A Pre-Read for the JP Morgan Healthcare Conference
I attended my first JP Morgan Healthcare Conference nineteen years ago, and for most of those years, I could have wandered around Union Square from Sunday afternoon to Thursday morning, reading every name tag on every banker, investor relations person, CEO, or scientist without finding a soul associated with in vitro fertilization (IVF) or reproductive medicine.
This weekend, I’ll fly out to San Francisco again, my schedule filled with IVF innovators.
It’s tempting to assume that real innovation in IVF arrived over the past ten years, catalyzed by advances in automation, digitalization, robotics, microfluidics, and every flavor of artificial intelligence. Indeed, we are experiencing a golden age of innovation in IVF, as we match the superb science of the past four and half decades with twenty-first-century engineering. The steady digitalization of IVF, following a technology playbook (standardize, automate, scale), will inevitably lead to an open marketplace, with power and choice for patients, and a many times larger addressable market waiting to reward thoughtfully assumed risk.
But the IVF world has been a theme park for discovery and process improvement for decades, and the wonder that my junior colleagues will create over the next decade will continue an almost five-decade tradition.
My first encounter with IVF was as a junior resident covering the labor floor, dodging the IVF team as they frantically rushed a patient for her egg retrieval in the middle of the night, her Pergonal-only stimulation regimen giving no protection against premature, in vivo, ovulation. A week into the stimulation, the patients had to produce urine sample after urine sample, every few hours, to detect the earliest hint of an LH surge. The IVF did not schedule the egg retrieval — the lead follicle’s first sign of luteinization did. Pergonal, a reasonably well-purified extract from the urine of menopausal nuns, still had to be given by deep intramuscular injections with bruising 1 1/2” needles. Twice a day, often leading to a dangerous ovarian hyperstimulation syndrome (OHSS) characterized by pounds of fluid accumulating in the patients’ abdomens. On any given day, just about every IVF program had someone hospitalized with OHSS.
The retrievals were performed by laparoscopy under general anesthesia. Without the benefit of ultrasound guidance, follicles deep within the ovary were invisible and often left behind. Once retrieved, the eggs were incubated with sperm. Some fertilized, some did not; in male factor cases few if any fertilized. We incubated the embryos for two days, hoping to transfer at the four-cell stage. Implantation rates were in the single digits per embryo so we transferred three or four or more at a time. I the first years of IVF, embryos were transferred fresh, or they were discarded. Embryo freezing was a frustrating science experiment, and egg freezing was decades away, so preserving the fertility of young women with cancer, about to undergo sterilizing chemo or radiation therapy, would have to wait.
And biopsy an embryo to check for aneuploidy or the mutations that cause cystic fibrosis or sickle cell disease or spinal muscular atrophy? Science fiction.
But in the magical years between the mid-1980s and the late 1990’s, one technique after another expanded the scope of the problems that IVF could solve. Patients whom we were powerless to help in January were called back into the office in June — their cases are now routine. The procedure grew more patient-friendly, less painful, and less risky, with fewer trade-offs between the cycle outcome and later difficulties with the pregnancy itself.
We replaced Pergonal-only stimulation with purified and then recombinant hormones, which were less irritating and could be given with tiny needles, just under the skin. A second class of medication, GnRH agonists/antagonists prevented in vivo ovulation. The combination of transvaginal ultrasound, a precise needle guide, and a specially designed pump took away the need for incisions, the laparoscope, and general anesthesia. All follicles were seen and aspirated, and their eggs were delivered to the embryologist for in vitro fertilization.
These clinical advances were more than matched by innovation in the lab. What was originally a passive process during which the sperm and eggs and wishful thinking were combined in a Petri dish evolved into the most micro of precise microsurgeries, at first creating small openings in the outer wall of the egg or embryo to promote fertilization or development, ultimately leading to the quantum leap that made IVF pregnancy a reality for the 50% of patients with moderate to severe male factor infertility — intracytoplasmic sperm injection, or ICSI.
It’s difficult to overstate how the IVF world changed in 1992 when ICSI was developed. Patients who had been told they had no hope became routine cases almost overnight. Charts were pulled out of file cabinets and archives. Teams of urologists and embryologists examined testicular biopsy specimens in azoospermic men — men whose semen contained *zero* sperm, identified individual sperm cells in the biopsied tissue, and used the individual sperm cells to create pregnancies. In the 300,000 years of human existence, no one in that situation had ever conceived.
And for most of our 300,000 years, no one would have imagined that a couple with a history of recurrent pregnancy loss, possibly from an inherited errant, misplaced piece of one chromosome translocated to another chromosome that affected most of the eggs or sperm, a couple with five or ten or twelve pregnancies, none of which made it past the mid-second trimester, would undergo in vitro fertilization, have the embryos biopsied and tested to find the one or two with normal karyotypes — and have one normal pregnancy after another, the cloud of recurrent pregnancy loss lifted. Or a couple that had a young child die of a genetic disease like spinal muscular atrophy could take the risk of a subsequent child suffering the same syndrome from 25% to zero, by doing IVF and using preimplantation genetic testing.
I won’t need to squint at name tags to recognize the current generation of IVF innovators next week at JP Morgan. Their challenge is to match innovation with scale, to make the technology that has created twelve million families over forty years scale to the world’s need of a million a month. The technology will be different, but the next golden age of IVF will be defined the same way as the last one — by more and more people having children who never could before.
See you in San Francisco.