The harms we never learn about
Only after I became obsessed with Makena did I rethink my own history, and the tumor we always thought was a random fluke.
After the traumatic preterm birth of my sister and the death of her twin in 1973, my parents were relieved when I was born full term and healthy two years later. But 6 weeks after that, while my mom nursed me, she noticed something in my eyelid that suddenly changed everything.
It turned out to be a hemangioma, a non-cancerous tumor of the blood vessels around my eye. It took 2 years of cortisone treatments, radiation to my head (not the standard today but it was the 70s!), and finally surgery to remove it. It left me with crossed eyes, needing a second surgery 4 years later and eye patches and glasses throughout my childhood.
My tumor changed our life course as a family, too. First of all, I stopped breastfeeding soon after that. My mom said the shock and stress of having another sick baby dried up her milk.
She also had to bring me for treatments back to the hospital where my sister had been in the NICU for three months, and where her other daughter had died. My sister would scream the whole time “almost like she remembered the trauma” my mom would tell me.
Meanwhile, my dad couldn’t handle the stress, felt shame when strangers stared at me, and we never really bonded. My parents divorced a few years after my treatments ended and he and I eventually became estranged.
Despite it shaping my life in such significant ways, I never wondered much where my hemangioma came from. I always assumed we couldn’t know.
When I was becoming a midwife, I learned that one theory is that hemangiomas grow from placental tissue that embeds in the fetus. I thought that was almost mystical given my profession (to have a placenta wrapped around my vision center? How cool is that?), but still ultimately a fluke — some kind of bend in the course of nature.
When I found myself in late 2019 laid off from an investor-funded start up focused on scaling up midwifery, I had a lot of time on my hands and a lot to say about profiteering in pregnancy. And when I thought about who the shameless profiteers are, one example stood out.
I thought to myself: what ever happened to Makena, the controversial progesterone drug that had been caught up in a pricing scandal years earlier?
A moment of curiosity turned out to be a rabbit hole that would have me poring over corporate tax filings, talking to researchers and doctors, watching youtube videos about pharmaceutical regulation, and generally becoming mildly obsessed. I did all of this so you wouldn’t have to, and wrapped up what I learned before the FDA hearings that fall in an article that turned a lot of heads at the time.
While my stint as an unpaid investigative journalist was brief, I continued tracking Makena’s movements through the labyrinthine FDA process as a bit of a past-time over the last few years, writing a white paper for Medicaid leaders, assembling an interest group and resource library, giving a community update to stakeholders ahead of the 2022 FDA hearings, and ultimately testifying at those hearings.
But it was only after three years of talking to doctors, midwives and patients about both the science and the history of this drug that it dawned on me in October to google, “Can progesterone in pregnancy cause infantile hemangioma.”
Um, yes.
I found a bunch of studies showing an association between synthetic progesterone use and infantile hemangioma — it’s actually the only known modifiable risk factor that I could find. I also found an explanation of why it is an association that can easily go unnoticed in safety research: Unlike other fetal anomalies, many hemangiomas (like mine) don’t become visible for weeks or months. They also don’t generally require hospitalization unless or until surgery, which is often years later. So they won’t be found if you’re only tracking birth or hospital data.
You can’t see what you don’t measure.
I don’t know if my mom had progesterone or any other hormone treatment when she was pregnant with me. This was the mid-1970s. Just a few years prior, the DES tragedy had been discovered.
Although sales of that drug were declining by the time I was born and eventually ceased, many obstetricians still believed in a hormonal component to preterm birth prevention and moved on from DES, which affected estrogen receptors, to formulations that worked on progesterone pathways, including Delalutin, the brand name for hydroxyprogesterone caproate before it was known as Makena. If there was a hormone du jour in 1975, it was almost certainly offered to my mom. With her history of a preterm birth and a neonatal loss, she would have been a top candidate for prophylactic treatments.
I may never know if my hemangioma was caused by it, but our rampant use of prenatal progesterone treatments including Makena likely drives at least some hemangioma cases according to population-based studies — even though we’re not measuring it in controlled trials or birth defect registries.
And even if we’re not measuring them, hemangiomas deeply impact people and families, and cost substantial healthcare resources, like they did for me.
And if someone who has been paying attention to Makena and reading the research didn’t even think to ask the question, what other harms are we missing?
Although there are known risks discussed on the Makena safety label, including an elevated incidence of stillbirth and miscarriage, we are still in the early days of learning what we will learn about the long-term effects of Makena and other synthetic progestins. We know Makena crosses the placenta and enters the fetal brain and reproductive organs. Both animal and human studies suggest synthetic progestins can affect the developing fetal brain leading to learning and behavior differences in childhood. Finally, a recent study showed increased risks for cancer in children who were exposed in-utero, a tragic mirroring of the history of DES.
The FDA has now been trying to remove Makena from the market for more than three years, not because of its safety profile but because it simply doesn’t work, no matter how you wrangle the data from the two trials. Its owner, private-equity-backed Covis Pharmaceuticals, has dragged its feet through appeals and lawsuits while they keep cashing in to the tune of billions in additional sales.
Despite their antics, however, Covis’s payday is likely to finally wind down. After a resounding 14–1 vote, an FDA advisory panel in October called for sales of Makena and its generic equivalents to cease, with an announcement of the FDA’s final decision and plan expected in the coming weeks.
Questions remain about whether 17-OHP will continue to be available via compounding pharmacies or in research trials, but it’s likely that patients or providers who are motivated will still be able to access the drug. It’s also clear that many clinicians are shifting to vaginal formulations of progesterone, even though evidence doesn’t support this either.
But I hope before we blindly move on to the next pill, shot, or suppository, we will stop and reassess the whole picture of progesterone use in pregnancy, and of prevention of preterm birth. If we don’t, history is likely to repeat itself.
DES was proven not to work in 1953, but its use only began to cease when a link was proven to an atypical form of vaginal cancer in offspring in the early 1970s, and eventually other reproductive and genital anomalies in both first and second generation offspring. It took patient advocates, scientists, regulators, and lawmakers all to act to get accountability for those harmed and ultimately to get DES removed completely from the market — which didn’t happen until 2000.
We need the same kind of diligence when it comes to Makena and other progesterone use in pregnancy. Just like advocates and lawmakers did after DES’s harms started to come into view, let’s demand and fund more research to understand the full consequences of marketing an ineffective drug for over a decade and exposing hundreds of thousands of pregnant people and their children to risks without counterbalancing benefits.
While we are at it, we should analyze and publish what was learned from the multiple state-sponsored programs and pay-for-performance schemes designed (surely with some input from industry) to drive higher prescriptions and increase patient adherence — some of which are still in place.
And we should investigate the historic profits generated by Makena’s string of owners through gaming the FDA system, financial engineering and litigation — not through innovation — and the cost to taxpayers, employers, and all of us. And we should ask what we didn’t invest in as a result, and whether this has contributed to our worsening maternal and infant health outcomes.
Lastly we should take a systemic look at strategies to reduce and close disparities in rates of preterm birth — a condition that is broadly accepted to be multifactorial and unlikely to be preventable with pharmaceutical approaches. (More on this in an upcoming article.)
There’s much to learn from the Makena era that could help us provide safer care in pregnancy and invest more wisely in prevention strategies.
Are we willing to learn it?
Hemangioma image source: https://commons.wikimedia.org/wiki/File:HE_infantile_hemangioma.jpg
