Recurrent Pregnancy Loss and Thin Endometrium: PRP to Promote Embryo Implantation
Recurrent pregnancy loss (or recurrent spontaneous abortion) is classically defined as three or more consecutive spontaneous pregnancy losses. However, many specialists today consider it important to identify the causes after just two consecutive miscarriages, especially in women over 35 or in those experiencing difficulty conceiving.
Repeated implantation failure, on the other hand, is the term used to refer to a context of medically assisted reproduction in which the embryo fails to implant multiple times, especially in the case of euploid blastocysts.
There are many possible causes of recurrent pregnancy loss, including genetic abnormalities in the parents or the embryo, uterine anomalies (such as septa or fibroids), hormonal dysfunctions, thrombophilic disorders, autoimmune diseases (for example, antiphospholipid antibody syndrome), and others. However, in about 50% of cases, no clear cause can be identified, a condition referred to as idiopathic recurrent miscarriage. In recent years, particular attention has been paid to the quality of the endometrium – the tissue lining the inside of the uterus – as a crucial factor for embryo implantation and the continuation of pregnancy. A “thin” or poorly receptive endometrium may contribute to embryo implantation failure or very early pregnancy loss.
Importance of Endometrial Thickness
Before implantation, during hormonal stimulation in assisted reproduction treatment (ART) the endometrium proliferates and reaches an ideal thickness generally between 8 and 14 mm (as measured by transvaginal ultrasound). An endometrial thickness below approximately 7 mm is considered not optimal and is often associated with lower pregnancy rates in assisted reproduction techniques.
Clinical studies confirm that, in patients undergoing IVF (in vitro fertilization), an endometrium measuring <7 mm at the time of embryo transfer is correlated with lower implantation rates and a higher risk of treatment failure. Even in natural pregnancies, a uterus with an excessively thin lining may fail to provide a suitable environment for the embryo, leading to implantation failure or early miscarriage. Several conditions can result in a thin endometrium, including chronic uterine infections or inflammation (endometritis), damage from surgical curettage or previous miscarriages (Asherman’s syndrome, intrauterine adhesions), insufficient hormonal stimulation, or unexplained individual factors.
To date, doctors have tried various strategies to improve endometrial thickness in preparation for pregnancy. These include increasing doses of estrogen (administered orally, via patches, or by injection) during the proliferative phase, sometimes in combination with vasodilators such as pentoxifylline to enhance uterine blood flow. In some cases, local administration of growth factors (e.g., G-CSF, a granulocyte colony-stimulating factor, instilled into the uterus) has been explored, with variable results. However, many women with refractory endometrium continue to face difficulties despite these interventions. For this reason, endometrial PRP therapy has begun to be investigated as a potential option for these ‘hard-to-treat’ patients.
Endometrial PRP involves the administration of platelet-rich plasma (PRP) directly into the uterine cavity, with the aim of regenerating or stimulating the endometrium. PRP is rich in growth factors – including PDGF, TGF, VEGF, EGF, IGF, and interleukins – which can promote cell proliferation, angiogenesis, and tissue repair. In simple terms, introducing PRP into the uterus provides the endometrium with powerful molecular signals that encourage it to grow more effectively. This may create a more receptive environment for embryo implantation, especially in the context of assisted reproductive technologies (ART), where even small improvements in endometrial receptivity can make a meaningful difference.
The results of recent research, although still preliminary, are very promising. Clinical studies and meta-analyses have indicated that intrauterine PRP infusion can increase endometrial thickness in patients with thin endometrium unresponsive to standard therapies. For example, women whose endometrium previously measured only 5-6 mm have shown increases to values considered acceptable for embryo transfer (8-9 mm) after PRP treatment. More importantly, PRP appears to improve embryo implantation and pregnancy rates. The most recent 2024 meta-analysis reported a statistically significant increase in both endometrial thickness and clinical pregnancy rates. In addition, a significant reduction in miscarriage rates has been observed in women treated with PRP – an encouraging result for cases of idiopathic recurrent miscarriage. In practice, PRP may enhance the ‘hold’ of implantation: a thicker and more receptive endometrium helps the embryo attach and continue its development, reducing early pregnancy loss. It should be noted that much of this evidence comes from cases of assisted reproduction (IVF/ICSI), where the impact of PRP can be measured more precisely, but the rationale may apply to natural conception for women experiencing recurrent miscarriages without an identifiable cause.
How Endometrial PRP Therapy Is Performed
The procedure is relatively simple and similar to intrauterine insemination. After preparing PRP from the patient’s blood, the gynecologist inserts a thin catheter through the cervix into the endometrial cavity. No anesthesia is required, as the procedure is quick and causes only mild discomfort, comparable to a Pap test. The PRP is then slowly infused into the uterus through the catheter, spreading across the endometrial lining. The entire procedure takes only a few minutes.
It is generally performed during the late ovulatory phase or early luteal phase, depending on the protocol. For example, in an assisted reproduction cycle, the infusion is typically done 3–5 days before embryo transfer to allow sufficient time for PRP to act. The procedure does not require hospitalization: after 15–20 minutes, the patient can return home and resume normal activities, with the only precaution being to avoid sexual intercourse on the day of the infusion to prevent interference.
In current protocols, a single PRP infusion per cycle is often sufficient. For example, in patients undergoing IVF, PRP is administered during the transfer cycle itself (a few days before the procedure, as previously mentioned). However, in cases of particularly unresponsive endometrium, some doctors have tried two infusions within the same cycle (one during the follicular phase and one during the luteal phase). There is no theoretical limit to the number of PRP applications, provided that there is sufficient time for preparation and a medical rationale for each infusion.
Intrauterine PRP is considered safe. It does not introduce foreign substances (since it involves autologous plasma) and the risk of infection is effectively zero when performed using aseptic techniques (similar to those used for insemination or transfer). Some patients may experience mild uterine cramping during or shortly after the infusion, but this is usually temporary. No increase in abnormal uterine contractions or negative effects on the embryos have been reported (in fact, PRP is often used immediately before embryo transfer without any problems). As with all intrauterine procedures, it should be avoided in cases of active infection (e.g., acute endometritis) or undiagnosed pregnancy. Overall, it is a minimally invasive procedure that is generally well tolerated.
Status of Evidence and Prospects
The use of PRP in this field is relatively recent (with the first publications appearing around 2015–2016) but the number of studies is growing rapidly. Nevertheless, the results remain uncertain, and ESHRE guidelines do not yet recognize PRP as a validated treatment for promoting embryo implantation or increasing endometrial thickness. Many additional studies are needed before PRP therapy can be consolidated or validated for improving endometrial thickness, treating recurrent pregnancy loss, or addressing repeated implantation failure. Some leading ART centers already offer PRP as part of their protocols for patients with thin endometrium or repeated implantation failure. This personalized approach aims to enhance endometrial receptivity, which is often the critical missing factor in cases where oocytes and embryos are of good quality but pregnancy is not achieved. There are no absolute guarantees – unfortunately fertility depends on many factors – but existing data suggest that PRP can improve the chances of success. An interesting aspect is that, being an autologous therapy, PRP may also exert a beneficial immunomodulatory effect on the uterine environment (reducing subclinical micro-inflammation that interferes with implantation). Further research will clarify the mechanisms and optimize the method (e.g., ideal platelet concentration, optimal timing within the cycle, etc.). But for now, PRP represents a new frontier in regenerative medicine, giving hope to couples who have already faced many disappointments.
FAQ – Thin Endometrium, Recurrent Pregnancy Loss and Endometrial PRP
A thin endometrium refers to a uterine lining whose thickness, measured by transvaginal ultrasound during the pre-ovulatory (advanced proliferative) phase, remains below values considered optimal for implantation. Generally, endometrial thickness below 7 mm is considered thin. An ideal endometrium for pregnancy has a trilaminar appearance and is at least 8 mm thick around the day of ovulation. When the endometrium is too thin, the embryo may not implant properly. The underlying causes must be investigated: it could be due to damage (previous curettage that has caused adhesions), poor hormone production, chronic inflammation, or even individual predisposition.
The main indicator is endometrial thickness measured by ultrasound, but this is not the only one. Some centers perform more advanced tests, such as the ERA (Endometrial Receptivity Array), an endometrial biopsy that analyzes gene expression to determine the optimal timing for implantation and evaluate whether the endometrium is “receptive” at the molecular level. Other tests can detect chronic endometritis (e.g., histological examination or hysteroscopy with biopsy), which can interfere with implantation. A reproductive gynecologist also assesses the endometrium appearance (thickness, structure) using ultrasound during hormonal stimulation. If the endometrium repeatedly remains thin and pregnancy does not occur, this may indicate a receptivity problem. In such cases, after excluding major uterine pathologies (fibroids, septa, polyps – detectable via ultrasound or hysteroscopy), therapies like PRP can be considered to improve endometrial receptivity.
Endometrial PRP involves infusing the patient’s own platelet-rich plasma into the uterus. The procedure is very similar to an embryo transfer or intrauterine insemination: a thin catheter is inserted through the cervix, and the PRP is injected within seconds. The procedure is generally not painful; at most, patients may feel a mild cramp or slight discomfort during catheter insertion, but it is well tolerated and does not require anesthesia. The entire process takes about 5 minutes. Afterwards, the patient remains lying down for a few minutes and can then go home. No significant recovery is necessary, although some doctors recommend avoiding strenuous activity on the same day. Since PRP is autologous plasma, it does not cause burning or allergic reactions. Overall, it is a quick and painless procedure for most women.
It is typically performed around ovulation, during the follicular phase. In assisted reproductive technology (ART) cycles, such as IVF, many clinics perform PRP approximately 3–5 days before embryo transfer. For example, if the transfer is scheduled for day 5 post-ovulation, PRP is performed on day 0 or 1 post-ovulation. Some protocols perform PRP on day +21 of the previous cycle and then again in the transfer cycle. In short, the timing may vary because the technique is new and still being studied. PRP should be administered during the advanced proliferative phase or early secretory phase to maximize its potential benefits for the implantation window. Your doctor will determine the best timing based on your individual treatment protocol.
If recurrent miscarriages are caused (or partially contributed to) by a suboptimal endometrial environment, then PRP may play a beneficial role. The challenge in these cases is identifying the reasons why the endometrium is not functioning optimally. When issues such as thin endometrial thickness or an altered implantation window are present, PRP can promote better endometrial development and improve synchronization between the endometrium and the embryo. Studies involving women with recurrent implantation failure or unexplained miscarriages have shown increased pregnancy rates after the use of PRP. However, if miscarriages are due to genetic abnormalities in the embryos or other conditions (such as an undiagnosed uterine septum or untreated thrombophilia), PRP alone cannot resolve the underlying problem. For this reason, a complete evaluation is essential in cases of recurrent miscarriage (typically including karyotyping, coagulation tests, and ultrasound or hysteroscopy) to identify and treat all possible contributing factors. PRP can be considered as an additional aid, especially when known causes have been excluded or treated but miscarriages continue. In these situations, PRP may help improve an important but hard-to-measure factor: endometrial quality.
In addition to conventional treatments (estrogens, vasodilators, antibiotics when endometritis is present, and various supplements), another approach being studied is the instillation of recombinant growth factors like G-CSF. Acupuncture and physiotherapy may likewise help enhance uterine blood flow. Overall, PRP is gradually becoming the most practical and immediate solution for cases of refractory endometrium, since it uses the patient’s own blood and can be repeated each cycle. Extreme cases of Asherman’s syndrome (severe intrauterine adhesions) require surgery (operative hysteroscopy to remove the adhesions), possibly followed by PRP to promote healing. In the future, the use of platelet gels or engineered matrices for the endometrium may become more widespread. For now, PRP is among the most advanced options available to fertility centers.
PRP is considered very safe. The potential risks are those common to any intrauterine procedure: a theoretical risk of infection (minimized by the sterility of the procedure), minor cervical trauma if the catheter encounters resistance (which is rare, as most women have a fairly permeable cervix; otherwise, a mild dilator is used). Since no medications are used, there are no systemic side effects. Patients generally do not report significant pain or bleeding, at most slight spotting. Important: PRP must be performed in a controlled, sterile environment. Non-sterile conditions can lead to acute endometritis; this risk can be entirely avoided by performing the procedure in proper facilities. In summary, intrauterine PRP is well tolerated and free from major complications. Of course, it should be avoided in cases of ongoing pregnancy: PRP is not performed in women who are already pregnant. Pregnancy is typically excluded beforehand using a beta-hCG test.
Book an appointment
If you have had repeated miscarriages or difficulties with embryo implantation (e.g., several failed IVF attempts) and have been diagnosed with a thin or unreceptive endometrium, book a consultation with Dr. Giovanni Buzzaccarini. Together, you will develop a personalized diagnostic and treatment plan, which may include innovative therapies, such as endometrial PRP, to enhance the chances of a successful pregnancy.