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A. Epidemiologynavigator

  1. Overall incidence of spontaneous abortion (misscarriage) ~30%
    1. Occurs in ~15% of known pregnancies
    2. Up to 1/5 may occur without clinical suspicion
    3. Actual level of miscarriage may be closer to 50% of conceptions
  2. Recurrent miscarriage defined as at least 2 or 3 consecutive pregnancy losses
    1. At least 2 consecutive pregnancy losses in ~5% of couples trying to conceive
    2. At least 3 consecutive pregnancy losses in ~1% of couples trying to conceive
  3. Risk of recurrent abortion increases with each spontaneous abortion
    1. After 2 consecutive losses, risk of 3RD loss is ~20%
    2. After 3 consecuitve losses, risk of 4TH loss is ~40%
  4. Spontaneous abortion is a risk factor for major depressive disorder [5]

B. Etiologynavigator

  1. Conception and Development
    1. Maximum fecundity (probability of conception during one menstrual cycle) ~30%
    2. Implantation of conceptus >10 days after ovulation associated with pregnancy loss [9]
    3. 50-60% of all conceptions progress beyond 20 weeks of pregnancy
    4. Fever in pregnancy is not a risk factor for fetal death [3]
  2. Genetic Causes of Recurrent Abortion
    1. Most common cause of 1st trimester spontaneous abortion
    2. Fetal aneuploidy causes >60% of cases (most are lethal genetic anomalies)
    3. Autosomal trisomy accounts for >50% of chromosome anomalies
    4. Other common types include XO (Turner's) and XXY (Klinefelter's)
    5. Polyploidy accounts for ~22% of genetic anomalies
    6. Triploidy ~75%, Tetraploidy ~20%
    7. Parental genetic abnormalities: ~2.5%
    8. Coagulation protein mutations are clear risk factor (see below) [4]
  3. Hyperhomocysteinemia - 1.5X increased risk for spontaneous abortion [14]
  4. Maternal Anatomic Causes
    1. Cervical incompetence - second trimester losses
    2. Congenital uterine anomalies - septa, bicornate or unicornate uterus
    3. Adhesions and Leimyomas most common acquired uterine anomalies
  5. Maternal Environmental Causes [8]
    1. Smoking Tobacco - increased risk 1.8X for spontaneous abortion
    2. Cocaine Abuse - increased risk 1.4X for spontaneous abortion
    3. Moderate caffeine intake is NOT associated with increase in spontaneous abortion [10]
    4. Infection
  6. Infections (Fetal Wastage)
    1. Toxoplasma gondii - TORCH infection
    2. Chlamydia
    3. Ureaplasma and Mycoplasma
    4. Listeria monocytogenes
  7. Antiphospholipid Syndrome (APLS)
    1. Nearly all patients have anti-phospholipid Abs and/or lupus anticoagulant
    2. Some of these have frank SLE
    3. Autoreactive type 1 T helper cells may play a role in abortion in some patients
    4. Likely that the anti-phospholipid Abs induce endothelial damage and/or thrombosis
    5. Antiphospholipid Abs include anticardiolipin or antiprothrombin Abs
    6. Prothrombin is cleaved to fragment 1 and prethrombin
    7. Eleven of 19 women with spontaneous abortion had anti-prothrombin (prethrombin) Abs [13]
    8. Treatment with prednisone+aspirin does not improve birth rate [6]
    9. Heparin, with careful monitoring for osteoporosis, may reduce risk of spontaneous abortion
  8. Endocrine
    1. Luteal phase defect (<11 days)
    2. Abnormal Thyroid Function
    3. Diabetes Mellitus
    4. ? Abnormal prolactin
  9. Coagulopathy [4]
    1. These are generally hereditary disorders
    2. Antithrombin and Protein C deficiencies have variable influence on fetal loss risk [4]
    3. Protein S deficiency associated with 7-14 fold increased risk for fetal loss
    4. Factor V Leiden or Factor II (prothrombin) mutation each increases risk ~2-7 fold [7,11]
    5. APLS - see above
    6. Consider screening women for these genetic predispositions
    7. Anticoagulation should NOT be used in women without evidence of coagulopathy
    8. However, anticoagulation is effective in antiphospholipid syndrome and should be considered in women with genetic predispositions
    9. Hyperhomocysteinemia may contribute to coagulopathy [14]
  10. Caffeine Intake [12]
    1. Caffeine passes readily through placenta to the fetus
    2. No association between caffeine intake and first-trimester abortion in smokers
    3. Caffeine intake associated with slight increase in first-trimester abortion in nonsmokers
    4. Magnitude of effect in non-smokers 1.3-2.0X for caffeine 100mg to >500mg/day
    5. This corresponds to 1 to >5 cups of coffee per day
    6. Some reduction in caffeine intake in first trimester may be beneficial in some women

C. Evaluationnavigator

  1. History
    1. Family History
    2. Previous surgeries
    3. Endometritis, Pelvic Inflammatory Disease
    4. Autoimmune Disease (including Raynaud's phenomenon, Lupus)
    5. Idiopathic Deep Vein Thrombosis (DVT)
    6. Endocrinopathies
  2. Physical
    1. Pelvic Exam: Double cervix, midline uterine depression, leiomyomas
    2. Vaginal Discharge
    3. Temperature curves (daily for 1-2 months)
  3. Laboratory Tests
    1. Thyroid Function Tests, glucose tolerance test
    2. CBC and Cultures, ? Serology for infectious agents
    3. Autoimmune screen: APTT, Antiphospholipid Abs, ANA, etc.
    4. HLA Typing - ? efficacy, role. Both partners.
    5. Karyotyping of affected partners as indicated - modaics or translocation
    6. Progesterone levels (if abnormal luteal phase suspected)
  4. Hysterosaplingogram, hysteroscopy

D. Management Overview navigator

  1. Progesterone - begin early 1st trimester; modest benefit on reducing miscarriage rate
  2. Metformin (Glucophage®) - may be beneficial in polycystic ovarian syndrome, diabetes
  3. Heparin + Aspirin - for use in APLS
  4. Immunomodulation - no good evidence for benefit (possibly in APLS)
  5. Embryo aneuploidy screening
  6. In vitro fertilization
  7. Depression is very common and should be treated

E. In Vitro Fertilization (IVF) navigator

  1. Variety of methods for augmenting rates of sperm-egg fertilization
  2. Overall success rate is about 12% per cycle of IVF
  3. Factors Associated with Reduced Success Rates
    1. Age <25 (slight reduction) and >30 years (increasing failure with age)
    2. Lack of prior pregnancy or live birth
    3. Increasing number of failed previous cycles
    4. Male sperm abnormalities
    5. Increasing duration of infertility
  4. New methods involving direct sperm injection into egg are being evaluated
    1. Great concern about bypassing "natural" sperm-egg compatibility processes
    2. Potential for increased DNA damage on sperm introduction into egg
    3. This method is called intracytoplasmic sperm injection

References navigator

  1. Rai R and Regan L. 2006. Lancet. 368(9535):601 abstract
  2. Norwitz ER, Schust DJ, Fisher SJ. 2001. NEJM. 345(19):1400 abstract
  3. Andersen AMN, Vastrup P, Wohlfahrt J, et al. 2002. Lancet. 360(9345):1552 abstract
  4. Rey E, Kahn SR, David M, Shrier I. 2003. Lancet. 361(9360):901
  5. Neugebauer R, Kline J, Shrout P, et al. 1997. JAMA. 277(5):383 abstract
  6. Laskin CA, Bombardier C, Hannah ME, et al. 1997. NEJM. 337(3):148 abstract
  7. Ridker PM, Miletich JP, Buring JE, et al. 1998. Ann Intern Med. 128(12):1000 abstract
  8. Ness RB, Grisso JA, Hirschinger N, et al. 1999. NEJM. 340(5):333 abstract
  9. Wilcox AJ, Baird DD, Weinberg CR. 1999. NEJM. 340(23):1796 abstract
  10. Klebanoff MA, Levine RJ, DerSimonian R, et al. 1999. NEJM. 342(22):1639
  11. Martinelli I, Taioli E, Cetin I, et al. 2000. NEJM. 343(14):1015 abstract
  12. Cnattingius S, Signorello LB, Anneren G, et al. 2000. NEJM. 343(25):1839 abstract
  13. Akimoto T, Akama T, Saitoh M, et al. 2001. Am J Med. 110(3):188 abstract
  14. George L, Mills JL, Johansson AL, et al. 2002. JAMA. 288(15):1867 abstract