The Atlanta Journal-Constitution
How safe are IVF drugs?
Industry says fertility drugs safe; critics worry about overprescription.
Logan Andreotta had been told she was an ideal candidate for in vitro fertilization. Though unable to get pregnant, the Bowling Green, Kentucky, woman was just 24 and in terrific health. But three days after she began taking fertility drugs, her ovaries went haywire and swelled with 50 eggs — four years’ worth in a single go.
“I felt like my insides were going to bust out of my stomach,” Andreotta recalled.
This was ovarian hyperstimulation syndrome — OHSS for short — a potentially fatal complication the U.S. fertility industry describes as extremely rare. But the incidence of OHSS and the broader long-term safety of hormone-boosting fertility drugs remain open to debate, even as the clinics have blossomed into a multibillion-dollar industry serving hundreds of thousands of women a year.
Industry critics wor ry that unregulated providers are overprescribing the drugs, glossing over potential hazards and failing to properly repo rt problems when they arise. One recently published study, for example, blamed “increasingly aggressive treatment protocols” for incidents of OHSS, while another argued that most cases are completely “avoidable.”
Some researchers have theorized that in addition to their link to OHSS, the drugs could have a potential lead to heart disease, depression, endocrine system disorders, cancer and a host of other conditions. The few published studies are conflicting or inconclusive, however. And unlike many developed countries with
government-provided health care, the United States makes no effort to track health outcomes in fertility treatments.
“Every fertility doctor says to every fertility patient, ‘There are no known risks.’ Well, there are no known risks because no one has looked,” said Diane Tober, a medical anthropologist at the University of California at San Francisco who studies reproductive technology.
Industry advocates note that more than 8 million children have been born worldwide through IVF and other fertility treatments since the first “test-tube baby” arrived 40 years ago. Alan Penzias, an associate professor at Harvard’s medical school who chairs the practice committee of the American Society for Reproductive Medicine (ASRM), said he has been “reasonably reassured” the drugs pose no long-term threat to women’s health.
“We’re at a time point when, if there were anything major, we would have seen it by now,” said Penzias, who also serves as surgical director at Boston IVF. “Fortunately, we haven’t seen anything negative.”
OHSS is an exception. As the most brutal and immediate complication of fertility treatment, it can strike anyone taking medication to induce the ovaries to ripen multiple eggs — a fundamental step in egg freezing, in vitro fertilization (IVF) and egg donation that occurs about 240,000 times a year.
Strategies for identifying high-risk patients and treating the condition have advanced in recent years. ASRM, which represents most U.S. clinics, calls OHSS “an uncommon but serious complication” that is estimated to occur in moderate or severe form in just 1 percent to 5 percent of cycles. Fertility doctors frequently cite research showing that severe OHSS occurs in 0.03 percent of cycles.
Penzias said hospitalization for OHSS “is almost unheard of now” compared with 20 years ago. Still, a Washington Post analysis of national emergency room data found that the numbers remain significant. More than 9,000 women sought help for OHSS at hospitals between 2006 and 2014, the most recent year for which statistics are available — about 1,000 women a year.
In Sweden, Canada and Britain — countries where governments regulate assisted reproduction and track patient outcomes — medical societies tell patients that an estimated onethird of procedures trigger at least mild OHSS symptoms.
This year, Britain’s independent fertility regulator, the Human Fertilization and Embryology Authority, launched an investigation into a discrepancy between OHSS cases reported by fertility clinics and the largernumber logged in hospital admissions data. While the watchdog group did not find evidence of systematic underreporting, it announced clinic-byclinic audits, saying the data raise “significant concerns and questions about the safety of patients undergoing IVF.”
Geeta Nargund, a fertility specialist in Britain, is urging Parliament to update reporting requirements to track drugs and dosages given during IVF, and to link IVF treatment logs to hospital registries to enable better tracking of adverse reactions.
“I feel more concerned now than ever before,” Nargund said. “It is extremely important that we do not make healthy women ill as a result of IVF treatment.”
Known fatalities are rare but are also difficult to track, public health officials say. When the ovaries are overstimulated, the body produces excess fluid that can drown vital organs, leading to a cascade of potentially fatal problems.
In one prominent 2005 case, Temilola Akinbolagbe, 33, collapsed at a London bus stop shortly after beginning a course of drugs for IVF. The fluid buildup from OHSS led to a clot in a pelvic vein and, ultimately, a heart attack.
The coroner listed the cause of death as “misadventure” — the result of a risk taken voluntarily — a category more often applied in cases of drug overdose and blue moon occurrences such as fatal falls while taking selfies.
Customized dosage
When fertility-stimulating medications hit the market in the late 1960s, they were hailed as “wonder drugs” and were initially used to induce ovulation in women who were unable to produce eggs on their own. By the time the first commercial fertility clinic opened in 1979 in Norfolk, Virginia, doctors realized that the drugs could be used far more aggressively.
Ordinarily, a single egg ripens in a woman’s ovaries each month and is released into her uterus. Few of those eggs are destined to become babies; the rest are abnormal or defective in some way.
Collecting one egg at a time would be maddeningly inefficient for IVF. So the drugs are calibrated to trigger a batch of eggs to ripen — ideally, about 10 to 15, according to recent studies. Any fewer and a woman’s chances of having a baby go down. Any more and a woman’s own health might be endangered.
Figuring out which and how much medication to use is tricky, however. Given that IVF can cost $15,000 to $30,000 per attempt, doctors and patients often feel pressure to produce a large number of eggs in every round.
Fertility groups have developed standard dosing regimens, but each protocol must be customized to fit an individual woman’s size and health. Meanwhile, there is nothing to stop doctors who want to use bigger doses, and there is no systematic way to track dosages or outcomes.
Specialists have long argued that the short burst of estrogen, usually 10 days in IVF, is unlikely to have a profound long-term effect on a woman’s body. Researchers have argued for more research, noting that estrogen is known to promote some cancers.
The largely academic debate erupted into public alarm in 2003, when Jessica Grace Wing, a Stanford University graduate and threetime egg donor, died of metastatic colon cancer at age 32. Wing’s mother, Jennifer Schneider, a physician who focuses on internal medicine, began pressing Congress and states to pass laws requiring better tracking of fertility patients and more funding for research into complications.
“As a scientist, I cannot say that I’m 100 percent sure it was the fertility drugs” that caused the cancer, Schneider said in an interview. “All I can say is the absolute lack of any other reason for her to get colon cancer so young.”
Schneider also published pieces in medical journals that attracted the attention of researchers abroad. Large studies soon followed, involving 50,000 women who took fertility drugs in Denmark and 24,000 in Sweden. The research showed no connection between the drugs and ovarian cancer.
The latest data, presented in June at a conference in Europe, also showed no increased risk of ovarian cancer. And a study published in July found no increased risk of two other types of cancer — invasive uterine and breast — among 250,000 British women who underwent fertility treatment.
Current ASRM guidelines say “there does not appear to be a meaningful increased risk” of invasive ovarian, breast or endometrial cancer for fertility patients “based on available data.” For borderline ovarian tumors, the group acknowledges that “several studies have shown a small increased risk.”
The guidelines make no mention of colon cancer, perhaps because there is no consensus. A study in the Netherlands published in 2016 found — “reassuringly,” the researchers wrote — that women who undergo IVF do not appear to have an increased risk of colon cancer compared with the general population. However, IVF patients were nearly twice as likely to develop colon cancer as women who received nonIVF fertility treatments, such as tubal surgery or intrauterine insemination, prompting the researchers to suggest that “further research is warranted.”
Schneider notes that the studies tend not to differentiate among women who take fertility drugs for different reasons. Some are infertile, some are fertile but in treatment because of their partners and some are elective egg freezers and egg donors. Schneider argues that these populations are distinct — and often very different in ages and hormone levels.
“The results are mixed because women in fertility treatment are a diverse group,” Schneider said, adding that no studies focus solely on elective egg freezers and egg donors.
Ovarian hyperstimulation
Unlike cancer, there is little doubt about the link between fertility drugs and OHSS. Complaints about the condition fill fertility blogs and online support groups.
In interviews, a dozen OHSS sufferers described feelings of confusion and chaos when the symptoms began. Most said they had never heard of ovarian hyperstimulation syndrome before they became ill.
Asya Ulanova, 22, an egg donor from New York, said she was watching television in November when she suddenly felt a “visceral” pain in her abdomen and had trouble breathing. An emergencyroom doctor told her that she had a buildup of fluids in her abdomen and gave her medicine for constipation. Only much later did Ulanova learn that she had been suffering from OHSS.
Emily Ley, 34, an entrepreneur from Pensacola, Florida, was preparing for IVF in 2014 when she gained 22 pounds in 48 hours. She nearly died and spent eight days in the hospital with a tube in her abdomen to drain the fluid.
“Looking back, I didn’t know how scary my situation was,” said Ley, who learned while hospitalized that she was pregnant with twins.
Logan Andreotta said her fertility doctors described the risk of OHSS as “ridiculously low.” As a result, she “wasn’t mentally prepared” when she woke one morning in 2014 to find her abdomen bulging as if she were suddenly 20 weeks pregnant.
Andreotta was rushed to the fertility clinic, where a doctor used a giant needle to “tap” the fluid in her abdomen.
“It was liters and liters and looked like the Coca-Cola you buy at the store — a brownish red liquid,” she recalled.
The first day, they filled four to five bottles. They filled two to three more in subsequent visits. Andreotta said her recovery took nearly four weeks.
Despite the harrowing experience, Andreotta, now 29, said she does not regret taking the drugs. Of 50 eggs retrieved from her ovaries, four tested normal. One resulted in a daughter, Bonnie, now 4. Two years ago, Bonnie gained a sister, Audrey, who was conceived without IVF.
But Andreotta said she would advise other women taking fertility drugs to report any unusual symptoms immediately.
“I feel super fortunate,” she said. “They said if I kept waiting, I literally could be dead.”
Cardiovascular connection
In the early 2000s, so many women were showing up at hospital emergency rooms bloated with excess fluids and suffering from congestive heart failure or other organ shutdown that the situation caught the attention of Jacob Udell, a medical intern in Canada.
“We were perplexed. They didn’t have many risk factors, but the common theme was that they had been getting fertility medicines,” Udell recalled. “They were getting high doses and trying to get pregnant.”
Udell and his colleagues wondered whether these ER patients “could be the tip of the iceberg” and whether high levels of estrogen from fertility drugs might be injuring the lining of the blood vessels. Water leaking out of those compromised blood vessel walls could explain the fluid buildup in OHSS. Could it also be damaging the heart?
One study, from Sweden, suggested as much. It reported higher rates of hypertension and possibly stroke among fertility patients. But a Canadian study with a similar design showed no connection.
So Udell, now an assistant professor of medicine at the University of Toronto, teamed up with Natalie Dayan from McGill University in Montreal to conduct what is believed to be the first large analysis of the association between fertility drugs and cardiovascular disease.
Published last year in the Journal of the American College of Cardiology, the study looked at data from 42,000 fertility patients. While the treatments appeared to have no impact on the risk of heart attack, they did show a potential but not-quite statistically significant increase in the risk of stroke.
Udell said it is impossible to tell whether the differences are due to the fertility drugs or to the women’s underlying fertility problems, age or other factors.
The results, he said, highlight the need to follow fertility patients much more closely.
“We may not be seeing a lot of immediate catastrophic illness,” but “there may be milder-level, potential longterm ‘echo’ effects,” Udell said.
“Sometimes after pregnancy, everyone turns to the baby. But maybe Mom should be thought of, too.”