In one line
Recurrent pregnancy loss is a clinical problem of probability, not pathology — the commonest cause of any single loss is embryonic aneuploidy and roughly half of couples have no cause found at all, so the consultant's job is to run a short, evidence-based work-up that finds the few genuinely treatable conditions (antiphospholipid syndrome above all), to not offer the long list of unproven and harmful "treatments" the field is littered with, and to give the couple an honest, individualised prognosis with supportive early-pregnancy care.
Much of the management here is in knowing what not to do. The Intermediate groundwork on a single sporadic miscarriage — its mechanism, expectant/medical/surgical management — is assumed; revise it at recurrent pregnancy loss basics and spontaneous miscarriage. This chapter defends a work-up and a treatment plan from the primary literature, against guidelines that do not fully agree even on the definition.
Mechanism & pathophysiology
Each individual miscarriage is overwhelmingly a chromosomal event in the embryo, not a maternal disease. Around half of all clinically recognised miscarriages carry a fetal chromosomal abnormality — usually a sporadic autosomal trisomy, monosomy X or triploidy arising from a non-disjunction error at meiosis — and the proportion rises steeply with maternal age as oocyte aneuploidy accumulates. This is why recurrent loss is, for most couples, recurrent bad luck: independent aneuploid events stacking up by chance, their probability set largely by maternal age. It is also why a karyotypically normal (euploid) loss is more informative than an aneuploid one — a euploid miscarriage is the one more likely to reflect a maternal or uterine factor you can act on.
Layered on top of that baseline are the minority of genuinely recurrent mechanisms, and they are worth understanding mechanistically because the mechanism dictates whether treatment helps.
Antiphospholipid syndrome (APS) is the one acquired cause with a proven, mechanistic treatment effect. Antiphospholipid antibodies — lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein-I — bind β2-glycoprotein-I displayed on the syncytiotrophoblast surface and at the maternal–fetal interface. The injury is not simply intervillous thrombosis (the old "placental infarction" model is incomplete). The antibodies impair trophoblast proliferation, invasion and hCG secretion, and they activate complement (C5a) and a local inflammatory placentopathy that disrupts spiral-artery remodelling. This matters for the treatment argument: heparin's benefit in obstetric APS is plausibly as much anti-complement and anti-inflammatory at the trophoblast as it is anticoagulant — which is why prophylactic, not therapeutic, dosing is the obstetric standard, and why the drug that "thins blood" helps a disease that is not primarily about clots. The full pharmacology and the thrombotic-versus-obstetric phenotype split are developed in Sle and antiphospholipid syndrome; APS is the cause you must not miss because it is the cause you can treat.
The inherited-thrombophilia story is the instructive opposite. Factor V Leiden, prothrombin G20210A, protein C/S and antithrombin deficiency have a weak and largely epidemiological association with late loss, and the mechanistic logic ("maternal hypercoagulability → placental thrombosis → loss") was always shakier than it looked, because early loss is an implantation/embryonic event, not a uteroplacental thrombotic one. The field spent fifteen years anticoagulating these women on that logic — and the randomised evidence (ALIFE2, below) has now shown it does not work. The pathophysiology lesson is that a plausible mechanism is not evidence of a treatable one.
Genetic causes split into two layers. The common layer is the sporadic embryonic aneuploidy above. The rare-but-actionable layer is a parental structural chromosome rearrangement — most often a balanced reciprocal or Robertsonian translocation carried by one partner (found in ~2–5% of RPL couples). The carrier is phenotypically normal, but at meiosis produces a high proportion of unbalanced gametes, generating embryos with partial trisomies/monosomies that miscarry. This is the one genetic finding that changes counselling: it gives a recurrence mechanism and opens a specific intervention (genetic counselling ± pre-implantation genetic testing for structural rearrangements, PGT-SR).
Uterine factors act by distorting implantation and placentation. The septate uterus — a failure of resorption of the midline müllerian septum, leaving a fibrous, poorly vascularised septum — is the canonical anatomical association with mid-trimester loss, although (TRUST, below) its treatment is now contested. Submucous fibroids and intrauterine adhesions (Asherman) similarly compromise the implantation site. Cervical insufficiency is a distinct entity causing painless mid-trimester loss/extreme preterm birth and is mechanistically and managerially separate from first-trimester RPL.
Endocrine and emerging mechanisms round it out: overt hypothyroidism and poorly controlled diabetes are biologically plausible and treatable; chronic endometritis — persistent low-grade endometrial inflammation, often with plasma-cell infiltrate on CD138 staining — is an emerging association where the causal and treatment evidence is still maturing. Each of these is a candidate for the work-up, but the honest mechanistic summary is that for the majority of couples no single mechanism is found, and the dominant driver across the population is age-related embryonic aneuploidy.
Assessment
The assessment has two jobs that pull in opposite directions: find the treatable minority, and avoid over-investigating a couple whose losses are stochastic. A focused, guideline-anchored work-up does both. The first decision is when to investigate at all, and this is where the guidelines openly disagree (developed under Guidelines compared).
History. Number, gestation and nature of each loss (first- vs second-trimester; the pattern matters — late losses point harder at APS, cervix and uterine factors); whether any products were karyotyped; menstrual and subfertility history; thyroid, diabetes and autoimmune symptoms; thrombotic and obstetric history (VTE, prior pre-eclampsia/FGR/stillbirth — the obstetric-APS clinical criteria); drug, alcohol, smoking and weight history; consanguinity and family history of losses or translocations; and the couple's own emotional trajectory, because the intervention that most reliably "works" is supportive care.
Examination. General (BMI, signs of thyroid or autoimmune disease, hirsutism/acanthosis suggesting PMOS) and pelvic.
Investigations — and what each result means:
- Antiphospholipid panel is the load-bearing test: lupus anticoagulant (LAC), anticardiolipin IgG/IgM, anti-β2-glycoprotein-I IgG/IgM. A single positive does not diagnose APS — the assays shift transiently with pregnancy and thrombosis, so classification demands a repeat positive ≥12 weeks apart. The LAC is a functional clotting assay (dRVVT) and is uninterpretable once a woman is anticoagulated, so draw it before any heparin starts. Persistent positivity + the relevant obstetric morbidity = obstetric APS = a treatable diagnosis.
- Cytogenetics — and this is a real point of guideline divergence. The more informative modern test is karyotyping the products of conception (POC) of a further loss: a sporadic aneuploid result reassures (it explains the loss and points away from a parental cause), whereas a euploid loss raises the index of suspicion for a maternal/uterine factor. Parental peripheral-blood karyotyping detects the ~2–5% with a balanced translocation but has a low yield and high cost, so the current direction is to test the POC first and karyotype the parents selectively — e.g. when POC shows an unbalanced structural rearrangement, or there is a family history.
- Pelvic imaging for uterine anatomy: 3D transvaginal ultrasound is the first-line modern tool and, with saline infusion sonography, reliably distinguishes a septate from a bicornuate uterus (the critical distinction, because only the septum is intracavitary and potentially resectable). MRI is reserved for ambiguous müllerian anomalies. Plain 2D ultrasound under-calls the septum.
- Thyroid: TSH and free T4 to detect overt thyroid disease; TPO antibodies identify the euthyroid-autoimmune group — but note in advance that finding them does not mandate treatment (TABLET, below).
- Targeted, not reflexive, endocrine/metabolic tests: HbA1c/glucose if diabetes is suspected; prolactin if symptomatic; an assessment for PMOS (previously PCOS) where the phenotype fits.
- What you should not routinely order: inherited (hereditary) thrombophilia screening — factor V Leiden, prothrombin gene, protein C/S, antithrombin, MTHFR — is not recommended as part of an RPL work-up (weak association, and now no treatment benefit — ALIFE2). Routine TORCH serology, routine "natural killer cell" testing and the commercial reproductive-immunology panels are not evidence-based and should not be sent.