Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL) is a distressing reproductive problem where a couple suffers repeated miscarriages. For NEET PG, the highest-yield angles are the definition, the causes (especially antiphospholipid antibody syndrome — the most treatable cause), the APAS diagnostic criteria, and the low-dose aspirin + LMWH treatment protocol.

Definition & classification

Recurrent pregnancy loss (recurrent miscarriage / habitual abortion) is classically defined as three or more consecutive spontaneous pregnancy losses before 20 weeks of gestation (or fetal weight < 500 g).

However, definitions differ between bodies — a very common exam trap:

Body	Definition of RPL	Number of losses	Consecutive?
Classical / WHO	3 or more	≥ 3	Yes, consecutive
ASRM (American)	2 or more clinical pregnancies	≥ 2	Need NOT be consecutive
ESHRE (European, 2017)	2 or more	≥ 2	Need not be consecutive; includes non-visualised (biochemical) losses
RCOG	3 or more consecutive	≥ 3	Consecutive

High-yield: The classical NEET PG answer for the definition of RPL is "three or more consecutive abortions before 20 weeks." But know that ASRM/ESHRE now use "two or more" losses to start evaluation — pick based on how the question is worded.

Classification by timing:

• Primary RPL — woman has never had a viable pregnancy (no previous live birth).
• Secondary RPL — recurrent losses occurring after a previous successful (viable) pregnancy.
• Tertiary RPL — multiple losses interspersed with normal pregnancies.

Classification by gestational age:

• Pre-embryonic / embryonic (early, < 10 weeks): usually chromosomal / genetic in origin.
• Fetal (late, > 10 weeks) and second-trimester losses: more often due to antiphospholipid syndrome, cervical insufficiency, uterine anomalies, or thrombophilias.

High-yield: Early losses → think genetic/chromosomal. Late (second trimester) losses → think APAS, cervical incompetence, uterine anomaly. This timing clue is repeatedly tested.

Etiology

Causes of RPL can be grouped into genetic, anatomical, endocrine, immunological, thrombophilic, infective, and unexplained. In nearly 50% of couples no cause is found (unexplained/idiopathic).

1. Genetic / chromosomal (commonest single identifiable cause of early loss)

• Sporadic miscarriage: most are due to fetal aneuploidy (autosomal trisomies — trisomy 16 is the single most common; also 45,X / Turner, triploidy, polyploidy).
• In RPL specifically: the relevant parental cause is a balanced translocation in one parent (≈ 2–5% of couples) — most commonly a balanced reciprocal or Robertsonian translocation.
• A parent with a balanced translocation is phenotypically normal but produces unbalanced gametes → recurrent loss.

High-yield: Parental balanced translocation is the classic structural chromosomal cause of RPL. Investigation = peripheral blood karyotyping of both partners (± karyotyping/microarray of products of conception).

2. Anatomical / uterine (15–20%)

• Congenital Müllerian anomalies: septate uterus is the uterine anomaly most strongly associated with recurrent loss (poorest reproductive outcome). Bicornuate, unicornuate, didelphys also implicated.
• Acquired: submucous fibroids, intrauterine adhesions (Asherman syndrome), endometrial polyps.
• Cervical insufficiency (incompetence): causes painless, second-trimester loss with cervical dilatation and bulging membranes.

High-yield: Septate uterus = worst obstetric outcome among Müllerian anomalies; treatment = hysteroscopic septal resection (metroplasty). Cervical incompetence → mid-trimester painless dilatation → McDonald or Shirodkar cerclage.

3. Endocrine

• Poorly controlled diabetes mellitus and overt thyroid dysfunction (hypo/hyper), thyroid autoimmunity (anti-TPO antibodies).
• PCOS (insulin resistance, hyperandrogenism, raised LH).
• Luteal phase defect / low progesterone, hyperprolactinaemia.

4. Immunological — antiphospholipid antibody syndrome (APAS)

The single most important treatable cause of RPL and the most heavily tested topic. Covered in detail below.

5. Inherited thrombophilias

• Factor V Leiden mutation (commonest inherited thrombophilia), prothrombin G20210A mutation, protein C, protein S, antithrombin deficiency, hyperhomocysteinaemia/MTHFR.
• More associated with later (second-trimester) losses.

6. Infective & environmental

• TORCH group, bacterial vaginosis (especially second-trimester loss), listeria.
• Smoking, alcohol, excess caffeine, obesity, advanced maternal age.

Antiphospholipid antibody syndrome (APAS) — the star topic

APAS is an acquired autoimmune thrombophilia characterised by antiphospholipid antibodies causing arterial/venous thrombosis and adverse pregnancy outcomes. It is the most common treatable cause of RPL and the most frequently asked.

Pathophysiology

Antiphospholipid antibodies are directed against phospholipid-binding plasma proteins, chiefly β2-glycoprotein I and prothrombin. They promote:

• A prothrombotic state → placental thrombosis and infarction → uteroplacental insufficiency.
• Impaired trophoblast invasion and differentiation, complement activation, and inhibition of the protein C pathway.

Net effect → recurrent loss (often late), pre-eclampsia, IUGR, and placental abruption.

Revised Sapporo (Sydney) classification criteria

Diagnosis requires at least ONE clinical plus at least ONE laboratory criterion.

Criterion type	Components
Clinical	(a) Vascular thrombosis — ≥1 arterial, venous, or small-vessel thrombosis. (b) Pregnancy morbidity: • ≥1 unexplained death of a morphologically normal fetus ≥ 10 weeks, OR • ≥1 premature birth < 34 weeks due to eclampsia/severe pre-eclampsia/placental insufficiency, OR • ≥ 3 unexplained consecutive losses < 10 weeks
Laboratory	(1) Lupus anticoagulant (LA) present in plasma; (2) Anticardiolipin antibody (aCL) IgG/IgM in medium–high titre (> 40 GPL/MPL or > 99th percentile); (3) Anti-β2-glycoprotein-I antibody IgG/IgM (> 99th percentile)

High-yield (most-tested fact): A laboratory criterion must be positive on TWO occasions at least 12 WEEKS apart to confirm APAS (avoids labelling transient antibodies). Older texts say "6 weeks apart" — the revised Sydney criteria say 12 weeks.

High-yield: The three antibodies tested in APAS = Lupus Anticoagulant + Anticardiolipin antibody + Anti-β2-glycoprotein-I. Of these, lupus anticoagulant carries the strongest correlation with adverse outcome.

Mnemonic for APAS labs — "LAC-B": Lupus Anticoagulant, antiCardiolipin, anti-Beta-2-glycoprotein-I.

Note on lupus anticoagulant: despite its name, in vivo it causes thrombosis, but in vitro it paradoxically prolongs phospholipid-dependent clotting tests (prolonged aPTT that does NOT correct on mixing study because it is an inhibitor, not a factor deficiency). Confirmed by tests like dilute Russell viper venom time (dRVVT).

High-yield: APAS is a cause of a falsely positive VDRL/RPR (biological false-positive syphilis serology) because the test uses cardiolipin antigen.

Clinical features

• A clear history of repeated miscarriages; ask carefully about gestational age at each loss (early vs late), presence of fetal cardiac activity, and circumstances (painless dilatation suggests cervical incompetence).
• Features pointing to APAS: prior venous/arterial thrombosis, stroke at young age, thrombocytopenia, livedo reticularis, false-positive VDRL, SLE features.
• Features of PCOS (oligomenorrhoea, hirsutism), thyroid disease, or diabetes.
• A late painless mid-trimester loss with cervical dilatation → cervical insufficiency.

Diagnosis & investigations

Evaluation is offered after the relevant number of losses (≥ 2 per ASRM/ESHRE, or ≥ 3 classically). A structured work-up:

Stepwise approach: History & examination → Parental karyotyping (± POC karyotype) → Pelvic USG / saline sonohysterography / hysteroscopy / MRI for uterine anatomy → APAS panel (LA, aCL, anti-β2GPI) repeated ≥ 12 weeks apart → Thrombophilia screen → Endocrine tests (TSH, anti-TPO, HbA1c, prolactin) → if all normal = unexplained RPL.

Suspected cause	Investigation of choice
Genetic	Parental peripheral blood karyotyping (both partners); microarray/karyotype of products of conception
Uterine anatomy	3D ultrasound / saline infusion sonohysterography; hysteroscopy (gold standard for cavity); MRI to differentiate septate vs bicornuate
Cervical insufficiency	Clinical history + serial transvaginal cervical length USG
APAS	Lupus anticoagulant + anticardiolipin + anti-β2-glycoprotein-I, repeated ≥ 12 weeks apart
Inherited thrombophilia	Factor V Leiden, prothrombin G20210A, protein C/S, antithrombin, homocysteine
Endocrine	TSH, anti-TPO, fasting glucose/HbA1c, prolactin; ovarian reserve if indicated

High-yield: Hysteroscopy is the gold standard for evaluating the uterine cavity, but MRI / 3D USG is preferred to distinguish a septate uterus (normal external fundal contour) from a bicornuate uterus (cleft fundal contour) — a distinction that changes management.

Management

Management is cause-specific. Treat the identified cause; for unexplained RPL, supportive care and reassurance significantly improve live-birth rates.

APAS — the protocol you MUST know

• Low-dose aspirin (75–150 mg/day) started preconception/early pregnancy PLUS prophylactic LMWH (e.g., enoxaparin) started once a viable intrauterine pregnancy is confirmed.
• This aspirin + heparin combination raises live-birth rates to ~70–80%.
• LMWH is preferred over unfractionated heparin (better safety, less heparin-induced thrombocytopenia and osteoporosis).
• Continue aspirin + LMWH through pregnancy; thromboprophylaxis is extended into the postpartum period (high VTE risk), especially with prior thrombosis.
• Warfarin is teratogenic (fetal warfarin syndrome) and is avoided in pregnancy; heparins do not cross the placenta.

High-yield (drug of choice): APAS in pregnancy = Low-dose aspirin + LMWH. Steroids are NOT used for obstetric APAS (no benefit, more harm). This aspirin+heparin combination is the classic single-best-answer.

Mnemonic — "APAS needs A PAH": Aspirin (low dose) Plus Anticoagulant Heparin (LMWH).

Cause-specific therapy

Cause	Management
Parental balanced translocation	Genetic counselling; option of PGT-SR (preimplantation genetic testing for structural rearrangements) with IVF, or donor gametes
Septate uterus	Hysteroscopic septal resection (metroplasty)
Submucous fibroid / polyp / adhesions	Hysteroscopic myomectomy / polypectomy / adhesiolysis
Cervical insufficiency	Cervical cerclage (McDonald or Shirodkar), usually 12–14 weeks; ± vaginal progesterone
Inherited thrombophilia + prior loss	LMWH ± low-dose aspirin (individualised)
Thyroid disease / autoimmunity	Levothyroxine; treat overt dysfunction; consider in raised anti-TPO
Hyperprolactinaemia	Cabergoline / bromocriptine
Luteal phase / unexplained	Progesterone supplementation (esp. if prior unexplained early losses — PROMISE/PRISM data support vaginal progesterone in women with bleeding + prior losses)
Unexplained RPL	Reassurance + supportive antenatal care ("tender loving care"); folic acid; lifestyle optimisation

High-yield: Empirical vaginal progesterone improves live births specifically in women with early pregnancy bleeding AND a history of ≥ 1 previous miscarriage (PRISM trial). Routine progesterone for all RPL is not recommended.

Complications

• Recurrent pregnancy loss itself; late losses can present with bleeding, retained products, infection.
• APAS carries risk of maternal thrombosis, pre-eclampsia, IUGR, placental abruption, preterm birth, stillbirth, and rarely catastrophic APAS (multi-organ thrombosis).
• Anticoagulation complications: bleeding, HIT and osteoporosis (more with UFH), bruising.
• Psychological burden: anxiety, depression, grief — counselling is integral.

Key differentials / things to distinguish

• Sporadic miscarriage vs RPL: a single or two non-consecutive losses are common and usually aneuploidy-related; RPL implies a pattern warranting work-up.
• Cervical insufficiency vs preterm labour: insufficiency = painless dilatation, mid-trimester; preterm labour = painful contractions.
• Septate vs bicornuate uterus: external fundal contour (smooth = septate; clefted = bicornuate) — guides surgery vs observation.
• APAS vs inherited thrombophilia: APAS is acquired/autoimmune (antibody-mediated, treat with aspirin+LMWH); inherited thrombophilias are genetic.
• Ectopic / molar pregnancy must be excluded in any early pregnancy loss presentation.

Recently asked / exam angle

• Definition of RPL — "three or more consecutive abortions before 20 weeks" (classical) vs "two or more" (ASRM/ESHRE).
• Most common identifiable / most treatable cause = APAS — very frequent single-best-answer.
• APAS antibodies — Lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein-I; must be repeated 12 weeks apart.
• APAS treatment = low-dose aspirin + LMWH (NOT steroids).
• Commonest chromosomal abnormality in sporadic miscarriage = autosomal trisomy (trisomy 16); in RPL couples = parental balanced translocation.
• Uterine anomaly with worst outcome = septate uterus; treat by hysteroscopic resection.
• Lupus anticoagulant prolongs aPTT, does not correct on mixing, and causes false-positive VDRL.
• Investigation of genetic cause = karyotyping of both partners.
• Cervical incompetence = painless mid-trimester loss → cerclage.

Rapid revision

1. RPL = ≥ 3 consecutive losses < 20 weeks (classical); ASRM/ESHRE use ≥ 2.
2. ~50% of RPL is unexplained; APAS is the most common treatable cause.
3. Early losses → genetic/chromosomal; late (2nd trimester) losses → APAS, cervical incompetence, uterine anomaly.
4. Commonest cause of sporadic miscarriage = autosomal trisomy (trisomy 16).
5. RPL genetic cause = parental balanced translocation → karyotype both partners.
6. APAS labs = Lupus anticoagulant + anticardiolipin + anti-β2-glycoprotein-I, repeated ≥ 12 weeks apart (revised Sydney/Sapporo).
7. APAS treatment = low-dose aspirin + LMWH; steroids are NOT used.
8. Lupus anticoagulant → in vitro prolongs aPTT, no correction on mixing, false-positive VDRL, but in vivo causes thrombosis.
9. Septate uterus = worst reproductive outcome → hysteroscopic metroplasty; MRI/3D USG differentiates from bicornuate.
10. Cervical insufficiency = painless mid-trimester dilatation → McDonald/Shirodkar cerclage.
11. Factor V Leiden = commonest inherited thrombophilia; warfarin is teratogenic, heparin is safe in pregnancy.
12. Vaginal progesterone helps women with early bleeding + prior miscarriage (PRISM trial); supportive care improves outcomes in unexplained RPL.