Recurrent Pregnancy Loss

1
Recurrent Pregnancy Loss

• Erin Saunders
• August 12, 2004

2
Educational Objectives

• Genetic basis of RPL
• Most common causes of first trimester loss
• Work up of RPL
• Treatment of RPL
• Counseling on RPL

3
Definition of RPL

• Traditionally, RPL defined as 3 consecutive
  losses
• 30-45 risk of SAB after 3 previous SABs similar
  to 30 seen after 2 SABs, therefore 2 SABs
  warrants a RPL workup.

4
Normal Statistics

• Early pregnancy loss loss before 20 wks or less
  the 500gms
• 15 of all recognized pregnancies 4-20 wks end in
  SAB.
• 50 of all pregnancies end in SAB since 2-4 wk
  pregnancies will often go unnoticed.
• 30 lost between implantation and the 6th week.
• 70 of first trimester losses due to chromosomal
  abnormalities.

5
Statistics

• Rate of loss increases with age and is as great
  as 75 over age 40.
• Once FHT are seen on USG rate of loss in normal
  women 3-5.
• With RPL-once FHT seen loss rate is 4-5 times
  greater (22.7)

6
Genetics

• 70 1st trimester losses, 30 of 2nd, and 3 of
  3rd trimester losses due to chromosomal
  abnormalities.
• If abnormal karyotype with SAB then 50 chance
  next fetus is normal.
• Most abnormalities are due to translocation and
  nondisjunction.
• Most common chromosomal abnormality is autosomal
  trisomy (13, 16, 18 21, 22)
• 2nd most common 45x followed by polyploidies

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Genetics

• All pts with RPL should be offered karyotype
  testing of parents.
• Karyotyping of POCs is controversial and
  definite recommendations for routine karyotyping
  has not been proven.
• Benefits are, if aneuploid a maternal cause of
  pregnancy loss is excluded and results may
  provide comfort to the pt.

8
Etiology of RPL

• Genetic Factors
• Environmental
• Endocrine Factors
• Anatomic Causes

• Infectious causes
• Thrombophilias
• Immunologic problems

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Environmental

• Associated with increased risk of RPL Smoking,
  ETOH, Anesthetic Gases, Tetrachloroethylene (used
  in dry cleaning), Accutane
• NOT associated Caffeine, electric blankets,
  exercise.
• Bed rest will not prevent SAB

10
Endocrine Factors

• The truth about COMMON MISCONCEPTIONS
• Mild or subclinical endocrine disease is NOT
  associated with RPL, but significant Thyroid dz
  or uncontrolled DM may lead to increased risk of
  SAB, therefore, routine screening for TSH, PRL,
  and DM is not warranted.
• Endometriosis is NOT associated with increased
  RPL
• Elevated LH from PCOS does NOT increase SAB risk
  it is associated with anovulation and infertility.

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Endocrine Factors

• THE TRUE FACTS
• Inadequate luteal phase IS associated with RPL,
  but treatment with progesterone or its
  metabolites has failed to show statistical
  significance in the treatment of RPL.
• DX of LPD 2 consecutive EMBX laging 2 days
  behind menstrual dating
• Although luteal phase progesterone is always
  checked with RPL, studies have NOT proven its
  efficacy

12
Endocrine Factors

• As with infertility, treatment of RPL with
  clomid, progesterone or dopamine agonist (if
  elevated prolactin) has shown some benefit if
  luteal phase is less than 11 days.
• HCG has been used as a Tx to stimulate the corpus
  luteum, statistical significance has not been
  proven.
• Some have suggested empiric treatment with clomid
  if no other cause of RPL can be found.

13
Anatomical

• Most common anomaly is septated uterus.
• Others include large fibroids, polyps,
  Ashermans syndrome, DES exposure, mullerian
  anomalies (bicornate, unicornate uterus etc.)
• Anomalies can limit vascularization to fetus.
• Dx by Hysterosalpingogram, hysteroscopy,
  Sonohysteroscopy
• Surgical repair of anomalies has shown 70-80
  cure rate of RPL, but these results are being
  questioned due to selection bias.

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Mullerian anomalies
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Infectious Causes

• There has been NO true association found between
  Bacterial or viral organisms and RPL, although
  Chlamydia, Mycoplasma, Listeria, Toxoplasma,
  rubella, HSV, CMV, measels, coxackievirus have
  been associated with SABs.
• Endometrial Ureaplasma has been associated with
  RPL
• Antichlamydial Ab has been found in women with
  RPL, but chlamydia is NOT associated with RPL.

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Infectious

• Routine screening for these infections is not
  recommended by ACOG.
• Tx of Ureaplasma and Mycoplasma with Abx has been
  beneficial.
• Tx both partners with Doxycycline 100mg b.i.d. x
  14 days or EES 250mg q.i.d. x 14 days if positive
  culture.

17
Thrombophilia

• Thrombophilias have been found to be associated
  with late losses and increased risk of
  thrombosis.
• Hypercoaguable conditions Antithrombin III
  deficiency or mutation, Prot C and Prot S
  deficiency or mutation, Factor V Leiden mutation,
  Prothrombin gene G20210A mutation, APA syndrome

18
Thrombophilias

• Mutations in Prothrombin gene and Factor V Leiden
  (European descent) most common.
• Factor V Leiden mutation is a mutation at a
  specific site on the protein C gene.
• Elevated homocysteine levels have been
  associated with thrombosis and early RPL, but
  results are not clear cut at this time.

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Thrombophilias

• Thrombophilia screening Antithrombin III,
  Protein C and S, Activated protein C resistance
  ratio, PT, PTT, Anticardiolipin Ab, Lupus
  anticoagulant, Fibrinogen, Prothrombin G
  mutation, Homocystine level, CBC
• Screening warranted for any pt with unexplained
  RPL especially if PMH or FH of thromboembolism.
• Tx LMW heparin

20
Immunologic

• Factors suggesting immunologic cause
• Many SABs
• No recent full term pregnancies
• Less than 35yo
• SAB with normal karyotype
• One loss after 1st trimester

21
Immunologic

• Autoimmunity An immunological response is
  directed against a specific component of the host
  (Antiphospholipid syndrome, Auto antibodies to
  thyroid, Antinuclear AB)
• Alloimmunity immunologic differences between
  individuals (foreign antigens)

22
Autoimmunity

• Antiphospholipid syndrome Presence of Lupus
  anticoagulant and/or anticardiolipin Ab (IgG,
  IgM), on 2 occasions 6 wks apart.
• Ab are directed against platelets which causes
  thrombosis and vasoconstriction by interrupting
  prostacyclin formation.
• Associated with increased RPL (second trimester),
  fetal wastage, thrombosis, fetal growth
  retardation and fetal death.
• Tx low dose aspirin and low dose heparin 1st
  trimester

23
Autoimmunity

• Autoantibodies to Thyroid antigens inconclusive
  as to if there is an association with RPL
• Antinuclear antibodies 15 of women with RPL,
  but no association with RPL is proven. Tx with
  ASA and Prednisone did NOT improve pregnancy
  outcomes.

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Alloimune Disorders

• Theories
• Partners share HLA typing therefore mother wont
  make blocking Ab to prevent rejection of fetal
  antigens
• Female fails to produce serum blocking factor
• Female partner produces antileukocytotoxic Ab
  against paternal leukocytes.
• Dysregulation of the maternal-fetal immune
  mechanisms

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Alloimmune

• There is no way to test for these disorders.
• Tx options immunize fm with m leukocytes or
  infuse IVIG into fm which blocks Ab mediated
  immune damage.
• Neither of these have been proven Tx and are not
  recommended by ACOG.

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Summary
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Conclusion and Counseling

• These patients require an understanding,
  sympathetic and supportive doctor.
• Multiple visits during the first trimester.
• 60-70 of pts with 1st trimester RPL will have a
  successful pregnancy.
• Pts with 2nd trimester losses have a poorer
  prognosis.