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Recurrent Pregnancy Loss Dr.Narendra Gupta Vivekanand


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Title: Recurrent Pregnancy Loss Dr.Narendra Gupta Vivekanand

Recurrent Pregnancy Loss
  • Dr.Narendra Gupta
  • Vivekanand hospital and fertility center, Jaipur

Vivekanand hospital and fertility center
  • Superspeciality center for the treatment of
    infertile couples
  • IUI
  • IVF
  • ICSI
  • Endoscopy
  • Sperm bank

  • A recurrent pregnancy loss is defined as 3 or
    more consecutive, spontaneous pregnancy losses.
    Pregnancy losses are in the form of abortions,
    rhesus isoimmnisation, cervical incompetence and
    recurrent preterm labor where the losses occur
    after 20 weeks of gestation.
  • Recurrent abortion or miscarriage where the
    pregnancy loss is always under 20 weeks
  • Recently 2 or more spontaneous
    abortions/pregnancy loss have also been put in
    this category-
  • i. Since the risk of a recurrent loss is fairly
    high even after 2 losses (26), we are justified
    to start work-up after 2 losses.
  • ii. Nowadays women start their reproductive
    career in their late twenties or early
    thirties.They do not have the time to wait for a
    third loss.
  • Recurrent miscarriage affects 1 (0.5-3 ) of
    all women

Impact of RPL
  • RPL results in great psychological trauma to the
    couple specially the woman.
  • They feel devastated and fear that this should
    not happen to them again.
  • It results in severe anxiety and depression.

Types of RPL
  • Preclinical or very early pregnancy losses- B-HCG
    positive pregnancies. This is due to poor
    implantation and LPD.
  • Clinical pregnancy loss- An ultrasound evidence
    of Gestation sac 10-15
  • First trimester loss- Almost 80 of RPL occur in
    the first 12 weeks
  • Midtrimester loss- 12 to 28 weeks
  • Late fetal loss- between 28 weeks to term

Approach to a patient with RPL
  • A detailed clinical history is useful. Every
    miscarriage and gestational age should be noted
  • Very early (lt 6 weeks), 7-12 weeks and more than
    12 weeks
  • Missed abortion or spontaneous live fetal

Clinical Approach
  • Try to find out a cause. In more than two third
    of the cases an etiological factor can be found.

  • Investigations should be directed to find out a
  • Male partner- Semen analysis-look for OAT and
  • Female partner
  • Full blood count
  • Blood group
  • Thyroid function tests
  • HbA1C,Blood sugar/OGTT if needed
  • Karyotyping
  • Hormonal profile LH,FSH,T1,PRL,DHEAS
  • LA and ACA IgG and AgM
  • Thrombophilia screen
  • Transvaginal sonography
  • Hysteroscopy
  • Thyroid peroxidase antibody
  • Autoantibody screen
  • Total homocysteine
  • Rubella status
  • Free androgen index
  • SHBG

Transvaginal sonography
  • TVS at 6 weeks is recommended to detect cardiac
  • Cervical length should be carefully assessed in
    patients with RPL
  • Color flow studies of corpus luteum and uterine
    artery are helpful
  • Role of 3 D scanning for anatomical defects of
    the uterus is undisputed

Recurent Miscarriage
Genetic factors
Enviromental factors
Infective agents
Anatomical factors
Immune factors
Thrombophilic defect
Bacterial Vaginosis
Paternal karyotyping
Uterine Abnormalities
  • Uterine abnormalities detected on USG can be
    further investigated by 3 D scan, Hysteroscopy or
    HSG if necessary
  • The finding of uterine anomaly does not
    necessarily imply causation and surgical
    treatment may not be indicated

Diagnosis of Uterine Anomalies
  • Transvaginal sonography
  • 3D Ultrasound
  • Laparoscopy
  • Hysteroscopy
  • MRI
  • Hysterosalpingogram (HSG)

Uterine anomalies
  • The reported prevalence of uterine anomalies in
    recurrent miscarriage populations range between
    1.8 and 37.6.
  • The prevalence of uterine malformations appears
    to be higher in women with late miscarriages
    compared with women who suffer early miscarriages
    but this may be related to the cervical weakness
    that is frequently associated with uterine
  • untreated uterine anomalies has a term delivery
    rate of only 50.
  • Open uterine surgery is associated with
    postoperative infertility and carries a
    significant risk of uterine scar rupture during
    pregnancy. These complications are less likely to
    occur after hysteroscopic surgery but no
    randomised trial assessing the benefits of
    surgical correction of uterine abnormalities on
    pregnancy outcome has been performed.

  • If fibroids are detected on the inside of the
    uterus (termed submucous fibroids) and distort
    the uterine lining, they are a significant cause
    of reproductive problems and should be removed

Uterine anomalies
  • Mullerian anomalies particularly the Bicornuate
    and unicornuate uterus are associated with RPL
  • Septum resection, release of intrauterine
    synechiae and removal of polyp under
    hysteroscopic guidance have a better prognosis

Cervical incompetence
  • Cervical incompetence is common in patients of
    RPL due to repeated D Cs
  • TVS diagnosis of cervical length is diagnostic
  • Cervical cerclage offers a good pregnancy outcome

Genetic factors
  • Chromosome Testing on Fetal (Miscarriage) Tissue
  • This can only be done right at the time of
  • It is an analysis of the genetic makeup of the
  • It can indicate genetic problems that lead to
  • Many miscarriages are caused by chromosomal
    abnormalities that are unlikely to repeat. To
    know if the problem is likely to recur, it is
    necessary to study the genetics of both parents
    as well.
  • Karyotyping of Parents
  • each Chromosome analysis of blood of both
  • It can show if there is a potential problem with
    one of the parents that leads to miscarriage, but
    often has to be done in conjunction with fetal
    testing to provide answers.
  • These tests help rule out the 3 or so of
    partners that carry a "hidden" chromosomal
    problem called a balanced translocation.

  • It is a display of an individuals chromosome
  • Process Sample of blood is taken.
  • Cells are chemically stimulated to undergo
    mitosis. Mitosis is stopped at metaphase.
  • Chromosomes are separated out, viewed with a
    microscope and photographed.
  • The photograph is then rearranged to show the
    paired chromosomes. Size, shape and banding
    pattern are used to pair up the chromosomes.

Polycystic ovaries
  • PCOS are associated with increased incidence of
    pregnancy loss.
  • Evidence suggest that hypersecretion of LH,
    hyperandrogenemia and luteal phase defects is
    associated with poor reproductive outcome.
  • Treatment is HCG, metformin and progesterone

  • Endometriosis not only is responsible for
    infertility, it also causes RPL.
  • Though exact role is uncertain, probably it
    relates to poor egg quality seen in patients of

Immunology of RPL
  • 40 of losses in RSA could be due to immunology
  • 1. Alloimmune
  • 2. Auto immune

Pregnancy and immunological miracle of immune
  • Why should the mother tolerate the fetus?
  • How does the mother tolerate the fetus ?

  • A conceptus of 3000 gms is tolerated, protected
    and nourished by the mother for 280 days
  • after birth even 30 gms of say renal tissue of
    that conceptus is not tolerated and immune
    rejection occurs why?
  • Husbands renal tissue transplanted in the mother
    during pregnancy is not accepted
  • How his conceptus is accepted?

Alloimmune response
  • At fetomaternal interface when the mothers
    immune system senses that a different system has
    arrived it mounts a protective response.
  • This is through the syncitiotrophoblast
  • Functioning of trophoblast is such that it will
    sense only immunologically distinct identity.
  • In fact if it is immunologically similar the
    syncitiotrophoblast will not sense and the
    mothers immune sysyem will destroy it.
  • This can occur repeatedly and results in RPL.

  • This can be applied to renal transplants or any
    other transplant.
  • If transplant scientists can create an artificial
    trophoblast like shield around the donated organ,
    once again the receptor will protect it and there
    will be no rejection.
  • In fact HLA testing will become obsolete because
    you will require the donor and the recipient to
    be different and not similar as in the case of
    the conceptus.

  • The role of HCG is believed to be much beyond
  • It is believed to have a very strong role that
    generates changes in the endometrium.
  • This explains the abrupt and graded rise of HCG
    levels as soon as blastocyst is formed.
  • Some perceive HCG as the master of the orchestra
    that brings about the entire process of nidation
  • Immune substance first thought to be similar to
    growth factor
  • Subsequently proved to be growth factor itself

  • Progesterone plays an important role in
  • Micronised progesterone in varying doses have
    proven to be successful in reducing spontaneous
    abortion rate

Auto immune
  • Many syndrome antibodies are implicated
  • But most influential and consistent have been
    anti phospholipid antibody syndrome.

  • Negative lt 10 GPL units
  • Low positive 10-20
  • Moderately positive 20-100
  • Strongly positive gt 100
  • Once the diagnosis is well established treatment
    plans are instituted
  • Mainstay is heparin, low dose aspirin

  • In interval period-
  • For low and moderate aspirin in a dose of 1-2
    mg/kg/day till conception. Allow conception-
    continue aspirin from 12 weeks upto 36 weeks
  • For high positive-aspirin in a dose of 1-2
    mg/kg/day till conception in the interval period.
    Allow conception. Continue aspirin upto 36 weeks
  • add heparin in a dose of 1000 IU/day from
    conception till 36 weeks
  • Low molecular weight heparin is also being used
    effectively- convenience of dosing schedule and
    less bleeding episodes.
  • In pregnancy-
  • for these cases we give only the post conception
    protocol of aspirin or aspirin heparin as

Lymphocyte Immnunization therapy (LIT therapy)
and IV Immunoglobulins
  • Indications- Unexplained infertility
  • For two-thirds of the known causes," he said,
    "there is a specific treatment. Then you have
    about 40 percent where you don't know exactly
    what has caused it. So there are some empirically
    unproven treatments out there that are highly
  • One theory explaining why some women repeatedly
    miscarry is that the immune system somehow fails
    to recognize and protect a pregnancy, and instead
    mounts antibodies to attack it.
  • This idea has led doctors to try two treatments
    intended to to restore normal immune function.
    One is intravenous immunoglobin therapy, a blood
    product pooled from thousands of donors and used
    to regulate abnormal responses of the immune
    system. The other is lymphocyte immune therapy,
    which uses blood from a woman's partner to prompt
    her immune system to recognize a pregnancy.
  • A report in the literature (THE LANCET Vol. 354,
    July 31, 1999, 365) indicates that women who have
    received LIT may have a higher incidence of
    subsequent miscarriage than women who did not
    receive such cellular products.
  • Whether LIT uses cells/cellular products from the
    woman's partner or from other donors, the
    manufacturing/preparation and administration of
    such cells/cellular products presents risks to
    the recipient (e.g., administration of
    non-sterile cellular products, transmission of
    communicable diseases).

Immunotherapy for recurrent miscarriage
TF Porter, Y LaCoursiere, JR Scott Cochrane
Database of Systematic Reviews 2008 Issue 3
  • Objectives- The objective of this review was to
    assess the effects of any immunotherapy,
    including paternal leukocyte immunization and
    intravenous immune globulin on the live birth
    rate in women with previous unexplained recurrent
  • Main results
  • Twenty trials of high quality were included. The
    various forms of immunotherapy did not show
    significant differences between treatment and
    control groups in terms of subsequent live
    births paternal cell immunization (12 trials,
    641 women), Peto odds ratio (Peto OR) 1.23, 95
    confidence interval (CI) 0.89 to 1.70 third
    party donor cell immunization (three trials, 156
    women), Peto OR 1.39, 95 CI 0.68 to 2.82
    trophoblast membrane infusion (one trial, 37
    women), Peto OR 0.40, 95 CI 0.11 to 1.45
    intravenous immune globulin, Peto OR 0.98, 95 CI
    0.61 to 1.58. Authors' conclusions
  • Paternal cell immunization, third party donor
    leukocytes, trophoblast membranes, and
    intravenous immune globulin provide no
    significant beneficial effect over placebo in
    improving the live birth rate.

Diabetes and thyroid disorders
  • Routine screening for occult diabetes and thyroid
    disease with oral glucose tolerance and thyroid
    function tests in asymptomatic women presenting
    with recurrent miscarriage is uninformative
  • well-controlled diabetes mellitus is not a risk
    factor for recurrent miscarriage, nor is treated
    thyroid dysfunction

  • There is insufficient evidence to assess the
    effect of hyperprolactinaemia as a risk factor
    for recurrent miscarriage.

  • Hyperhomocysteinemia is associated with an
    approximately 2-fold to 3-fold increased risk for
    pregnancy-induced hypertension, abruptio
    placentae, and intrauterine growth restriction.
    Cobalamin deficiency is associated with HELLP
    syndrome, abruptio placentae, intrauterine growth
    restriction, and intrauterine fetal death.
  • Deficiencies of the vitamins folic acid,
    pyridoxine (B6), or B12 can lead to high
    homocysteine levels.
  • Supplementation with pyridoxine, folic acid, B12
    or trimethylglycine (betaine) reduces the
    concentration of homocysteine in the bloodstream.
  • Normal fasting homocysteine plasma levels are
    between 5,0 and 15,9 mmol/l.

  • TORCH (toxoplasmosis rubella, cytomegalovirus and
    herpes simplex virus), other congenital syphilis
    and viruses, screening is unhelpful in the
    investigation of recurrent miscarriage.
  • For an infective agent to be implicated in the
    aetiology of repeated pregnancy loss, it must be
    capable of persisting in the genital tract and
    avoiding detection or must cause insufficient
    symptoms to disturb the women. Toxoplasmosis,
    rubella, cytomegalovirus, herpes and Listeria
    infections do not fulfill these criteria and
    routine TORCH screening should be abandoned.

Bacterial vaginosis
  • Screening for and treatment of bacterial
    vaginosis in early pregnancy among high risk
    women with a previous history of second-trimester
    miscarriage or spontaneous preterm labour may
    reduce the risk of recurrent late loss and
    preterm birth.

Environmental factors
  • Exposture to noxious or toxic substances are
    known to be associated with recurrent miscarriage
    ( social drugs, cigarettes, alcohol and caffeine
    ,anesthetic gases, petrolium products )

One stop Recurrent miscarriage clinic
  • Dedicated clinic governed by evidence based
  • More extensive investigations and tailored
  • Supportive care

  • Full blood count
  • Thyroid function tests
  • HbA1C
  • Karyotyping
  • Hormonal profile LH,FSH,T1,PRL,DHEAS
  • LA and ACA IgG and AgM
  • Thrombophilia screen
  • TVS
  • Hysteroscopy
  • TORCH profile
  • Thyroid peroxidase antibody
  • Autoantibody screen
  • Total homocysteine
  • Rubella status
  • Free androgen index
  • SHBG

Frequency of possible etiological factors in 189
For unexplained RPL
  • For those women with no documented abnormality,
    supporting care, including USG is valuable.
  • Studies have shown this type of therapy to
    improve the prognosis,with the rate of live birth
    in the subsequent pregnancy upto 86 ,although
    the outcome is age related.

Obstetric outcome in patients with H/O recurrent
pregnancy loss
  • Patients with H/O RPL are more likely to have
  • threatened abortion
  • APH
  • preterm labour
  • depressed APGAR at 1 minute
  • IUGR

Management of pregnancy
  • These patients should be followed up in a
    specially dedicated facility
  • Round the clock assistance should be available

Last but very important !
  • RPL management should have a back-up of very
    efficient and modern neonatal care unit. It
    should have a good track record of salvaging
    infants weighing more than 1 Kg.
  • A sympathetic and caring attitude along with
    pediatric care can fulfill the desire of
    parenthood of many of these couples.

Some new messages for clinical practice
  • Past performance is important in prognosticating
    the outcome.
  • Live abortion indicate the anatomical cause.
    Cervical encerclage has a very important role in
    treating incompetent cervix.
  • Chromosomal causes are not always gloomy
  • Immunological causes are most prevalent
  • APA syndrome has a oxidative stress complex but
    is easy to treat.
  • Corticosteroids are not used anymore. Aspirin-
    heparin combination give best results.
  • Pregnancy following treatment of RSA are still
    high risk pregnancies
  • These patients should be followed very closely
    and possibility of them undergoing preterm labor
    should be kept highest in our mind. Timely
    administration of Betamethasone is a must for
    fetal lung maturity.

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