Forty-three years ago this summer, news of a birth in Manchester, England splashed across headlines worldwide.
The newborn, Louise Joy Brown, dubbed “the test tube baby,” was the first conceived by in vitro fertilization (IVF) as a way to help her infertile mother give birth. Providers removed an egg from an ovary of her mother’s and fertilized it with her father’s sperm, forming the embryo that was to become Louise. The providers then transferred the embryo to the uterus of Louise’s mother. Louise arrived, healthy, on July 25, 1978.
The storm of publicity and debate that followed seems quaint today. By 2018, more than 8 million infants worldwide had arrived as a result of IVF. In 2019, more than 83,000 infants in the United States alone were born after assisted reproductive technology (ART), with IVF being by far the most common technique for couples struggling with infertility.
It is, however, a complex and demanding solution. The treatment regimen requires extensive hormone treatments – sometimes spanning several cycles – as well as procedures to retrieve eggs, fertilize them to create an embryo culture and transfer the embryo to the uterus. All of that, of course, precedes pregnancy and childbirth.
The success of IVF and its growing acceptance is a testament to the expertise of the specialists who assist women through the treatments. But that success conceals at least one important fact: more than four decades after Louise Joy Brown arrived, relatively little is known about the potential long-term effects of IVF for mothers.
A pilot study now underway at the University of Colorado School of Medicine on the Anschutz Medical Campus intends to shed light on the possible post-partum health risk for mothers who received IVF treatments. They seek to test for changes in blood pressure and blood vessel function that increase risk for future cardiovascular disease. The study is funded by a one-year Child and Maternal Health Pilot Grant from the Colorado Clinical and Translational Sciences Institute (CCTSI).
Women enrolled in the study will have three visits with the research team, including initial screening and two follow-ups, each lasting one to three hours. The visits will include blood pressure screenings, blood draws, surveys and non-invasive tests, like ultrasounds, to study how the blood vessels are functioning. Researchers aim to recruit 75 women: 25 women who delivered after fresh embryo transfers, 25 after frozen embryo transfers and 25 controls.
“The study will compare differences in blood pressure and vascular function between women who delivered healthy pregnancies conceived through unassisted reproduction and those who had IVF pregnancies,” said principal investigator Lyndsey DuBose, PhD, a postdoctoral fellow with the School of Medicine’s Division of Geriatric Medicine. Dr. Cassandra Roeca, an assistant professor in Reproductive Endocrinology and Infertility at CU who practices and teaches residents and fellows at Shady Grove Fertility Colorado, is co-investigator for the trial.
If the study reveals increased risk for women who delivered after IVF, further research could potentially lead to new treatments or “changes in clinical monitoring for moms,” DuBose said. She added that the study could demonstrate that there is no cardiovascular risk posed by IVF. That information, too, would be valuable.
Researchers have not ignored the risks that problems during pregnancy, such as gestational hypertension, gestational diabetes and preeclampsia, could pose for women’s long-term cardiovascular health, DuBose noted. However, these studies have “commonly excluded or not studied women who go through assisted reproductive technologies,” including the most common, IVF, she explained.
That gap spurred her interest, as did a study by Swedish researchers of women with post-partum high blood pressure. The researchers, who reviewed the medical records of women for up to nine years following delivery, found that those who had conceived through IVF were at 27% greater risk of developing high blood pressure than women who had naturally conceived pregnancies. That was regardless of age, body mass index or smoking status. The risk seemed to develop one to five years after delivery.
“This suggests that there may be something going on with IVF itself that increases or alters the normal aging of blood vessels and may increase the risk of cardiovascular disease in moms,” DuBose said. The sheer numbers of IVF births demand further research, she added.
“We think it’s an area that is relatively understudied, especially when you consider that not everyone gets pregnant the first time with IVF. Sometimes it requires multiple rounds of treatment,” DuBose said.
There is much to factor into that risk analysis, added Roeca. She noted that as access to IVF has increased – in 2017 there were just shy of 500 fertility clinics in the United States – more couples are requesting it. That is tied, in part, to more women delaying childbirth, which increases the risk of infertility. Add to that the increased risk of hypertension during pregnancy for women 35 years of age and older, along with the bodily challenges of IVF, and the need for more study is apparent, Roeca said.
“We’re trying to assess the true risk factors – IVF itself versus a history of infertility versus age,” she said. “If you have a diagnosis of infertility, does this risk already exist or is there something about the treatment that affects the vasculature that we’re not taking into account?”
Both Roeca and DuBose emphasized that their study is not meant to discourage women from considering IVF to treat their infertility. Instead, Roeca said, “We want to make sure we are practicing socially responsible IVF treatments and also that we care for our patients properly.”
“We think that a woman’s and a couple’s right to start a family is really important,” DuBose added. “We just want to know if there is risk and if so we want to study the mechanisms needed to establish a standard of care to track that risk or make an intervention to mitigate it.”
Anne Kercsmar is not part of the pilot study, but she can speak to the physical and emotional challenges of IVF. A program manager with CU’s Institute for Healthcare Quality, Safety & Efficiency, Kercsmar, now 36, said she and her husband did not anticipate any problems when they decided to try to start a family in 2016. But after about a year without success, Kercsmar got bloodwork that showed her hormone levels were not where they should be. That led to visits with a reproductive endocrinologist and the start of a “long journey” into the world of IVF that proceeded along a rugged road.
Tests showed that Kercsmar had “diminished ovarian reserve,” meaning that her ovaries produced fewer eggs than expected at her age, which was still just 32. The diagnosis, which explained her infertility, was unexpected and difficult to process, she recalled, particularly because she’d always been in generally good health.
“I had no idea it was coming,” she said. “I thought once we started trying, I’d have a baby and everything would happen on schedule. It makes you realize you don’t have nearly as much control as you thought.”
Kercsmar began IVF treatments in October 2017, starting with twice-a-day hormone shots in the abdomen to stimulate egg growth. Three cycles of egg retrievals followed, along with optional testing to ensure she and her husband had a chromosomally normal embryo. In the fall of 2018, after “a lot of hope and sadness,” they had one.
But their hopes were dashed when the attempt to transfer the embryo to the uterus failed. The embryo attached outside the uterus, causing an ectopic pregnancy and ending hopes for a birth. With that, the couple’s reproductive endocrinologist concluded their best hope lay in finding an egg donor.
Their anonymous donor went through the same routine of hormone treatments and egg retrievals. Fertilization with Anne’s husband’s sperm produced several viable embryos, some of which they froze. Anne then went through yet another round of hormone treatments to prepare her for another embryo transfer to her uterus.
There were no disappointments this time. The pregnancy went well, the only blip being a C-section scheduled two weeks before Anne’s due date because the baby was breech. A bit undersized but otherwise healthy, baby Anderson arrived at UCHealth University of Colorado Hospital on October 28, 2019. He’s now “the chunkiest kid in the world,” Anne declared in early September.
As for her own health, Anne said she recovered from the C-section smoothly and is healthy. She had high blood pressure going into the pregnancy and took a low-dose medication prescribed by her UCHealth primary care physician, Dr. Mitra Raghazzi, to control it. She continues today on the medication at the same dose.
Despite the “difficult, emotional” process of IVF, Anne said the final result “made it worth it. It also made me appreciate what science can do and how far we’ve come” in treating infertility. She credited her medical team, husband, family and friends for supporting her through the lengthy, demanding process.
Had she met all the qualifying criteria, Anne added, she would have joined the pilot IVF study. That’s because her experience revealed the demands that IVF places on a woman’s body.
“We are learning how much hormones affect women, especially during key phases in life, such as pregnancy or menopause,” she said. “Then when you layer in IVF, you are introducing external hormones in guiding your body where to go.”
Further study, she added, could help people better understand the risks and benefits of IVF “and take necessary actions.”
The need to gather data to assist women like Anne Kercsmar is vital because IVF is “here to stay,” as Roeca stressed.
“We are interested in having healthy moms and healthy babies,” she said. “We want to make sure that we are doing our due diligence, advocating for patients and doing what we need to do to make the best use of the technology that is available.”
For more information about the IVF study, contact Lyndsey DuBose at [email protected].
The study was supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535.
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