Recurrent Pregnancy Loss Dr.Narendra Gupta Vivekanand

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Recurrent Pregnancy Loss

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

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Vivekanand hospital and fertility center

• Superspeciality center for the treatment of
  infertile couples
• IUI
• IVF
• ICSI
• Endoscopy
• Sperm bank

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Definition

• 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
  gestation
• 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

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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.

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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

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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
  expulsion

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Clinical Approach

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

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Investigations

• Investigations should be directed to find out a
  cause
• Male partner- Semen analysis-look for OAT and
  pyospermia
• 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

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Transvaginal sonography

• TVS at 6 weeks is recommended to detect cardiac
  activity
• 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

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Recurent Miscarriage
Explained
Un-explained
Genetic factors
Enviromental factors
Infective agents
Endocrine
Anatomical factors
Immune factors
Thrombophilic defect
Bacterial Vaginosis
Body
Cervix
APS
Paternal karyotyping
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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

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Diagnosis of Uterine Anomalies

• Transvaginal sonography
• 3D Ultrasound
• Laparoscopy
• Hysteroscopy
• MRI
• Hysterosalpingogram (HSG)

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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
  malformation.
• 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.

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Fibroids

• 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
  hysteroscopically

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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

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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

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Genetic factors

• Chromosome Testing on Fetal (Miscarriage) Tissue
• This can only be done right at the time of
  miscarriage.
• It is an analysis of the genetic makeup of the
  fetus.
• It can indicate genetic problems that lead to
  RPL.
• 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
  parents.
• 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.

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Karyotyping

• It is a display of an individuals chromosome
  pairs.
• 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.

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Karyotyping
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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
  supplementation

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Endometriosis

• 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
  endometriosis

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Immunology of RPL

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

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Pregnancy and immunological miracle of immune
tolerance

• Why should the mother tolerate the fetus?
• How does the mother tolerate the fetus ?

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Alloimmune

• 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?

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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.

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• 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.

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HCG

• The role of HCG is believed to be much beyond
  hormones
• 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

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progesterone

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

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Auto immune

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

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Diagnosis

• 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

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Protocol

• 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
  specified.

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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
  debatable."
• 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).

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Immunotherapy for recurrent miscarriage
TF Porter, Y LaCoursiere, JR ScottCochrane
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
  miscarriages
• 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.

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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

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Hyperprolactinemia

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

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Hyperhomocysteinemia

• 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.

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Infections

• 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.

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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.

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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 )

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One stop Recurrent miscarriage clinic

• Dedicated clinic governed by evidence based
  guidelines
• More extensive investigations and tailored
  treatment
• Supportive care

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Investigations

• 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

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Frequency of possible etiological factors in 189
couples
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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.

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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

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Management of pregnancy

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

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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.

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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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Thank You !