Miscarriage%20-%20spontaneous Signs and Symptoms

• Miscarriage is the loss of pregnancy before 20 weeks gestation or delivery of a fetus weighing <500 g, in the absence of elective medical or surgical measures to terminate pregnancy
  • Early loss is considered if it occurred before menstrual week 12 or in the 1st trimester
  • Late loss refers to those that occurred from menstrual weeks 12 to 20
• May occur in 15-20% of pregnancies
• 75% of affected women will have a subsequent successful pregnancy but decreases as the number of miscarriages and the age of the mother increase
• Also known as spontaneous abortion, spontaneous pregnancy loss or early pregnancy failure
  • The terms miscarriage, spontaneous pregnancy loss and early pregnancy failure are often used in patients to differentiate those associated with elective termination of pregnancy and to acknowledge the emotional aspects of losing a pregnancy

• Up to 50-75% of cases will not have a clearly defined etiology

Cytogenetic Abnormalities 

• May cause 2-5% of recurrent pregnancy loss
• Studies have shown that most early pregnancy losses are linked with sporadic chromosomal anomalies (ie trisomies), which may be age-related
  • There is 9-12% risk of sporadic miscarriage in women <35 years old between 6 and 12 weeks of gestation, which increases in women >35 years old due to high incidence of trisomic pregnancies
• Peripheral karyotyping, if available, may be done to parents to identify any balanced structural chromosomal abnormalities
  • Preimplantation genetic testing (PGT), amniocentesis, or chorionic villus sampling are options to identify genetic abnormality in the offspring when either of the parents has a structural genetic abnormality

Antiphospholipid Syndrome (APS)

• A group of symptoms of vascular thrombosis or unfavorable pregnancy outcomes in association with antiphospholipid antibodies
• Antiphospholipid antibodies may cause inhibition of villous cytotrophoblast differentiation and extravillous cytotrophoblast invasion into the decidua, induction of syncytiotrophoblast apoptosis, and initiation of maternal inflammatory pathways on the syncytiotrophoblast surface
• Diagnosed if patient has either 1 of the clinical criteria and 1 of the laboratory criteria
  • Clinical criteria
    • Vascular thrombosis
    • ≥1 unexplained deaths of morphologically normal fetus after the 10th week of gestation by ultrasound or direct examination of the fetus
    • ≥1 premature births of morphologically normal neonate before the 34th week of gestation because of severe preeclampsia/eclampsia or recognized features of placental insufficiency [positive abnormal or non-reassuring cardiotocography features, presence of abnormal wave on doppler on examination of fetal blood flow, oligohydramnios, low birth weight (<10th percentile)]
    • ≥3 unexplained consecutive spontaneous miscarriages before the 10th week of gestation with no maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes
  • Laboratory criteria
    
    • ≥2 positive plasma lupus anticoagulant taken at least 12 weeks apart
    • ≥2 positive serum or plasma anticardiolipin antibody in medium or high titer taken at least 12 weeks apart
    • ≥2 positive serum or plasma anti-β2 glycoprotein-I antibody of IgG and/or IgM isotype in titer >99th percentile taken at least 12 weeks apart)
• May cause 8-42% of recurrent pregnancy loss
  • Thrombophilia is associated more with late pregnancy loss than for early pregnancy loss
• Patient should be screened for lupus anticoagulant, anticardiolipin IgG or IgM antibody, anti-β2 glycoprotein-I
• Low-dose Aspirin and Heparin are the standard management for patients diagnosed with antiphospholipid syndrome

Anatomic Factors 

• May be responsible for 1.8-37.6% of recurrent pregnancy loss
  • Studies have shown that patients with septate, bicornuate, and arcuate uteri have high incidence of pregnancy loss
• Congenital uterine abnormalities may cause 2nd trimester pregnancy loss and other complications like preterm labor, fetal malpresentation, and increased rates of cesarean delivery
• Cervical weakness is a common cause of 2nd trimester miscarriage which is preceded by spontaneous rupture of membranes or cervical dilatation
• Hysterosalpingography or sonohysterography may be used for screening patients
  • Congenital Mullerian tract anomalies are often detected by hysterosalpingography and more characterized by MRI or 3-D ultrasound imaging

Hormonal and Metabolic Factors 

• Diabetes and thyroid dysfunction should be evaluated in patients with recurrent pregnancy loss
  • Thyroid hormone disorders and elevated thyroid peroxidase (TPO) antibodies are associated with disorders in folliculogenesis, spermatogenesis, fertilization and embryogenesis which can lead to pregnancy loss  
  • Well-controlled diabetes mellitus (DM) and treated thyroid dysfunction are not risk factors for recurrent pregnancy loss
• Prolactin, thyroid stimulating hormone (TSH), or hemoglobin A1c may be used for screening patients
  • Ovulatory dysfunction may be secondary to elevated prolactin levels which may be associated with recurrent pregnancy loss through alterations in the hypothalamic-pituitary-ovarian axis that results in impaired folliculogenesis and oocyte maturation, and/or short luteal phase
    
    • Normalization of prolactin levels with dopamine agonist improved subsequent pregnancy outcomes in patients with recurrent pregnancy loss
      • Treatment with Bromocriptine resulted in 85.7% live born rate
• Inadequate secretion of progesterone in early pregnancy has been associated with miscarriage
  • Progesterone supplementation in pregnancy to prevent a miscarriage lacks sufficient evidence
• Presence of polycystic ovary syndrome is associated with higher miscarriage rate compared to the general obstetric population
  • Exact mechanism is not known but loss may be due to high luteinizing hormone levels, elevated testosterone and androstenedione concentrations or insulin resistance
• Live birth rate does not improve with suppression of high luteinizing hormone levels in women with recurrent miscarriage and polycystic ovaries

Infection 

• Infective agents that persist in the genital tract and avoid detection or do not cause sufficient symptoms to affect the woman are implicated in the etiology of repeated pregnancy loss
  • Ureaplasma urealyticum, Mycoplasma hominis, chlamydia, Listeria monocytogenes, Toxoplasma gondii, rubella, cytomegalovirus, herpes virus and other pathogens are identified in women with sporadic miscarriage
  • Bacterial vaginosis in the 1st trimester has been shown as a risk factor for 2nd trimester miscarriage
• A study has shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease 2019 (COVID-19) in the 1st trimester of pregnancy does not predispose to early pregnancy loss
• Association with recurrent pregnancy loss lacks convincing data
  • No clear indication for routine testing for above pathogens
  • Use of antibiotics is not warranted due to lack of prospective studies

Inherited Thrombophilias 

• Studies have shown that inherited thrombophilia is associated with fetal deaths more than recurrent early pregnancy losses
• Routine testing of women with recurrent pregnancy loss for inherited thrombophilias is not recommended
  • Screening may be warranted in patients with personal history of venous thromboembolism in the setting of a non-recurrent risk factor or a 1st-degree relative with a known or suspected high-risk thrombophilia
• Live birth rate is improved with Heparin therapy during pregnancy in women with 2nd trimester miscarriage but not with recurrent 1st trimester miscarriage due to insufficient evidence

Lifestyle, Environmental, Occupational Factors 

• Cigarette smoking, obesity, cocaine use, 3-5 alcoholic drinks per week, and consumption of >3 cups of coffee have been associated with risk of miscarriage
  • Cigarette smoking has been shown to have an adverse effect on trophoblastic function and is associated to an increased risk of sporadic pregnancy loss
  • Heavy consumption of alcohol is toxic to the embryo and the fetus; moderate consumption per week may increase the risk of sporadic miscarriage