Recurrent Pregnancy Loss- Dr.SIRISHA

 

  1. DEFINITION
    RPL

Loss of 2 or more pregnancies.

2. RISK FACTORS

  1. Chronic endometritis:
  • Further research is needed before screening for endometritis can be recommended

2.Occupational and environmental factors:

  • Few small studies: – Heavy metals – Micronutrients
  • Pesticide: increase risk of PL
    Although exposure to possible hazardous substances should be avoided during pregnancy (for all pregnant women) there are insufficient data to recommend protection against a certain occupational or environmental factor in women with RPL.

3. Stress:
No evidence that stress causes RPLs

4. Age:

  • Risk of PL
  • Lowest between 20 to 35 years §rapidly increases after the age of 40.

5.Obesity or Significantly underweight:

  • Obstetric complications
  • Negative impact on chances of a live birth and general health.
  • Healthy normal range BMI is recommended

6.Smoking:

  • Negative impact on chances of a live birth
  • Cessation of smoking is recommended.

7.Caffeine intake

  • An association between caffeine and late PL.
  • Not all studies
  • Based on the evidence, it is unclear whether caffeine intake is a risk factor for PL

 

3. INVESTIGATIONS

Medical and family history

  • Used to tailor diagnostic investigations.
  1. Anatomical
    2. Endocrinological
    3. Thrombophilia
    4. Male
    5. Immunologic
    6. Genetic
    7. unexplained
  2. Anatomical factors
  3. Pelvic US:
  • To assess
  • uterine anatomy
  • congenital uterine abnormalities.
  • The preferred technique
    TV 3D US
    {1. high sensitivity and specificity
    2. distinguish between uterus septum and bicornuate uterus}.
  1. Sonohysterography (SHG)
  • More accurate than HSG in diagnosing uterine malformations.
    Used to evaluate uterine morphology when 3D US is not available, or when tubal patency has to be investigated
  • MRI
    not recommended for the assessment of uterine malformations in women with RPL.
  1. Endocrinologic factors
  2. Thyroid screening
  • TSH
  1. Prolactin testing

not recommended in absence of clinical symptoms of hyperprolactinemia and if h/o irregular cycles

  • Not routinely recommended

 

  • PCOS
  • fasting insulin and fasting glucose
  • Ovarian reserve testing
  • Luteal phase insufficiency testing
  • Androgen testing
  • LH testing
  • Measurement of homocysteine plasma levels
  • Testing vit D status

III. Thrombophilia screening

  • Screening for inherited thrombophilia not recommended.
    {No or weak association}
  1. Screening for antiphospholipid antibodies
  • LA
  • ACA IgG and IgM
  • aβ2GPI
  1. Male factors
  2. Assess life style factors
  • Smoking
  • Alcohol consumption
  • Exercise pattern, and
  • Body weight.
  1. Assessing sperm DNA fragmentation can be considered based on indirect evidence.
  2. Immunological screening
  3. Antinuclear antibodies (ANA) testing could be considered for explanatory purposes.
  • Not recommended:
  • HLA determination:
  • Only HLA class II determination (HLA-DRB1*15, DRB1*07 and HLA-DQB1*0501/2) could be considered in secondary RPL after the birth of a boy, for prognostic purposes
  • Measurement of anti-HY antibodies
  • Cytokine testing or cytokine polymorphisms
  • NK cell testing: S
  • Testing anti-HLA antibodies
  1. Screening for genetic factors
  2. Genetic analysis of pregnancy tissue
  • not routinely recommended but it could be performed for explanatory purposes.

 

  • For genetic analysis of the pregnancy tissue,
    array-CGH is recommended {based on a reduced maternal contamination effect}.
  1. Parental karyotyping
  • not routinely recommended.
  • could be carried out after individual assessment of risk.

In case of established carrier status:

the long-term prognosis of a live birth is good in carriers of a structural chromosome abnormality (LBR of 71% in 2 years).

  1. TREATMENT

Risk factors

  • Couples with RPL should be informed that smoking, alcohol consumption, obesity and excessive exercise could have a negative impact on their chances of a live birth.

Cessation of smoking
2. Normal body weight
3. Limited alcohol consumption

  1. Normal exercise pattern is recommended.

 

  1. Treatment for uterine abnormalities
  • Uterine septum:
    §Whether hysteroscopic septum resection has beneficial effects (improving LBR, and decreasing miscarriage rates, without doing harm), should be evaluated.
  • Didelphic uterus
    insufficient evidence in favor of metroplasty.
  • Bicornuate uterus
    §Metroplasty is not recommended.
  • Unicornuate uterus
    Uterine reconstruction is not recommended.
  • Intramural fibroids
    §Surgical removal is not recommended.
  • Fibroids distorting the uterine cavity.

insufficient evidence to recommend removing.

  • Submucosal fibroids or endometrial polyps No evidence supporting hysteroscopic removal.
  • Intrauterine adhesions
  • insufficient evidence of benefit for surgical

removal.
§After hysteroscopic removal of intrauterine adhesions, precautions to

prevent recurrence.

 

Justification

  1. Small observational studies have shown that this may decrease miscarriage rates in women with RPL.
  2. Uterine surgery is a known cause for adhesions, and treatment should attempt to prevent recurrence of adhesions.

 

  • History of recurrent 2nd trimester PLs and
  • suspected cervical weakness
  • Serial cervical sonographic surveillance.
  • History of recurrent 2nd trimester PL
  • Attributable to cervical weakness §Singleton pregnancy
  • Cerclage could be considered.
    §No evidence that this treatment increases perinatal survival
  1. Treatment of endocrinologic abnormalities
  • Clinical hypothyroidism §Levothyroxine.
  • Subclinical hypothyroidism:
  • Treatment may reduce the risk of miscarriage, but the potential benefit of treatment should be balanced against the risks.
    §If women with SCH and RPL are pregnant again
  • TSH level should be checked in early gestation (7-9 w) §eventual hypothyroidism should be treated with levothyroxine.
  • Thyroid autoimmunity
    §TSH level should be checked in early gestation (7-9 w)
    §eventual hypothyroidism should be treated with levothyroxine.
  • Euthyroid women with thyroid antibodies insufficient evidence to support treatment with levothyroxine.
  • Hyperprolactinemia
    §Bromocriptine treatment is recommended to increase LBR.
  • Luteal phase insufficiency.
    §insufficient evidence to recommend the use of progesterone.
    §insufficient evidence to recommend the use of hCG.
  • PCOS
    §Insufficient evidence to recommend metformin.
  • Pituitary suppression before induction of ovulation could be an option to reduce the risk of PL.

III. Treatment of Thrombophilia

  • Inherited thrombophilia
    §Not to use antithrombotic prophylaxis unless in the context of research.
  • APS
    §low-dose aspirin (75 to 100 mg/d), and §heparin (UFH or LMWH) starting at date of a positive pregnancy test .
  1. Treatment of Male factor
  • Cessation of smoking
    §Normal body weight
    §Limited alcohol consumption
    §Normal exercise pattern is recommended. §Sperm selection not recommended as a treatment in couples with RPL.
  • Antioxidants

have not been shown to improve the chance of a live birth.

  1. Treatment of immunological factors

No immunological biomarker, except for high-titer antiphospholipid antibodies can be used for selecting RPL patients for specific treatments.

  1. Genetic factors
  • An abnormal fetal or parental karyotype
    §genetic counseling
    §may be informed about the possible treatment options available including their advantages and disadvantages.

VII. Treatment for unexplained RPL

  • Lymphocyte immunization therapy
    §should not be used.
    {no significant effect and there may be serious adverse effects}.
  • Intravenous immunoglobulin (IvIg) not recommended.
  • Glucocorticoids not recommended.
  • Heparin or low dose aspirin does not improve LBR.
  • Low dose folic acid
    §prevent NTD
    §Not prevent pregnancy loss.
  • Vaginal progesterone
    §does not improve LBR.
  • Intralipid therapy
    §should not be used.
    {it could be harmful for the mother}
  • G-CSF =granulocyte colony stimulating factor insufficient evidence to recommended.
  • Endometrial scratching no evidence to be recommended.
  • Multivitamin supplements

{As there is no conclusive evidence, they are not recommended as treatment.
If women with RPL prefer to use, they should be advised on the use of multivitamin supplements that are safe in pregnancy.
However, based on the possible harms associated with some vitamin supplements (vitamin E), the GDG recommends advice on safe options.}

  1. CONCLUSIONS

Routine Investigations after two consecutive miscarriages:

  1. 3 DUS or Sonohysterography
  2. TSH,TPOAb
    3. Antiphospholipid antibodies
  3. Sperm DNA fragmentation

Treatment of possible causes

  1. Uterine septum, submucous fibroid, severe IU adhesions: Hysteroscopic surgery.
  2. Cervical incompetence: cervical cerclage
  3. Hypothyroidism or SCH: Eltroxin
  4. APA: Low dose aspirin & heparin.
  5. High SDF: Life style changes
  6. Hyperprolactinemia: Dopamine agonist

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