Recurrent Pregnancy Loss: Evidence-Based Evaluation, Treatment, and Legacy Practices

Introduction

Understanding Recurrent Pregnancy Loss as a Syndrome Rather Than a Single Disease

The term RPL describes an outcome pattern, but it does not identify a single underlying mechanism. Embryonic aneuploidy, a parental structural chromosome rearrangement, a uterine cavity abnormality, APS, uncontrolled endocrine disease, and unexplained euploid loss are all clinically distinct problems. Treating them as one uniform disease encourages the use of the same broad test panel and the same empiric prescription for every patient.[1-3]

The American Society for Reproductive Medicine (ASRM) now defines RPL as two or more spontaneous pregnancy losses, including pregnancies documented by urine or serum human chorionic gonadotropin, while explicitly excluding confirmed ectopic and molar pregnancies. Importantly, these losses do not need to be consecutive. The European Society of Human Reproduction and Embryology (ESHRE) similarly uses a two-loss definition. The Royal College of Obstetricians and Gynaecologists (RCOG) retains three first-trimester miscarriages as its formal definition, but it explicitly permits evaluation after two losses when the pattern may be pathologic rather than sporadic.[1-3]

For a U.S.-anchored practice algorithm in 2026, initiating an evaluation after the second documented loss is entirely reasonable. The depth of that evaluation should still reflect maternal age, gestational timing, whether the losses were consecutive, tissue chromosome results, prior live births, comorbid diseases, and the patient’s overall reproductive timeline.[1-3]

The Diagnostic Pivot: Starting the Evaluation With the Loss Itself

The most important change in the 2026 ASRM approach is sequencing. Instead of ordering a broad “RPL panel” right out of the gate, clinicians should evaluate miscarriage tissue for a chromosomal explanation when feasible, and then add tests that remain relevant after that result is known. Array-based chromosome testing avoids some of the limitations of conventional culture-based karyotyping and can provide a definitive explanation for many first-trimester losses. ASRM recommends offering tissue testing at the second miscarriage or in a patient who already meets criteria for RPL.[1]

An aneuploid result usually identifies the proximate explanation for that specific loss. It does not prove that every prior loss was aneuploid, nor does it erase clinically important history. Conversely, a euploid result, an unbalanced structural rearrangement, or the absence of usable tissue completely changes the next diagnostic branch.[1-3]

Table 1. High-value testing after recurrent pregnancy loss

Evaluation	2026 role	Practical limit
Miscarriage-tissue chromosome analysis	Core first step when tissue is available	Prefer an array-based method; no platform detects every abnormality.[1-3]
Uterine cavity assessment	Core anatomic evaluation	Use 3D transvaginal ultrasound, saline infusion sonography, HSG, or hysteroscopy according to the question.[1-3]
Parental karyotypes	Selective	Highest yield after an unbalanced tissue result or when tissue testing is unavailable.[1-3]
APS laboratory testing	Criteria-driven or guideline-directed	A single low-titer positive result is not APS; persistence is required.[1,3]
Serum TSH	Reasonable, especially after euploid or untested loss or with thyroid risk	Treat thyroid dysfunction, not antibody status alone.[1,3,12,13]
HbA1c	Risk-based	Use for diabetes risk, symptoms, obesity, prior gestational diabetes, or other metabolic concern.[1]
Prolactin	Symptom-based	Reserve for galactorrhea, anovulation, or another clinical indication.[1]
Chronic endometritis evaluation	Selective or investigational	Diagnostic thresholds vary; routine antibiotics have not shown clear live-birth benefit.[1,3]
Sperm DNA fragmentation	Selective	May be discussed in otherwise unexplained RPL or coexisting infertility; treatment benefit is unproven.[1,3]
Inherited thrombophilia panel, including MTHFR	Not routine	Test only for a separate thrombosis-related indication or selected second-trimester context.[1,3,11]
Immune, receptivity, and microbiome panels	Not routine	Results are poorly standardized and do not identify a validated treatment pathway.[1-3]
AMH or ovarian reserve testing	Not an RPL test	Use only when the result would answer a separate fertility-management question.[1]

Building the Clinical Phenotype Before Ordering Broad Test Panels

A high-value history should reconstruct each pregnancy rather than simply recording the total number of losses. Useful details include whether the pregnancy was biochemical or ultrasound-confirmed, the gestational age, the presence of fetal cardiac activity, fetal or placental findings, pathology reports, tissue genetics, the medical or surgical treatment of the loss, any post-procedure infections or adhesions, and whether a live birth occurred before or between the losses.[1-3]

This same review should actively look for features that might redirect the diagnostic algorithm. These include a history of thrombosis, later fetal death, severe placental disease, preterm preeclampsia, autoimmune disease, thyroid symptoms, diabetes risk, galactorrhea, anovulation, infertility, congenital anomaly history, and medication or toxic exposures.

A second-trimester loss should never be treated as merely a later version of an early aneuploid miscarriage. It warrants a phenotype-specific obstetric or maternal-fetal medicine evaluation, with close attention to fetal, placental, cervical, anatomic, and APS-related causes.[1,3]

Uterine Evaluation Is Evidence-Based, but Reflex Surgery Is Not

Assessment of the uterine cavity is a standard component of the RPL evaluation. Three-dimensional transvaginal ultrasound or saline infusion sonography often provides all the information needed, while hysteroscopy is highly valuable when direct visualization or concurrent treatment is likely. MRI is usually reserved for complex anomaly classification rather than being used as a first-line test.[1-3]

However, finding an anatomic abnormality does not automatically prove causation. A septum, adhesion, retained tissue, endometrial polyp, or submucosal fibroid may be relevant, but the expected benefit of surgery differs drastically based on the specific lesion, the degree of cavity distortion, patient symptoms, prior procedures, and the actual evidence supporting the intervention.[1,3-5]

A randomized trial evaluating septum resection enrolled women with a septate uterus and a history of subfertility, pregnancy loss, or preterm birth. Live birth occurred in 31% of patients after septum resection compared to 35% with expectant management. The confidence interval was wide, and one uterine perforation occurred. Because the study was small and heterogeneous, it does not prove that surgery is never useful. It does, however, perfectly illustrate why septum incision should be a shared decision rather than an automatic reflex to an imaging finding.[1,3,5]

Similarly, the 2026 HELP Fertility? randomized trial attempted to test the hysteroscopic removal of small polyps and submucosal fibroids in patients with infertility or recurrent miscarriage. Recruitment stopped at just 35 of a planned 1,120 participants. Live birth rates were 15.8% with resection and 18.8% without resection, but the trial was far too underpowered to establish definitive benefit or harm. The appropriate clinical conclusion here is uncertainty, not equivalence, and certainly not proof of futility.[4]

Antiphospholipid Syndrome Is Actionable, but the Diagnosis Must Be Rigorously Earned

APS is the clearest example of a diagnosis in which targeted treatment can fundamentally change management. Testing thresholds do differ slightly across guidelines. RCOG recommends acquired thrombophilia testing in recurrent miscarriage, whereas ASRM emphasizes testing patients who meet compatible clinical criteria. Regardless of the initial screening threshold, a true APS diagnosis requires an appropriate clinical history plus persistent antiphospholipid antibodies, never just one isolated laboratory result.[1,3]

The laboratory evaluation includes lupus anticoagulant, anticardiolipin IgG and IgM, and anti-beta-2 glycoprotein I IgG and IgM. A preliminarily positive result must be repeated at least 12 weeks later to establish persistence. False-positive and low-titer results are common enough that indiscriminate testing can easily create a diagnosis that the patient does not actually have.[1]

For confirmed obstetric APS, low-dose aspirin plus prophylactic heparin or low-molecular-weight heparin is strongly guideline-supported. Patients with thrombotic APS may require full therapeutic anticoagulation. Hematology, rheumatology, reproductive endocrinology, maternal-fetal medicine, and obstetric teams may all need to be involved, because dosing, timing, bleeding risk, delivery planning, neuraxial anesthesia, and postpartum thromboprophylaxis are highly patient-specific.[1,3]

Why Inherited Thrombophilia Testing and Empiric Anticoagulation Are Usually Legacy Practices

Factor V Leiden, prothrombin variants, protein C, protein S, antithrombin, homocysteine, and MTHFR frequently appear on commercial RPL panels. For recurrent first-trimester loss, routine testing for these is simply not supported. MTHFR testing is particularly unhelpful because it does not identify an evidence-based miscarriage treatment.[1,3]

The ALIFE trial found no live-birth benefit from aspirin alone or aspirin plus low-molecular-weight heparin in unexplained recurrent miscarriage. The subsequent ALIFE2 trial specifically addressed patients with inherited thrombophilia and recurrent miscarriage. Live birth occurred in 72% of patients receiving low-molecular-weight heparin and 71% of those receiving standard care. Anticoagulation may still be indicated to prevent maternal venous thromboembolism in a patient with a personal thrombosis history or a high-risk thrombophilia, but that is a completely separate indication from treating RPL.[10,11]

This distinction matters immensely because aspirin and heparin are not benign symbols of simply “doing something.” They add bruising, bleeding, injection-site reactions, financial cost, monitoring burdens, and significant periprocedural and delivery-management consequences.[1,3]

Ensuring Thyroid and Metabolic Testing Identifies Truly Treatable Disease

Serum TSH is a reasonable component of the evaluation, especially when miscarriage tissue is euploid or untested, or when the patient has thyroid symptoms or risk factors. Overt hypothyroidism should always be treated. ASRM recommends treatment when TSH exceeds 4 mIU/L or the laboratory upper limit in the relevant RPL setting, while clinicians should also follow current pregnancy-specific thyroid guidance and laboratory ranges.[1]

Thyroid peroxidase (TPO) antibody testing illustrates a genuine guideline disagreement. RCOG recommends thyroid function and TPO antibody testing, whereas ASRM does not recommend routine antibody screening. The practical takeaway is much more stable than the screening debate itself: levothyroxine has not improved live-birth rates in euthyroid, TPO antibody-positive patients in either the TABLET or T4LIFE randomized trials.[1,3,12,13]

HbA1c should be targeted to diabetes risk or symptoms. Glycemic control before conception is vital when diabetes is present. Prolactin belongs in the workup only when galactorrhea, anovulation, or another clinical clue exists, never as a universal RPL test. Metformin should be prescribed for an established metabolic or ovulatory indication, not simply because the patient has experienced recurrent losses.[1]

Progesterone Supplementation Depends Entirely on the Clinical Phenotype

Asking whether we should use “progesterone for RPL” is too broad a question. The evidence differs drastically between an asymptomatic patient with unexplained recurrent miscarriage and a patient experiencing vaginal bleeding in a new intrauterine pregnancy.[1,3,6-9]

For asymptomatic unexplained RPL, the PROMISE trial did not show a significant live-birth benefit from first-trimester vaginal progesterone. Furthermore, a 2025 Cochrane review concluded that progestogen probably makes little or no difference to live birth in recurrent miscarriage of unclear cause. Routine serum progesterone testing in unassisted pregnancies, followed by supplementation based on that single level, is also completely unsupported.[1,6,7]

However, for early-pregnancy bleeding in a patient with at least one previous miscarriage, the PRISM trial’s prespecified subgroup findings support a very different approach. NICE recommends vaginal micronized progesterone at 400 mg twice daily after ultrasound confirmation of an intrauterine pregnancy in a patient with bleeding and a prior miscarriage. If fetal cardiac activity is confirmed, NICE advises continuing the treatment through 16 completed weeks. RCOG provides a similar recommendation for recurrent miscarriage accompanied by early bleeding.[3,8,9]

This specific regimen should not be generalized to every patient with RPL, every low serum progesterone value, a pregnancy of unknown location, or a suspected ectopic pregnancy. Product labeling, formulation availability, contraindications, and approved indications vary by jurisdiction, so clinicians must verify local prescribing information.[3,9]

Genetic Counseling Is High Value, whereas Routine PGT-A Is Not

When miscarriage tissue shows an unbalanced structural rearrangement, or when tissue testing is repeatedly unavailable, parental karyotyping can identify a balanced rearrangement in one partner. This result should immediately trigger genetic counseling that addresses recurrence risk, natural conception, prenatal diagnosis, donor gametes, and preimplantation genetic testing for structural rearrangements (PGT-SR).[1-3]

It is vital to understand that PGT-SR for a known rearrangement is not the same as PGT-A for unexplained RPL. Routine IVF with PGT-A has not been shown prospectively to improve live birth or shorten the time to a successful pregnancy compared with expectant management in RPL. It can be discussed selectively, including with some patients older than 40 who have a proven aneuploid loss, but counseling must include a frank discussion of ovarian response, embryo attrition, mosaic results, biopsy and laboratory limitations, high costs, and the absence of proven overall live-birth superiority.[1,3]

Chronic Endometritis and Male-Factor Testing Should Remain Highly Selective

Chronic endometritis has been associated with RPL, but studies frequently use inconsistent biopsy timing, plasma-cell thresholds, staining methods, and definitions. ASRM permits selective consideration in otherwise unexplained RPL or concurrent infertility. The society also cites a high-quality randomized trial, presented in abstract form, in which two weeks of doxycycline did not improve miscarriage or live-birth outcomes. Routine endometrial biopsy, broad microbiome testing, Mycoplasma or Ureaplasma panels, and empiric antibiotics therefore should not become a default branch of the diagnostic algorithm.[1,3]

Male health still absolutely belongs in the clinical assessment. Smoking, febrile illness, environmental exposures, advanced age, metabolic disease, medications, varicocele, and coexisting infertility may all matter. Standard semen parameters do not appear to predict RPL. ASRM allows sperm DNA fragmentation testing to be considered in otherwise unexplained RPL or concurrent infertility, but RCOG does not recommend routine sperm DNA testing outside of research settings. Even when fragmentation is high, evidence that a specific intervention improves live birth remains limited.[1,3]

Immune Panels and Unproven Add-On Therapies Should Stay Outside Routine Care

Natural killer cell assays, HLA matching, cytokine panels, broad autoantibody testing outside of APS, endometrial receptivity tests, and proprietary immune profiles lack sufficient standardization and validated treatment pathways for routine RPL care. The exact same caution applies to empiric intralipid infusions, intravenous immunoglobulin, glucocorticoids, granulocyte colony-stimulating factor, and other immune or endometrial add-ons when used outside a clinical trial or a separate established medical indication.[1-3]

A plausible biologic mechanism is not proof of clinical benefit. An abnormal result from a poorly validated assay can easily create a false diagnosis, leading to repeated treatment cycles and substantial financial cost without ever improving the outcome that actually matters: a healthy live birth.[1-3]

Matching Treatment to the Diagnosis or Phenotype

Table 2. Treatment matched to diagnosis or phenotype

Finding or scenario	Evidence-based action	What to avoid
Confirmed obstetric APS	Low-dose aspirin plus prophylactic heparin or LMWH with specialist coordination.[1,3]	Treating one transient or low-titer antibody result
Maternal thrombosis indication	Anticoagulate according to thrombosis and pregnancy guidance.[1,3]	Presenting VTE prophylaxis as an RPL treatment
Overt thyroid disease or diabetes	Optimize disease before conception and during pregnancy.[1,3,12,13]	Treating euthyroid antibody positivity as though it were hypothyroidism
Early bleeding plus prior miscarriage	Consider the NICE/RCOG vaginal micronized progesterone regimen where applicable.[3,8,9]	Routine progesterone for every asymptomatic RPL pregnancy
Septum, adhesion, retained tissue, polyp, or submucosal fibroid	Individualize by anatomy, symptoms, cavity distortion, evidence, and procedural risk.[1,3-5]	Automatic surgery based only on an imaging label
Unbalanced tissue result or parental rearrangement	Genetic counseling; discuss natural conception, prenatal diagnosis, and PGT-SR.[1-3]	Equating PGT-SR with routine PGT-A
Unexplained RPL	Prognostic counseling, preconception optimization, early-access plan, and supportive care.[1-3,10,11]	Empiric aspirin, LMWH, antibiotics, or immune add-ons
Coexisting infertility	Evaluate and treat infertility on its own merits.[1,3]	Assuming IVF or ovarian reserve testing treats RPL

A Practical Step-by-Step Algorithm for 2026

• At or immediately after the second loss: Confirm that the event meets the working RPL definition. Document gestational timing and imaging findings. Arrange chromosome analysis of miscarriage tissue when feasible, including a concrete plan for tissue collection if surgical management is not chosen. Review warning signs for ectopic pregnancy and address acute clinical needs first.[1]
• During the interval evaluation: Review the complete reproductive and medical phenotype. Assess the uterine cavity. Use the tissue result to direct genetic counseling and determine the intensity of further testing. Order TSH and other endocrine tests according to current guidance and clinical context. Test for APS according to the patient’s pregnancy and thrombosis history and the specific practice guideline being followed, then confirm persistence before formally assigning the diagnosis. Reserve parental karyotypes, HbA1c, prolactin, chronic endometritis evaluation, and sperm DNA fragmentation strictly for their defined indications.[1-3]
• Before the next conception: Optimize chronic disease, medications, folate intake, tobacco exposure, and other modifiable health factors. Document clearly in the chart which treatments are indicated, which have been considered and declined, and which are explicitly not recommended. Build a contact plan for a positive pregnancy test, pain, bleeding, and early ultrasound.[1-3]
• In the next pregnancy: Use diagnosis-specific treatment. Confirm pregnancy location when clinically appropriate. For bleeding with a prior miscarriage, consider guideline-supported vaginal micronized progesterone after an intrauterine pregnancy is visualized. For confirmed APS, initiate the agreed-upon anticoagulation plan. Continue ordinary prenatal risk assessment rather than attributing every later obstetric complication to RPL.[1,3,9]

Supportive Care Is a Vital Part of Treatment, but It Must Be Described Honestly

RPL is heavily associated with anxiety, depression, trauma symptoms, guilt, and a profound loss of trust in the body and the healthcare system. A dedicated clinic, continuity of care, rapid access for symptoms, clear communication of results, early ultrasound when appropriate, and mental-health referrals are all evidence-aligned components of comprehensive care.[1-3]

However, psychological support should not be marketed as a biologic cure. Older observational “tender loving care” studies cannot separate the actual effect of surveillance from selection bias, behavioral changes, and other confounding variables. The defensible claim is that structured support provides vital continuity, improves communication, and addresses a serious psychological burden while the ultimate pregnancy outcome remains uncertain.[1-3]

Discussing Prognosis: Reassuring Statistics That Must Not Be Generic

ASRM estimates that 50% to 80% of patients will have a successful subsequent pregnancy without any specific medical intervention. That range is intentionally broad. Maternal age, the number and sequence of losses, prior live births, gestational timing, tissue karyotype, coexisting infertility, and identified diseases all heavily affect an individual’s specific probability.[1]

The correct counseling message is neither that “nothing is wrong” nor that a long, expensive list of add-ons is necessary. The message is that many patients will ultimately have a live birth, a small minority have a specific actionable diagnosis, and unexplained RPL remains a very real, valid clinical condition even when exhaustive testing does not reveal a clear mechanism.[1-3]

 

References

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2. ESHRE Guideline Group on Recurrent Pregnancy Loss; Bender Atik R, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023;2023(1). https://doi.org/10.1093/hropen/hoad002 PMID: 36873081; PMCID: PMC9982362. Official guidance: https://www.eshre.eu/guidelines-and-legal/guidelines/recurrent-pregnancy-loss Accessed August 12, 2026.
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9. National Institute for Health and Care Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. NICE guideline NG126. Management of miscarriage. Updated June 17, 2026. https://www.nice.org.uk/guidance/ng126/chapter/Management-of-miscarriage Accessed August 12, 2026.
10. Kaandorp SP, Goddijn M, van der Post JAM, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362(17):1586-1596. https://doi.org/10.1056/NEJMoa1000641 PMID: 20335572. https://pubmed.ncbi.nlm.nih.gov/20335572/ Accessed August 12, 2026.
11. Quenby S, Booth K, Hiller L, et al.; ALIFE2 Block Writing Committee and ALIFE2 Investigators. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet. 2023;402(10395):54-61. https://doi.org/10.1016/S0140-6736(23)00693-1 PMID: 37271152. https://pubmed.ncbi.nlm.nih.gov/37271152/ Accessed August 12, 2026.
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