Recurrent Miscarriage Overview

Recurrent Miscarriage (RPL)

• Defined as 3 or more consecutive pregnancy losses before 20 weeks of clinically confirmed pregnancy
• Workup is usually indicated after 2 losses (and doesn't need to be consecutive)
• Affects 1% of all women
• Risk of 2 consecutive losses is 5%
• Risk of 3 or more consecutive losses is 1%
• Independent risk factors include age (risk increases to 50% by age 40 due to increased aneuploidy) and number of previous miscarriages

Types of RPL

• Primary RPL: women with no previous viable pregnancy
• Secondary RPL: women with a previous live birth (has a better prognosis)

Etiology of RPL: Genetic Causes

• Occur in 3-5% of couples
• Usually, one partner carries chromosomal abnormalities; common types include balanced reciprocal translocations and Robertsonian translocations
• Carriers are typically phenotypically normal, but 50-75% of their gametes will be unbalanced

Genetic Testing

• Karyotyping is carried out on all patients, especially young women and those with relatives married in first degree, to detect chromosomal abnormalities
• If abnormal karyotype is identified, refer the couple to a geneticist for genetic counseling
• Cytogenetic analysis (karyotyping) of products of conception is done if there is a failed pregnancy

Etiology of RPL: Uterine Abnormalities

• Associated with second-trimester miscarriage
• Found in 10-30% of women with RPL (compared to 7% in the general population)
• Includes uterine fusion anomalies, Asherman's syndrome, polyps, and fibroids
• Often associated with cervical weakness
• Routine HSG (hysterosalpingography) is not recommended for screening in RPL due to patient discomfort, radiation exposure, and increased risk of pelvic inflammatory disease (PID). It is not more sensitive than transvaginal ultrasound.

Etiology of RPL: Congenital Uterine Abnormalities

• All women with RPL should undergo pelvic ultrasound to assess uterine anatomy and morphology
• Three-dimensional ultrasound is promising and may replace diagnostic laparoscopy and hysteroscopy

Etiology of RPL: Cervical Weakness

• A cause of second-trimester miscarriage and preterm labor
• Usually diagnosed based on history
• Cerclage (cervical stitch) is associated with surgical risks and may stimulate contractions, so it should only be considered in a carefully selected group of patients
• Transvaginal scan assessment of the cervix helps predict preterm labor

Etiology of RPL: PCOS (Polycystic Ovary Syndrome)

• Patients with PCOS have a 20% risk of miscarriage
• Metformin may reduce the risk of miscarriage

Etiology of RPL: Diabetes, Obesity, and Thyroid Dysfunction

• Controlled diabetes, obesity, and thyroid dysfunction are not associated with RPL
• Routine screening for DM in asymptomatic patients with RPL is not recommended
• Clinical and subclinical thyroid dysfunction is associated with RPL
• Strict control of any endocrine abnormality is recommended before pregnancy

Etiology of RPL: Luteal Phase Insufficiency

• Progesterone use for miscarriage prevention is not supported
• Difficulty assessing luteal phase insufficiency
• Progesterone may prevent preterm labor between weeks 16-24 in patients with a history of preterm labor before week 34
• Oral progesterone is less effective due to rapid metabolism; vaginal and intramuscular routes are more effective

Etiology of RPL: Antiphospholipid Syndrome

• 5-20% of patients with RPL test positive for antiphospholipid antibodies (aPLs)
• Antibodies target vascular endothelium and platelets, causing vasoconstriction and thrombosis, resulting in placental infarcts and abortion
• aPLs clinical criteria:
  • One or more episodes of vascular thrombosis
  • Three or more consecutive miscarriages before 10 weeks
  • One or more miscarriages (morphologically normal) after 10 weeks
  • One or more preterm births before 34 weeks due to preeclampsia, eclampsia, or placental insufficiency
• Lab criteria: Two or more positive anti-body tests at least 6-12 weeks apart, either anti-cardiolipin antibodies (detected with ELISA) or lupus anticoagulant antibodies (detected using a dilute Russell's viper venom time test)

Etiology of RPL: Antiphospholipid Syndrome - Treatment

• Aspirin plus low-molecular-weight heparin (LMW-H) increases the live birth rate to about 70% (compared to 40% with aspirin alone)
• Unfractionated heparin can be used with aspirin
• LMW-H has fewer side effects than unfractionated heparin (bleeding, thrombocytopenia, and osteopenia)
• Steroids and immune therapy are not effective for improving live birth rates

Etiology of RPL: Inherited Thrombophilia

• Established causes of thrombosis, but their association with RPL is questionable
• Routine screening is not recommended in the absence of risk factors

Etiology of RPL: Infections

• Infections (e.g., TORCH-related and other infections), including bacterial vaginosis and certain STIs, may cause sporadic miscarriages, but do not cause RPL. Screening for these infections is generally not helpful in patients with RPL
• Screening and treatment for bacterial vaginosis is limited to higher-risk groups, such as those with a history of second-trimester abortion or spontaneous preterm labor.
• Screening and treatment for Chlamydia is often controversial.

Etiology of RPL: Hyperprolactinemia, Stress, and Exercise

• These are not causes of RPL
• Routine testing for prolactin levels is not indicated in women with regular cycles.

Etiology of RPL: Unexplained Recurrent Miscarriage

• Has an excellent prognosis with supportive care alone. Live birth rates of 50-75% are achievable without drug therapy, but the prognosis worsens with increasing maternal age and number of losses
• Empirical treatment is unnecessary and should be avoided

Workup for RPL

• Indicated after 2 losses (not necessarily consecutive)
• History: characteristics of miscarriage (anembryonic, live embryo, gestational age), history of congenital abnormalities, menstrual irregularity, history of thrombosis, history of instrumentation
• Examination: signs of endocrine disorders (hirsutism, galactorrhea), pelvic exam for cervical or uterine abnormalities, mental health evaluation
• Tests:
  • Ultrasound (transabdominal and transvaginal) for uterine and renal abnormalities (3D if available); more accurate than MRI in diagnosing uterine abnormalities
  • Antiphospholipid antibodies (aPLs)
  • Thyroid stimulating hormone (TSH) and thyroid antibodies
  • Hemoglobin A1c (HbA1c)
  • Prolactin level (in patients with irregular cycles)
  • Karyotype
• Additional tests: Sonohysterography (Saline Infusion Sonohysterography (SIS)) for uterine anomalies, HSG which is not accurate for septate or bicornuate uterus, , Hysteroscopy and laparoscopy (standard for diagnosis and treatment, but considered invasive and expensive), MRI (can differentiate septate and bicornuate uteri, less invasive than laparoscopy).

Treatment Principles

• Optimizing lifestyle factors
• Controlling underlying medical conditions
• Pregnancy planning with preconception counseling
• Genetic counseling if indicated
• Surgical or nonsurgical treatments based on etiology
• Frequent follow-up visits to monitor pregnancy and address concerns
• Cytogenetic studies of products of conception if losses continue
• Psychological support and counseling

Specific Treatments

• PCOS: Metformin
• Antiphospholipid Syndrome: Aspirin + Low-molecular-weight heparin
• Obesity: Weight reduction
• Thyroid/Prolactin issues: adjust hormone levels