Anatomical Causes of Recurrent Pregnancy Loss (RPL)

Overview of Uterine Development

1. Failure of one or more Mullerian ducts to develop
2. Abnormal fusion of the ducts
3. Failure of uterine septal absorption

A. Congenital Anatomical Abnormalities

1. Uterine Septum (Septate Uterus) - Most Common and Strongest Association

• Results from incomplete resorption of the median septum after Mullerian duct fusion
• Carries the strongest association with RPL of all congenital anomalies
• Miscarriage risk may be as high as 60% in women with an intrauterine septum
• Losses most frequently occur in the second trimester, though first-trimester losses also occur
• Mechanism: if an embryo implants on the poorly vascularized fibromuscular septum, abnormal placentation results
• 3D ultrasound is the preferred diagnostic modality (distinguishes septate from bicornuate uterus); hysterosalpingography (HSG) and sonohysterography are also used
• Treatment: Hysteroscopic metroplasty; success rates of 60-90% (some series >90%) for subsequent live birth after surgical correction

2. Bicornuate Uterus

• Results from incomplete fusion of the two Mullerian ducts (defect of lateral fusion)
• Produces two uterine horns with a single cervix (partial) or two cervices (complete)
• Associated with second-trimester losses and preterm labor; weaker association with first-trimester RPL than septate uterus
• Diagnosis: 3D ultrasound or MRI (concave fundal contour on external surface)
• Surgical correction: Strassman metroplasty

3. Unicornuate Uterus

• Results from failure of one Mullerian duct to develop fully
• Only one functional uterine horn forms
• Associated with RPL, preterm labor, malpresentation, and intrauterine growth restriction
• May have a rudimentary (non-communicating or communicating) contralateral horn, which can itself be the site of ectopic pregnancy

4. Didelphys Uterus (Uterus Didelphys)

• Complete failure of Mullerian duct fusion
• Two separate uterine bodies, two cervices, and often a longitudinal vaginal septum
• Paradoxically, carries a better reproductive prognosis than other anomalies
• Associated with late-trimester losses and preterm labor

5. Arcuate Uterus

• Minimal midline indentation of the uterine fundus; considered a normal variant by most authorities
• Reproductive outcomes are similar to women with a normal uterine cavity
• Studies that exclude arcuate uterus show lower rates of Mullerian anomalies in RPL patients (3-7% vs. 6.3-16.7%) - Creasy & Resnik, p. 981

6. DES (Diethylstilbestrol) Exposure - Congenital

• Prenatal exposure to maternally ingested DES causes complex congenital uterine, cervical, and vaginal changes
• The most common anomaly is uterine hypoplasia ("T-shaped uterus")
• Contributes to first- and second-trimester losses, cervical incompetence, and premature labor
• Less common since DES was withdrawn from use (1971 in the USA), but daughters of exposed women remain at risk

7. Congenital Cervical Insufficiency

• Congenital weakness of the internal cervical os leads to painless dilation of the cervix in the second trimester
• Presents as characteristic second-trimester losses
• Can be primary (congenital) or secondary to prior cervical trauma
• Treatment: Prophylactic cervical cerclage (McDonald or Shirodkar technique)

8. Congenital Anomalies of the Uterine Arteries

• Aberrant arterial supply can adversely alter blood flow to the implanted blastocyst and developing placenta, contributing to early pregnancy loss - Berek & Novak's Gynecology, p. 1803

Molecular/Genetic Basis of Congenital Anomalies

B. Acquired Anatomical Abnormalities

1. Intrauterine Adhesions (Asherman Syndrome)

• Fibrotic bands and synechiae within the uterine cavity, most commonly following curettage after pregnancy (postabortal, postpartum), intrauterine infection, or surgery
• Endometrium overlying synechiae is inadequately vascularized, impairing implantation and placentation
• Spectrum from minor adhesions to complete obliteration of the cavity
• Diagnosis: Hysteroscopy (gold standard), HSG, sonohysterography
• Treatment: Hysteroscopic adhesiolysis

2. Uterine Leiomyomas (Fibroids)

3. Endometrial Polyps

• Focal overgrowths of endometrial glands and stroma
• Hypothetically impair implantation by occupying or distorting the endometrial cavity
• Association with RPL is controversial; evidence is limited
• Diagnosis: Sonohysterography, hysteroscopy
• Treatment: Hysteroscopic polypectomy

4. Chronic Endometritis

• Histopathologic finding of plasma cells in the endometrial stroma
• Identified by CD138 (syndecan-1) immunohistochemistry or H&E staining
• Possible (though controversial) cause of RPL
• Treated with antibiotics (most commonly doxycycline)

C. Cervical Factors

Cervical Incompetence (Cervical Insufficiency)

• Structural weakness of the cervix leading to painless, progressive dilation typically at 14-24 weeks gestation
• Classic presentation: painless second-trimester loss without preceding contractions
• Causes include prior cervical trauma (LEEP, cone biopsy, forceful dilation), congenital weakness, and DES exposure
• Diagnosis: Clinical (history-based); transvaginal ultrasound showing short cervix (<25 mm) or funneling
• Treatment: Cerclage (history-indicated, ultrasound-indicated, or exam-indicated)

D. Diagnostic Evaluation (ASRM/ESHRE Guidelines)

E. Prognosis After Correction

Summary Table

• Berek & Novak's Gynecology, Ch. 33 (Recurrent Pregnancy Loss), pp. 1801-1803
• Creasy & Resnik's Maternal-Fetal Medicine, Ch. 41, pp. 981-982

1. Definition

2. Etiology - Overview

3. Etiology - Detailed

A. Genetic Factors

Fetal Aneuploidy (Most Common Cause of Individual Losses)

• At least 60% of preclinical and early clinical losses are from de novo fetal aneuploidy
• In women ≥35 years with RPL, chromosomal abnormalities account for >80% of losses
• Most common: autosomal trisomy (60-70%), monosomy X (~10-20%), polyploidy (~10-20%)
• Modern chromosomal microarray analysis (CMA) finds genetic abnormalities in 53.7% of miscarriage tissue samples
• Anembryonic pregnancies (blighted ova) are the typical presentation
• De novo aneuploidy is a confounding factor in RPL research - must be documented

Parental Chromosomal Rearrangements (3-5% of RPL)

• Types: balanced reciprocal translocations (most common), Robertsonian translocations, inversions, insertions, mosaicism
• Diagnosis: Metaphase karyotype with G-banding for both partners (NOT microarray - cannot detect balanced rearrangements)
• Robertsonian translocation: fusion of long arms of acrocentric chromosomes (13-15); unbalanced forms cause trisomies/monosomies → miscarriage
• ESHRE: parental karyotyping not routinely recommended unless history of genetically abnormal fetus/newborn; ASRM recommends it
• All patients with balanced rearrangements should receive genetic counseling

B. Anatomic Abnormalities (10-12% of RPL)

Congenital Mullerian Anomalies

Acquired Uterine Anomalies

• Asherman syndrome (intrauterine adhesions): Post-curettage/infection; poorly vascularized endometrium over synechiae impairs placentation
• Submucosal fibroids: Distort cavity; strongest fibroid-RPL link; evidence controversial (ASRM, ESHRE)
• Intramural fibroids ≥5 cm: Associated with pregnancy loss; removal may improve outcomes
• Endometrial polyps: Controversial association
• Chronic endometritis: Plasma cells in stroma (CD138+); possible RPL cause

Cervical Factors

• Cervical insufficiency: Painless, progressive dilation at 14-24 weeks; 2nd trimester loss
• Causes: congenital weakness, prior cervical trauma (LEEP, cone biopsy), DES exposure

C. Immunologic Factors

Antiphospholipid Syndrome (APS) - ~15% of RPL; only proven immune cause

• ≥3 unexplained consecutive losses before 10th week
• ≥1 unexplained fetal death of morphologically normal fetus ≥10 weeks
• ≥1 premature birth of morphologically normal neonate <34 weeks from placental insufficiency/preeclampsia/eclampsia

• Lupus anticoagulant (LA)
• Anticardiolipin (aCL) IgG and/or IgM
• Anti-beta2-glycoprotein I (aβ2GPI) IgG and/or IgM

Cellular Immune Mechanisms (Under Investigation)

• TH1/TH2 imbalance: Successful implantation requires a TH2-dominant environment; shift toward TH1 inflammatory responses at the maternal-fetal interface may cause RPL
• Elevated TNF-α in early pregnancy correlates with RPL
• NK cell dysregulation: Investigated but not proven causative
• MHC class II genotypes may influence susceptibility
• Testing for TH1/TH2 cytokine dysregulation and NK cells in peripheral blood: NOT recommended (unproven clinical benefit)

D. Endocrine Abnormalities

E. Thrombophilias (Inherited)

• Factor V Leiden (FVL): OR 2.4 for RPL; OR 10.7 for ≥2 second/third trimester losses; heterozygous FVL alone may not significantly increase first-trimester loss
• Prothrombin G20210A: Possible weak association
• MTHFR mutations (C677T, A1298C): Most experts now consider NOT associated with RPL
• Protein C, S, antithrombin deficiencies: Insufficient data

F. Male Factors

• Standard semen analysis parameters (count, motility, morphology) do NOT predict RPL
• Sperm DNA fragmentation: Increased fragmentation index correlates with RPL; 40% of men with normal semen analysis but partner RPL had sperm aneuploidy (by FISH)
• Mechanism: Likely contributes to embryo aneuploidy
• No established role in routine evaluation yet; more research needed

G. Infection

• Certain uterine infections (mycoplasma, ureaplasma, chlamydia) may contribute
• No single infectious agent is consistently proven to cause RPL
• Cervical cultures may be considered but not standard

H. Environmental and Lifestyle Factors

4. Preconception Evaluation

Recommended Testing (ASRM/ESHRE Guidelines)

Uterine Imaging Options

• 3D transvaginal ultrasound - preferred (can distinguish septate from bicornuate); noninvasive
• Sonohysterography (SIS) - best for polyps and adhesions
• Hysterosalpingography (HSG) - assesses tubal patency and cavity
• MRI - complex anomalies; only if 3D USS unavailable per ESHRE
• Hysteroscopy - gold standard diagnostic and therapeutic; proceeds after imaging suggests correctable anomaly

Tests with Unproven Utility (Under Investigation)

• Ovarian reserve (day-3 FSH, estradiol, AMH) - gaining support
• Anti-thyroid peroxidase antibodies (rapidly gaining support)
• Endometrial biopsy for chronic endometritis

Tests NOT Recommended

• Thrombophilia panel (FVL, prothrombin mutation, protein C/S, antithrombin, MTHFR, homocysteine) - unless personal/family VTE history
• TH1/TH2 cytokine testing
• NK cell testing (peripheral blood or endometrial)
• Antinuclear antibodies (ANA)

5. Management

A. Genetic Abnormalities

• Parental balanced translocation: Genetic counseling + options:
  • Natural conception (expectant - still high chance of live birth)
  • PGT-SR (preimplantation genetic testing for structural rearrangements) via IVF - selects embryos with balanced/normal chromosomes; reduces miscarriage rate but still investigational for some indications
  • Donor gametes
• De novo aneuploidy: Expectant - favorable overall prognosis

B. Anatomic Anomalies

• Uterine septum: Hysteroscopic metroplasty - live birth rate improves from 61.5% → 81.3% with surgery (though no RCT; Cochrane found no randomized trials of metroplasty vs expectant management)
• Asherman syndrome: Hysteroscopic adhesiolysis - 71% live birth rate post-lysis
• Submucosal fibroids: Hysteroscopic myomectomy; significant reduction in subsequent miscarriage in one study
• Cervical insufficiency: Prophylactic cerclage (McDonald or Shirodkar); history-indicated, ultrasound-indicated, or exam-indicated

C. APS - The Only Proven Immune/Thrombophilic Treatment

• Low-dose aspirin (LDA) 81 mg/day + Low molecular weight heparin (LMWH) (e.g., enoxaparin 40 mg SC daily) OR unfractionated heparin (UFH), started with positive pregnancy test, continued through pregnancy
• Live birth rate with treatment: 70-90% (vs ~30% without treatment in some series)
• Aspirin alone is NOT effective for APS-related RPL

• Anticoagulation is based on individualized VTE risk, NOT miscarriage prevention (no RCT evidence supports anticoagulation to prevent miscarriage in non-APS thrombophilia)

D. Endocrine Management

• Thyroid disease: Levothyroxine to achieve trimester-specific TSH targets
• Hyperprolactinemia: Bromocriptine (dopamine agonist) - 30% increase in live birth rate
• PCOS/Insulin resistance: Metformin may be beneficial in insulin-resistant RPL women, but insufficient evidence for routine use
• Luteal phase defect: Progesterone supplementation remains controversial:
  • Cochrane 2018: Possible reduction in miscarriage (RR 0.73)
  • Large RCT (PRISM-type): Treatment with vaginal progesterone at positive pregnancy test did NOT improve outcomes in all RPL women
  • Current evidence supports: Vaginal progesterone 400 mg twice daily in women with RPL + first-trimester bleeding in the current pregnancy (PROMISE trial reanalysis)

E. Progesterone Supplementation - Nuanced Position

• Vaginal micronized progesterone (Utrogestan) 400 mg twice daily or dydrogesterone 10 mg twice daily
• Most benefit: Women with RPL + first-trimester vaginal bleeding in current pregnancy
• NOT shown to benefit all RPL women as routine supplementation
• Earlier start (luteal phase) may be more beneficial - still under study

F. Immunologic Treatments

G. Anticoagulation for Non-APS

• Large RCTs show no benefit of aspirin alone or aspirin + heparin in unexplained RPL
• Aspirin in early pregnancy may even increase isolated spontaneous loss risk (conflicting data)

H. Lifestyle Modifications (All RPL patients)

• Smoking cessation (complete)
• Abstinence from alcohol during conception and pregnancy
• Avoid illicit substances
• Achieve healthy BMI (both underweight and obesity increase risk)
• Limit caffeine <200 mg/day
• Folic acid supplementation (at least 0.4-1.0 mg/day)

I. Psychological Support

• Risk of major depression is >2-fold increased after pregnancy loss
• Empathetic communication; acknowledge suffering
• Refer to support groups and counselors
• Self-help: meditation, yoga, exercise, biofeedback
• Remind patients that the majority will achieve a live birth

6. Postconception Management (Once Pregnant)

• Serial serum β-hCG monitoring
• Early transvaginal ultrasound (documentation of fetal cardiac activity = prognostic; live birth rate ~77% after cardiac activity confirmed at 5-6 weeks in unexplained RPL)
• Chromosome analysis of products of conception from any subsequent loss (chromosomal microarray preferred)
• Psychological support throughout

7. Prognosis

8. Unexplained RPL (~50% of couples)

• No identifiable cause found despite full workup
• Most likely reflects high background rate of de novo aneuploidy
• Management: Reassurance, supportive monitoring, lifestyle optimization, and psychological support
• No proven pharmacological intervention improves outcomes over placebo in well-designed RCTs
• Tender loving care (TLC) - supportive early pregnancy monitoring - has been shown to improve live birth rates in some studies (possibly up to 80% in supportive care clinics)

• Berek & Novak's Gynecology, Ch. 33 (Recurrent Pregnancy Loss), pp. 1791-1835
• Creasy & Resnik's Maternal-Fetal Medicine, Ch. 41, pp. 978-988
• Australasian RPL Clinical Management Guideline 2024 Part I (PMID 38934264)
• Australasian RPL Clinical Management Guideline 2024 Part II (PMID 38934293)
• SOGC Guideline No. 464: RPL 2025 (PMID 41176277)

Antiphospholipid Antibody (aPL) Positive - Diagnosis & Management

1. What Counts as "aPL Positive"?

2. Does aPL Positivity = Antiphospholipid Syndrome (APS)?

• ≥3 unexplained consecutive losses before 10 weeks gestation
• ≥1 unexplained death of a morphologically normal fetus ≥10 weeks gestation
• ≥1 premature birth before 34 weeks due to preeclampsia, eclampsia, or placental insufficiency

• Prior arterial or venous thrombosis

3. Management by Risk Category

Key practical points:

• LDA alone is NOT sufficient for confirmed obstetric or thrombotic APS - it must be combined with heparin/LMWH
• Heparin/LMWH is generally started once pregnancy is confirmed and continued throughout gestation
• Anticoagulation continues at least 6 weeks postpartum given ongoing thrombotic risk in the puerperium
• With appropriate treatment, live birth rates of 50-90% have been reported (compared to much lower rates untreated)

4. Why aPL Matters Beyond Miscarriage

• Placental insufficiency
• Oligohydramnios
• Fetal growth restriction (IUGR)
• Fetal death
• Preeclampsia (often early-onset/severe)
• Maternal thrombosis (arterial or venous)

5. If Standard Treatment Fails (Refractory APS)

• Hydroxychloroquine - emerging evidence for benefit in improving outcomes, though not yet confirmed in prospective RCTs
• IVIg, corticosteroids, and plasmapheresis have been proposed but are not recommended by ACR guidelines due to insufficient evidence and side-effect burden
• These refractory/high-risk cases should be managed jointly with maternal-fetal medicine, hematology, and rheumatology

6. If aPL Is Positive But Doesn't Meet Criteria

7. Bottom Line - What to Ask Next

Management Plan for This Patient

• Low-dose aspirin (81 mg/day) - start as soon as pregnancy confirmed (ideally preconception or very early)
• PLUS prophylactic-dose LMWH (e.g., enoxaparin 40 mg subcutaneously once daily) - started once intrauterine pregnancy is confirmed
• Aspirin alone is not adequate for this category - the combination is what improves live birth rates (70-90% reported with treatment vs much lower untreated)

• Serial growth ultrasounds (risk of fetal growth restriction from placental insufficiency)
• Umbilical artery Doppler studies, especially third trimester
• Close blood pressure surveillance and preeclampsia screening (aPL carries elevated preeclampsia risk, often early-onset)
• Early confirmation of fetal cardiac activity - reassuring prognostic sign (studies show ~77-86% of aPL-positive RPL patients who reach fetal cardiac activity on ultrasound go on to have that pregnancy continue past the point of prior losses)

• Continue LDA + prophylactic LMWH for at least 6 weeks after delivery - thrombotic risk is highest in the puerperium even without prior thrombosis history

• Consider adding hydroxychloroquine (emerging evidence, not yet RCT-confirmed)
• IVIg, corticosteroids, plasmapheresis are proposed but not recommended by ACR due to weak evidence and side effects
• Refer for joint management with maternal-fetal medicine, hematology, and rheumatology