Recurrent Pregnancy Loss

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Recurrent Pregnancy Loss

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• R1. ???

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• Spontaneous pregnancy loss is, in fact, the most
  common complicadon of pregnancy.
• About 70 of human conceptions fail to achieve
  viability
• estimated 50 are lost before the first missed
  menstrual period.
• Most of preg. Losses are unrecognized.
• Actual rate of preg. Loss after implantation is
  31(by hCG assay)
• Clinically recognized, loss occures in 15 before
  20wks of gestation.

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Recurrent abortion

• Definition 3 or more clinically recognized
  pregnancy losses before 20wks from LMP.
• -gtincidence 1/300
• Clinical investigation should be started after
  two consecutive spontaneous abortions,
  especially
• when fetal heart activity had been identified
  prior to the pregnancy loss
• when the women is older than 35 yrs of age
• when the couple has had difficulty conceiving

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Proposed Etiologies
Table 28.1

• Genetic Factors 3.5-5
• Anatomic Factors 12-16
• Endocrine Factors 17-20
• Infectious Factors 0.5-5
• Immunologic Factors 20-50
• Other Factors 10

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Genetic Factors

• Balanced translocations the most common inborn
  parental chromosomal abnormalities.
• Monosomy in vitro fertilization
• Viable only that of X-chromosome
• Trisomy (13, 18, 21) tolerated than monosomy.
• Family history alone , or history of prior term
  births is not sufficient to rule out a potential
  parental chromosomal abnomiality.
• Others inversion , insertion
• Recently, inherited thrombophilias in recurrent
  pregnancy loss.

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Inherited Thrombophilias
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Anatomic Abnormalities

• uterine cervix ,the uterine body
• Congenital Uterine anomaly? ??
• complete mullerian duct fusion
• incomplete septum resorption
• uterine cervical anomalies
• intrauterine septum (exposure DES)
• 60 risk for spontaneous abortion
• Occur during 2nd trimester.
• Acquired anomaly? ??
• Adhesions, uterine fibroids, endometriosis

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Endocrine Abnormalities

• Normal pregnancies luteal-placental shift (7 to
  9 weeks of gestation)
• Luteal-phase insufficiency or luteal-phase
  defects (LPDs)
• inadequate or improperly timed endometrial
  development at potential implantation sites.
• LH secretion? effect
• Developing oocyte
• Endometrium
• PCOS -gt elevated androgen levels.
• DM -gt directly linked to embryonic damage
• Thyroid disease
• Antithyroid antibodies(ATA)

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Maternal Infections

• Most controversial
• Most common form
• Mycoplasma, Ureaplasma, Chlamydia, ß-
  Streptococcus
• response to pathologic organism? ?? immunologic
  activation -gt recurrent preg. Loss

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Immunologic phenomena

• Innate response first line of defense
• C activation phagocytosis by macrophage, lysis
  by NK cell by (TCR-?d)T-cell.
• Acquired immune respnose
• Antigen specific
• Mediated by T, B cell

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• Cellular Immunity
• Humoral Immunity

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Cellular immunity

• Resident endometrial and decidual cells
• Immune cell education and homing
• Antigen presentation
• In situ immunoregulation

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Resident endometrial and decidual cells

• T cells, macrophage, and NK-like cells, but very
  few B cells
• TCR-aß and TCR-?d cells are present, TCR-?d
  cells increase in early pregnancy.
• NK-like, large granular lymphocytes (decidual NK
  cells) accumulate at sites of Implantation.
• NKT cells and suppressor macrophage.

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Immune cell education and homing

• The implanting fetus represents the most common
  model of allograft acceptance.
• Thymic versus extrathymic education.
• Possible in situ education and maintenance.
• Integrins and vascular ligand pairs and mucosal
  homing.

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Antigen Presentation at the Maternal-Fetal
tnterface

• implanting trophoblastic allograft could
  potentially immune detection by the matemal host
  would be by making itself antigenically
  invisible.
• Downregulation of expression of MHC encoded
  antigen.
• Class II MHC molecules are not expressed in the
  placenta.
• Classic class 1 MHC molecules HLA-A and HLA-B are
  not expressed in the placenta.
• Extravillous cytotrophoblast cells express HLA-C,
  HLA-E, and HLA-G.

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In situ immunoregulation

• TH1- IFN-?, IL-2, TNF-ß, TNF-a -gt harmful
• TH2- IL-4, IL-5, IL-6, IL-10 ,TNF-a -gt normal

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• Hormonal immunomodulation
• Progesterone
• Estrogen
• Human chorionic gonadotropin (hCG)
• Others
• Tryptophan metabolism and indolamine
  2,3-dioxygenase (IDO)
• Leukemia-inhibiting factor (LIF)
• Blastocyte implantation? ???.

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Humoral Immune Mechanisms.

• Fetal antigens are recognized by the maternal
  immune system, and humoral responses are mounted
• Organ nonspecific autoantibody
• Anticardiolipin antibodies
• Lupus anticoagulant
• Anti-ß2 glycoprotein 1 and (anti-ß2) antibodies
• Antiphosphatidlyserine antibodie'
• Organ-specific autoantibodies
• Antithyroid antibodies
• Antisperm antibodies
• Antitrophoblast antibodies
• Blocking antibodies
• HLA sharing
• Trophoblast and lymphocyte cross-reactive
  antibodies (TLX)

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Ofher Factors

• Altered uterine receptivity (integrins, adhesion
  molecules)
• Environmental
• Toxins
• lllicitdrugs
• Alcohol, cigarettes and caffeine
• Placental abnormalities (circumvallate,
  marginate)
• Medical illnesses (cardiac, renal, hematologic)
• Male factors
• Coitus
• Exercise
• Dyssynchronous fertilization

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Recurrent pregnancy loss (II)

• 2003. 9. 9
• R1 ???

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Preconception Evaluation

• Hystory
• Physical examination
• Laboratory

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• Hystory
• Pattern, trimester, characteristics of prior
  pregnancy losses
• History of subfertility or infertility
• Menstrual history
• Prior or current gynecologic or obstetric
  infections
• Sings or symptoms of thyroid, prolactin, glucose
  tolerance, hyperandrogenic disorders (PCOS)
• Personal or familial thrombotic history
• Features associated with the antiphospholipid
  syndrome (thrombosis, false-positive test results
  for syphilis)

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• Other automimune disorder
• Medication
• Environmental exposures, illicit and common drug
  use (particularly caffeine, alcohol, cigarettes,
  in utero DES exposure)
• Genetic relationship between reproductive
  partners
• Family history of recurrent spontaneous abortion,
  obstetric complications, or any syndrome
  associated with embryonic or fetal losses
• Previous diagnostic tests and treatments

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• Physical examination
• - obesity
• - hirsuitism and acanthosis
• - thyroid examination
• - breast examination and galactorrhea
• - pelvic examination
•      anatomy
•      infection
•      trauma
•      estrogenization

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• Laboratory
• parental peripheral blood karyotype
• hysterosalpingography, followed by hysteroscopy
  or laparoscopy, if indicated
• Luteal-phase endometrial biopsy
• Anticardiolipin antibody level
• Thyroid-stimulating hormone level, serum
  prolactin level, if indicated
• Lupus anticoagulant
• Complete blood count with platelets

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• Tests with unproven or unknown utility
•  
• - evaluation of ovarian reserve using day 3 serum
  follicle-stimulating hormone
• - testing for serologic evidence of PCOS using LH
  or androgen values levels or the clomiphene
  challenge test
• testing for peripheral evidence of Th1 and Th2
  cytokine dysregulation
• - testing for hypercoagulability using the aPTT
  or for the presence of a hereditary thrombophilia
  
• - the prevalence and activity of peripheral NK
  cells
• testing for the presence of a variety of
• autoantibodies (antiphosphatidylserineand anti-?2
  glycoprotein1) -gt placental pathology
• - testing for antithyroid antibodies
• testing for congenital or acquired defects in
  homocysteine metabolism -gt the measurement of
  blood levels of homocysteine
• - cervical cultures for mycoplasma, ureaplasma
  and chlamydia

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Postconception Evaluation

• close monitoring
• to provide psychological support and to confirm
  intrauterine pregnancy and its viability
• serum levels of ?-hCG
• serum  ?-hCG levels should be serially monitored
  from the time of a missed menstrual period until
  the level is about 1500 mIU/mL , at which time an
  ultrasonographic scan is performed and blood
  sampling is discontinued.

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• ultrasonographic examination
• ultrasonographic assessment is then performed
  every 2weeks until the gestational age at which
  previous pregnancies were aborted
• maternal serum for a-fetoprotein assessment
• at 16-18 weeks of gestation
• amniocentesis
• to assess the fetal karyotype after the pregnancy
  has progressed past the time of prior losses

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Therapy

• Genetic abnormalities
• Anatomic Anomalies
• Endocrine Abnormalities
• Infection
• Immunologic Factors
• Antithrombotic Therapy
• Psychological Support

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Genetic abnormalities

• antithrombotic therapy
• for patients with inherited thrombophilias
• assisted reproductive technologies, including PGD
  (preimplantation genetic diagnosis)
• the removal of a single cell from an in
  vitro-matured embryo
• Genetic testing can be performed on this cell to
  rule out gross chromosomal abnormalities or the
  presence of specific genetic diseases
• embryos that are diagnosed with genetic
  abnormalities would not be chosen for replacement
  into the uterine cavity
• genetically normal would be considered
  appropriate for transfer into the uterus.
• use of either donor oocyte or donor sperm
• depending on the affected partner

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Anatomic Anomalies

• hysteroscopic resection
• submucous leiomyomas, intrauterine adhesions,
  intrauterine septa, patients with DES exposure,
  hypoplastic uteri, complicating septal anomalies
• in the operating room, general anesthesia
• ultrasonographically guided transcervical
  metroplasty
• safe and effective, ambulatory, office-based
  procedures
• placement of a cervical cerclage
• for patients with a history of loss secondary to
  cervical incompetence
• performed early in the second trimester

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Endocrine Abnormalities

• luteal-phase insufficiency
• stimulating folliculogenesis with ovulation
  induction
• hyper androgen and LH hypersecretion disorders,
  especially following pituitary desensitization
  with gonadotropin-releasing hormone agonist
  therapy - this treatment also remains
  controversial
• luteal-phase support with progesterone
• PCOS, hyperandrogenism, hyperinsullinemia
• insulin-sensitizing agents
• overt diabetes mellitus
• prepregnancy glycemic control
• hypothyroidism
• thyroid hormone replacement with synthroid

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Infection

• an infectious organism has been identified
• appropriate antibiotics should be administered to
  both partners
• followed by posttreatment culture
• empiric antibiotic treatment has been used for
  couples with recurrent abortion.
• its efficacy is unproven

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Immunologic Factors

• Immunostimulating Therapies-Leukocyte
  Immunization
• Immunosuppressive Therapies

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Immunostimulating Therapies-Leukocyte Immunization

• stimulation of the maternal immune system using
  alloantigens on either paternal or pooled donor
  leukocytes
• a number of reports support possible mechanism
  for potential therapeutic value
• however, there is no credible clinical or
  laboratory method to identify a specific
  individual who may benefit from such therapy
• leukocyte immunization also poses significant
  risk to both the mother and her fetus
• graft-versus-host disease, severe intrauterine
  growth retardation, and autoimmune and isoimmune
  complications

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Immunosuppressive Therapies

• To antiphospholipid antibodies and to
  inappropriate cellular immunity toward the
  implanting fetus
• intravenous immunoglobulin
• progesterone

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intravenous immunoglobulin

• theory
• an overzealous immune reactivity to their
  implanting fetus
• Mechanism
• decreased autoantibody production and increased
  autoantibody clearance, T-cell and Fc receptor
  regulation, complement inactivation, enhanced
  T-cell suppressor function, decreased T-cell
  adhesion to the extracellular matrix, and
  downregulation of Th1 cyokine synthesis
• disadvantage
• expensive, invasive, and time-consuming,
  requiring multiple intravenous infusions over the
  course of pregnancy
• side effects
• nausea, headache, myalgias, hypotension,
  anaphylaxis

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progesterone

• Mechanism
• inhibits Th1 immunity
• shift from Th1-to Th2 type responses
• administered
• intramuscularly
• intravaginally
• may increase local, intrauterine concentration
• averting any adverse systemic side effects

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Antithrombotic Therapy

• the combined use of low-dose aspirin (75-80mg/dl)
  and subcutaneous unfractionated heparin (5000unit
  twice daily)
• antiphospholipid antibody syndrome
• aspirin (80mg every day) beginning
• after pregnancy has been confirmed, 5000 IU
  unfractionated sodium hearin is administered
  subcutaneously twice daily, throughout gestation.
  
• an aPTT should be obtained weekly
• increased risk for preterm labor, premature
  rupture of the membranes, intrauterine growth
  restriction, intrauterine fetal demise, and
  preeclampsia.
• gastirc bleeding, osteopenia, and abruptio
  placenta.

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• LMWH
• increased antithrombotic ratio, fewer bleeding
  side effects. a decreased incidence of
  thrombocytopenia and osteoporosis. a long
  half-life, less frequent dosing and monitoring
• protein C concentrates
• favorable pregnancy outcome in a patient with a
  history of thrombosis, recurrent fetal losses,
  and protein C deficiency
• vitamins B6, B12 and folate
• important in homocysteine metabolism, and
  hyperhomocysteinemia is linked to recurrent
  pregnancy loss

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Psychological Support

• guilt among patients with recurrent losses
• the risk for major depression is increased
  greater than twofold among women with spontaneous
  pregnancy loss, in most women, it arises in the
  first weks after delivery
• a caring and empathetic attitude is prerequisite
  to all healing.
• referrals to support groups and counselors should
  be offered.
• self-help measures, such as meditation, yoga,
  exercise, and biofeedback, may also be useful.

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Prognosis

• the prognosis for successful pregnancy depends
• the potential underlying cause of pregnancy loss
• the unmber of prior losses.

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• the chance of a viable birth
• even after four prior losses 60
• cytogenetic etiology 20-80
• corrected anatomic anomalies 60-90
• corrected endocrinologic abnormalities higher
  than 90
• women receiving therapy for antiphospholipid
  antibodies 70 - 90