Recurrent Pregnancy Loss: When to Ask for a Workup

If you are reading this after a second or third loss, I want to start where the clinical literature now starts. Two losses is not bad luck minimised. It is two losses, and you are entitled to ask why. The phrase "we wait until the third" is no longer the only defensible answer, and this post explains what changed, what a thorough workup actually includes, and the evidence behind the question every patient asks me: does progesterone help.

I want to name what I see in clinic. Couples come in after a second miscarriage having been told to "just try again" or that "two is just bad luck." They are sitting with grief that compounds in a way single losses do not, and a quieter question underneath it: is something wrong with me. Most of them also arrive having read conflicting things about recurrent miscarriage and progesterone, and want a straight answer on whether to ask for it. The international guidelines have moved with you. In 2022, the European Society of Human Reproduction and Embryology (ESHRE) lowered the threshold for recurrent pregnancy loss from three consecutive losses to two, consecutive or not.¹ The American Society for Reproductive Medicine (ASRM) has used the two-loss threshold for over a decade.² The Royal College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline No. 17 still names three consecutive first-trimester losses as the formal criterion in the UK, while acknowledging that earlier evaluation is appropriate in many situations.³ If you have had two losses and you want a workup, the literature backs you.

What recurrent pregnancy loss means now

The shift in definition is not a paperwork detail. It changes whether your insurance pathway or your NHS referral route opens up for investigation.

ESHRE's 2022 guideline defines recurrent pregnancy loss (RPL) as two or more pregnancy losses before 24 weeks of gestation, consecutive or not.¹ The definition excludes ectopic pregnancy, molar pregnancy, and pure implantation failure in IVF cycles where no clinical pregnancy was confirmed. Importantly, biochemical (chemical) losses are now included if a pregnancy was confirmed by a positive hCG, even without an ultrasound or histological diagnosis. This matters because a couple who has had two chemical losses used to fall through every guideline crack. They no longer do.

ASRM defines RPL as two or more clinical pregnancy losses, confirmed by ultrasound or histopathology.² It is similar to ESHRE in threshold, slightly stricter in what counts as a pregnancy. RCOG retains the three-loss threshold in formal guidance but states that an earlier workup is reasonable in older patients or where other risk factors are present.³

The prevalence of RPL by the two-loss definition is about 1 to 2 percent of couples trying to conceive. Meaningful. Not rare. If this is you, you are not the only person in your friend group, even if no one is talking about it.

Why losses happen, what we can and cannot explain

I want to give you the honest baseline before we move into testing, because the workup is more bearable when you know what it can and cannot deliver.

Approximately 50 to 60 percent of all early miscarriages are caused by chromosomal abnormalities in the embryo that arose at fertilisation. These are sporadic, not recurring, and not typically inherited. Even after two losses, the chance of a future live birth without any intervention is still around 60 to 75 percent for people under 35, and the prognosis is meaningfully informed by maternal age, number of prior losses, and what (if anything) the workup finds.⁷

The harder sentence to say in clinic is this one. Even after a full, well-conducted workup, roughly half of recurrent loss cases remain unexplained.¹ That is not a failure of the workup. It reflects the limits of what current science can identify. I tell this to every patient before we start, because the workup is harder to bear if it has been sold as the answer. The workup is a process that finds treatable causes when they exist, names risk factors that change the next-pregnancy plan, and rules out things you should not be paying out of pocket to investigate.

What a thorough workup actually includes

Here are the categories. The companion post on recurrent loss workup tests walks each test individually and tells you which ones to skip when private clinics offer them. Stay with me for the overview.

Anatomic: a pelvic ultrasound is the starting point. Beyond that, the workup usually includes a saline-infusion sonohysterography (SIS) or a hysterosalpingogram (HSG), and sometimes pelvic MRI. We are looking for a uterine septum, large fibroids distorting the cavity, intrauterine adhesions, or, occasionally, a previously undiagnosed Mullerian anomaly. ESHRE 2022 supports cavity assessment as routine in the RPL workup.¹

Endocrine: TSH, with treatment if elevated, especially in the presence of thyroid peroxidase antibodies. Prolactin in some cases. HbA1c or fasting glucose if there is diabetes risk or features of metabolic syndrome. Ovarian reserve markers (AMH, antral follicle count) when planning the next attempt, especially over 35.

Genetic: parental karyotype is selective, not universal. ESHRE 2022 recommends it when there is a family history of recurrent loss, congenital abnormality, or stillbirth, or after specific patterns of loss.¹ Where surgical management of a loss is performed, sending products of conception (POC) for cytogenetic analysis is high-yield. A trisomic POC result tells you the loss was almost certainly sporadic and chromosomal; a euploid POC raises the question of a maternal or paternal factor and changes the testing focus.

Antiphospholipid syndrome (APS): this is the workup's clearest treatable yield. The test panel is lupus anticoagulant, anticardiolipin antibodies (IgG and IgM), and anti-β2-glycoprotein I antibodies. Diagnosis requires a positive result confirmed on a repeat test at least 12 weeks later. APS is one of the conditions where evidence-based treatment in the next pregnancy meaningfully improves live birth.¹

Thrombophilia screening: this is where the workup most often goes wrong in private settings. ESHRE 2022 and ASRM both caution against routine inherited thrombophilia screening (Factor V Leiden, prothrombin G20210A, MTHFR, protein C/S/antithrombin deficiency) outside specific indications.¹,² The link with first-trimester loss is weaker than once thought, and anticoagulation in non-APS thrombophilia has not improved outcomes in RCTs. If a clinic is selling you a thrombophilia panel as routine, ask why.

Immune and NK cell testing: not standard of care. ESHRE 2022 explicitly does not recommend routine natural killer cell testing or HLA typing for recurrent loss outside research settings.¹ The methodology is variable, there is no validated threshold, and there is no treatment with evidence behind it. This is the area where vulnerable readers get exploited financially.

Lifestyle: a real conversation about BMI extremes, smoking, alcohol, recreational drugs, and occupational exposures. Not as a moral assessment. As modifiable factors that influence the next pregnancy.

The aggregate picture of a defensible workup: structural assessment, thyroid and prolactin, glucose if indicated, antiphospholipid panel with the 12-week repeat, POC cytogenetics on a recurrence, parental karyotype selectively. That is most of what the major guidelines agree on.

Recurrent miscarriage and progesterone: what the trials show

I want to be precise here because the internet is not.

The single most important recent evidence on recurrent miscarriage and progesterone is the PRISM trial, published in the New England Journal of Medicine in 2019.⁴ PRISM randomised over 4,000 women with vaginal bleeding in early pregnancy (a threatened miscarriage) to vaginal micronised progesterone 400 mg twice daily or placebo, from presentation until 16 weeks of gestation. In the overall trial population, progesterone did not significantly increase live birth (75% vs 72%). In the pre-specified subgroup of women with one or more prior miscarriages and current early-pregnancy bleeding, the live-birth difference was modest. In the subgroup with three or more prior miscarriages and current early-pregnancy bleeding, progesterone improved live birth from 57% to 72%. That is a clinically meaningful difference and the basis on which many UK and international clinics now offer progesterone to that exact population.

What PRISM did not show is also important. PRISM does not support progesterone for everyone with recurrent loss, regardless of bleeding. The earlier PROMISE trial, also published in NEJM in 2015, randomised women with unexplained recurrent miscarriage but without early pregnancy bleeding to progesterone or placebo from positive test through 12 weeks. PROMISE found no benefit on live birth.⁵ That is the trial that most patients have not read about online.

So when does progesterone help, and when does it not. The honest answer from current evidence: vaginal micronised progesterone 400 mg twice daily, from a positive pregnancy test until 16 weeks, is appropriate when a person has had one or more prior miscarriages and presents with early-pregnancy bleeding, especially in those with three or more prior losses. It is reasonable to discuss with your RE in two-loss cases with bleeding, given the direction of the data. It is not evidence-based for unexplained recurrent loss without bleeding.

This is one of the conversations I find myself having most. Patients ask me about progesterone suppositories for recurrent miscarriage with hope and dread in equal measure, because the internet has often told them it will save the next pregnancy. The truthful framing is: it helps a defined subgroup, it does not help all subgroups, and the dose your clinic gives you should be vaginal micronised progesterone 400 mg twice daily where indicated.

A separate conversation applies to confirmed APS. The evidence-based protocol in pregnancy is low-dose aspirin plus low-molecular-weight heparin (LMWH), started in early pregnancy, per ESHRE 2022 consensus.¹ This is a different track from progesterone and is added on, not substituted.

Recurrent Pregnancy Loss: When to Ask for a Workup: infographic — At a glance: Recurrent Pregnancy Loss: When to Ask for a Workup

How to start the conversation

The exact language that opens a workup, which I encourage patients to use, sounds like this. "I have had two losses. I would like to be evaluated for recurrent pregnancy loss under ESHRE or ASRM guidance. What tests are you offering me, what are you not offering me, and what is your reasoning."

Bring records. Beta-hCG values from the prior pregnancies, ultrasound reports, any POC results, the date and gestational age of each loss. If you are switching to a new clinician, request your records before the appointment, not at the appointment.

Ask what changes for the next pregnancy beyond the workup itself. Specifically: early reassurance scans, threshold for vaginal progesterone if bleeding occurs, plan for serial beta-hCG, plan for thyroid optimisation if indicated. The workup is one half of the conversation. The plan for the next pregnancy is the other half, and many patients leave without the second half because no one offers it.

Ask explicitly about mental health support. Recurrent pregnancy loss is associated with high rates of post-traumatic stress, anxiety, and depression in the year following. The Farren study published in AJOG documented PTSD-range symptoms in roughly 18 percent of women one month after early loss and in around 4 percent at nine months, with higher rates after recurrent loss specifically. Mental health support is part of the workup, not an optional add-on. If your team does not raise it, you can. The companion post TTC grief and when to see a therapist walks the actual routes to finding help.

What you can do this week

You are not waiting for the perfect appointment. You can move on a few things now.

Gather your records from each prior loss. Beta values, scan reports, any POC results, dates of bleeding and management. Put them in one folder.
Identify whether your current care pathway uses ESHRE, ASRM, or RCOG framing. If your local pathway is RCOG (three losses), and you have had two, you can ask for earlier evaluation citing ESHRE 2022.
Write down the three things you most want answered. Bring the list to the appointment. The cognitive load of grief makes appointments hard to use well unless you arrive with a written list.
Book a therapy consultation in parallel, not after the workup. The workup will take 8 to 12 weeks. The grief is happening now.

What's normal, what's a red flag

Normal in this setting is a workup that takes time, finds a partial answer, or finds nothing. Half of well-conducted workups come back without an identified cause. That does not mean nothing is happening. It means current testing cannot characterise it.

Red flags for escalation include recurrent late-first-trimester or second-trimester losses (which raise the question of cervical insufficiency or uterine cavity issues), three or more chromosomally aneuploid POC results (which strengthens the case for parental karyotype), and a personal or strong family thrombosis history (which justifies a specialist-led thrombophilia workup that is separate from a routine panel).

On recurrent miscarriage and progesterone, the short version: it helps a small, specific subgroup, the PRISM trial gives us the cleanest evidence, and a routine offer to every patient is not what the data support.

What's next

If you want the test-by-test detail and the language to ask your clinic for: the recurrent loss workup, tests worth asking for
If you have PCOS and you are wondering whether it is contributing: PCOS and recurrent pregnancy loss
If you are deciding when to try again: trying again after miscarriage
If you are starting to think about a different path: changing direction, from IVF to donor, adoption, or childfree
If the grief is heavier than the workup: TTC grief and when to see a therapist

Sources

ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open 2023;2023(1):hoad002. https://doi.org/10.1093/hropen/hoad002
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. https://doi.org/10.1016/j.fertnstert.2012.06.048
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. RCOG; 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/
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://doi.org/10.1056/NEJMoa1813730
Coomarasamy A, Williams H, Truchanowicz E, et al. A randomized trial of progesterone in women with recurrent miscarriages (PROMISE). N Engl J Med 2015;373(22):2141-2148. https://doi.org/10.1056/NEJMoa1504927
Kaandorp SP, Goddijn M, van der Post JAM, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage (ALIFE). N Engl J Med 2010;362(17):1586-1596. https://doi.org/10.1056/NEJMoa1000641
Lund M, Kamper-Jørgensen M, Nielsen HS, Lidegaard Ø, Andersen AMN, Christiansen OB. Prognosis for live birth in women with recurrent miscarriage: what is the best measure of success? Obstet Gynecol 2012;119(1):37-43. https://doi.org/10.1097/AOG.0b013e31823c0413

Common questions

After how many losses can I ask for a recurrent pregnancy loss workup?

The threshold has moved. ESHRE's 2022 guideline defines recurrent pregnancy loss as two or more losses before 24 weeks, consecutive or not, and ASRM has used a two-loss threshold for over a decade. RCOG in the UK still names three consecutive first-trimester losses as the formal criterion but acknowledges earlier evaluation is appropriate in many situations. If you have had two losses and want a workup, the literature backs you.

Does progesterone help prevent recurrent miscarriage?

It helps a defined subgroup, not everyone. The PRISM trial found vaginal micronised progesterone 400 mg twice daily improved live birth from 57 to 72 percent in women with three or more prior miscarriages and current early-pregnancy bleeding. The PROMISE trial found no benefit for unexplained recurrent miscarriage without bleeding. A routine offer to every patient is not what the data support.

What does a thorough recurrent loss workup include?

A defensible workup covers structural assessment of the uterine cavity, thyroid (TSH) and prolactin, glucose if indicated, an antiphospholipid panel with a repeat test at least 12 weeks later, products of conception cytogenetics on a recurrence, and parental karyotype used selectively. These are the categories the major guidelines broadly agree on.

Should I get tested for inherited thrombophilia or NK cells?

Generally no, not as routine. ESHRE 2022 and ASRM both caution against routine inherited thrombophilia screening outside specific indications, because the link with first-trimester loss is weaker than once thought and anticoagulation has not improved outcomes in non-APS cases. Routine natural killer cell testing and HLA typing are explicitly not recommended outside research settings. If a clinic sells these as routine, ask why.

Will a workup always find a cause for my recurrent losses?

No. Even after a full, well-conducted workup, roughly half of recurrent loss cases remain unexplained. That is not a failure of the workup; it reflects the limits of current science. The workup finds treatable causes when they exist, names risk factors that change the next-pregnancy plan, and rules out things you should not be paying to investigate.