Evaluation and treatment of recurrent pregnancy loss: a committee opinion

The American Society for Reproductive Medicine (ASRM) defines recurrent pregnancy loss (RPL) as the spontaneous loss of two or more pregnancies, excluding confirmed molar or ectopic pregnancies. Pregnancies confirmed by urinary or blood human chorionic gonadotropin (HCG) are sufficient. Ultrasound or tissue confirmation is not required, as access to early pregnancy ultrasound and care is variable across patient populations. In addition, it has been established that biochemical pregnancy losses confer a similar impact on recurrence risk as clinical losses, supporting the inclusion of biochemical pregnancy losses in the definition of RPL (1–3). Recurrent pregnancy loss is a disease distinct from infertility, requiring its own specific evaluation and management. There are inconsistent definitions of miscarriage (or spontaneous abortion) in the literature to define pregnancy losses as less than 20 or 22 weeks. For the purpose of this document, we will use less than 22 weeks, which is consistent with the International Glossary of Infertility and Fertility Care (4). Pregnancy loss after 22 weeks is considered a stillbirth or fetal demise and is outside the scope of this document and covered by a dedicated American College of Obstetricians and Gynecologists (ACOG)/Society for Maternal-Fetal Medicine consensus guideline (5, 6).

Approximately 50%–60% of first-trimester miscarriages are due to embryonic aneuploidy (7). Sporadic aneuploidy is strongly correlated with maternal age. Aneuploidy plays a smaller role in second and third trimester losses and stillbirths, impacting 20% of stillborn fetuses at 22 weeks of gestation, 6% of stillborn infants at term, and 0.1%–5% of term live births (8). When compared with individuals with isolated miscarriage, patients with RPL have a higher likelihood of euploid miscarriage. The likelihood of euploid miscarriage further increases with the number of miscarriages. Large observational cohort studies show that women with RPL have an elevated risk of several serious health conditions later in life, including cardiovascular disease, stroke, diabetes, autoimmune disorders, and mental health disorders (9). Therefore, a complete evaluation of maternal and paternal health is essential in the setting of recurrent miscarriage, especially if ≥ 1 miscarriages are found to be euploid, termed ‟unexplained’’. The definition of RPL does not require miscarriages to be consecutive, due to a lack of definitive associations with consecutive miscarriages and known risk factors for RPL. However, clinicians are urged to use their judgment on when to initiate a partial or complete workup in the setting of nonconsecutive miscarriages, as limited data indicate that consecutive miscarriages have a poorer prognosis for live birth than nonconsecutive miscarriages in one observational cohort (10). Management of this traumatic diagnosis drives patients and providers to seek answers and attempt unproven therapies. However, counseling about the natural history of RPL is a key component and responsibility of the provider, as 50%–80% of patients will succeed in their subsequent pregnancy attempt with no specific interventions (11, 12). Although ASRM supports shared decision-making in the absence of high-quality data, taking care of patients with this multifactorial disorder should include an evidence-based approach in a supportive environment to minimize risks of harm because of unproven treatments.

In this document, we present a stepwise algorithm for the evaluation of RPL, with the recommendation to perform chromosome evaluation of the miscarriage, followed by additional testing as indicated (see Fig. 1, Table 1, and Table 2). The incremental benefit of adding miscarriage testing to the diagnostic workup of patients with recurrent miscarriage has been demonstrated in numerous studies (13–15).

Therefore, we propose a stepwise algorithm, which provides more explanations and substantial cost savings by avoiding unnecessary testing when miscarriages are explained. Although chromosome testing at the time of first miscarriage can be offered for explanatory purposes, a single euploid early miscarriage has not been shown to increase the risk of second loss (16); therefore, reflex testing for other causes of losses is not indicated after a single euploid miscarriage.

GENETIC EVALUATION OF MISCARRIAGE

The ASRM, European Society of Human Reproduction and Embryology (ESHRE), ACOG, and Royal College of Obstetricians and Gynaecologists (RCOG) have all suggested considering the genetic analysis of the miscarriage tissue in the evaluation of RPL for explanatory purposes and/or psychological benefit to patients (17–20). Given new data on cost-effectiveness, patient satisfaction, and emotional benefits, ASRM now recommends offering a genetic evaluation of miscarriage tissue to all patients experiencing their second miscarriage or with a history of recurrent miscarriage. Whole chromosome aneuploidy is the most commonly identified cause of sporadic and recurrent miscarriage (12, 21). The rate of aneuploidy is strongly correlated with maternal age and has been demonstrated in approximately 50% of miscarriages tested in young women (<35 years) and in 75% of miscarriages in women over 40 (22). Chromosome testing of miscarriage is highly desired by patients (23), as testing provides a psychological benefit by reducing feelings of guilt and self-blame. In addition, chromosome testing at the time of a second miscarriage has been shown to frequently provide an explanation (15) and reduce cost in the setting of RPL (13, 24). Chromosomal abnormalities account for the majority of first-trimester miscarriages, most of which are sporadic and nonrecurrent. Detecting the etiology of a miscarriage, especially if it is found to be a sporadic aneuploid event, can allow for the avoidance of an expensive RPL workup, guide counseling, and alleviate a couple’s anxiety and sense of guilt. Although surgical management of miscarriage is most likely to provide optimal material testing, at-home collection kits are available and can be successful after medical management (25). For many years, conventional metaphase G-banding karyotyping was the standard technique to evaluate miscarriage tissue for aneuploidy. However, this technique has significant limitations, including high rates of cell culture failure (10%–40%), maternal cell contamination (contributing to high rates of false negative results), inability to process samples already placed in formalin, and inability to detect microdeletions and microduplications <5 Mb (26–31).

Fluorescence in situ hybridization (FISH) has its own advantages, but it also has significant disadvantages (timeconsuming, probe-design dependent sensitivity, targeting only specific chromosomes) that limit its successful applicability to the diagnosis of common numeric chromosome abnormalities (18, 32).

Summary statement

• Given the association of uncontrolled DM with pregnancy complications and the need for glycemic control before conception to optimize outcomes, ASRM recommends measuring an HbA1C during the diagnostic workup of women with RPL if risk factors are present. Risk factors for DM include being overweight or obese (i.e., high body mass index [BMI]), family history of DM, age >40, polycystic ovary syndrome (PCOS), and history of gestational diabetes.

The use of metformin for women with PCOS

Polycystic ovary syndrome, obesity, and insulin resistance have been associated with increased risk of euploid miscarriage; however, the mechanisms are unclear (124, 125). The PCOS affects 5%–10% of the female population in the United States. Women with PCOS have difficulty conceiving and have been found to have an increased risk of miscarriage (126). Early miscarriage has been reported to be as high as 30%–50% in this population. Studies have implicated hyperinsulinemic insulin resistance as an independent risk factor for early miscarriage (127). Metformin, an insulin-sensitizing drug, has been shown to reduce the rate of early miscarriage in PCOS patients. Although not studied specifically in the setting of RPL, metformin has been shown to reduce miscarriage risk in women with PCOS in some observational studies (128–130). Metformin or placebo was administered to women with RPL and abnormal GTTs; miscarriage rates were significantly reduced after metformin therapy compared with placebo in women without PCOS (15% vs. 55%) (131). In a recent, large metaanalysis of 2,899 pregnant women with PCOS, the use of metformin significantly reduced the incidence of preterm delivery (3.86% vs 9.19%, RR 0.42, 95% CI 0.25–0.71, P = .001), early miscarriage (cumulative rate 6.58% vs 18.35%, RR 0.40, 95% CI 0.20–0.78, P = .007), and the use of insulin treatment throughout pregnancy (cumulative rate 2.14% vs 5.12%, RR 0.43, 95% CI 0.22–0.85, P = .01), all without any significant difference in serious maternal adverse events (132). However, continuous use of metformin throughout pregnancy, until delivery, has been associated with an increase in childhood obesity (133). A meta-analysis on the risks of metformin during pregnancy concluded that exposure to metformin during the first trimester of pregnancy does not increase the risk of birth defects (134). The currently available data are heterogeneous because of differences in patient populations and timing of initiation and discontinuation of metformin.

Summary statement

• Although the evidence of benefit in the setting of RPL is indirect, it is reasonable to consider metformin in women with PCOS, with evidence of insulin resistance and otherwise unexplained miscarriage. Further studies are needed to clarify the optimal patient population, dosage, and timing of initiation and discontinuation before definitive recommendations can be made.

PROLACTIN TESTING

Prolactin is often measured in women with anovulatory infertility, because elevated levels are associated with ovulatory dysfunction and possible luteal phase defect. The latter might be mediating a negative impact of hyperprolactinemia on pregnancy outcomes. Earlier studies suggested a possible association between hyperprolactinemia and recurrent miscarriage (135, 136). However, there is no high-quality evidence either linking prolactin disturbances to RPL or documenting a benefit of dopamine agonist treatments on the prevention of future miscarriages in women with RPL.

Summary statement

• Prolactin testing is not recommended in women with RPL, except in the evaluation of coexisting clinical symptoms, such as galactorrhea or anovulation.

USE OF EMPIRIC PROGESTERONE

Progesterone is necessary to achieve and maintain pregnancy because of its direct effect on the endometrium and immune-modulating properties. There have been several studies evaluating the effect of progesterone supplementation on women with recurrent miscarriage, with differing conclusions. The Progesterone in Recurrent Miscarriage (PROMISE) trial was a large multicenter, randomized, placebo-controlled trial which showed that vaginal progesterone treatment in the first trimester of pregnancy did not result in a significant increase in LBR compared with placebo among patients with a history of unexplained recurrent miscarriage (137). This study was limited by the use of progesterone after a confirmed pregnancy. In 2017, Stephenson et al. (138), reported an improved LBR among women with RPL who used vaginal progesterone starting 3 days after the LH surge and until 10 weeks of gestation. However, this study was retrospective and nonrandomized.

The Progesterone in Spontaneous Miscarriage trial looked at the use of vaginal progesterone in patients who presented with vaginal bleeding in early pregnancy; there was a 3% increase in LBR, which was not significant. In a subgroup analysis of these studies, women with a history of miscarriage who present with threatened miscarriage had a 5% increase in LBR after the use of vaginal progesterone compared with placebo, which reached statistical significance. The investigators acknowledge that this observation requires further validation because multiple comparisons were performed without statistical adjustment (139). There is no evidence supporting the practice of checking progesterone levels in unassisted pregnancies and supplementing based on the level.

Summary statement

• Additional prospective clinical trials are needed to determine if progesterone supplementation in women with RPL can improve live birth rates. Vaginal progesterone may be considered in early pregnancy in the setting of vaginal bleeding and/or recurrent unexplained miscarriage using a shared decision-making model.

PREIMPLANTATION GENETIC TESTING FOR ANEUPLOIDY

The most common cause of both sporadic and recurrent miscarriage is embryonic aneuploidy (140). Therefore, it has been hypothesized that IVF with preimplantation genetic testing for aneuploidy (PGT-A) could be an effective strategy to lower the rate of miscarriage and increase the LBR among individuals with recurrent miscarriage. However, PGT-A has not been shown to be effective at reducing miscarriage or increasing LBR in the setting of RPL in prospective studies (141).

In 2016, Murugappan et al. (142) performed a retrospective intent-to-treat analysis of IVF with PGT-A vs. expectant management (EM), where the decision to use PGT-A was based on provider recommendation and patient preference. In this study, an ‟attempt’’ was defined as one IVF cycle and frozen embryo transfer (FET) in the PGT-A group, as well as 6 months of trying to conceive in the EM group. The LBR in the two groups was similar, with 32% vs. 34% per attempt in PGT-A vs. EM. Furthermore, median time to pregnancy was longer in the cohort of women undergoing PGT-A vs. EM (6.5 vs. 3 months). In this analysis, improved LBR of PGT-A was only realized by patients >40 reaching euploid transfer (142).

In 2021, Bhatt et al. (143) performed a Society for Assisted Reproductive Technology – Clinic Outcome Reporting System (SART-CORS) analysis on IVF outcomes with or without PGT-A in individuals with RPL (N = 1,2631 cycles). The analysis was limited to couples with RPL, defined as a history of three or more miscarriages, undergoing FET with a primary outcome of live birth. In women with a diagnosis of RPL, the adjusted odds ratio (aOR) of live birth with FET with PGT-A vs. without PGT-A was 1.31 (95% CI: 1.12, 1.52) for age <35 years, 1.45 (95% CI: 1.21, 1.75) for ages 35–37 years, 1.89 (95% CI: 1.56, 2.29) for ages 38– 40, 2.62 (95% CI: 1.94–3.53) for ages 41–42, and 3.80 (95% CI: 2.52, 5.72) for ages >42 years. The aOR for clinical miscarriage with PGT-A vs. without PGT-A was 0.95 (95% CI: 0.74, 1.21) for age <35 years, 0.85 (95% CI: 0.65, 1.11) for ages 35–37 years, 0.81 (95% CI: 0.60, 1.08) for ages 38–40, 0.86 (95% CI: 0.58, 1.27) for ages 41–42, and 0.58 (95% CI: 0.32, 1.07) for ages >42 years. This study has several limitations, including its retrospective study design and the control group being IVF patients without PGT-A, which therefore may be skewed toward worse prognosis patients with coexisting infertility (143). In a 2025 meta-analysis of retrospective and observational studies comparing IVF without PGT-A with IVF with PGT-A, there was a statistical improvement in live birth per transfer with PGT-A, similar to that seen in the general IVF population (144). However, this analysis is similarly problematic to prior studies, as it did not analyze intent to treat per retrieval, cost, or time to pregnancy or include cycles with no embryos available for embryo transfer (ET), and, again, the control group (ET without PGT-A) is problematic in that IVF is not an established treatment for RPL. Although some observational studies demonstrate a reduction in miscarriage, miscarriage still occurs in 10%–20% of pregnancies after PGT-A (143, 144). Both studies, as well as the ASRM Practice Committee Opinion on the use of PGT-A, conclude that well-designed trials comparing outcomes of IVF with PGT-A to EM are needed before definitive recommendations can be made (143–145).

Summary statement

• Overall, PGT-A has not been shown to significantly reduce miscarriage or improve live births compared with EM in the setting of RPL. In women over 40 years with a proven aneuploid miscarriage, it is reasonable to discuss PGT-A using a shared decision-making model to reduce miscarriage because of aneuploidy. However, patients should be counseled that PGT-A has not been shown to reduce the time to successful pregnancy or increase LBR compared with EM. Prospective clinical trials in patients with RPL are needed.

THROMBOPHILIA WORKUP

In women with inherited thrombophilia, pregnancy can exaggerate the physiologically induced state of hypercoagulation and therefore increase the risk for thrombotic events. The possible role of inherited thrombophilias in RPL has generated a great deal of research interest, and an association between the two has been documented in a few meta-analyses. A recent systematic review of the prevalence of thrombophilia in women with RPL found it to be the same as that of the general population (146). Recommendations regarding testing are aimed at identifying women with RPL who might benefit from anticoagulation for the purposes of preventing recurrent VTE in pregnancy in accordance with current hematology guidelines.

Use of empiric thrombolytics

The pathogenesis of unexplained RPL and recurrent miscarriage because of APS have potential similarities (147). On the basis of these similarities, thrombolytics such as LMWH and/ or aspirin are often prescribed for patients with unexplained recurrent miscarriage. A randomized, placebo-controlled study (ALIFE) found that neither LMWH with aspirin vs. aspirin alone compared with placebo improved the LBR in patients with unexplained RPL (148). One study evaluated three different thrombolytic treatments (LMWH with aspirin, LMWH alone, aspirin alone) in women with RPL. Among patients who had a negative thrombophilia screen, all three treatments were equally effective when comparing LBR with miscarriage rate (149). A meta-analysis looked to compare the efficacy of heparin combined with aspirin vs. aspirin alone in patients with unexplained recurrent miscarriage. Four of the eight studies included in the meta-analysis included patients with thrombophilias. This study found that heparin with aspirin vs. aspirin alone increased the LBR in patients with unexplained RPL if the number of miscarriages was three or greater, but not after two miscarriages (150). A recent, international, multisite randomized controlled study examined the use of prophylactic use of LMWH in women with inherited thrombophilias and recurrent miscarriage (151). Outcomes were similar between treated and untreated women with LBRs of 72% (116/162) and 71% (112/158), respectively. A 2022 meta-analysis of seven randomized controlled studies including women with unexplained RPL did not show any benefit of LMWH or LMWH plus acetylsalicylic acid on miscarriage, live birth, or preeclampsia risk (152).

Summary statement

• Routine testing for thrombophilias is not recommended among women with RPL. The use of anticoagulants for the treatment of RPL with hereditary thrombophilias or unexplained RPL is not recommended, based on high-quality evidence showing no benefit on LBR or miscarriage rate.

OVARIAN RESERVE EVALUATION

Testing for ovarian reserve is not routinely recommended in the evaluation of women with RPL. However, some evidence exists suggesting a potential higher risk for miscarriage and RPL among younger women with diminished ovarian reserve (153–157). Studies are limited by small numbers, heterogeneity in the patient population, definition of diminished ovarian reserve, and tests utilized to determine the diagnosis, all of which limit the ability to pool the data and draw valid conclusions (153–157). Two large, prospective studies examining the association between antim€ ullerianhormone (AMH) and miscarriage have had conflicting results (158, 159). Further studies are needed to clarify the relationship between ovarian reserve testing, oocyte quality, ovarian function, and miscarriage before specific therapies can be proposed.

Summary statement

• The ASRM does not recommend routine testing for ovarian reserve in the evaluation of RPL because the association between RPL and ovarian reserve is unclear and no effective therapeutic interventions exist.

IMMUNE TESTING AND TREATMENT

The role of an altered immune environment as an etiology for unexplained RPL is supported by correlative studies and animal models demonstrating failed implantation and miscarriage in association with immune dysfunction. Clinical studies supporting a role for immune testing have been significantly limited by study design, specifically low patient volume, lack of standardized immune testing, and poor reproducibility.

Clinical trials evaluating immune therapies have similarly suffered from poor study design (i.e., limited RCTs) and nonspecific immunomodulating therapies without clear endpoints for treatment. Given the great interest in immune investigations and treatment by patients and reproductive immunologists, we must continue to investigate immune testing and treatment in subgroups of RPL patients most likely to benefit (i.e., those with recurrent euploid miscarriages) under research protocols before recommendations can be made.

Summary statement

• The ASRM does not recommend routine immune testing and treatment in the evaluation of RPL.

PREPREGNANCY EVALUATION AND CARE

Optimization of all maternal health, autoimmune conditions, and medications before pregnancy should be attempted for all women as part of a comprehensive preconception counseling (160).
All women planning pregnancy, regardless of fertility or miscarriage history, should be counseled for healthy lifestyle changes, prenatal folic acid support, and avoidance of toxic exposures during the periconception period. Tobacco usage and secondhand smoke are linked to an increased risk of sporadic miscarriage (161, 162). Cessation of tobacco and limiting exposure to secondhand smoke are recommended (19, 163). The role of alcohol and caffeine is less clear, and studies are mixed. However, there may be an interaction or dose response to these common exposures. Alcohol consumption (>3 drinks per week) and caffeine consumption (>99 mg/day) have been associated with an increased risk of miscarriage or recurrent miscarriage (164–166). The effect of stopping caffeine use has not been evaluated in any trial. Low or moderate exercise is not associated with miscarriage. The data on high-intensity exercise and occupational activities is less clear and has been associated with miscarriage in some studies (167). Obesity has also been found to be an independent risk factor for miscarriage in patients with recurrent miscarriage, and it has also been associated with euploid miscarriage in IVF-FET cycles (168, 169); however, no study has evaluated the impact of weight loss on miscarriage rate in this population.

Summary statement

• Although the data on lifestyle interventions on miscarriage risk are limited, given the known risk of certain exposures in pregnancy and the possible impact on miscarriage risk, these exposures should be reduced whenever possible preconception. Smoking cessation is strongly recommended.

PSYCHOLOGICAL FACTORS AND SUPPORT

It has long been recognized that women experiencing RPL are subject to significant psychological sequelae, including an increased risk of depression, anxiety, posttraumatic stress, guilt, and anger, with the incidence of depression approximately five times higher in women affected by RPL (170–172). Although most of the psychological data within RPL focuses on the female partner’s experience, there has been evolving research into the impact of RPL on the male partner. In a cross-sectional study in couples experiencing RPL, the investigators demonstrate that while women are more likely to experience depression and anxiety, male partners of women with RPL are also at significant risk for these symptoms, and both men and women reported limited social support (172). It is clear that miscarriage exacts an immense psychological toll on the affected couple as a dyad. Unfortunately, there is little data on the miscarriage experience of underrepresented groups, such as racial, ethnic, and sexual minorities; research is needed to address these gaps in knowledge. Healthcare professionals should validate the individual’s experience, implement screening for mood disorders and social support for women and their partners, and offer referral to mental health professionals for counseling support to all patients experiencing miscarriage, while simultaneously not assigning blame to patients and reminding patients that the most common cause of miscarriage is a genetically abnormal embryo.

Several studies, including a meta-analysis published in 2017, demonstrated a positive correlation between maternal stress and miscarriage (173). Two nonrandomized studies have examined the impact of supportive care in subsequent pregnancy (11, 174). A cohort of 158 couples with three or more otherwise unexplained consecutive miscarriages was divided into two groups, with one receiving routine obstetrical care during the next pregnancy (n = 42) and the other additionally receiving tender-loving care (TLC) (n = 116). The TLC was defined as psychological support with weekly medical and ultrasonographic examinations, as well as instructions to avoid heavy work, travel, and sexual activity. The difference in live births was significant: 36% in the control group and 85% in the TLC group.

Summary statement

• The RPL couples are at risk for psychological sequelae. Psychological support is an essential part of miscarriage care and should be offered to all couples experiencing miscarriage and planning future pregnancy.

SUMMARY

The following statements address specific aspects of testing and treating couples or individuals with RPL:

• ASRM defines recurrent pregnancy loss (RPL) as the spontaneous loss of two or more pregnancies, excluding confirmed molar or ectopic pregnancies. Pregnancies confirmed by urinary or blood HCG are sufficient.
• ASRM recommends chromosome analysis of miscarriage tissue, when feasible, as a first step in the evaluation of the couple with RPL. ASRM joins ESHRE and ACOG in recommending array-based technology for analysis of miscarriage tissue on the basis of its many technical advantages over traditional cytogenetic analysis. Options for at-home collection of tissue for miscarriage tissue testing should be discussed with patients at the time of miscarriage for patients who do not desire surgical management.
• A uterine cavity evaluation should be offered to all women with unexplained RPL and can be considered in patients with aneuploid miscarriages to evaluate for anatomic abnormalities that could lead to miscarriage or sequelae from prior miscarriages, such as adhesions and retained pregnancy tissue. It is reasonable to offer surgical treatment of a uterine septum and acquired uterine defects, including endometrial polyps, submucosal fibroids, retained pregnancy tissue, and intrauterine adhesions, in women with RPL.
• Screening for parental balanced structural chromosomal rearrangements should be offered when an unbalanced structural chromosome rearrangement is detected in miscarriage testing or when no chromosomal testing of miscarriages is available. Additional studies are warranted to determine the overall effectiveness of PGT-SR in the setting of parental chromosome rearrangements.
• A laboratory evaluation for antiphospholipid antibodies is recommended for individuals who meet clinical criteria for antiphospholipid antibody syndrome. Treatment should include a low-dose aspirin before conception or with initiation of prophylactic heparin at the time of clinical or laboratory evidence of a pregnancy.
• Women with RPL who have had euploid miscarriage or no testing of miscarriage tissue should be screened for hypothyroidism with measurement of TSH and treated if TSH >4 mIU/L or the upper limit of normal in the laboratory. Given the high-quality data demonstrating no benefit of treating euthyroid women with thyroid autoimmunity, we do not recommend screening for thyroid antibodies.
• Until recently, limited data existed to inform best practice, and some evidence suggested a benefit to screening and treating endometritis. However, a recent high-quality RCT presented as an abstract demonstrated no benefit of prescribing doxycycline for chronic endometritis in RPL patients.
• Sperm DNA fragmentation testing may be considered in patients with otherwise unexplained recurrent miscarriage or RPL and concomitant infertility. Further research is necessary to determine if treatment improves pregnancy outcomes.
• Given the association of uncontrolled DM with pregnancy complications and the need for glycemic control before conception to optimize outcomes, ASRM recommends measuring an HbA1C during the diagnostic workup of women with RPL if risk factors are present. Risk factors for DM include being overweight or obese (i.e., high BMI), family history of DM, age >40, PCOS, and history of gestational diabetes.
• Although the evidence of benefit in the setting of RPL is indirect, it is reasonable to consider metformin in women with PCOS, with evidence of insulin resistance and otherwise unexplained miscarriage. Further studies are needed to clarify the optimal patient population, dosage, and timing of initiation and discontinuation before definitive recommendations can be made.
• Prolactin testing is not recommended in women with RPL, except in the evaluation of coexisting clinical symptoms, such as galactorrhea or anovulation.
• Additional prospective clinical trials are needed to determine if progesterone supplementation in women with RPL can improve live birth rates. Vaginal progesterone may be offered in early pregnancy in the setting of vaginal bleeding and/or recurrent unexplained miscarriage using a shared decision-making model.
• Overall, PGT-A has not been shown to significantly reduce miscarriage or improve live births compared with EM in the setting of RPL. In women over 40 years with a proven aneuploid miscarriage, it is reasonable to discuss PGT-A using a shared decision-making model to reduce miscarriage because of aneuploidy. However, patients should be counseled that PGT-A has not been shown to reduce the time to successful pregnancy or increase live birth rate compared with EM. Prospective clinical trials in patients with RPL are needed.
• Routine testing for thrombophilias is not recommended among women with RPL. The use of anticoagulants for the treatment of RPL with hereditary thrombophilias or unexplained RPL is not recommended, on the basis of high-quality evidence showing no benefit on livebirth or miscarriage rate.
• ASRM does not recommend routine testing for ovarian reserve in the evaluation of RPL because the association between RPL and ovarian reserve is unclear and no effective therapeutic interventions exist.
• ASRM does not recommend routine immune testing and treatment in the evaluation of RPL.
• Although the data on lifestyle interventions on miscarriage risk are limited, given the known risk of certain exposures in pregnancy and the possible impact on miscarriage risk, these exposures should be reduced whenever possible preconception. Smoking cessation is strongly recommended.
• The RPL couples are at risk for psychological sequelae. Psychological support is an essential part of miscarriage care and should be offered to all couples experiencing miscarriage and planning future pregnancy

CONCLUSIONS

RPL is identified in a woman with the loss of two or more presumed intrauterine pregnancies before 22 completed weeks of pregnancy. An algorithm is presented that guides the diagnostic workup on the basis of the chromosome status of the second miscarriage, while still allowing for provider judgment for higher numbers of miscarriages or untested miscarriages.

In this updated Committee Opinion, etiologies and treatments for RPL are presented in the context of the latest research advances in the field. One of the biggest challenges of treating patients with unexplained recurrent miscarriage is the high percentage of patients who remain unexplained if chromosome testing of the miscarriage is not performed, which can compel patients to request unproven diagnostic tests and therapies. Although ASRM supports shared decision-making, counseling patients with this multifactorial disorder should include an evidence-based approach in a supportive environment to minimize risks of unproven treatments. Expectant management should be discussed as a viable option, as the success rate is 50%–80% for the majority of patients with unexplained RPL (11, 174). As researchers and providers, it is essential that we continue to work to find patients’ answers and effective treatments and to continue to critically evaluate the literature as it emerges. Further research is needed in several areas, such as genetic and immune predisposition to miscarriage, endometrial factors, and therapies to mitigate the psychological impact of miscarriage on families. Empiric use of other treatment modalities has been suggested for unexplained RPL. However, studies have not shown benefit to RPL patients with routine use of low-dose aspirin, enoxaparin, glucocorticoids, heparin, endometrial scratching, granulocytecolony stimulating factor (G-CSF), intralipid therapy, routine use vaginal progesterone, alloimmune causes, or treatment with intravenous immunoglobulin (IVIG), or lymphocyte immunization therapy. At the present time, the use of empiric thrombolytics is not recommended for unexplained RPL.

Acknowledgments

This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine (ASRM) as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committee and the Board of Directors of ASRM have approved this report. This document was reviewed by ASRM members, and their input was considered in the preparation of the final document. The following members of the ASRM Practice Committee participated in the development of this document: Clarisa Gracia, M.D., M.S.C.E.; Paula Amato, M.D.; Jake Anderson; Rebecca Flyckt, M.D.; Karl Hansen, M.D., Ph.D.; Micah Hill, D.O.; Tarun Jain, M.D.; Sangita Jindal, Ph.D.; Suleena Kalra, M.D., M.S.C.E.; Bruce Pier, M.D.; Denny Sakkas, Ph.D.; Anne Steiner, M.D., M.P.H.; Cigdem Tanrikut, M.D.; Belinda Yauger, M.D.; Torie C. Plowden, M.D., M.P.H.; Ryan Smith, M.D.; Mark Trolice, M.D., M.B.A.; Suneeta Senapati, M.D.; Robert Brannigan, M.D.; Amy Sparks, Ph.D., H.C.L.D; Elizabeth Ginsburg, M.D.; Jared Robins, M.D.; Chevis N Shannon, Dr.Ph., M.B.A., M.P.H.; and Madeline Brooks, M.B.A., M.P.H. The Practice Committee acknowledges the special contributions of Ruth B. Lathi, M.D.; Erin Masaba, M.D.; May-Tal Sauerbrun Cutler, M.D.; Irene Souter, M.D.; Quinton S. Katler, M.D., M.S.; Michael Strug, D.O., Ph.D.; Dana McQueen, MD; and Richard Reindollar, M.D., in the preparation of this document. All Committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest on the basis of the relationships disclosed did not participate in the discussion or development of the document.

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