The Pursuit of Parenthood

In-vitro fertilization has gone mainstream. When polled, a majority of Americans favor IVF and many readers likely know someone born from, or currently using, the technology.¹

Still, it is worth considering how, just 50 years ago, bioethicists, newspapers, and even scientists like Nobel Prize winner James Watson denounced the use of IVF and the creation of “test-tube” babies. Appreciating the long journey of assisted reproductive technology may provide clues for handling future developments.

In The Pursuit of Parenthood, sisters and co-authors Margaret Marsh and Dr. Wanda Ronner take readers through a deeply researched history of reproductive technology, from WWII-era experiments to cutting-edge developments in uterine transplants.² Along the way, they argue that political polarization around IVF has prevented federal-level regulation, resulting in a “Wild West” of reproductive technology — a state of affairs that has enabled some abuses (and ineffectual fertility treatments), but allows for greater innovative freedom overall.

Scientists have tried to fertilize mammalian eggs in vitro since at least 1878. But the story of IVF technology really begins in the 1930s with Dr. John Rock, a major figure in the development of oral contraceptive pills. Rock retrieved human eggs from ovarian tissue that had been removed from women undergoing surgeries at the Boston Free Hospital for Women and attempted to fertilize them in various ways; he carefully experimented with how the eggs were stored and the length of time each egg was incubated with sperm. After six years of such trials, Rock marveled as fertilized eggs formed zygotes and entered the cleavage stage of embryonic development. A 1944 TIME magazine article reported on Rock’s work in heroic terms:

"Man will never be happy until he has proved that he is at least as smart as nature. One thing he would like to show the world is that he can reproduce himself scientifically. Artificial insemination was one step. He took another step last week, with the first recorded fertilization of a human ovum outside the mother’s body."³

In their book, Marsh and Ronner contrast the positive public reaction to Rock’s work with the hostility that emerged decades later, both to IVF and to research involving human embryos. After 1973, when the U.S. Supreme Court ruled on Roe v. Wade, the pro-life movement reached widespread traction; but “few Americans were outright champions of the development of the new technology” at that time.

Some of the early scientific successes made by Rock and others may have also been illusory. For example, “between 1878 and 1953, numerous attempts were made to fertilize mammalian eggs in vitro,” according to a 2002 review on the history of IVF. But “although many reports were published claiming successful results, in the light of modern knowledge, most of these claims seem unjustified​​.” Early researchers did not know that fresh sperm cannot fertilize eggs. After ejaculation, sperm must first capacitate, or undergo a series of biochemical changes, before they can fertilize an egg.

Rock was not alone in reporting questionable experimental results. In 1961, Italian physician Daniele Petrucci claimed to have created 40 human embryos using in vitro fertilization, keeping at least one of them alive for as long as 29 days. Petrucci apparently destroyed the embryo, however, because it became “deformed and enlarged, a monstrosity,” according to a 2004 article in The New York Times. The scientific community was immediately skeptical of Petrucci’s claims because his results appeared in a Roman newspaper but never in a scientific journal.

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In 1978, evidence for the scientific merits of human IVF finally became incontrovertible when three British scientists with complementary skills — Patrick Steptoe, Robert Edwards, and Jean Purdy — announced the birth of the first IVF baby.

Dr. Steptoe, an obstetrician at the Centre for Human Reproduction in Oldham, brought his expertise in laparoscopy (a surgical technique that uses small holes and a camera to peer inside the body), access to patients, and private funding to the partnership. Steptoe had been a leading figure in the wider diffusion of laparoscopic techniques in gynecology, publishing the first English-language textbook on the subject in 1967. This procedure made collecting fresh eggs from patients much less invasive. Steptoe’s interest in laparoscopy, in turn, had been motivated by his work in a family planning clinic, in which a “diagnostic laparotomy” — a surgery in which physicians made large abdominal incisions to peer into a woman’s peritoneal cavity — was common practice.

In the early 1960s, these invasive surgical procedures were necessary to diagnose many gynecologic conditions. A French physician, Raoul Palmer, taught laparoscopy to Steptoe, just as subsequent advances by German and French device manufacturers improved its reliability. Steptoe and others applied laparoscopy in everything from diagnosis to sterilization, and Steptoe even tried directly applying sperm to the oviducts of infertile women, though without success.

Robert Edwards, an embryologist, read of Steptoe’s early forays into treating infertility with keen interest, and the two men teamed up in late 1968. Edwards had a deep knowledge of human oocyte (egg) maturation and mammalian embryology, which could now be paired with Steptoe’s ability to retrieve human ovarian follicles. The discovery of sperm capacitation in 1952⁴ also enabled a series of successes in embryology: in-vitro fertilization in rabbits (1959), hamsters (1963), rats (1972), and other species. Edwards (not Petrucci) was likely the first person to successfully fertilize human eggs in vitro, in 1969.

To induce ovulation, Edwards injected women with menopausal gonadotropin (HMG) containing high levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), derived from the urine of postmenopausal women.⁵ HMG induces superovulation, coaxing the ovaries to release multiple eggs in a single cycle and thereby allowing physicians to try retrieving many eggs in one go. Next, Steptoe retrieved the stimulated follicles with his laparoscopic technique. The retrieved eggs were fertilized with the capacitated sperm and sent to Edwards’ lab, where technicians tested different culture media and refined their formulas for embryonic development.

As the team gradually invented more reliable ways to retrieve human oocytes, fertilize them, and cultivate the resulting embryos, they began doing actual embryo transfers on patients. Signs of success came in 1974 when Edwards and Steptoe switched up the hormone regimen⁶ given to patients and also began implanting multiple embryos at once. 1975 saw the procedure create an ectopic pregnancy, and in 1978, the first live birth.

The first in-human IVF success, then, took no less than two decades of wet-lab refinement. These included the development and diffusion of less invasive surgical techniques (which itself required advances in medical device technology) and a more sophisticated understanding of, and ability to control, the human menstrual cycle. By the late 1980s, IVF became even easier; eggs could now be retrieved transvaginally with a needle and an ultrasound probe, instead of laparoscopic surgery, and companies began manufacturing hormones, including FSH, from engineered microbes rather than urine. Stand-alone clinics proliferated as access to fully-fledged operating rooms became unnecessary.

As the patient population of IVF clinics expanded, however, physicians began encountering more cases where male infertility was the key bottleneck to making babies. Various techniques for using abnormal sperm in fertilization were trialed through the late 1980s, but by 1995, the clear winner was intracytoplasmic sperm injection (ICSI). To perform ICSI, an embryologist injects a single live sperm directly into an oocyte, bypassing the zona pellucida, or thick coat surrounding ovulated eggs that normally keeps out “defective” sperm. ICSI made IVF much more useful for couples with male-factor infertility, which is estimated to account for between 20-60 percent of infertility cases. Today it’s used in the majority of IVF cycles in the United States.

In the 1980s, IVF became big business and the practice quickly spread outside of academic medical centers. In 1983, according to data presented at Congressional hearings, just 11 percent of IVF practices were private practices not affiliated with hospitals, but this number grew to 32 percent by 1988. Entrepreneurial physicians expanded the range of infertility conditions they treated with IVF, pushed the age of women they treated upwards, and began using donor eggs and sperm. Private physicians self-regulated through the professional organization Society for Reproductive Technology (SART), promulgating guidelines and publishing their clinic outcomes anonymously.

While ease of access and commercialization were good for most patients, some downsides emerged as IVF became a commercial enterprise. IVF was generally not covered by insurance and lacked federal regulation. Some physicians “cut corners … inflated and even invented success rates, or committed outright fraud,” spurring six congressional hearings from 1984 to 1989.

Despite the high saliency of IVF and its perceived “Wild West” character, it somehow avoided federal-level oversight. In The Pursuit of Parenthood, Marsh and Ronner argue that this is the result of widely divergent views of the procedure between Democrats and Republicans, which, in turn, prevented the formation of a policy consensus. At least four attempts at agreeing upon federal-level regulation failed. In 1984, for example, Representative Al Gore held hearings that sought to “build a consensus on the appropriate uses of the new reproductive technologies,” though the expert witnesses he gathered did not agree on much. Gore’s effort was followed in 1987 by a Select Committee on Children, Youth, and Families hearing on the implications of the technologies on children and families, but “the witnesses were unable to agree even on the basic nature of the problem they were facing.”

Subsequent bills seeking to mandate IVF coverage for federal employees or to criminalize paid surrogacy also failed to pass in Congress. While Democrats have long wanted federal regulation and insurance coverage, Republicans were historically opposed to federal intrusion into “family life” issues, especially if it seemed abortion-adjacent. Physicians and scientists wanted federal funding for embryo research but were ambivalent about oversight. “Physicians were also becoming more likely to oppose [regulation],” Marsh and Ronner write, viewing it “as interference with their professional autonomy.” In 1992, Representative Ron Wyden (OR-D) did manage to build consensus for light-touch legislation by framing the issue as one of consumer protection: resulting in the Fertility Clinic Success Rate and Certification Act, which requires the annual reporting of clinic success rates to HHS through the CDC.

Two other federal restraints on fertility treatments and research, however, have persisted to this day. The first is a ban on federal funding of embryo research, which began as a temporary pause, was considered by multiple commissions, and when it was due to be lifted, was resuspended by President Clinton. In 1996, it was finally codified by an appropriations rider (introduced by Senators Dickey and Wicker), an extra provision added to a government funding bill that includes policy changes or laws not directly related to the main purpose of the bill.

The second federal restraint on reproductive technology is a 2015 ban on the FDA from considering any new drug applications involving the genetic modification of human embryos. Because the FDA has asserted since 2001 that modification of human embryos would require its permission, this effectively bans even the testing of such technology in the U.S. This has hindered the application of mitochondrial replacement therapy (which uses the cytoplasm of another woman’s egg to replace diseased mitochondria in the genetic mother) in the U.S., while it proceeds elsewhere. This also rules out the more sci-fi visions of “designer babies” or even the prevention of genetic diseases through embryo editing. In 2019, House Democrats on a House Appropriations subcommittee briefly raised the possibility of removing this rule (known as the “Aderholt rider”) but backed off after House Republican objections.

At the time, critics of this attempted reform cited the proximity to He Jiankui’s clandestine use of CRISPR gene editing, in 2018, to alter the DNA of several human embryos, at least two of which were born and are now living in China. Jiankui, a Chinese scientist who had done his doctoral and post-doctoral training in U.S. universities, tried to “knock out” a gene associated with HIV resistance, but he didn’t perform sufficient in vitro testing to check that his knockout worked as intended.⁷

IVF pioneers had long speculated that their technology might do more than simply facilitate reproduction. In a biographical sketch, Edwards noted that at the beginning of his partnership with Steptoe, they “had a long afternoon session … about the complex ethical issues facing U.S. cloning, oocyte donation, surrogate pregnancies and sexing or otherwise genetically typing embryos.” Notably, He Jiankui cited Steptoe and Edwards as role models for moving ahead with a controversial technology even in the absence of scientific consensus, according to the film Make People Better.

Many of Edwards’ and Steptoe's speculations have come to fruition. Beginning in the 1990s, new procedures helped couples with single-gene genetic disorders like sickle cell anemia or Huntington's disease pick and choose disease-free embryos for implantation, preventing their transmission.

Gestational surrogacy, the practice of hiring women to carry an embryo on a prospective parent’s behalf, has also become more common, though it still only makes up about 1-2 percent of IVF embryo transfers. Surrogacy is still controversial, however, and Italy recently passed a law banning couples from going abroad to seek out surrogates. Critics cite the potential for exploitation, and supposed harm to the resulting children, and criticize the “commodification of women’s bodies.” Bucking its conservative stereotype, the U.S. is among the most liberal jurisdictions in regard to paid surrogacy, with “affluent Europeans, Asians, Australians … coming to the United States for surrogacy services.”

The demographics of IVF patients have also shifted with social trends and technological improvements, such as later childbearing and greater acceptance (and marriage rates) of LGBT couples. So has the rise of fertility preservation for medical or elective reasons through oocyte cryopreservation, exemplified by tech companies like Apple covering egg freezing for female employees and startups like Cofertility providing egg donors with free egg-freezing services as long as they donate half.

More recently, biotech startups like Conception, Vitra Labs, Ivy Natal, Dioseve, and Ovelle have been trying to transform regular cells (“somatic cells”) into oocytes — a feat that, if achieved, would radically reshape reproduction for older women, for whom IVF is generally ineffective.⁸ More speculatively, it would allow same-sex couples to have children that are genetically related to both parents. Other startups like Genomic Prediction and Orchid (and the earlier-stage Heliospect) are using more sophisticated methods of genetic testing to select embryos on the basis of common disease risks, like heart disease. Hank Greely, a professor at Stanford Law School, has explored the implications of these and other technologies in a recent series of books, starting with The End of Sex.

Though Marsh and Rooner try to argue otherwise, the absence of federal regulation of IVF has been, in aggregate, largely positive. In other words, the “Wild West” nature of IVF has offered relative reproductive freedom. U.S. consumers have access to a sophisticated network of IVF clinics, a range of donor eggs and sperm that the rest of the world envies (and tries to import), and multiple startups competing to address the most urgent fertility needs.

There are still areas of legitimate concern, however, including the aforementioned legal quagmire that some prospective parents and surrogates face with gestational surrogacy and the lack of access to affordable IVF for less well-off patients.⁹ Cases of physicians using their own sperm to impregnate patients also deserve legal sanction. Fixing such challenges with targeted federal legislation or sensible coverage decisions from government insurance is a reasonable goal, though some scholars have argued laws pertaining to reproduction may face Constitutional scrutiny.

Glenn Cohen, a law professor at Harvard Law School, has argued against the “Wild West” description of U.S. law vis-a-vis reproductive technology. Instead, he describes it as decentralized, self-regulated by professional norms, and constrained by tort law — a branch of civil law that helps people who have been harmed to litigate and seek compensation for damages. This incremental and patchwork process has its flaws but may be more self-correcting and protective of reproductive autonomy than the top-down approach that other jurisdictions have adopted. A more subtle problem is the shaky evidence base of some IVF add-ons, such as assisted hatching and mitochondria DNA load measurement, which increase the cost of the procedure but not its effectiveness.

The widespread use of questionable reproductive treatments is partially due to the unique legal context of IVF. While the drugs and devices used in IVF are regulated by the FDA, the practice of IVF itself is not; thus, changes in IVF protocols do not require FDA approval, and therefore, do not require randomized clinical trials. Since IVF in the U.S. is mostly paid for directly by patients, large payors (such as government or private insurance) cannot mandate (as they do with analogous surgeries) that IVF clinics only provide services supported by strong evidence.

There are also some characteristics of IVF that make it tricky to study: IVF is a multi-stage treatment, involving two or more individuals and many possible study endpoints. Trial designers also use inflated effect size estimates, leading to underpowered trials. In response, there has been a concerted push for studies to consistently report live births, the most relevant endpoint for patients, as well as for more realistic (lower) trial effect size estimates.

There are also some lingering uncertainties around the long-term outcomes of IVF. A review of studies comparing IVF offspring to their non-IVF siblings did find a higher risk of preterm birth, though the long-term consequences are unknown. More concerning is the finding that IVF may increase the risk of certain epigenetic imprinting disorders — a type of congenital disease that causes some genes to be abnormally expressed — though the absolute risk (given the rarity) is still very low. In response to these concerns, Marsh and Ronner argue for the CDC to carry out its 2014 “Action Plan” on infertility, which includes long-term follow-up on the effects of infertility treatment.

When new reproductive technologies emerge, new regulations may or may not be needed to prevent their misuse. One provocative hypothetical raised in Prof. Greely’s End of Sex, for example, is that of “unconsenting parenthood.” If it soon becomes possible to make eggs or sperm by reprogramming other types of cells, then discarded blood or saliva samples would be a liability. The blogger Gwern once jokingly proposed buying up the discarded memorabilia of long-dead celebrities; the implications for inheritance law in a world of artificial gametogenesis are left for the reader.¹⁰ However, even something as simple as requiring clinics to document the provenance of generated eggs and sperm could fix this issue should it ever arise.

More commonly, though, new technologies fix problems created by older ones. Many of the aforementioned “fertility fraud” cases were uncovered by unsuspecting children using consumer-grade DNA testing services, such as 23andMe, and future physicians will hopefully be deterred by the knowledge that chicanery is becoming easier to spot. The problem of triplet and higher-order births that made national news with the “Octomom” controversy is now mostly avoidable with the practice of single-embryo transfer, a product of higher IVF success rates and more attention to the greater risks of twin and triplet pregnancies.

Ultimately, while the relative lack of regulation requires ongoing patient vigilance, the story of IVF is an optimistic one — the gradual improvement of reproductive choice one innovation at a time.

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Willy Chertman is a Biotechnology Fellow at the Institute for Progress and an Adjunct Fellow at the Manhattan Institute. He was formerly a Biosecurity Fellow in the office of Senator Todd Young (R-IN) and completed his intern year in internal medicine at Holy Cross Hospital in Fort Lauderdale, Florida.

Thanks to Merrick Pierson Smela for reading a draft of this essay.

Disclaimer: Chertman is a former employee of Orchid, but does not hold any financial interest in the company.

Cite: Chertman, Willy. “The Pursuit of Parenthood.” Asimov Press (2024). DOI: https://doi.org/10.62211/47pr-89ty

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Footnotes

1. More than two-thirds of Americans say that “having access to IVF is a good thing,” according to a Pew Research Center article from May 2024.
2. All quotations in this article, unless otherwise noted, come from The Pursuit of Parenthood.
3. Even before Rock, earlier work in rabbits by Gregory Pincus and E. V. Enzmann received favorable coverage from TIME magazine.
4. Until laboratory methods of capacitation were developed, Steptoe would ask patients undergoing hysterectomies (removal of the uterus) to have intercourse before surgery, and subsequently retrieve the sperm for laboratory work.
5. When menopause renders the ovaries nonfunctional, there is no negative feedback on the amount of gonadotropins that the pituitary releases, so their levels skyrocket.
6. In a biographical sketch by Edwards, he describes their unlucky initial choice of hormone regimen, writing: "We elected to use a long-acting depot Primulot, a 17-hydroxyprogesterone caproate believed to avert threatened abortions and provide hormonal support to the uterus, quote unaware that it acted as an immediate abortifacient, as we proved comprehensively 10 years later. The embryos were replaced between days 2-5 after fertilization, and Primulot was given soon afterwards. As we now know, this procedure terminated embryo growth a day or so later. These concepts are easy to comprehend now, with hindsight, but not then when so many other factors could have impeded implantation." In addition to eliminating the medication Primulot, Edwards and Steptoe also stopped inducing superovulation in their patients. Instead, they relied on newly developed tests to track the natural ovulation cycle, and retrieved one egg at a time from patients. This was the technique used in their live births, including that of Leslie Brown in 1978.
7. Even if the procedure actually worked as intended, his critics argue that there was no clear justification for the knockout: existing IVF procedures (such as sperm washing) effectively prevent transmission of HIV from sperm to offspring and well-understood medication regimens can reduce the risk of HIV infection later in life to very low levels.
8. While IVF may help somewhat with age-related female infertility, past 35, and especially 40, the number of eggs retrieved per cycle, and the per-egg implantation rate, decrease quickly. About five to ten years before menopause occurs, IVF is mostly ineffective, unless a woman is willing to use donor eggs.
9. The average cost of an IVF cycle in the US is about $23,000, and since many patients undergo multiple cycles, an average patient will spend about $50,000. Specialized embryo testing services involve additional costs: PGT-A will typically be several hundred dollars per embryo, with PGT-M costs somewhat higher than PGT-A.
10. This is not possible with current technology. Even in the near- to medium-term, scientists would still need live cells (not just DNA) to make viable eggs or sperm from a dead person’s genome, so old letters and memorabilia couldn't be used.