Recurrent Spontaneous Early Pregnancy Loss

Chapter 28. Recurrent Spontaneous Early Pregnancy Loss

1st year of resident S.B. Cho M.D.




I. Introduction.



  • Recurrent spontaneous abortion : the occurrence of three or more clinically recognized pregnancy
    losses before 20 weeks from the last menstrual period
  • Incidence ; 1/300 pregnancies
  • Clinical investigation should be started after two consecutive spontaneous abortions, especially



    1. when fetal heart activity had been identified prior to the pregnancy loss
    2. when the women is older than 35 yrs of age
    3. when the couple has had difficulty conceiving



II. Etiology.


  • Table 28-1


    1. Genetic Factors.



    1. Parental chromosomal abnormalities : only undisputed cause of recurrent spontaneous abortions
    2. Most common form : balanced translocation : giving rise to trisomic conceptions
    3. By single gene defects ; mosaicism, inversion, X-linked disorders


    2. Anatomic Anomalies.


    A. Congenital abnormalities



    1. Intrauterine septum ; 60 % of risk & 2nd trimester loss is common
    2. In utero DES exposure ; uterine abnormalities → spontaneous abortion, incompetent cervix,
      preterm labor
    3. Uterine artery anomalies


    B. Acquired abnormalities



    1. Intrauterine adhesions, leiomyomas, : distort uterine cavity
    2. endometriosis : immunologic phenomena potentially involved

    3. Endocrine Abnormalities.



    A. Luteal phase deficiency : LH hypersecretion disease, DM, Thyroid disease

    B. Abnormal LH secretion


    1. Direct effect on the developing oocyte, causing premature aging & on the endometrium, causing
      dyssynchronous maturation
    2. May contribute to abortion indirectly by elevating testosterone levels

    C. Diabetes Mellitus


    1. Compromised blood flow to the uterus especially in case of advanced disease
    2. Elevated hemoglobin A1c => associated with recurrent abortion

    D. Hypothyroidism


    1. Ovulation or corpus luteum dysfunction
    2. Anti-thyroid antibodies


    4. Maternal Infections.


    A. Most common form : Mycoplasma, Ureaplasma, Chlamydia, β- Streptococcus

    B. Results from immunologic activation in response to pathologic organism


    5. Immunologic Phenomena.



    • Immunologic reponses : regulated by genes of major histocompatibility complex ( MHC ) , located on
      chromosome 6
    • MHC

      • ClassⅠantigen ; HLA-A, -B, -C
      • ClassⅡantigen ; HLA-DR, -DQ, DP
      • ClassⅠantigen ; important in rejection responses mediated by cytotoxic T-lymphocyte
      • ClassⅡantigen ; present antigen to T-lymphocyte & initiate immunity
      • HLA-G ; a non-classical truncated classⅠantigen in human cytotrophoblast

    A. Cellular Immunity Abnormalities


    • Immunity : more specifically regulated by CD4(+) T cell
    • CD4(+) T cell divided in



      1. T helper 1 (TH1) ; IFN-γ, IL-2, TNF-β, TNF-α
      2. T helper 2 (TH2) ; IL-4, IL-5, IL-6, IL-10


    • an abnormal TH1 cellular immune response : most recent hypothesis proposed for immunologic
      reproductive failure



      1. In affected women → trophoblast antigen activates macrophage & lymphocytes
        : causing cellular immune response mediated by the TH1 cytokines
      2. These cytokines : inhibit in vitro embryo development & trophoblast growth & function.



    • 60∼80 % of non-pregnant women with a history of otherwise unexplained recurrent spontaneous
      abortion : abnormal TH1 cellular immune response
    • 3 % of normal pregnant women : same response
    • Other cellular immune mechanisms



      1. Suppressor cell deficiency
      2. Macrophage activation


    B. Humoral Immunity abnormalities

    • Antiphospholipid antibody Syndrome

      1. Antiphospholipid antibody to either cardiolipin or phosphatidylserine : Ig G or Ig M directed
        against negatively charged phospholipid
      2. In vitro : prolonged phospholipid dependent coagulation test ( aPTT, Russell Viper Venom test)
        in vivo : causing thrombosis
      3. Association with spontaneous abortion, premature labor, PROM, stillbirth, IUGR, preeclampsia,
        antiphospholipid syndrome
      4. The proposed mechanism ; increased thromboxane & decreased prostacycline leading to platelet
        adhesion within placental vessels


    • Other antibody-mediated mechanisms : anti-sperm & anti-trophoblast antibodies & blocking
      antibody deficiency

    6. Other Factors.



    1. Metal toxicity & prolonged exposure to organic solvents
    2. Drugs ; anti-progestogens, anti-neoplastic agent, inhalation anesthetics, nicotine, ethanol, ionizing
      radiation
    3. Thrombocytosis ( > 1 million )



    III. Preconception Evaluation.


    1. History. : Table 28.2

    2. Physical Examination.


    1. To detect signs of metabolic illness
    2. During pelvic examination : signs of infection, DES exposure, previous trauma,
    3. The size & shape of the uterus : should be determined


    3. Laboratory Assessment.


  • Table 28.2



    IV. Postconception Evaluation.



    1. Following conception : close monitoring is needed.( ectopic pregnancy, molar pregnancy, spontaneous
      abortion)
    2. β- hCG level ; helpful
    3. Ultrasonography ; gold standard method, every 2 weeks with history of abortion
    4. Maternal serumα-fetoprotein at 16∼18 weeks of gestation



    V. Therapy.


    1. Chromosomal Aberrations



    1. No therapy is available
    2. With Robertsonian translocations => donor oocyte or donor sperm

    2. Anatomic Anomalies



    1. Hysteroscopic resection of intrauterine filling defect : submucous leiomyoma, intrauterine adhesions,
      intrauterine septa
    2. Cervical cerclage


    3. Endocrine Abnormalities



    1. Luteal phase insufficiency : progesterone supply ; controversial
    2. Hyperandrogen & hypersecretion disorders : ovulation induction
    3. Hypothyroidism : thyroid hormone replacement

    4. Infections


  • Appropriate antibiotics for certain organism



    5. Immunologic Factors



    A. Leukocyte Immunization



    1. Paternal leukocyte transfusion ; controversial & several complication ( graft-versus-host disease,
      severe IUGR, autoimmune or isoimmune complication, fatal thrombocytopenia )
    2. Immunoregulatory Therapies : intravenous preparations consisting of syncytotrophoblast
      microvillus plasma membrane vesicles

    6. Aspirin & Heparin


    A. Antiphospholipid antibody syndrome



    • Low dose aspirin ( 80 mg/day ) & subcutaneous heparin ( 5,000 ∼ 10,000 units twice daily )

    B. aPTT : check weekly


    7. Immunoglobulin



    1. IV immunoglobulin & plasmapheresis
      B. Immunoglobulin : T cell & Fc receptor regulation, complement activation, enhanced T cell
      suppressor function, down-regulation of TH1 cytokine synthesis --> may be of benefit in treating
      women with recurrent abortion related to TH1 immunity to trophoblast.

    8. Psychologic Support



    1. A caring, empathetic attitude

    2. Referrals to support groups & counselors

    3. Self-help measures


    VI. Prognosis.


  • Table 28.3




    1. The prognosis : depends on the potential underlying etiology of pregnancy loss & number of prior
      losses
    2. Ultrasonography : useful in predicting pregnancy outcome.


      • Documentation of fetal cardiac activity between 5∼6 weeks from the LMP ; 77 % of success rate.