Hydroxyprogesterone caproate, sold under the brand name Makena, was the pregnancy drug that clinical trials suggested could reduce the risk of recurrent preterm birth by roughly 35 percent in women who had previously delivered early. The injectable progesterone treatment was approved by the FDA in 2011 under its accelerated approval pathway, offering what appeared to be a meaningful intervention for one of obstetrics’ most persistent problems. For a woman who delivered her first child at 28 weeks and faced the anxiety of another early delivery, Makena represented a pharmacological safety net — weekly injections starting in the second trimester that aimed to keep the pregnancy going longer. However, the drug’s story took a dramatic turn when a confirmatory trial failed to replicate those early results, leading the FDA to withdraw its approval in 2023 after a protracted regulatory battle. This article examines what hydroxyprogesterone caproate is, how it was studied, why the FDA ultimately pulled it from the market, and what the controversy means for pregnant women today.
For readers of a brain health and dementia care site, the connection may not be immediately obvious, but preterm birth carries lasting neurological consequences. Babies born too early face elevated risks of cerebral palsy, cognitive delays, and emerging research suggests potential links to neurodevelopmental conditions that may affect brain health across the lifespan. Understanding the drugs designed to prevent prematurity is, in a real sense, understanding one of the earliest interventions in lifelong brain health. The saga of Makena also offers a case study in how medical evidence evolves, how accelerated drug approvals can go wrong, and why patients and families need to stay informed even after a treatment receives regulatory blessing. We will walk through the original clinical data, the failed confirmatory study, the FDA’s unprecedented withdrawal decision, and what alternative approaches remain for women at risk of delivering too early.
Table of Contents
- How Did Hydroxyprogesterone Caproate Become the Leading Drug to Reduce Preterm Birth Risk?
- Why the FDA Withdrew Makena and What the Confirmatory Trial Revealed
- Preterm Birth and the Brain — Why This Matters for Lifelong Neurological Health
- What Are the Current Alternatives for Preventing Preterm Birth?
- The Controversy Over Accelerated Approval and What It Means for Patient Trust
- The Role of Prenatal Care in Both Preterm Birth Prevention and Early Brain Development
- What the Future Holds for Preterm Birth Prevention Research
- Conclusion
- Frequently Asked Questions
How Did Hydroxyprogesterone Caproate Become the Leading Drug to Reduce Preterm Birth Risk?
The story begins with a 2003 study published in the new England Journal of Medicine, conducted by the Maternal-Fetal Medicine Units Network. that trial enrolled 463 women who had previously experienced spontaneous preterm birth and randomized them to receive either weekly injections of 17-alpha hydroxyprogesterone caproate (17P) or a placebo, starting between 16 and 20 weeks of gestation. The results were striking: the rate of delivery before 37 weeks dropped from 54.9 percent in the placebo group to 36.3 percent in the treatment group. This translated to roughly a 34 to 35 percent relative reduction in recurrent preterm birth, a figure that generated significant excitement in the obstetric community. Based on that single pivotal trial, compounding pharmacies began producing 17P for clinical use, and demand grew rapidly. In 2011, the FDA granted accelerated approval to AMAG Pharmaceuticals for a branded version called Makena, priced initially at around $690 per injection — a figure that sparked immediate controversy given that compounded versions had been available for a fraction of that cost.
The accelerated approval pathway requires manufacturers to conduct a confirmatory trial to verify the clinical benefit, and AMAG was obligated to complete one. For nearly a decade, Makena became a standard part of care for women with a history of spontaneous preterm delivery, endorsed by the American College of Obstetricians and Gynecologists and prescribed widely across the United States. The drug’s mechanism was rooted in the known role of progesterone in maintaining pregnancy. Progesterone helps keep the uterine lining stable and suppresses contractions. The hypothesis was that supplementing progesterone in women whose bodies might not produce enough of it — or whose cervical or uterine conditions predisposed them to early labor — could extend gestation. It was a biologically plausible theory, and the 2003 trial data seemed to confirm it. But medicine has learned, sometimes painfully, that promising early results do not always hold up under more rigorous scrutiny.
Why the FDA Withdrew Makena and What the Confirmatory Trial Revealed
The confirmatory study, known as the PROLONG trial, enrolled over 1,700 women across multiple countries and was designed to be the definitive answer on whether Makena actually worked. Published in 2019, the results were deeply disappointing for the drug‘s proponents. PROLONG found no statistically significant difference in preterm birth rates or neonatal outcomes between women receiving hydroxyprogesterone caproate and those receiving a placebo. The preterm birth rate before 35 weeks was 11.0 percent in the treatment group versus 11.5 percent in the placebo group — essentially identical. The discrepancy between the 2003 trial and the PROLONG trial ignited fierce debate. Critics of the confirmatory study pointed out that the PROLONG trial enrolled a different population with a lower baseline rate of preterm birth, included many international sites where standard prenatal care differed, and may have been underpowered to detect a meaningful effect in a lower-risk group.
Defenders of the drug argued that the original trial’s results were still valid for the specific high-risk American population it studied. However, the FDA’s Center for Drug Evaluation and Research concluded that the totality of evidence did not support a finding that Makena provided clinical benefit, and in April 2023, the agency issued a final order withdrawing the drug’s approval — an action that was virtually unprecedented for an obstetric medication. It is worth noting a critical limitation in interpreting this controversy: if you or someone you know is currently pregnant and has a history of preterm birth, the withdrawal of Makena does not mean that progesterone treatment is universally ineffective. Vaginal progesterone, a different formulation, has shown benefit in women with a short cervix detected on ultrasound, and some practitioners may still consider compounded 17P on a case-by-case basis. However, the branded product is no longer available, and clinical guidelines have shifted. Any decisions about progesterone therapy during pregnancy should be made with a maternal-fetal medicine specialist who can weigh individual risk factors.
Preterm Birth and the Brain — Why This Matters for Lifelong Neurological Health
The reason a dementia and brain health audience should care about preterm birth interventions is straightforward: the brain is the organ most vulnerable to the consequences of being born too early. Babies delivered before 37 weeks, and especially before 32 weeks, face significantly higher rates of intraventricular hemorrhage, white matter injury, and disrupted neural development. A child born at 26 weeks may spend months in a neonatal intensive care unit, and even with excellent medical care, the long-term cognitive effects can be substantial. Studies have shown that adults who were born very preterm score lower on measures of executive function, processing speed, and memory compared to peers born at full term. Emerging research has begun to explore whether preterm birth might also influence dementia risk decades later. A Swedish registry study published in the early 2020s found that extremely preterm birth was associated with subtle differences in brain structure that persisted into adulthood, including reduced volumes in regions associated with memory and cognitive processing.
While it would be premature to draw a direct causal line between preterm birth and Alzheimer’s disease or other dementias, the biological plausibility is there. The developing brain that is deprived of the final weeks of gestation — a period of rapid myelination and synapse formation — may enter adulthood with less cognitive reserve, a concept that researchers believe helps buffer against neurodegenerative decline. Consider the case of a family where a grandmother is living with early-stage Alzheimer’s and a daughter is facing a high-risk pregnancy. The connections between these two medical realities are not just emotional but potentially biological. Anything that reduces the risk of preterm birth is, in theory, an investment in that child’s brain health trajectory over the next seven or eight decades. this framing does not mean we should overstate the evidence, but it does underscore why the failure of a drug like Makena carries implications well beyond the delivery room.
What Are the Current Alternatives for Preventing Preterm Birth?
With Makena withdrawn, women at risk of preterm birth still have several evidence-based options, though none is a silver bullet. Vaginal progesterone — typically administered as a daily gel or suppository — has shown efficacy in women who have a short cervix, generally defined as less than 25 millimeters on transvaginal ultrasound performed in the second trimester. A meta-analysis led by Roberto Romero found that vaginal progesterone reduced the risk of preterm birth before 33 weeks by approximately 42 percent in this specific population, along with meaningful reductions in neonatal morbidity and mortality. This is a different patient group than the one Makena targeted, which is an important distinction. Cervical cerclage, a surgical procedure in which the cervix is stitched closed, remains an option for women with a history of cervical insufficiency or those who develop progressive cervical shortening during pregnancy. Cerclage has been studied for decades and is generally effective in the right clinical context, though it carries surgical risks including infection, bleeding, and in rare cases, cervical laceration.
The tradeoff between cerclage and vaginal progesterone depends on the individual patient’s history and cervical measurements, and some clinicians use both in combination for particularly high-risk cases. A newer intervention that has gained attention is the cervical pessary, a silicone device placed around the cervix to provide mechanical support. Results from clinical trials have been mixed, with some studies showing benefit and others failing to demonstrate a significant effect. As of recent reports, the pessary is not widely used in the United States but has more traction in European practice. For families weighing options, the most important step is a thorough evaluation by a maternal-fetal medicine specialist, including transvaginal cervical length screening and a detailed review of obstetric history. No single intervention works for every cause of preterm birth, and the underlying etiology — whether it is cervical insufficiency, infection, inflammation, or idiopathic — shapes which approach has the best chance of success.
The Controversy Over Accelerated Approval and What It Means for Patient Trust
Makena’s rise and fall exposed serious tensions in how the FDA’s accelerated approval pathway works. The program was created in 1992 to get treatments for serious conditions to patients faster, particularly when existing options are inadequate. Under accelerated approval, a drug can reach the market based on a surrogate endpoint — in Makena’s case, the reduction in preterm birth rates — with the requirement that the manufacturer later confirms actual clinical benefit. The problem is that “later” can stretch for years, and during that time, the drug is prescribed as though its benefits are proven. AMAG Pharmaceuticals took until 2019 to complete the PROLONG trial, nearly eight years after approval. During that period, Makena generated substantial revenue and became embedded in clinical practice guidelines.
When the confirmatory trial failed, the manufacturer fought the withdrawal, arguing that the drug still had value for a subset of patients. The FDA held an advisory committee meeting in 2022 where the panel voted overwhelmingly to recommend withdrawal, but the manufacturer requested a hearing, further delaying the process. The entire episode raised legitimate questions about whether the accelerated approval system creates perverse incentives — companies profit from drugs during the confirmation period and then have procedural tools to delay removal even when the evidence turns against them. For patients, the lesson is both empowering and sobering. A drug’s FDA approval does not guarantee that it works, particularly when that approval is accelerated. This does not mean patients should distrust their doctors or refuse medications, but it does mean that asking questions about the strength of evidence behind a treatment is always reasonable. In the context of preterm birth prevention, the Makena experience has made many obstetricians more cautious about pharmacological interventions and more attentive to non-drug approaches like cervical length screening and lifestyle modifications.
The Role of Prenatal Care in Both Preterm Birth Prevention and Early Brain Development
Beyond any single drug, comprehensive prenatal care remains the most broadly effective strategy for reducing preterm birth and optimizing fetal brain development. Regular monitoring allows clinicians to identify risk factors early — cervical shortening, gestational diabetes, preeclampsia, infections — and intervene before they precipitate early delivery. Women who receive consistent prenatal care are significantly less likely to deliver preterm than those who receive late or no care, a disparity that disproportionately affects low-income communities and communities of color.
For brain health specifically, prenatal nutrition plays an underappreciated role. Adequate intake of folate, omega-3 fatty acids, iron, and choline during pregnancy supports fetal neural development in ways that may have lasting consequences. A 2020 study from Cornell University found that maternal choline supplementation during the third trimester improved infant information processing speed, a marker that correlates with later cognitive function. While these nutritional interventions are not direct parallels to a drug like Makena, they represent the kind of low-risk, broadly beneficial approach that can complement medical interventions aimed at preventing preterm delivery.
What the Future Holds for Preterm Birth Prevention Research
The withdrawal of Makena has not ended research into progesterone-based therapies or other pharmacological approaches to preterm birth. Several clinical trials are ongoing or planned that investigate different formulations, dosing schedules, and patient populations. There is also growing interest in biomarker-based approaches that could identify which women are most likely to benefit from progesterone treatment, moving away from the one-size-fits-all model that may have contributed to the PROLONG trial’s null results.
Advances in understanding the maternal microbiome, inflammatory pathways, and genetic predisposition to preterm labor may eventually yield more targeted interventions. For the brain health community, these developments are worth watching. Every week of gestation gained translates to measurably better neurological outcomes for the child, and the ripple effects of those outcomes may extend across a lifetime. The Makena story is a reminder that medical progress is not always linear — promising results can be overturned, approved drugs can be withdrawn, and the search for better answers continues.
Conclusion
Hydroxyprogesterone caproate’s journey from a promising preterm birth intervention to a withdrawn medication encapsulates the complexity of modern drug development and the importance of rigorous confirmatory evidence. The original trial suggested a 35 percent reduction in recurrent preterm birth, but the larger PROLONG trial could not replicate that finding, leading to the FDA’s decision to pull Makena from the market. Women at risk of preterm delivery still have options — vaginal progesterone for short cervix, cerclage for cervical insufficiency, and comprehensive prenatal care — but the pharmacological landscape has narrowed.
For those focused on brain health and dementia care, the connection between preterm birth prevention and lifelong neurological outcomes deserves more attention than it typically receives. The developing brain is exquisitely sensitive to the timing of birth, and interventions that extend gestation even by a few weeks can have meaningful effects on cognitive trajectories. As research continues to explore new approaches to preventing prematurity, staying informed about the evidence — including when that evidence changes — is essential for families, caregivers, and anyone invested in brain health across the lifespan.
Frequently Asked Questions
Is Makena still available for use during pregnancy?
As of the FDA’s 2023 withdrawal decision, Makena is no longer commercially available in the United States. Some compounding pharmacies may still produce 17-alpha hydroxyprogesterone caproate, but its use is no longer supported by FDA approval. Women should discuss current options with their healthcare provider.
Does vaginal progesterone work the same way as Makena?
Not exactly. Vaginal progesterone is a different formulation with a different evidence base. It has shown benefit specifically in women with a short cervix detected by ultrasound, whereas Makena was indicated for women with a history of preterm birth regardless of cervical length. The two are not interchangeable, and the choice depends on the clinical scenario.
Can preterm birth cause long-term brain problems?
Yes. Preterm birth, particularly very preterm birth before 32 weeks, is associated with increased risks of cognitive delays, learning disabilities, attention problems, and in severe cases, cerebral palsy. Research is also exploring whether preterm birth may reduce cognitive reserve later in life, potentially influencing vulnerability to age-related cognitive decline.
What should I do if I have had a previous preterm birth and am pregnant again?
Seek care from a maternal-fetal medicine specialist as early in pregnancy as possible. They can assess your specific risk factors, monitor cervical length, and discuss available interventions including vaginal progesterone, cerclage, or other approaches tailored to your situation.
Why did the PROLONG trial get different results than the original 2003 study?
Several factors likely contributed, including differences in the patient populations studied, lower baseline preterm birth rates in the PROLONG trial, and the inclusion of international sites with varying standards of prenatal care. Some researchers believe the original trial may have overestimated the treatment effect, while others argue the PROLONG trial was not designed to capture benefits in the highest-risk subgroup.
