Definitions of Miscarriage:

• Miscarriage: Pregnancy loss before 20 weeks’ gestation or fetal weight <400 g
• Threatened Miscarriage: Vaginal bleeding prior to 20 weeks’ gestation
• Inevitable Miscarriage: Passage of POC of a non-viable IUP occurring or expected to occur imminently
• Incomplete Miscarriage: Some retention of POC of a non-viable IUP
• Missed Miscarriage: Ultrasound diagnosis of a non-viable IUP in the absence of vaginal bleeding
• Septic Miscarriage: Miscarriage complicated by infection
• Recurrent Miscarriage: Three or more consecutive miscarriages
• Complete Miscarriage: Full expulsion of POC of an IUP

Risk Factors for Early Pregnancy Loss

• Advanced Maternal Age:
  • Women aged 20 to 30 years: 9% to 17% incidence
  • Women aged 45 years: 75% to 80% incidence
• Prior History of Pregnancy Loss:
  • One miscarriage: 20% risk of future miscarriage
  • Two consecutive miscarriages: 28% risk
  • Three or more consecutive miscarriages: 43% risk
• First-Trimester Vaginal Bleeding:
  • Occurs in up to 25% of pregnancies, increasing the risk of loss
• Chronic Diseases:
  • Obesity
  • Diabetes
  • Hyperprolactinemia
  • Celiac disease
  • Thyroid disease
  • Autoimmune conditions, particularly antiphospholipid syndrome
• Infections:
  • Syphilis
  • Parvovirus B19
  • Zika virus
  • Cytomegalovirus
• Structural Uterine Abnormalities:
  • Congenital Müllerian anomalies
  • Leiomyoma
  • Intrauterine adhesions
• Intrauterine Device in Place during Pregnancy
• Chronic Stress:
  • Social determinants of health (e.g., racism, housing or food insecurity, threats of violence)
• Modifiable Risk Factors:
  • Alcohol consumption
  • Smoking
  • Cocaine use
  • High caffeine consumption (>3 cups of coffee daily)
• Environmental Contaminants:
  • Arsenic
  • Lead
  • Organic solvents

Epidemiology

• Clinically Recognized Pregnancies:
  • 10% to 20% end in early pregnancy loss
• Undiagnosed Miscarriages:
  • Higher incidence estimated at approximately 38%
• First-Trimester Bleeding:
  • 12% to 57% end in miscarriage

History and Physical Examination:

• General Principles:
  • Determine patient stability
  • Exclude differential diagnoses (e.g., ectopic or molar pregnancies)
  • Confirm pregnancy viability or stage of pregnancy loss if nonviable
• Clinical Features:
  • Asymptomatic (missed abortion): Regression of pregnancy signs/symptoms (e.g., nausea, fatigue)
  • Threatened, incomplete, or complete losses: Pelvic cramping, vaginal bleeding
  • Septic miscarriages: Uterine tenderness, purulent cervical/vaginal discharge, systemic signs (e.g., fever, tachycardia, hypotension)
• Physical Examination:
  • Assess vital signs, abdominal and pelvic examination
  • Abdominal exam: Peritoneal signs of ectopic pregnancy or extra-uterine septic abortion
  • Pelvic exam: Speculum visualization of cervix, bimanual palpation
  • Findings: Open/closed cervix, presence/absence of pregnancy tissue, vaginal bleeding, signs of septic abortion (e.g., purulent discharge, uterine/cervical motion tenderness)
  • Adnexal mass: Suggests ectopic pregnancy
  • Estimation of vaginal bleeding volume: Significant even without sepsis, similar or greater than typical menses suggesting early pregnancy loss

Management of Miscarriage

1. Threatened Miscarriage:
   • Treated expectantly
   • Increased risk of future miscarriage and pregnancy complications
   • Insufficient evidence for progesterone administration
2. Inevitable, Incomplete, and Missed Miscarriages:
   • Expectant Management:
     • Allow natural expulsion of POC
     • Inform patient about process length, pain, bleeding, and when to seek emergency assistance
     • Ongoing review at 1-2 weeks; repeat serum hCG at 3 weeks if pain and bleeding have ceased
     • Further assessment if positive serum hCG or no symptoms within 7-14 days
   • Medical Management:
     • Use of misoprostol for uterine evacuation
     • Effective when given vaginally or orally
     • Should be performed in experienced units
   • Surgical Evacuation:
     • Treatment of choice for haemorrhage or sepsis
     • May be chosen to avoid prolonged pain and bleeding
     • Contraindications include anticoagulant therapy
     • Complications: anaesthetic risks, haemorrhage, perforation, retained POC, and endometritis

MIST Trial Findings:

• Compared expectant, medical, and surgical management options
• Efficacy comparable, no significant difference in infection rates
• Higher unplanned hospital admissions in expectant (49%) and medical (18%) groups compared to surgical (8%)
• Surgical management required in 44% of expectant and 13% of medical groups
• 5% of surgical group required further procedures

Recurrent pregnancy loss (RPL)

• < 24 weeks
• Refer to specialist clinic after 2 pregnancy losses

Pregnancy loss by maternal age
Maternal age (years)	Rate of pregnancy loss (%)
20–24	11
25–29	12
30–34	15
35–39	25
40–44	51
>45	93

Common causes:

• Fetal chromosomal abnormality
• Idiopathic recurrent miscarriage

Uncommon causes:

• Antiphospholipid syndrome
• Cervical incompetence
• Parental chromosomal abnormality
• Uncontrolled diabetes

Etiology:

• Genetic:
  • Aneuploidy: Common cause of RPL.
  • Translocations: Balanced, reciprocal, and Robertsonian translocations in the fetus can lead to spontaneous miscarriages.
• Anatomic:
  • Congenital Uterine Anomalies:
    • Septate uterus (most common)
    • Unicornuate uterus
    • Bicornuate uterus
    • Didelphic uterus
    • Arcuate uterus
  • Prevalence: Congenital uterine defects are present in about 12.6% of patients with RPL.
  • Acquired Uterine Anomalies:
    • Fibroids
    • Polyps
    • Asherman syndrome
• Endocrine:
  • Diabetes: Must be evaluated and treated in RPL patients.
  • Thyroid Dysfunction: Requires evaluation and appropriate treatment.
  • Hyperprolactinemia: Possible association with RPL, but not proven.
• Antiphospholipid Antibody Syndrome (APLS):
  • Accounts for about 8% to 42% of RPL cases.
  • Causes increased thrombosis and placental insufficiency, leading to RPL.
• Environmental Factors:
  • Cigarette Smoking: Affects trophoblastic function and increases RPL risk.
  • Obesity: Independently associated with RPL in natural conception.
  • Alcohol Consumption: 3 to 5 drinks per week linked to increased RPL risk.
  • Cocaine Use: Associated with an increased risk of spontaneous miscarriages.
  • High Caffeine Consumption: More than 3 cups of coffee per day linked to RPL.
• Immunological:
  • Inherited Thrombophilias: Routine testing for inherited thrombophilias in women with RPL is not recommended.
  • Screening Indications: Personal history of venous thromboembolism with nonrecurrent risk factors or a relative with high-risk thrombophilia.
  • Research: Prospective cohort studies do not confirm a strong association between hereditary thrombophilia and fetal loss.

Investigations and management

Investigation summary for recurrent pregnancy loss
Investigations	Yes	Maybe	No
Anatomical	Two-dimensional/three-dimensional ultrasonography and sonohysterography or Combination laparosopy and hysteroscopy	MRI
Genetic	Karyotype: POC	Karyotype: parental
Thrombophilia	Acquired: APS	Anti-b2 glycoprotein	Congenital thrombophilia
Infection		LVS/HVS/chlamydia Endometrial biopsy and culture	TORCH
Immunological		Antinuclear antibody	HLA Natural killer cells (research only)
Endocrinological	TSH (FT3/4 and antibodies if TSH abnormal)	Prolactin
Male factor		Sperm DNA fragmentation index
APS, antiphospholipid syndrome; DNA, deoxyribonucleic acid; FT3, free triiodothyronine; FT4, free thyroxine; HLA, human leukocyte antigen; HVS, high vaginal swab; LVS, low vaginal swab; MRI, magnetic resonance imaging; POC, products of conception; TORCH, toxoplasmosis, other agents, rubella, Cytomegalovirus and Herpes simplex; TSH, thyroid-stimulating hormone

Treatment summary for recurrent pregnancy loss
Treatment	Yes	Maybe	No
Anatomical	Submucosal fibroid surgical management suggested	Uterine septa Endometrial polyps Uterine synechiae	Other Müllerian anomalies
Genetic	Pre-implantation genetic diagnosis (in known parental karyotypic abnormalities)	Pre-implantation genetic screening
Thrombophilia	Aspirin and unfractionated heparin in the context of APS		Aspirin
Infection	Antibiotics: if clinical evidence of infection		Prophylactic antibiotics
Immunological			Prednisone IVIG Partner lymphocyte transfusion Intralipid
Endocrinological	Control of diabetes mellitus Overt hypo/hyperthyroidism	Subclinical hypothyroidism Progesterone	Androgens β-hCG LH
Male factor	Lifestyle modification	PICSI IMSI Antioxidants
Environment/lifestyle	Smoking: cease Illicit drugs: cease Maintain normal BMI Specialised and individualised care in dedicated clinic	Limiting caffeine to ≤3 serves per day
APS, Antiphospholipid syndrome; β-hCG, beta human chorionic gonadotropin; BMI, body mass index; IMSI, intracytoplasmic morphologically selected sperm injection; IVIG, intravenous immunoglobulin; LH, luteinising hormone; PICSI, physiological intracytoplasmic sperm injection; TORCH, toxoplasmosis, other agents, rubella, Cytomegalovirus and Herpes simplex

• Genetic Causes of Recurrent Pregnancy Loss (RPL):
  • Balanced Chromosomal Anomalies:
    • Prevalence: 2-5% of couples with RPL have a partner carrying a balanced chromosomal anomaly.
    • Implications: Carriers are phenotypically normal but at increased risk of miscarriage or offspring with congenital abnormalities.
    • Guidelines:
      • RCOG: Recommends cytogenetic analysis on products of conception (POC) and peripheral blood karyotyping of parents if POC have unbalanced chromosomal abnormalities.
      • ASRM: Recommends peripheral karyotyping of all RPL parents independently of POC karyotyping.
      • ESHRE: Sceptical of routine karyotyping of parents and POC; notes issues with obtaining tissue, maternal contamination, and failed tests.
  • Genetic Counseling Options:
    • Pre-implantation genetic diagnosis (PGD)
    • Spontaneous conception with invasive testing (chorionic villus sampling or amniocentesis)
    • Gamete donation
  • Recommendation:
    • Karyotyping of parents and POC is recommended for couples with two or more pregnancy losses.
• Anatomical Causes of RPL:
  • Uterine Leiomyoma (Fibroids):
    • Types: Subserosal, intramural, submucosal
    • Diagnosis:
      • Gold standard: Combination hysteroscopy and laparoscopy
      • Effective alternatives: Sonohysterography or hysterosalpingography
    • Impact on Pregnancy:
      • Subserosal fibroids: No impact on fertility or miscarriage
      • Intramural fibroids: May decrease live birth and increase miscarriage rates
      • Submucosal fibroids: Decrease live birth rates and increase miscarriage rates
    • Guidelines:
      • ACCEPT: Recommends removing submucosal fibroids to improve pregnancy outcomes; uncertain evidence for removing intramural fibroids.
      • RCOG: Silent on the role of fibroids in miscarriage.
      • ESHRE: Recognizes controversy; recommends surgical management on a case-by-case basis.
  • Müllerian Anomalies:
    • Prevalence: Varies from 1.5% to 37% in RPL; 4% in women without RPL; 12.6% in women with RPL.
    • Association: Linked to second trimester loss and higher pregnancy loss rates.
    • Septate Uterus:
      • Associated with higher miscarriage rates.
      • Correction can reduce miscarriage rates.
    • Guidelines:
      • RCOG: Notes prevalence and suggests correction for septate uterus.
      • ASRM: Recommends correction for septate uterus.
      • ESHRE: Recommends surgical treatment in the context of a clinical trial.
  • Uterine Synechiae (Asherman’s Syndrome):
    • Symptoms: Menstrual disturbances (hypomenorrhoea, dysmenorrhea), infertility, increased miscarriage risk.
    • Guidelines:
      • RCOG: Does not mention uterine synechiae.
      • ASRM: Recommends correction after patient discussion, recognizing controversy.
      • ESHRE: Weak evidence for resection; notes surgery can promote adhesion formation; precautions needed perioperatively.
  • Recommendation:
    • Two-dimensional/three-dimensional ultrasonography with sonohysterography is recommended for couples with two or more pregnancy losses.
• Thrombophilia
  • Thrombophilia and Recurrent Pregnancy Loss (RPL):
    • Congenital Thrombophilia:
      • Types:
        • Factor V Leiden
        • Prothrombin gene mutation
        • Deficiencies in anti-thrombin, protein C, and protein S
      • Associated Risks: Increased risk of thromboembolism, Possible association with adverse pregnancy outcomes
      • Evidence: Weak and inconclusive studies linking these thrombophilias to RPL
      • Guidelines: No recommendation to investigate congenital thrombophilias outside of research settings
    • Acquired Thrombophilia:
      • Types:
        • Antiphospholipid syndrome (APS) and associated antibodies (anti-cardiolipin, lupus anticoagulant)
        • b2 glycoprotein1 (b2GP1) antibodies
      • Mechanisms:
        • Direct inhibition of placentation, Disruption of adhesion molecules, Thrombosis of placental vasculature
        • Guidelines:
          • Testing for APS in RPL is recommended by all guidelines
          • Both ASRM and ESHRE suggest including b2GP1 antibodies in investigations
        • Treatment:
          • For Acquired Thrombophilias (APS):
            • Combination of 75–100 mg aspirin daily with prophylactic doses of unfractionated heparin significantly reduces miscarriage rates
            • Aspirin alone is ineffective
      • Recommendations for Couples with Two or More Pregnancy Losses:
        • Testing for congenital thrombophilias is not recommended
        • Testing for acquired thrombophilias is recommended
        • For diagnosed acquired thrombophilias:
          • Initiate treatment with unfractionated heparin and low-dose aspirin
          • Refer to a specialized clinic
• Endocrinological Causes of Recurrent Pregnancy Loss (RPL):
  • Thyroid Function:
    • Hypothyroidism and Subclinical Hypothyroidism: Associated with RPL
    • Testing: All guidelines recommend testing for TSH levels
    • Controversy: Normal TSH levels and the significance of thyroid antibodies in euthyroid patients
    • Treatment: Treat overt hypothyroidism, consider treating subclinical hypothyroidism, and do not treat euthyroid patients with thyroid antibodies
  • Diabetes:
    • Controlled Diabetes: Not a risk factor for RPL
    • Poorly Controlled Diabetes: Risk factor for RPL
    • Routine Screening for PCOS: Not recommended for RPL investigation or treatment
  • Progesterone and Prolactin:
    • Prolactin: Elevated prolactin may cause ovulatory dysfunction, but its link to RPL is weak
    • Testing for Prolactin: Not recommended without clinical suspicion; ASRM allows consideration
    • Normalizing Hyperprolactinemia: Dopamine agonists like bromocriptine may improve live births
    • Progesterone: Conflicting evidence; Cochrane meta-analysis suggests benefit, but the largest RCT did not show a benefit
    • Guidelines: Do not recommend progesterone for RPL, but note no harm from its use
• Infection:
  • Overwhelming Infection: Can cause miscarriage, but no clear link between chronic infection and RPL
  • Bacterial Vaginosis: Linked to second-trimester miscarriage; weak evidence for first-trimester link
  • TORCH Infections: No established link to RPL
• Immune System:
  • Immunology and RPL: Includes HLA typing, natural killer cells, and immunomodulation (e.g., IVIG, corticosteroids)
  • Evidence: No good evidence supporting immunomodulation for RPL
  • Investigations: Autoimmunity tests outside of APS are not recommended
• Environment and Lifestyle:
  • Cigarette Smoking: Linked to miscarriage due to trophoblastic dysfunction
  • Alcohol and Caffeine: Increase miscarriage risk in a dose-dependent manner
  • Illicit Drugs: Cocaine use increases miscarriage risk
  • Stress: Not a direct cause of RPL, but a supportive environment decreases miscarriage risk
  • Obesity: Linked to increased miscarriage rates and other complications
  • Recommendations:
    • Cease smoking and alcohol consumption
    • Limit caffeine intake to fewer than three cups per day
    • Normalize BMI
    • Provide care in a specialized clinic for support
• Male Factors:
  • Lifestyle Factors: Normalization of BMI, cessation of smoking, and reduction of alcohol intake recommended
  • Semen Analysis: Not predictive of miscarriage; conflicting evidence on high sperm DNA fragmentation
  • Guidelines: ASRM does not recommend routine sperm DNA fragmentation indexing; ESHRE allows it for explanation purposes
• Unexplained RPL:
  • Prevalence: Up to 50–75% of cases remain unexplained
  • Management: Multidisciplinary care improves outcomes
  • Prognosis: Successful pregnancy rates can be beyond 50–60%, depending on age and previous parity

Conclusion:

• RPL is defined as two or more pregnancy losses, affecting less than 5% of couples
• Comprehensive evaluation and multidisciplinary care are crucial for management and counseling
• Investigations and management strategies are outlined in respective tables and figures, emphasizing the importance of specialized expertise.