that produce ovarian hyperstimulation may have the same adverse impact on health that IVF has, but we can only guess at the number of multiple pregnancies and potentially adverse health outcomes for the infants that come out of those procedures,” he says. He suspects that the numbers are significant because the procedures are less expensive than IVF, but because they are not monitored, there are no good data for estimating how many.
The cause
The looming question is whether the differences seen in IVF babies — from low birthweight and preterm delivery to cancer risk — are the result of the IVF treatment itself or other issues, such as the parent’s infertility.
“It is difficult to disentangle the effects of the technology from the effects of the underlying conditions that cause the infertility in the first place,” Macaluso says. “Attributing specific adverse outcomes to the technology or the infertility itself is difficult.
On the other hand, it is clear that transferring more than one embryo into the uterus is the main cause of the large excess of multiple pregnancies, and that in turn must be the cause of a large proportion of the adverse health outcomes associated with IVF.”
Encouraging a better way
Macaluso believes that one way to improve outcomes, regardless of the cause, is to get more insurance companies to cover the IVF procedure. He advocates that health insurers cover repeated single embryo transfers, which would eliminate the risk of multiple pregnancies and lower the number of preterm births and their associated problems, while keeping the overall success rates high.
“Today many insurance policies and some state regulations allow up to a certain number of IVF cycles; couples who choose single embryo transfer do the right thing but are punished by this system. Instead, they should be given the incentive of free additional cycles to reward their safe choice.”
While at the CDC, Macaluso worked with a national health insurer to develop a benefit that covers two sequential single embryo transfer cycles. If the first one fails, a couple gets a second try, still covered by insurance. “The success rates are a little lower with single transfers,” he says, “but that would be offset by the benefit of replacing the multiple births with singletons.”
Looking over the long term
Another way to improve outcomes is to get a long view of how people born from IVF are faring, something Macaluso hopes to do at Cincinnati Children’s. He sees an opportunity to develop a longitudinal study with what he terms a “well-knit network of neonatologists” in this region.
“The possibility exists that we could get very rich information about the outcomes of assisted reproduction techniques,” he says. “This could provide us with the next level of information if we could put together the right study.”
The study might replicate and expand on an initiative he started with several states while at the CDC. “We would link the mode of conception and assisted reproduction procedure used with the information available from vital records kept by the state departments of health.”
The goal would be to link information from the IVF clinics and the vital record to hospital discharge summaries as well as disease and cancer registries, providing a long view of the individual’s health.
Without question, assisted reproduction has brought happiness to hundreds of thousands of couples and has given life to millions. But it also has raised important health questions for those millions of people — questions that Macaluso believes merit further exploration.
“It is important that we understand how interventions in the reproductive cycle link to health problems later in life,” Macaluso says. “Investing in better reproductive health is a very effective way of preventing disease in the next generations.”
