Fertility Drugs In The Water, Preschool Classroom Design And Safety In The IVF Lab

This chapter was too out there, even for me, and won’t be in the book*.

(*Democratizing IVF: Using Science, Medicine, And Engineering (And Venture Capital) To Help Build Families)

Safety in IVF means clean air and clean water and uncluttered work spaces, and it means not bumping into each other while balancing Petri dishes containing embryos on the palms of your hands. And more than anything it means not mixing up one person’s eggs or sperm or embryos with somebody else’s.

Every field has its UFU’s, the mistakes that you never want to have happen. Short for “ultimate screw up,” these mistakes have two things in common: 1) they should, in theory, be pretty easy to avoid and 2) the damage they cause is enormous if not.

In IVF the UFU is mixing up the name on the little plastic dish containing eggs, sperm or embryos. You can see how this could happen: all the dishes look alike, clear plastic circles with clear plastic lids, and whether looked at by a naked eye or under a microscope, there are no identifying characteristics of the specimens inside. We keep track of whose stuff is whose by labeling the dishes or the test tubes. Depending on the lab, the labeling may be a sticky note with a combination of name, birth date, social security number, maybe a patient ID number of some sort, and often the date the specimen was obtained and possibly the initials of the scientist or technician handled it. It may be a piece of blue tape with something written down using a marker. Or it may be a printed label with a barcode or radio frequency identification (RFID) tag.

Regardless of method, we’re solving for one problem: making sure that in their journey from body to container to lab to dish to microscope stage to another dish and back to body, with maybe stops along the way into and out of freezers and incubators, we always know to whom the specimen belongs.

As IVF labs manage exponentially increasing numbers of specimens, as well as the data generated creating them, how should we evolve the engineering of the industry to match this far larger scale?

Let’s consider what we can do now, in 2020, to build a sound foundation for a far larger and more complex IVF ecosystem.

But first, a story about a mid-twentieth century preschool.

I attended kindergarten at the Pleasantdale School (renamed the Mark and Scott Kelly School after its most notable alumni) in West Orange, NJ. My preschool class probably had 20 students. Inside, one of the classroom’s four walls had windows that faced the playground and Greenwood Avenue, one had chalkboards, one had storage closets, and one side wall had storage cubicles for the students, called cubbies. Well built out of pine and sanded smooth, they occupied the lower half of the wall, and were about four feet high and ten inches wide, separated into three compartments, small ones on top and bottom and a long one in the middle.

My cubby had a piece of masking tape with my name written in magic marker. My name was also on my jacket and on my lunchbox (the teacher checked both on the first day of school), both of which occupied specific places within the cubby: a hook on the right wall, and a shelf above. The sneakers that I changed into for gym class (we had to wear leather soled shoes at all other times) sat at the base of the cubby, toes in, with my initials written on bottom in magic marker. We stood in front of our cubbies while they were inspected each morning, after which we went to our desks and recited the Pledge of Allegiance.

The job of building a system to efficiently deliver and store coats, school supplies, lunches and footwear from 8AM to 3PM, Monday to Friday, September to June, while mitigating the risk of one child eating another’s lunch, losing an umbrella or going home with another child’s windbreaker, involved facility design and build-out by architects and contractors, process implementation by the teacher and process adherence by the students. Overall the system worked well, and the occasional mishap was quickly fixed by a call to Miss Brooks, the school secretary, or a visit to the lost and found closet in the lobby.

Now let’s play quality control engineer and stress test the system a bit.

Let’s assume that asbestos is discovered in the Lincoln Junior High building, across Pleasant Valley Way from us, and the town mandates that the 7th-9th grade classes have to move into our building. The two kindergarten classes combine, forty students instead of twenty. Extra chairs are brought in, and we share desks. We share cubbies: each piece of masking tape now has two names, separated with a slash. Two coats occupy each hook, and sneakers are piled on top of each other; not a perfect situation, but a manageable one. Miss Brooks fields a few more calls each week, but the lost and found closet remains neat. The department of education decides to ride out the asbestos abatement period with only minor operational modifications, and leaves the physical plant untouched.

Meanwhile, unknown to us, a pharmaceutical company a mile away, on Eagle Rock Avenue, has been developing a new fertility drug and unwittingly releases active metabolites into the drinking water. A formal census is years away, and the increase in the West Orange birth rate resulting from fertility drugs in the water supply has been so gradual that not even the already busy obstetricians and pediatricians notice, and they naturally assume that their practices are growing from referrals for their good work.

After five years, these children are ready to enroll in Pleasantdale’s kindergarten, coincidentally now in the second year of a prolonged asbestos abatement program across the street. The kindergarten classes feel this first. The twenty cubbies now hold fifty-five pairs of sneakers, coats and lunchboxes.

A couple of years, and more fertility drug babies, more construction delays, and a city budget crisis later, and the school is in disarray. The superb kindergarten teachers manage to meet all of the required educational objectives, and by replacing individual desks with tables and smaller chairs, the classroom squeezes adequate student space to keep functioning. But the combination of too many grades, K through 9, being crammed into a K through 6 facility, and the gradual and accelerating birth rate predict an inevitable system failure. The only question is where.

And, wouldn’t you know, the where turns out to be the at the cubbies.

There is only so much writing space on a ten inch wide piece of masking tape, and soon none of the kids remembers where they are supposed to store their lunch boxes or coats, some of which have been labeled, some not (there were too many to check on the first day of school, and no one looked after that.) There are only so many coats that fit on a single hook so they migrate to the least crowded space, and soon lunch bags and sneakers are piled on top on each other and spill onto the floor. Children with the same initials search for their sneakers in a common pile of similar looking Keds and PF Flyers. There are fights and tears and detentions — in kindergarten! And Miss Brooks resigns rather than field the nonstop phone calls from angry parents, who shout and curse at each other while trying to find their children’s coats and shoes in the overflowing and disorganized lost and found closet.

And so on.

Over the past twenty years, IVF has changed from a single-site (IVF clinic), linear production process with predictable inventory management and control limited to the pre-production inputs (ie equipment, media, glass and plastic-ware) to a complex multi-site process (satellite, IVF lab, storage facilities), with exponentially growing post-production inventory management challenges for frozen specimens. Unfortunately, much of the system is still managed on a site-only, with as-needed coordination often created on the fly between one site and the next. And while the overall efficiency of each node of this chain or production and chain of specimen ownership functions pretty well on its own, the lack of an agreed-up and standard set of protocols for specimen management, specimen movement and data collection make it increasingly likely that any two sites of care, whether one clinic receiving a specimen from another or a clinic sending a specimen and receiving data back, can lose a specimen, transmit inaccurate data, or misidentify one patients eggs, sperm or embryos, as those of another patient.

UFU’s.

The laboratory failure of 2018 clearly demonstrated that system, as it exists today, can fail at current volumes and throughput.

The problem is that the volumes and throughput are increasing, and the rate of increase, after adjustments for the 2020 pandemic-related artifact of a few months of cycle shut-down, is accelerating.

We are at the cubby doubling-up stage of IVF expansion. The students are a little more stressed, a few coats have been lost, but to the clinics that have not yet felt a strain or seen evidence of a bad outcome, it all seems manageable. What we are not planning for is the fertility-drugs in the water bump, which will arrive year by year, gradually demonstrating the limited benefits of incremental fixes to a system with inadequate capacity.

So how do we start to address the foundation of the IVF infrastructure as a whole?

In our preschool class, we need to address not only the inadequate capacity of the facility, but how we tackle data. We need additional storage space — a box under each chair? Relocation of non-current supply space offsite and conversion into an out of the classroom coat/locker room? Equally important, we need to go beyond writing initials on the bottoms of sneakers and taping handwritten names. Something as simple as a label maker and the adoption of name/birthday combinations will be precise enough for the 3–4 fold increase from 20 students.

For IVF, going from tens of thousands of specimens to millions, with the number increasing each year, we need far more ambitious plans, even for similar problems. Just as overlap in students’ initials resulted in one kid wearing another’s shoes, different clinics and storage facilities identifying procedures (name, birth date, date of procedure, social security number or a randomly generated ID) can result in lots of identification mistakes when the number of specimens generated and the number of interventions per specimen increases into the millions, and those ever increasing numbers rise in the face of increased number of sites that each specimen can occupy, whether or not the specimen stays in one multi-site clinic practice or moves among several.

I have argued before that by adopting a central source for assigning a unique identifier, a single source of truth of identity for every specimen, the IVF industry could eliminate this source of specimen error — errors that results at a minimum in the need to dispose of an irreplaceable egg, sperm sample or embryo, and at worst a baby born with disputed parenthood — truly a UFU.

Whether industry comes together or its own to develop this centralized ID process, whether it comes ivfOPEN and IBM, who are working on it together (disc: I chair ivfOPEN) or whether a single company develops a tool or product that gets adopted as an industry standard does not matter. With cycle volumes rising, with frozen specimen volumes per each cycle rising and with indications for IVF beyond infertility increasing, the risk of a bad outcome from identification failure will increase at an increasing rate.

Of course improving specimen identification is just the start, and thankfully industry is working at improving data management upstream from specimen creation. Witnessing systems for specimen procedures, digital tagging and surveillance, specimen transport systems that have been successfully developed for frozen tissue storage in oncology and organ transplant, plus increasingly sophisticated storage monitoring and notification systems for on-site storage are all proactive ways for the IVF industry — clinics, reference labs, tissue repositories and doctors’ offices — to anticipate that the wall of cubbies that they have relied upon for years will inevitably become inadequate, and that a new, better replacement will be in place and in use before parents are throwing punches or embryos are misplaced or mislabeled.

Unlike many areas of medicine, where care has centralized with the consolidation of huge hospital systems, resulting in aggregate data management as a norm, IVF — still decentralized and largely independent, has not had this type of data discipline imposed on it. If IVF follows a path of rapid consolidation, evolution to more aggressive and comprehensive data management will follow, as result of standard operation procedure of huge organizations. If not, the rate at which the industry adopts data standards which foster inertia-free specimen movement, tracking and monitoring will determine its ability to grow through innovation and discovery rather than evolve by serially reacting to the failures of a system with insufficient capacity and bandwidth.

bio fund manager, Columbia prof, ex-reproductive endocrinologist, roadie for @PriyaMayadas