The Recurrent Loss Workup: Tests Worth Asking For

If you are reading this, you have probably been told you meet criteria for a recurrent miscarriage workup, and you have probably also been told that "in about half of cases we never find a reason." Both can be true. This post walks the recurrent miscarriage tests UK and international clinics actually offer, separates the evidence-based core from the fringe, and gives you the language to ask for what is worth your time and to decline what is not.

I want to name two things at once. Recurrent loss is its own category of grief, and each loss carries the previous ones with it. The workup is partly diagnostic and partly the act of being taken seriously. Both matter. You are not wasting NHS time, your RE's time, or your own time by asking for it.

Who qualifies, and under which guideline

Different healthcare systems use different thresholds, which is why patients often arrive confused.

The UK's Royal College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline No. 17 traditionally defines recurrent miscarriage as three or more consecutive first-trimester losses, though it accepts earlier evaluation in older patients or where other risk factors are present.³ The American Society for Reproductive Medicine (ASRM) defines recurrent pregnancy loss as two or more clinical pregnancy losses.² ESHRE's 2022 update lowered the European threshold to two or more pregnancy losses, consecutive or not, including biochemical losses when hCG was positive.¹ NICE NG126 in the UK aligns broadly with RCOG but supports individualised earlier review.⁵

If your local pathway is RCOG-strict and you have had two losses, the literature supports an early review. The Lancet 2021 Miscarriage matters series argued explicitly for graded care that begins after the first loss and intensifies with each subsequent one, instead of waiting for a numerical threshold.⁶ Citing this in your clinic conversation is reasonable.

The evidence-based core, what most guidelines agree on

These are the recurrent miscarriage tests UK, US, and European guidelines consistently support. If your workup includes most of these, you are receiving defensible care.

Antiphospholipid antibody screen: lupus anticoagulant, anticardiolipin IgG and IgM, and anti-β2-glycoprotein I antibodies. Critically, a positive result on a single test does not diagnose antiphospholipid syndrome (APS). The lab must be repeated at least 12 weeks later for confirmation. APS is the single most reliably treatable cause of recurrent loss, which is why this panel is the centrepiece of the workup.¹,²,³

Uterine cavity assessment: a saline-infusion sonohysterogram (SIS), 3D ultrasound, or hysteroscopy. Looking for a uterine septum, large submucosal fibroids, polyps, or intrauterine adhesions. A 2D pelvic scan alone is insufficient.¹

Thyroid function and TPO antibodies: TSH, free T4, and anti-thyroid peroxidase antibodies. Uncontrolled hypothyroidism, and especially TPO-antibody-positive subclinical hypothyroidism, has been associated with worse pregnancy outcomes. The TABLET trial in NEJM 2019 showed that levothyroxine in euthyroid TPO-positive women with prior loss or infertility did not improve live birth, so the trial helps refine when treatment is actually appropriate.⁷

Parental karyotype, in selected cases: not routine. ESHRE 2022 supports it when there is a family history of recurrent loss, a child with a chromosomal abnormality, or specific patterns of loss.¹ More relevantly, sending products of conception (POC) for cytogenetics when surgical management is performed has become a high-yield test. A trisomy result points to sporadic chromosomal error and modifies the conversation. A euploid POC raises the index of suspicion for maternal factors.

Glucose screening: HbA1c or fasting glucose, particularly if PCOS is in the picture, BMI is elevated, or there is a family history of type 2 diabetes. Uncontrolled hyperglycaemia at conception is associated with higher miscarriage risk.

Semen analysis for the male partner: standard parameters plus DNA fragmentation testing when there is a clinical reason (advanced paternal age, varicocele, oxidative stress markers, prior poor IVF performance). Routine sperm karyotype is not indicated.

That, in short, is the evidence-based core. If your clinic is doing the antiphospholipid panel with the 12-week repeat, the cavity assessment, the thyroid screen, the glucose if indicated, and offering POC cytogenetics on a future loss, you are receiving guideline-concordant care.

Tests where the evidence is weaker, and what that means

This is the section to read before you accept any panel offered by a private clinic charging out of pocket. These tests are offered widely. They are not supported by current guidelines.

Inherited thrombophilia panel: Factor V Leiden, prothrombin G20210A, MTHFR, protein C, protein S, and antithrombin deficiency. ESHRE 2022 and RCOG do not recommend routine screening.¹,³ The link between inherited thrombophilias and first-trimester loss has weakened with better-designed studies, and the ALIFE trial showed no benefit of aspirin or aspirin plus heparin in unexplained recurrent loss.

Natural killer (NK) cell testing, peripheral or uterine. ESHRE 2022 explicitly does not recommend.¹ Methodology varies between labs, there is no validated threshold, and no treatment based on NK results has reliable RCT evidence.

HLA typing of the couple: not recommended outside research.¹

Th1/Th2 cytokine panels: not recommended.¹

Endometrial biopsy for receptivity or immune profiling: limited evidence for changing management.

MTHFR variant testing in isolation: common variants in the general population. Not associated with recurrent loss in well-conducted studies. Folate supplementation at standard preconception doses is the only relevant action, and it is already routine.

I want to be specific about why this matters. These tests are heavily marketed by private clinics. They can run into thousands of pounds or dollars when added together, and the results often lead to expensive empirical treatments (IVIG, intralipid, anticoagulation) that themselves lack evidence. If a clinic offers you any of the above as part of a standard package, it is reasonable to ask which guideline supports them and whether the result will change management.

After IVF-related recurrent loss

Two extra tests sometimes appear in this setting.

Pre-implantation genetic testing for aneuploidy (PGT-A) on future embryos: the STAR trial and subsequent analyses showed that PGT-A reduces per-transfer miscarriage but does not increase cumulative live birth in younger patients. In older patients or after recurrent aneuploid loss, the calculation may differ. It is a real conversation, not a yes-or-no.

Endometrial receptivity testing (ERA): once heavily marketed for "personalised transfer windows," recent RCT data have not supported routine use. Discuss with your RE; in most situations the cost is hard to justify.

What to ask the clinic to do

Copy this list. Take it to your next appointment.

• "Which of the ESHRE 2022 or RCOG recommended tests are you doing for me?"
• "Are you sending products of conception for cytogenetics if there is another loss?"
• "Am I getting the full antiphospholipid panel, including the 12-week repeat?"
• "Is a saline-infusion scan or hysteroscopy planned?"
• "What is your reasoning for any test you are recommending that is outside core guidelines?"
• "If everything comes back normal, what is the plan for the next pregnancy specifically?"
• "Do you offer reassurance scans early in the next pregnancy?"

That last question matters more than people realise. The "tender loving care" model, which dates back to observational data from the 1990s and has been refined since, includes early and frequent reassurance scans plus dedicated clinic contact in recurrent loss patients. The evidence is observational and the mechanism is partly psychological, but the pattern of improved outcomes is consistent across cohorts. If your clinic does not offer early scans, ask if they can refer you to one that does.

Treatments with evidence when something is found

The point of the workup is the plan for the next pregnancy. Here is what the evidence actually supports.

Confirmed APS: low-dose aspirin plus low-molecular-weight heparin (LMWH) in pregnancy. Well-established across ESHRE, RCOG, and ASRM consensus.¹,²,³

Hypothyroidism: levothyroxine titrated to a TSH ideally below 2.5 mIU/L preconception, especially with positive TPO antibodies. The TABLET trial cautions against treating euthyroid TPO-positive patients without other indication.⁷

Uterine septum: hysteroscopic septoplasty. Evidence on improved live birth is debated; individualise with a hysteroscopy-experienced specialist.

Balanced parental translocation: genetic counselling. PGT for structural rearrangements (PGT-SR) in IVF is an option for some couples.

Recurrent loss with early-pregnancy bleeding: vaginal micronised progesterone 400 mg twice daily, from a positive pregnancy test through 16 weeks of gestation. The PRISM trial showed clinically meaningful benefit in the subgroup with prior losses and current early bleeding, with the strongest effect in those with three or more prior losses.⁴ This is the most important recent shift in evidence for recurrent loss, and the dose detail matters: 400 mg vaginally, twice daily, not oral.

Recurrent loss without identifiable cause: the honest answer is that no specific empirical treatment reliably improves live birth. The cumulative live-birth rate over the next several years is still in the 65 to 75 percent range for unexplained RPL, particularly in those under 35.¹

When the workup comes back normal

About half of well-done workups will. This is the hardest result to receive, because it feels like the door has closed without anyone answering it.

What we can offer in this situation is a structured next-pregnancy plan. Early reassurance scans. Low threshold for vaginal progesterone if early bleeding occurs. Optimisation of any borderline endocrine or metabolic parameters. Mental health support in parallel. The cumulative live-birth statistic is honest: most people in this category do eventually have a successful pregnancy. That sentence does not erase the difficulty of getting there.

Some clinics will offer empirical aspirin or empirical PGT-A in this setting. Both have weak evidence. Ask the question, weigh the answer, decline if the data are thin and the cost is real.

What you can do this cycle

1. Print the evidence-based core list above. Bring it to your next appointment.
2. If you are paying privately, decide in advance which fringe tests you will and will not pay for. The cost runs up there.
3. If another loss occurs, ask for cytogenetic analysis of the tissue. It is one of the highest-yield tests in the workup.
4. Book a mental health consultation in parallel. Most workups take 8 to 12 weeks, and the grief is not on that timeline.

When to call

Heavy bleeding, signs of infection, severe pain are the usual loss and pregnancy red flags. After getting test results, book the follow-up promptly. Results without an attached plan are worse than waiting.

The honest summary on recurrent miscarriage tests UK clinics actually offer: a small evidence-based core is worth pushing for, a long list of fringe tests can usually be declined, and a clear next-pregnancy plan matters more than any single result.

What's next

• For the full overview of recurrent loss including the progesterone evidence: recurrent pregnancy loss, when to ask for a workup
• If PCOS is part of the picture: PCOS and recurrent pregnancy loss
• If you are deciding on timing for the next pregnancy: trying again after miscarriage
• If you are considering a different path: changing direction, from IVF to donor, adoption, or childfree

Sources

1. ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open 2023;2023(1):hoad002. https://academic.oup.com/hropen/article/2023/1/hoad002/7034959
2. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012;98(5):1103-1111 (reaffirmed 2020). https://www.asrm.org/practice-guidance/practice-committee-documents/evaluation-and-treatment-of-recurrent-pregnancy-loss-a-committee-opinion/
3. Royal College of Obstetricians and Gynaecologists. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. Green-top Guideline No. 17; 2011. https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/the-investigation-and-treatment-of-couples-with-recurrent-miscarriage-green-top-guideline-no-17/
4. Coomarasamy A, Devall AJ, Cheed V, et al. A randomized trial of progesterone in women with bleeding in early pregnancy (PRISM). N Engl J Med 2019;380(19):1815-1824. https://www.nejm.org/doi/full/10.1056/NEJMoa1813730
5. National Institute for Health and Care Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. NICE Guideline NG126; 2019 (updated 2023). https://www.nice.org.uk/guidance/ng126
6. Quenby S, Gallos ID, Dhillon-Smith RK, et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet 2021;397(10285):1658-1667. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00682-6/fulltext
7. Dhillon-Smith RK, Middleton LJ, Sunner KK, et al. Levothyroxine in women with thyroid peroxidase antibodies before conception (TABLET trial). N Engl J Med 2019;380(14):1316-1325. https://www.nejm.org/doi/full/10.1056/NEJMoa1812537