Frozen embryo transfer (FET) has confidently migrated from an auxiliary strategy to a core component of modern assisted reproductive technologies. With fewer complications compared to fresh transfers and increasingly sophisticated cryopreservation methods, FET cycles now represent a major avenue toward safer and more predictable pregnancy outcomes. Yet, despite these advances, live birth rates (LBRs) remain far from uniform. The journey from embryo transfer to successful term delivery still depends on intricate biological interactions—many of which clinicians attempt to modulate using adjunctive therapies.

One of the most intriguing candidates among these adjuncts is vaginal sildenafil citrate. Although popularized in a completely different branch of medicine, sildenafil possesses notable vascular effects that may be leveraged to improve uterine blood flow and endometrial receptivity. The study forming the basis of this review evaluated over 10,000 women undergoing their first hormone-replacement FET—one of the largest data sets ever used to evaluate sildenafil in reproductive medicine.

Below is a comprehensive, clinically grounded synthesis of the findings, mechanisms, and wider implications of this impressive research, written in clear scientific English, accessible to clinicians, embryologists, and scholars in reproductive medicine.

Understanding the Rationale Behind Vaginal Sildenafil Use in FET

The use of sildenafil citrate in reproductive medicine is not new, though for years it remained confined to anecdotal reports and studies involving thin endometrial linings. The drug’s mechanism—enhancing nitric-oxide–mediated vasodilation—suggests a promising role for improving uterine perfusion. Yet, evidence had remained fragmentary, and, more importantly, no data on live birth rates had been available until this large-scale investigation.

The authors recognized this gap and aimed to evaluate sildenafil not merely as a tool for thickening the endometrium, but as a potential modifier of endometrial quality, embryonic implantation environment, and early pregnancy stability. The reasoning was grounded in several physiological principles. Enhanced uterine artery flow could allow a more favorable implantation milieu, supporting trophoblastic development. Moreover, improved oxygenation during early gestation may reduce the risk of early miscarriage—an area of persistent concern among IVF patients.

This perspective alone marks a shift in how sildenafil is conceptualized: not as an emergency tool for thin endometrium, but as a broader modulator of endometrial receptivity even in women with adequate thickness. This change also aligns with emerging data suggesting that implantation success is only partially dependent on thickness and more heavily influenced by microvascular quality.

Study Design and Patient Selection: A Methodological Strength

A key strength of the dataset lies in its vast sample size—10,069 women undergoing their first HRT-FET cycle between 2013 and 2018. Among them, 1,098 used vaginal sildenafil, while 8,971 served as controls. Crucially, all included women had an endometrial thickness of ≥7 mm, ensuring that the study did not skew toward those with thin linings, where sildenafil would normally be applied.

This methodological choice is essential: it allowed investigators to evaluate sildenafil’s effects independent of its ability to increase endometrial thickness, thereby clarifying its true biological significance.

Equally important is the exclusion of factors that could confound reproductive outcomes. Women were excluded if they had:

recurrent miscarriage,
stage III–IV endometriosis,
congenital uterine anomalies,
metabolic disorders such as diabetes or hypertension,
or were above age 40.

Each patient underwent only her first FET cycle, eliminating bias from previous failed cycles. This careful design addresses limitations found in earlier case–control studies, which often lacked proper control groups, adequate sample sizes, or adjustment for confounding variables.

Treatment Protocol and Vaginal Sildenafil Administration

Patients underwent a standardized hormone-replacement therapy regimen. Estradiol was initiated on day 3 of the cycle, with progesterone added once endometrial thickness reached at least 7 mm. Depending on embryo developmental stage, transfer occurred three to five days later.

In the sildenafil group, 100 mg of vaginal sildenafil citrate was administered daily from cycle day 8 until the day before embryo transfer. For optimal local delivery, the blue outer membrane of the tablet was carefully removed, creating a suppository intended to limit systemic absorption and maximize uterine concentration.

This method has practical advantages. Vaginal delivery reduces side effects such as headache and hypotension, provides proximity to the target organ, and allows patients to manage administration independently. Importantly, laboratory conditions for embryo culture and thawing were identical for both groups throughout the study period, ensuring a controlled comparison.

Baseline and Cycle Characteristics: Confirming Equivalence

One of the study’s reassuring findings lies in the comparable baseline characteristics between groups. Maternal age, BMI, smoking status, infertility duration, and causes of infertility showed no meaningful differences. Hormonal profiles including FSH, LH, estradiol, and testosterone were likewise similar, as were antral follicle count values.

These similarities confirm that any differences in outcomes cannot be attributed to demographic or reproductive history biases. Cycle characteristics—including the number of transferred embryos, fertilization method, embryo stage at freezing, and embryo quality—were also virtually identical.

Remarkably, endometrial thickness did not differ between groups either at progesterone initiation or at embryo transfer. This is a core finding: sildenafil does not exert its benefit through increasing endometrial thickness, challenging a long-held assumption in reproductive practice.

Pregnancy and Birth Outcomes: Where Sildenafil Makes a Difference

The most compelling results relate to pregnancy outcomes. The vaginal sildenafil group demonstrated significantly better reproductive metrics across several critical domains.

Live Birth Rates

Sildenafil group: 40.3%
Control group: 36.1%

Even after adjusting for twelve confounding variables—including age, BMI, infertility cause, embryo quality, and method of fertilization—the benefit remained significant, with an adjusted odds ratio of 1.31 (95% CI 1.14–1.49). For a field where incremental improvements are often measured in single percentages, this represents a clinically meaningful difference.

Miscarriage Rates

The miscarriage rate was substantially lower among sildenafil users:

10.6% vs 18.2%

This reduction was particularly pronounced in early miscarriage rates, suggesting that sildenafil may influence peri-implantation stability and early gestational support. Statistical adjustment preserved this difference, with an adjusted OR of 0.58, implying nearly a 42% reduction in risk.

Ongoing Pregnancy Rates

Sildenafil users also had higher ongoing pregnancy rates:

41.3% vs 37.3%

This improvement supports the hypothesis that sildenafil not only enhances implantation but contributes to sustaining pregnancy beyond the first trimester.

Multiple Gestations and Birth Outcomes

Interestingly, the sildenafil group had fewer multiple pregnancies despite similar implantation rates. Although birth weights and preterm delivery rates were comparable, this observation raises questions about sildenafil’s potential influence on peri-implantation cytokine environments—a topic that merits further mechanistic evaluation.

Why Sildenafil May Work: Mechanisms Beyond Thickness

One of the study’s most scientifically interesting conclusions is that sildenafil likely exerts its beneficial effects through enhancing endometrial blood flow and receptivity, not through thickening the endometrium. Several lines of evidence support this premise.

1. Nitric-oxide–mediated vasodilation

Sildenafil potentiates cGMP accumulation, improving vascular relaxation. Animal models demonstrate increased uterine artery flow, improved placental development, and reduced fetal mortality in compromised pregnancies.

2. Trophoblast Support

Sildenafil has been shown to:

prevent trophoblast apoptosis under oxidative stress,
enhance trophoblast invasion,
modulate integrin and VEGF expression in the endometrium.

These molecular effects may collectively stabilize early placentation.

3. Immunological Modulation

Sildenafil may shift cytokine microenvironments and reduce NK cell activity, which could reduce implantation-stage losses and early miscarriage.

Together, these findings indicate that endometrial receptivity is a complex multidimensional condition—not measurable solely by ultrasound thickness—and that sildenafil may act at several levels to promote healthy implantation and sustained pregnancy.

A Balanced View: Strengths, Limitations, and Future Directions

The extraordinary size of this retrospective cohort study is its greatest strength. No previous research on sildenafil in embryo transfer cycles comes close to this scale or statistical rigor. Moreover, reporting live birth rates—the most clinically relevant outcome—addresses a major gap in the literature.

But limitations are inherent to observational research. As a retrospective cohort study, it cannot eliminate all confounding influences. Patient preference influenced whether sildenafil was used, and the investigators acknowledge that prospective randomized trials are needed to confirm these results. Furthermore, mechanistic pathways remain largely speculative, requiring controlled studies and possibly translational research involving endometrial biopsies.

Still, the findings open the door for reconsidering sildenafil’s role in broader IVF populations—not merely those with thin endometrium or repeated implantation failure.

Conclusion

This extensive analysis demonstrates that vaginal sildenafil citrate meaningfully improves live birth rates, ongoing pregnancy rates, and reduces miscarriage among women undergoing their first hormone-replacement FET cycle. Crucially, these benefits occur without altering endometrial thickness, indicating a deeper role in modulating endometrial receptivity and uteroplacental hemodynamics.

The findings support the inclusion of sildenafil as a promising adjuvant therapy in selected IVF patients and encourage the development of randomized controlled trials to define optimal dosage, duration, and patient selection criteria. As the reproductive medicine community continues to strive for more predictable and humane infertility treatment outcomes, vaginal sildenafil may well become one of the most valuable additions to FET practice in the coming years.

FAQ

1. Does vaginal sildenafil increase endometrial thickness?

No. This large study confirmed that sildenafil does not significantly increase endometrial thickness. Its benefits relate instead to improved uterine blood flow, endometrial receptivity, and early gestational stability.

2. Is vaginal sildenafil safe during FET cycles?

Yes. No increases in adverse events, preterm birth, or abnormal birth weights were observed. Vaginal administration minimizes systemic exposure, reducing the risk of hypotension or headache.

3. Should sildenafil be used for all FET patients?

Not necessarily. While results are promising, the study was retrospective. Sildenafil may be particularly beneficial in women with prior miscarriages, marginal endometrial perfusion, or unexplained implantation failure, but randomized trials are needed before universal adoption.