IVF from Fine Young Cannibals and Tone Loc to Now

It’s 3AM on labor and delivery in 1989…

End of summer perspective on how far IVF has come.

Let’s rewind to 1989. It’s 3 AM, and I’m the intern covering M8, the labor and delivery floor at New York Hospital- Cornell Medical Center, which the senior doctors call The Old Lying-In. “Funky Cold Medina” plays from the radio at the nurses’ station.

As I move from room to room, looking at fetal monitor strips and talking to the patients and nurses, I hear a gurney being pushed quickly down the hall. An attending and a senior resident rush one of the IVF patients into the procedure room for an egg retrieval. The patient had been collecting and checking urine LH levels every few hours, looking for the luteinizing hormone (LH) rise that signaled that the most mature eggs were about to ovulate independently. We needed to retrieve them and get them into the lab first.

In the 1980’s, we were transitioning from laparoscopic egg retrieval under general anesthesia to trans-vaginal, ultrasound-guided egg retrievals. The old method had a lot of disadvantages. Laparoscopy was more invasive, had a more painful post-operative period, and was a less efficient way to identify where the eggs were. Since eggs develop in fluid-filled follicles, and ultrasound detects and lights up the interfaces between fluid and tissue, ultrasound is an ideal way to figure out where to point the aspiration needle. If you played video games as a kid, you intuitively know how to do transvaginal, ultrasound-guided egg retrieval.

Looking through a laparoscope directly at the ovary, on the other hand, you blindly puncture the inside of the ovary again and again and hope for the best.

Like today, our patient had gone through a regimen of fertility drug injections; in this case, the drug was probably Pergonal, a 50:50 mix of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) extracted from the urine of menopausal nuns in a convent in Switzerland (look it up.) Pergonal was an effective drug, too effective in many cases. The excess LH in the drug differentially stimulates the stroma of the ovaries to make hormones like testosterone at levels far above what the maturing eggs and thickening uterine lining need. This excess stimulation put the patient at higher risk for ovarian hyperstimulation syndrome (OHSS) and may have decreased the pregnancy potential for the embryos that resulted from the stimulation.

Since Pergonal was a urine-derived drug, it was more irritating to the body when injected; instead of the 1/4” subcutaneous injections that patients endure today, Pergonal needed to be injected 2” deep, the needle aimed where the upper, outer rivet on the back pocket of a pair of jeans, twice a day.

The bruising was epic, as was the inconvenience of needing to recruit an injector to give the shot, whether at home, at work, or wherever.

There were probably one or two patients in the hospital at the time under observation for OHSS, with ovaries three or four times the standard size and at risk for twisting on their vascular pedicles and choking off the blood supply (a surgical emergency) and an abdomen rapidly filling with fluid, the patients could become extremely unstable. Intensive care admissions were not uncommon, and rare deaths occurred. The critical time period for women with OHSS was ten days to two weeks after the egg retrieval when the early pregnancy starts to produce HCG, the hormone that we mean when we refer to a “pregnancy test.” The HCG fuels the fire for the enlarged, supercharged ovaries. When a patient with OHSS told us that her symptoms suddenly got worse, we had conflicting emotions: joy that the patient was pregnant but worry that she could get very, very sick.

Fast forward to today. What’s different?

To start, the stimulation is easier. We’ve replaced Pergonal with drugs manufactured using laboratory techniques not requiring urine; the increased purity lets us inject them just below the skin, a procedure that the patient can usually do herself and, while not painless, one that is less irritating, even when done twice a day for two weeks. We also found that by adding a second hormone to the regimen that minimizes the risk of the eggs ovulating on their own before they can be retrieved for the lab, we gain control over the retrieval schedule and no longer need the mad rush to the operating room.

The development of vaginal ultrasound-guided egg retrieval made everyone’s lives better. For patients, it meant less pain and less anesthesia; for the clinical staff, it meant one less nurse (laparoscopy needs a scrub and circulating curse) and dispensing with the cumbersome incision-fill the abdomen with carbon dioxide-setup up and insert the scope, awkwardly immobilize the ovaries and blindly stab away where at the bumps in the surface where you think the eggs might be. For the embryologists, retrieval could be done adjacent to the laboratory rather than at the site of whatever operating suite was used in the particular facility.

We can’t finish discussing the egg retrieval procedure without mentioning an IVF variant that was still widely practiced in the late 1980s and early 90s: gamete intrafallopian transfer, or GIFT. In these early decades, with embryo implantation rates in the low single digits, many thought that minimizing the time the eggs and embryos spent in the laboratory was a good idea, so in many cases, during the laparoscopy, we combined the just-retrieved eggs with a fresh sperm prep, threaded a catheter through the end of one or both of the fallopian tubes and deposited the eggs and sperm about midway through the tube, close to where fertilization occurs in unassisted reproduction. Variants of this procedure included zygote intrafallopian transfer (ZIFT) and tubal embryo transfer (TET), depending on where the transfer occurred in the embryo development cycle.

There was an ongoing and occasionally fierce debate about whether IVF or GIFT produced better outcomes. Unfortunately, the pregnancy rates for both were too low for anyone to feel confident about the outcome of a cycle. To compensate for the low probability of success for each egg or embryo returned to the body, we returned a lot of embryos all at once, so when it did work, it worked too well: rates of twins, triplets, and higher order multiple pregnancies jumped, each one representing a much higher risk for both mother and babies — risks of preterm delivery, risks of pregnancy-associated diabetes and blood pressure complications, difficult deliveries and risks of bleeding after delivery. Newborn intensive care units filled with infants prematurely delivered 8, 10, 12, or more weeks early, the incubator-connected babies often in a row with their siblings. (This demographic bump later challenged local school boards.)

IVF patients and their medical teams in 1989 faced a tricky balance: to have even anywhere near a decent chance of having a child from the cycle, what might turn out to be a too-high number of embryos needed to be transferred. Compounding that dilemma was that we were not all that great at assessing which embryos to put back. The typical IVF embryo transfer in 1989 might happen two days after the egg retrieval when an “ideal” embryo contained only four cells. As we now know, embryos often “declare themselves” in the subsequent three days as they progress to what is known as the blastocyst stage; many decent-looking embryos at day four stop along the way, and it is difficult to predict which embryos would. We could not continue to nourish embryos, so on day two, we put back a bunch of them and hoped for the best.

Yet another significant factor in the transfer decision was that we were figuring out how to freeze and store embryos to use later. So faced with a one-shot-only chance of a good outcome from the stimulation (20+ deep shots with a long needle, high risk of hyperstimulation syndrome, a surgical laparoscopy under general anesthesia), it was easy to justify a more is better than less approach to embryo transfer, up to and including “what the hell, just put ’em all back.”

We have a long way to go to reach the 30 million five thousand dollar IVF cycles to produce 25 million babies a year model that would address all of the good we can do with this remarkable procedure. Looking at how far we have come makes it easier to envision how continued innovation will get us there. Those of us who remember just how quickly the world changed when we figured out that by injecting sperm directly into the eggs themselves, we could treat almost any case of male factor infertility — how, on a Tuesday in 1993, we could only offer the use of donor sperm because IVF had truly dismal results with very low sperm counts or motility — and then on Wednesday we called the same patients back, telling them “never mind what we told you yesterday. We can help you now.”

Millions of people worldwide are waiting for that type of phone call.