Overview
Recurrent Miscarriage
1. Clinical Overview
Summary
Recurrent Miscarriage (RM), also known as Recurrent Pregnancy Loss (RPL), is defined as the occurrence of three or more consecutive spontaneous pregnancy losses before 24 weeks gestation (RCOG definition). The European Society of Human Reproduction and Embryology (ESHRE) defines it as two or more losses. It affects approximately 1% of couples trying to conceive. Despite thorough investigation, in 50% of cases, no cause is identified (Unexplained/Idiopathic). Known causes include Antiphospholipid Syndrome (APS) – the most treatable cause – parental chromosomal abnormalities (Balanced Translocations), uterine anomalies (Septum), and endocrine factors (Thyroid disease, Uncontrolled Diabetes). The key message for patients is that even after three miscarriages with no identified cause, the prognosis for the next pregnancy is good (60-75% success) with supportive care. Treatment is cause-specific: Aspirin + LMWH for APS, Progesterone support (PRISM trial), and genetic counselling for translocations. [1,2,3]
Clinical Pearls
"Three Strikes = Investigate": In UK practice, investigation typically starts after 3 consecutive losses (RCOG). Some start after 2 (ESHRE).
APS is the One NOT to Miss: Antiphospholipid Syndrome is TREATABLE. Aspirin + LMWH increases live birth rate from ~10% to ~70%.
"Most Couples Succeed Next Time": Even unexplained RM has 60-75% live birth rate in subsequent pregnancies with supportive care alone.
Progesterone (PRISM Trial): Vaginal progesterone may benefit women with bleeding in early pregnancy and a history of miscarriage.
2. Epidemiology
Demographics
| Factor | Notes |
|---|---|
| Prevalence | RM affects ~1% of couples trying to conceive. |
| Sporadic Miscarriage | Affects ~15-20% of all recognised pregnancies. |
| Risk Increase with Age | Maternal age >35 significantly increases miscarriage risk (Oocyte aneuploidy). |
Definitions
| Term | Definition |
|---|---|
| Miscarriage | Spontaneous pregnancy loss less than 24 weeks gestation. |
| Early Miscarriage | Loss less than 12 weeks (First trimester). Most common. |
| Late Miscarriage | Loss 12-24 weeks (Second trimester). Consider cervical incompetence/Anatomical. |
| Primary RM | No previous live births. |
| Secondary RM | At least one previous live birth, followed by recurrent losses. |
3. Aetiology
Known Causes (~50% of Cases)
| Cause | Prevalence | Notes |
|---|---|---|
| Antiphospholipid Syndrome (APS) | 15% | Autoimmune. Causes placental thrombosis. TREATABLE (Aspirin + LMWH). |
| Parental Chromosomal Abnormality | 3-5% of couples | Balanced translocation in one parent → Unbalanced embryos. Karyotype both parents. Refer to Genetics. |
| Uterine Anomalies | 10-15% | Septate uterus (Most common correctable anomaly), Fibroids (Submucosal), Asherman's Syndrome. |
| Endocrine Factors | 5-10% | Poorly controlled Diabetes, Thyroid disease (Hyper/Hypo), PCOS (Controversial). |
| Thrombophilia (Inherited) | Controversial | Factor V Leiden, Prothrombin G20210A. Routine screening NOT recommended by RCOG (No proven treatment benefit). |
Unexplained/Idiopathic (~50% of Cases)
- No identifiable cause despite thorough investigation.
- Prognosis is GOOD (60-75% live birth with supportive care).
- "Tender Loving Care" (TLC) approach with reassurance and early scanning improves outcomes.
4. Pathophysiology
Antiphospholipid Syndrome (APS)
- Autoantibodies: Anticardiolipin Ab, Anti-β2 Glycoprotein-1 Ab, Lupus Anticoagulant.
- Placental Thrombosis: Antibodies cause thrombosis in placental vessels.
- Placental Insufficiency: Reduced blood flow → Fetal loss.
- Treatment Rationale: Anticoagulation (LMWH) prevents thrombosis. Aspirin has anti-inflammatory/antiplatelet effects.
Chromosomal Abnormality (Parental)
- Balanced Translocation: Parent has rearranged chromosomes but normal total genetic material (Hence healthy).
- Gamete Formation: Meiotic segregation can create unbalanced gametes with missing/extra chromosomal segments.
- Unbalanced Embryo: Results in miscarriage or congenital abnormality.
- Options: Genetic counselling, Natural conception with prenatal diagnosis (CVS/Amnio), PGT-SR with IVF.
Uterine Anomalies
- Septate Uterus: Fibrous septum reduces implantation success and blood supply to embryo.
- Submucosal Fibroids: Distort endometrial cavity.
- Asherman's Syndrome: Intrauterine adhesions (Post D&C) reduce implantation surface.
5. Clinical Presentation
History Questions
| Question | Rationale |
|---|---|
| Number of Losses | ≥3 consecutive = RM. |
| Gestation at Each Loss | Early (less than 12w) = Chromosomal/APS. Late (>12w) = Anatomical/Cervical. |
| Karyotype of Products | Recurrent normal karyotype losses suggest maternal/placental cause. |
| Previous Live Births | Primary vs Secondary RM. |
| Previous DVT/PE/Stroke | Suggests APS or Thrombophilia. |
| Autoimmune History | SLE, APS, Thyroid disease. |
| Family History | Miscarriages, Chromosomal abnormalities. |
| LMP / Cycle Length | Confirm dating. |
Examination
| Finding | Notes |
|---|---|
| General Examination | Thyroid goitre, SLE rash, Signs of PCOS (Hirsutism, Acne). |
| Pelvic Examination | Uterine size/shape, Masses (Fibroids), Cervical competence (Often assessed later via USS). |
6. Investigations
Antiphospholipid Antibody Testing
| Test | Notes |
|---|---|
| Lupus Anticoagulant (LA) | Functional clotting assay. |
| Anticardiolipin Antibodies (IgG/IgM) | Medium-High titres significant. |
| Anti-β2 Glycoprotein-1 Antibodies (IgG/IgM) | Part of APS diagnostic criteria. |
| Positive Criteria | Must be positive TWICE, at least 12 weeks apart, to confirm APS. |
Parental Karyotyping
| Test | Notes |
|---|---|
| Peripheral Blood Karyotype (Both Parents) | Identifies balanced translocations, Inversions, Robertsonian translocations. |
| If Abnormal | Refer to Clinical Genetics for counselling and PGT options. |
Thrombophilia Screen
| Test | Notes |
|---|---|
| NOT Routinely Recommended (RCOG) | No proven benefit of treatment for inherited thrombophilias in RM. |
| May Consider If: | Personal/Family history of VTE, Stillbirth, Severe early-onset pre-eclampsia. |
| Includes: | Factor V Leiden, Prothrombin G20210A, Protein C/S, Antithrombin III. |
Uterine Assessment
| Modality | Findings |
|---|---|
| Transvaginal Ultrasound (TVUS) | Basic uterine anatomy. |
| 3D Ultrasound / MRI Pelvis | Best for Mullerian anomalies (Septate vs Bicornuate). |
| Saline Infusion Sonography (SIS) | Assesses cavity (Polyps, Fibroids, Septum). |
| Hysteroscopy | Direct visualisation and potential treatment (Septal resection). |
Other Investigations
| Test | Rationale |
|---|---|
| Thyroid Function Tests (TSH) | Uncontrolled thyroid disease = Miscarriage risk. |
| HbA1c | Poorly controlled diabetes. |
| Fasting Glucose | Diabetes screening. |
7. Management
Management Algorithm
RECURRENT MISCARRIAGE INVESTIGATION
(≥3 consecutive losses OR ≥2 if ESHRE criteria)
↓
INVESTIGATIONS
- Antiphospholipid Antibodies (LA, aCL, anti-β2GP1) x2, 12 weeks apart
- Parental Karyotype (Both partners)
- Pelvic USS / 3D USS / MRI (Uterine anatomy)
- TFTs, HbA1c
- (Thrombophilia screen NOT routine)
↓
CLASSIFY BY CAUSE
┌────────────────┴────────────────────────────────┐
CAUSE IDENTIFIED UNEXPLAINED (50%)
↓ ↓
TREAT CAUSE SUPPORTIVE CARE
Cause-Specific Treatment
| Cause | Treatment |
|---|---|
| Antiphospholipid Syndrome (APS) | Low-Dose Aspirin 75mg OD (From positive test until delivery) + LMWH (Enoxaparin/Dalteparin) subcutaneously daily (From positive pregnancy test until delivery). Increases live birth from ~10% to ~70%. |
| Uterine Septum | Hysteroscopic Septal Resection (Metroplasty). Improves outcomes. |
| Submucosal Fibroids | Hysteroscopic Myomectomy. |
| Balanced Translocation | Genetic Counselling. Options: Natural conception with CVS/Amnio for diagnosis, OR IVF + PGT-SR (Preimplantation Genetic Testing for Structural Rearrangements) to select balanced/normal embryos. |
| Thyroid Disease | Optimise thyroid function (TSH less than 2.5 mIU/L in pregnancy). |
| Diabetes | Optimise glycaemic control before conception. |
Unexplained Recurrent Miscarriage
| Intervention | Notes |
|---|---|
| Reassurance | 60-75% will have successful pregnancy with supportive care ALONE. |
| Supportive Care ("TLC") | Early pregnancy unit access, Early viability scans, Dedicated clinic. Shown to improve outcomes. |
| Progesterone (PRISM Trial) | Vaginal Micronized Progesterone 400mg BD from positive test until 16 weeks. Evidence suggests benefit in women with bleeding in early pregnancy and prior miscarriage. Now recommended by NICE. |
| Folic Acid | Standard preconception supplementation (400mcg OD). |
| Lifestyle | Avoid smoking, Limit alcohol, Healthy weight. |
What NOT to Do
| Intervention | Notes |
|---|---|
| Immunotherapy (IVIg, Steroids, Intralipids) | NOT recommended. No proven benefit and potential harm. |
| hCG Injections | No evidence of benefit. |
| Routine Empirical LMWH (Without APS) | No proven benefit for unexplained RM or inherited thrombophilia. |
8. Complications
| Complication | Notes |
|---|---|
| Psychological Trauma | Grief, Anxiety, Depression. Offer psychological support. |
| Relationship Strain | Couples counselling may help. |
| Recurrent Treatment Failure | May need specialist tertiary referral. |
| Complications of Pregnancy if Successful | APS pregnancies need monitoring for Pre-eclampsia, Growth restriction. |
9. Prognosis and Outcomes
| Scenario | Live Birth Rate |
|---|---|
| Unexplained RM (Supportive Care) | 60-75% |
| APS (Aspirin + LMWH) | 70-80% (vs ~10% untreated) |
| Parental Translocation (Natural Conception) | Variable (Depends on type). Many couples have successful pregnancies. |
| After 1 Miscarriage | 80-85% success next time. |
| After 2 Miscarriages | 75% success next time. |
| After 3 Miscarriages | 60-75% success next time. |
10. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Investigation and Treatment of Couples with RM | RCOG GTG 17 (2011) | Investigation after 3 losses. APS testing. Thrombophilia not routine. |
| Recurrent Pregnancy Loss | ESHRE (2022) | Investigate after 2 losses. Progesterone in early pregnancy with bleeding. |
| Ectopic Pregnancy and Miscarriage | NICE NG126 (2021) | Progesterone support for those with bleeding and prior miscarriage. |
Landmark Trials
| Trial | Findings |
|---|---|
| PRISM (2019) | Vaginal progesterone in women with bleeding in early pregnancy + Prior miscarriage = Increased live birth rate. Benefit greatest with ≥3 prior losses. |
| PROMISE (2015) | Progesterone did NOT improve outcomes in idiopathic RM WITHOUT current bleeding. |
| ALIFE2 (2023) | LMWH does NOT improve live birth rate in women with inherited thrombophilia and unexplained RM. |
11. Patient and Layperson Explanation
Why did I have a miscarriage?
Most early miscarriages happen because the embryo had a random genetic abnormality ("Nature's quality control"). This is usually a one-off event and NOT caused by anything you did – not stress, lifting, exercise, or that glass of wine before you knew.
Why do I keep miscarrying?
We don't always find a cause, even after tests. But sometimes we find treatable problems:
- Sticky blood (Antiphospholipid Syndrome): Treated with blood-thinning injections.
- Genetic rearrangement in a parent: May need specialist genetic advice.
- Uterine shape problems: Sometimes fixable with keyhole surgery.
Will I ever have a baby?
YES. Even after three miscarriages with no cause found, about 3 out of 4 women go on to have a healthy baby next time with supportive care alone.
What treatment can you offer?
- If we find a cause, we treat it specifically.
- If we don't find a cause, supportive care (Early scans, Reassurance, clinic access) helps. Progesterone pessaries may be offered if you have bleeding in early pregnancy.
Is there anything I should avoid?
- Smoking (Increases miscarriage risk).
- Excessive alcohol.
- We recommend taking folic acid before and during early pregnancy.
12. References
Primary Sources
- Royal College of Obstetricians and Gynaecologists. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage (GTG 17). 2011.
- Coomarasamy A, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy (PRISM). N Engl J Med. 2019;380(19):1815-1824. PMID: 31067371.
- ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004. PMID: 31486805.
13. Examination Focus
Common Exam Questions
- Definition: "How many losses define recurrent miscarriage (RCOG)?"
- Answer: ≥3 consecutive first-trimester losses.
- Most Treatable Cause: "What is the most important treatable cause of RM?"
- Answer: Antiphospholipid Syndrome (APS).
- APS Treatment: "What is the treatment for APS in pregnancy?"
- Answer: Low-Dose Aspirin 75mg OD + LMWH (From positive pregnancy test until delivery).
- Unexplained RM Prognosis: "What is the live birth rate with supportive care alone?"
- Answer: 60-75%.
Viva Points
- Lupus Anticoagulant is a Misnomer: It is PRO-thrombotic (Causes clotting), not anticoagulant.
- PRISM vs PROMISE: Progesterone helps with BLEEDING in early pregnancy + Prior loss (PRISM). Does NOT help idiopathic RM without bleeding (PROMISE).
- Thrombophilia Screening: NOT routine (ALIFE2 trial – No benefit of LMWH in inherited thrombophilia).
- Genetic Counselling: Essential for parental balanced translocation. Discuss PGT options.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.