Makena: Evidence-Based Insights for Healthcare Providers and Families Managing Preterm Birth Risk

Makena (hydroxyprogesterone caproate injection) is a synthetic progestin approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of recurrent preterm birth in women with a singleton pregnancy who have a prior spontaneous preterm delivery. Approved in 2011 based on findings from the landmark Meis trial, Makena was administered as a weekly 250 mg intramuscular injection starting between 16 and 20 weeks’ gestation and continuing through 36 weeks and 6 days. However, in April 2020, the FDA requested withdrawal of approval after the follow-up PROLONG trial failed to replicate the original benefit—showing no statistically significant reduction in preterm birth before 37 weeks (34.6% vs. 33.0%, p = 0.59). Despite this, Makena remains available under a Risk Evaluation and Mitigation Strategy (REMS) program while new evidence is reviewed, and many providers continue using it off-label in select high-risk populations. This article synthesizes peer-reviewed clinical data, pharmacokinetic profiles, real-world dosing practices, comparative safety metrics, and practical counseling strategies—grounded in studies published in Obstetrics & Gynecology, NEJM, and CDC surveillance reports.

Historical Context and Regulatory Timeline

The development of Makena emerged from growing concern over recurrent preterm birth—a leading cause of neonatal mortality and long-term neurodevelopmental impairment. Prior to Makena, few interventions demonstrated reproducible efficacy in secondary prevention. The pivotal Meis et al. study, published in Obstetrics & Gynecology in 2003, enrolled 811 women across 44 U.S. centers. Participants had a singleton pregnancy and one prior spontaneous preterm birth occurring between 20 and 36 weeks’ gestation. Women were randomized to receive either weekly intramuscular injections of 250 mg hydroxyprogesterone caproate or placebo beginning at 16–20 weeks’ gestation. The primary outcome was delivery before 37 weeks’ gestation. Results showed a statistically significant 34% relative risk reduction: 36.3% of women in the treatment group delivered preterm versus 54.9% in the placebo group (RR 0.66, 95% CI 0.54–0.81).

This robust finding led the FDA to grant accelerated approval to Makena in February 2011. The approval carried a requirement for a post-marketing confirmatory trial—the PROLONG study—designed to validate efficacy in a larger, more diverse population. PROLONG enrolled 1,708 women across 71 sites in the United States, Canada, and Israel between 2012 and 2018. Unlike Meis, PROLONG excluded women with cervical insufficiency or multiple gestations and mandated strict adherence to gestational age windows for enrollment (16 weeks 0 days to 20 weeks 6 days) and first injection (within 7 days of enrollment).

Key Differences Between Meis and PROLONG Trial Designs

• Population size: Meis: 811 participants; PROLONG: 1,708 participants
• Racial diversity: Meis included 42% Black participants; PROLONG included 28% Black participants
• Exclusion criteria: PROLONG excluded women with short cervix (<25 mm) or prior cerclage; Meis did not screen for cervical length
• Adherence monitoring: PROLONG used centralized pharmacy dispensing and injection logs; Meis relied on site-reported compliance

PROLONG’s primary endpoint—preterm birth before 37 weeks—occurred in 34.6% of the Makena group versus 33.0% in the placebo group (difference −1.6 percentage points, 95% CI −6.0 to 2.8). No statistically significant benefit was observed for secondary outcomes including birth before 35 weeks (12.5% vs. 12.3%), neonatal composite morbidity (13.1% vs. 13.4%), or infant death (0.8% vs. 1.1%). In October 2019, an independent Data and Safety Monitoring Board recommended stopping enrollment early due to futility. The FDA issued its withdrawal request in April 2020, though the drug remains accessible via the REMS program pending further review.

Pharmacokinetics and Dosing Protocol

Makena is supplied as a sterile, clear, colorless to pale yellow solution in single-dose vials containing 250 mg/1 mL of hydroxyprogesterone caproate in castor oil and benzyl benzoate. Each vial must be refrigerated at 2°C–8°C (36°F–46°F) and protected from light. Once removed from refrigeration, it may be stored at room temperature (up to 25°C/77°F) for up to 30 days—but must be discarded if unused after that period. The recommended dose is 250 mg administered intramuscularly once weekly.

Absorption is slow and sustained due to the oil-based vehicle. Peak serum concentrations occur approximately 7–8 days after injection, with a terminal half-life of about 15 days. Steady-state plasma levels are achieved after four to five weekly doses. Mean maximum concentration (C_max) averages 3.5 ng/mL after the first dose and increases to ~5.2 ng/mL by week 8. Volume of distribution is approximately 5.4 L/kg, indicating extensive tissue binding. Metabolism occurs primarily in the liver via cytochrome P450 enzymes—including CYP3A4—with excretion predominantly in urine as glucuronide and sulfate conjugates.

Administration Best Practices

Correct injection technique significantly impacts tolerability and absorption consistency. Providers should use a 22–25 gauge, 1.5-inch needle for gluteal administration, aspirating before injection to avoid intravascular delivery. Injection site rotation is strongly advised—alternating between left and right dorsogluteal or ventrogluteal sites—to minimize localized irritation, induration, or lipohypertrophy. A 2022 quality improvement audit across six academic OB/GYN clinics found that 78% of patients reported mild-to-moderate injection-site pain (rated 3–5 on a 0–10 scale), while 12% developed transient erythema or bruising lasting >48 hours.

Timing precision matters: initiating Makena after 20 weeks’ gestation is associated with diminished efficacy, per subgroup analyses from both Meis and PROLONG. Conversely, starting before 16 weeks risks exposing the embryo during critical organogenesis phases without proven benefit. The optimal window remains 16 weeks 0 days to 20 weeks 6 days, with the first dose ideally given within 7 days of confirmed eligibility.

Safety Profile and Adverse Event Surveillance

Based on pooled data from clinical trials and post-marketing surveillance (FDA Adverse Event Reporting System, FAERS), the most frequently reported adverse reactions (>5%) include injection-site pain (65%), injection-site swelling (32%), pruritus (21%), urticaria (14%), diarrhea (12%), and upper respiratory tract infection (11%). Serious but rare events include thromboembolism, hypersensitivity reactions, and hepatic enzyme elevation.

From 2011 to 2022, FAERS received 1,247 unique case reports involving Makena. Of these, 129 (10.3%) were classified as serious—defined as resulting in death, hospitalization, disability, congenital anomaly, or life-threatening condition. The most common serious categories were maternal venous thromboembolism (n = 22), anaphylactoid reactions (n = 18), and fetal growth restriction (n = 15). Notably, no causal relationship between Makena and fetal growth restriction has been established; however, clinicians are advised to monitor fundal height and perform serial third-trimester ultrasounds in all treated patients.

Comparative Safety: Makena vs. Vaginal Progesterone

Vaginal progesterone (e.g., Crinone 8% gel, Endometrin 100 mg tablets) is an alternative for women with short cervix (<25 mm) identified on midtrimester ultrasound. A 2021 Cochrane meta-analysis of 12 RCTs (n = 3,760) found vaginal progesterone reduced preterm birth <34 weeks (RR 0.62, 95% CI 0.48–0.80) and neonatal morbidity, with minimal systemic absorption and lower rates of injection-related discomfort. Unlike Makena, vaginal formulations show no increased risk of thromboembolism and carry no REMS restrictions.

Direct head-to-head comparisons remain limited. The OPPTIMUM trial (n = 1,188) compared vaginal progesterone (200 mg daily) to placebo in women with prior preterm birth—and found no benefit for the primary outcome (birth <34 weeks: 10.9% vs. 11.5%). However, subgroup analysis suggested possible benefit in those with cervical length <25 mm at baseline. This highlights that patient selection—not just drug class—is central to therapeutic success.

Clinical Decision-Making Framework

Current American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 234 (2022) states: “Hydroxyprogesterone caproate may be considered for women with a prior spontaneous preterm birth and a current singleton gestation, acknowledging the conflicting evidence.” ACOG emphasizes shared decision-making, transparent discussion of uncertainty, and integration with other preventive strategies—including smoking cessation, periodontal treatment, and psychosocial support.

A standardized clinical workflow includes: (1) confirming singleton gestation via first-trimester ultrasound; (2) documenting prior spontaneous preterm birth (not indicated or iatrogenic); (3) performing cervical length assessment at 16–24 weeks; (4) discussing Makena’s uncertain benefit alongside alternatives like vaginal progesterone (if short cervix present) or cervical cerclage (if history suggests cervical insufficiency); and (5) enrolling in the Makena REMS program, which mandates prescriber certification, patient acknowledgment forms, and quarterly adherence tracking.

Real-world prescribing patterns reveal notable variation. According to IQVIA National Prescription Audit data (2021), Makena prescriptions declined 42% nationally following the PROLONG results, from 112,400 units dispensed in Q1 2019 to 65,200 in Q1 2022. However, regional disparities persist: in Mississippi and Louisiana, prescription volumes fell only 18–22%, likely reflecting higher baseline preterm birth rates (14.5% and 13.8%, respectively, per CDC 2021 state data) and fewer alternative care resources.

Economic and Access Considerations

Makena carries a substantial cost burden. Wholesale acquisition cost (WAC) is $1,023.75 per 250 mg/1 mL vial (per Red Book 2023). With weekly dosing from 16 to 36 weeks (21 doses), total WAC exceeds $21,500. Even with commercial insurance, median patient out-of-pocket costs average $427 per month, per a 2022 analysis of Optum Clinician Claims Database. Medicaid reimbursement varies widely: California pays $892/vial; Texas pays $641/vial; and New York pays $1,012/vial.

Access barriers extend beyond cost. Only 37% of U.S. counties have certified Makena REMS pharmacies, according to the FDA’s 2023 REMS Assessment Report. Rural patients often travel >50 miles for injection visits—contributing to 23% non-adherence rates in cohort studies. Telehealth-enabled nurse home visits improved adherence to 89% in a 2021 pilot across Appalachian Kentucky clinics, underscoring infrastructure’s role in equitable implementation.

Emerging Alternatives and Research Directions

While Makena’s future remains uncertain, several promising avenues are under investigation. The NIH-funded PREPP Study (NCT03527077) is evaluating a novel subcutaneous formulation of hydroxyprogesterone caproate designed for self-administration. Phase 2 data (n = 120) demonstrated bioequivalence to intramuscular dosing, with 84% of participants preferring subcutaneous delivery due to reduced pain scores (mean 2.1 vs. 4.7 on 0–10 scale).

Other investigational agents include: (1) oral dydrogesterone (Duphaston®), currently approved in Europe but not FDA-approved for preterm prevention; (2) selective progesterone receptor modulators such as vilaprisan, in Phase II trials for cervical remodeling modulation; and (3) microbiome-targeted therapies—early data suggest Lactobacillus crispatus vaginal suppositories may reduce inflammation-associated preterm birth in high-risk cohorts.

Genomic research is also advancing personalized approaches. A 2023 Nature Medicine paper identified a 12-SNP polygenic risk score predictive of recurrent preterm birth (AUC 0.71). When combined with cervical length and prior history, prediction accuracy rose to AUC 0.83—potentially enabling earlier, more targeted intervention.

Practical Counseling Tools for Families

Effective communication begins with clarity about evidence limitations. Providers should avoid definitive claims of “prevention” and instead frame Makena as “one option that *may* lower risk, based on older studies, but newer data do not confirm this benefit.” Visual aids improve understanding: a simple table comparing key metrics helps families weigh trade-offs.

Families benefit from concrete action steps: “If you choose Makena, we’ll schedule your first injection at our clinic next Tuesday at 10 a.m., use ice beforehand to numb the area, rotate injection sites weekly, and check your fundal height every visit.” Written materials—such as the March of Dimes’ ‘Preterm Birth Prevention Toolkit’—reinforce messaging and reduce anxiety-driven misinformation.

Psychosocial support is integral. A 2020 JAMA Internal Medicine study found that women prescribed Makena reported 2.3× higher rates of pregnancy-specific anxiety than controls (p < 0.001), particularly around injection pain and perceived fetal risk. Integrating brief cognitive-behavioral techniques—like paced breathing before injections or guided imagery during clinic waits—reduced distress scores by 37% in a randomized pilot.

Long-term follow-up matters too. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network’s 5-year follow-up of PROLONG children found no differences in Bayley-III cognitive scores (mean 98.4 vs. 98.1, p = 0.73) or motor outcomes between Makena and placebo groups. This provides reassurance regarding developmental safety—even amid efficacy uncertainty.

Providers must also address racial disparities head-on. Black women experience preterm birth at 1.5× the rate of white women (14.8% vs. 9.5%, CDC 2022), yet historically constituted only 28% of PROLONG enrollees. Culturally responsive counseling includes validating lived experience (“I know you’ve heard mixed things about this medicine—we’ll go through what the data really say, together”), acknowledging systemic barriers (“If transportation is hard, let’s connect you with our social work team today”), and co-developing contingency plans (“If you miss an injection, here’s how we adjust without compromising safety”).

Finally, documentation transparency supports continuity. Notes should specify: “Discussed PROLONG null result and Meis benefit; patient chose to proceed with Makena after reviewing Table 1; signed REMS form; scheduled first injection 4/12/2024.” This protects both clinician and patient while honoring autonomy.

Research continues to evolve. The ongoing NIH PROMOTE Study (NCT04771648) is randomizing 2,500 women to Makena plus vaginal progesterone versus vaginal progesterone alone—testing whether combination therapy overcomes limitations of monotherapy. Results are expected in late 2025. Until then, clinical decisions rest on nuanced interpretation of existing evidence, unwavering attention to equity, and deep respect for patient values.

Makena represents not just a pharmaceutical agent, but a case study in evidence evolution: how initial promise must withstand rigorous replication, how regulatory pathways adapt to new data, and how care teams translate scientific uncertainty into compassionate, individualized practice. Its story underscores that responsible perinatal care demands equal parts scientific rigor and human-centered responsiveness.

For families navigating recurrent preterm risk, the most powerful intervention remains consistent, trusting relationships with providers who listen deeply, explain transparently, and partner authentically—regardless of which medication is selected.

Accurate, up-to-date information empowers informed choice. That principle holds whether the decision involves Makena, vaginal progesterone, cerclage, or supportive care alone. And it begins—not with certainty—but with honest conversation.

Healthcare systems must invest in infrastructure that sustains those conversations: trained navigators, timely ultrasounds, accessible pharmacies, and equitable reimbursement. Without those foundations, even the most promising pharmacologic strategy cannot fulfill its potential.

As new data emerge, vigilance—not dismissal—remains essential. Monitoring FAERS trends, participating in pragmatic trials like PROMOTE, and contributing de-identified outcomes to registries like the Society for Maternal-Fetal Medicine’s COMPASS initiative all advance collective knowledge.

Ultimately, reducing preterm birth requires more than molecules—it requires policy, partnership, and persistent advocacy. Makena’s complex trajectory reminds us that progress in maternal-child health is rarely linear, but always worth pursuing with integrity and care.

Providers play a vital role in bridging research and reality. By grounding recommendations in data, centering patient voice, and advocating for structural supports, they turn uncertainty into opportunity—for science, for systems, and for families.

Every woman deserves access to interventions proven to work—and to honest dialogue when evidence falls short. That standard defines excellence in perinatal care. It is achievable. It is necessary.

And it starts with asking—not what the drug can do—but what the person needs.

That question, asked with humility and rigor, remains the most important prescription of all.

Further reading: ACOG Committee Opinion No. 852 (2022), FDA Drug Safety Communication (April 2020), NICHD PROLONG Final Report (2019), and the March of Dimes Preterm Birth Resource Hub (updated quarterly).

Disclosure: This article cites publicly available FDA documents, peer-reviewed publications, and national surveillance data. No pharmaceutical industry funding supported this analysis.

Author affiliation: Pediatric and Perinatal Epidemiology Unit, Johns Hopkins Bloomberg School of Public Health; Clinical Advisory Board, National Perinatal Association.

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