Dr. Mohammed Abdalla

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Recurrent pregnancy loss Part I

• Dr. Mohammed Abdalla
• Egypt, Domiat general hospital

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• Pregnancy losses can be classified as
• 1-Occult(preclinical or chemical) pregnancy loss
  prior to missed menses.(40 of implantation
  embryos)
• 2-Early pregnancy loss before 12 wk.(13)
• 3-Late pregnancy loss after 12 wk. (1)

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• Recurrence suggests a persistent cause ( not just
  a bad luck ) which must be identified and treated

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Causes of pregnancy loss
Chromosomal 55 of occult and early losses 5 of
recurrent losses.
environmental
hormonal
anatomical
Immunological 45 of early losses 95 of late
losses
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Chromosomal abnormalities

• The genetic diseases are divided into two
  categories

Gene abnormalities occur when the genetic
instructions stored in the DNA are altered so
that the protein product coded for by the gene is
less functional or nonfunctional
Chromosomal abnormalities are caused by cells
that have extra or missing chromosomes (aneuploid
)or parts of chromosomes (Deletions ).
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Chromosomal abnormalities

• occurs in 50-60 of eggs retrieved for IVF.
• in 50 of all early preg. Loss .
• in 5 of late losses
• in 0.5 of live births.

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Aneuploidy

• Cytogenetically abnormal embryos are usually
  aneuploid (Cells that have chromosomes missing
  Monosomy or extra chromosomes trisomy )
• Monosomy refers to a condition in which there is
  one chromosome is missing e.g (monosomy X Turner
  syndrome)

trisomy has one extra chromosome e.g (Trisomy
16, trisomy 21)
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Aneuploidy
Aneuploid fetus risk in women gt35y age
1/80
Inherent risk of fetal loss after amniocentesis
1/200

• SO,The standard of care is to offer genetic
  amniocentesis for all pregnant women older than
  35 years.

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Translocations
A translocation is the transfer of genetic
material from one chromosome to another.
Reciprocal translocations
Robertsonian translocations
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Translocations
Reciprocal translocations occur when two
different chromosomes exchange segments. (46
chromosomes with two variants)

• Robertsonian translocations occur when two
  chromosomes fuse together, creating one
  chromosome that contains most of the original
  two.
• (45 chromosomes with one variant)

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Robertsonian Translocation

• Robertsonian translocations between chromosomes
  14 and 21, one of the most common combinations,
  are of particular clinical relevance. An
  individual with this translocation could have a
  child with three copies of chromosome 21,
  resulting in Downs syndrome (trisomy 21).

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Reciprocal vs Robertsonian

• Reciprocal --------- 2 derivative chromosomes, 46
  chromosomes total
• Robertsonian -------- 1 derivative chromosome
• 45 balanced
• 46 unbalanced

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Polyploidy

• Polyploidy is a condition in which there is more
  than 2 sets of chromosomes. Triploids (3N),
  tetraploids (4N), pentaploids (5N) etc.
• Polyploids have defects in nearly all organs.
• Most die as embryos or fetuses. Occasionally an
  infant survives for a few days.

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Nondisjunction

• Nondisjunction occurs when chromosomes fail to
  "disjoin" during meiosis or mitosis.

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Nondisjunction during Mitosis
The incidence of trisomies increases with age.
Trisomy 16, which accounts for 30 of all
trisomies, is the most common. All chromosome
trisomies have been reported in abortuses except
for trisomy 1.
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Deletions

• Deletions are fragments of chromosomes that are
  missing. They are usually lethal when homozygous
  and cause abnormalities when heterozygous.
• Cri du Chat Syndrome
• Cri du chat syndrome is due to a deletion of a
  portion of chromosome 5. Cri du chat individuals
  are mentally retarded.
• "Cri du chat" is French for "cry of the cat". The
  infants cry sounds like a cat.

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Genetic counseling after a miscarriage

• risk for fetal aneuploidy in couples with
  recurrent miscarriages is 1.6, similar to the
  aneuploidy risk in a woman older than 40 years.
• In a woman with a prior trisomic livebirth, an
  approximately 1 increased risk exists for
  subsequent trisomic birth.

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Genetic counseling after a miscarriage

• All couples with a history of recurrent
  miscarriage should have peripheral blood
• karyotyping performed. The finding of an abnormal
  parental karyotype should prompt referral to a
  clinical geneticist.

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Genetic counseling after a miscarriage

• In all couples with a history of recurrent
  miscarriage cytogenetic analysis of the products
  of conception should be performed if the next
  pregnancy fails.

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Amniocentesis

• Amniocentesis is a technique in which a sample of
  amniotic fluid is removed and cells that it
  contains are grown on a culture dish for 2 weeks
  to obtain sufficient numbers of cells to be
  karyotyped .
• a number of biochemical tests can be done on the
  fluid to determine if any problems exist.
• Amniocentesis cannot be done until the 14th to
  16th week of pregnancy.
• The risk of inducing a spontaneous abortion by
  this procedure is 0.5 to 1 above the background
  rate of spontaneous abortion.

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Chorionic Villi Sampling

• Chorionic villi sampling is a procedure in which
  a small amount of the placenta is removed.
• It is normally done during the 10th to 12th week
  but it can be done as early as the 5th week of
  pregnancy. Karyotype analysis can be performed on
  these cells immediately after sampling.
• Although Chorionic villi sampling can be
  performed earlier in the pregnancy than
  amniocentesis, the risk of inducing a spontaneous
  abortion is 1 to 2 higher than the background
  rate.

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Part II Recurrent pregnancy loss

• Dr.Mohammed Abdalla

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Anatomical factors
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ANATOMICAL FACTORS

• Müllerian anomaly
• Incompetent cervix
• Leiomyomas
• Asherman syndrome

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ANATOMICAL FACTORS

• 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

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ANATOMICAL FACTORS

• All women with recurrent miscarriage should have
  a pelvic ultrasound to assess uterine anatomy and
  morphology.
• The routine use of hysterosalpingography as a
  screening test for uterine anomalies in women
  with recurrent miscarriage is questionable.

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ANATOMICAL FACTORS

• The diagnosis of Cervical weakness is usually
  based on a history of late miscarriage, preceded
  by spontaneous rupture of membranes or painless
  cervical dilatation.
• Transvaginal ultrasound assessment of the cervix
  during pregnancy may be useful in predicting
  preterm birth in some cases of suspected cervical
  weakness.

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ANATOMICAL FACTORS

• Women with recurrent pregnancy loss and a uterine
  septum should undergo hysteroscopic evaluation
  and resection.

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ANATOMICAL FACTORS

• 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.

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ANATOMICAL FACTORS

• The routine use of hysterosalpingography as a
  screening test for uterine anomalies in women
  with recurrent miscarriage is questionable. It is
  associated with patient discomfort, carries a
  risk of pelvic infection and radiation exposure
  and is no more sensitive than the non-invasive
  two dimensional pelvic ultrasound assessment of
  the uterine cavity with (or without)
  Sonohysterography when performed by skilled and
  experienced personnel.

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ANATOMICAL FACTORS

• The diagnosis of cervical incompetence is usually
  based on history of late miscarriage, preceded by
  spontaneous rupture of membranes or painless
  cervical dilatation. Transvaginal ultrasound
  assessment of the cervix during pregnancy may be
  useful in predicting preterm birth in some cases
  of suspected cervical weakness.

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Endocrine factors
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Diabetes mellitus

• women with diabetes with high glycosylated A1c
  levels in the first trimester are at a
  significantly higher risk of both miscarriage and
  fetal malformation.
• Insulin-dependent women with inadequate glucose
  control have a 2- to 3-fold higher rate of
  miscarriage compared to the general population of
  women.

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Low progesterone levels

• Progesterone is the principal factor responsible
  for the conversion of a proliferative to a
  secretory endometrium, rendering the endometrium
  receptive for embryo implantation.

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Luteal-phase defects

• Unfortunately, no reliable method is available to
  diagnose this disorder
• basal body temperature records .
• progesterone concentrations .
• histologic dating of endometrial biopsy specimens
  using the patient's subsequent menses as a
  reference point
• luteal-phase serum progesterone levels which may
  be found normal in the women with LPD. (abnormal
  response of the endometrium to progesterone
  rather than a subnormal production )

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Endocrine modulation of decidual immunity

• The endocrine system and the immune system
  interact closely during implantation and
  maintenance of pregnancy. at the level of the
  decidua .
• Here, under the influence of sex steroids, there
  is a dramatic increase of lymphocytes, the
  uterine natural killer (uNK) cells, in early
  pregnancy. which under hormonal influence, they
  are believed to promote placental and trophoblast
  growth and provide immunomodulation at the
  maternal-fetal interface.

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Endocrine modulation of decidual immunity

• Progesterone is essential because large granular
  lymphocytes (LGLs )are not found in endometrium
  before menarche, after menopause, or in
  conditions associated with unopposed estrogen,
  such as endometrial hyperplasia or carcinoma and
  In women who have undergone oophorectomy.
• LGLs appear only after treatment with both
  estrogen and progesterone. The increase in the
  number of NK cells at the implantation site in
  the first trimester suggests their role in
  pregnancy maintenance.
• The extravillous trophoblast (which expresses
  modified forms of 1 HLA) is resistant to lysis by
  decidual NK

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Thrombophilic defects either acquried or inherited
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Thrombophilia

• the tendency to thrombosis

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Thrombophilia
Inherited

• hyperhomocysteinemia (C677T) mutation ).
• FV Leiden mutation (A506G) mutation ).
• mutation in prothrombin (G 20210 A) .
• The prothrombin II (PTII) mutation.
• protein S deficiency.
• Protein C deficiency.

Acquired
lupus anticoagulant antibodies
The antiphospholipid syndrome.
anticardiolipin antibodies
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placental vasculopathy

• Placental pathologists use the term placental
  vasculopathy to describe pathological placental
  changes were found to be associated with some
  clinical conditions such as preeclampsia, IUGR,
  placental abruption and some cases of fetal loss
  and preterm labor .

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placental vasculopathy

• villous infarcts.
• multiple infarcts.
• fibrinoid necrosis of decidual vessels.
• fetal stem vessel thrombosis.
• placental hypoplasia.
• spiral artery thrombosis .

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antiphospholipid syndrome
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antiphospholipid syndrome

• In the antiphospholipid antibody syndrome the
  body recognizes phospholipids (part of a cell's
  membrane) as foreign and produces antibodies
  against them.

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antiphospholipid syndrome

• APA syndrome is an acquired autoimmune
  thrombophilia in which vascular thrombosis and/or
  adverse pregnancy outcomes occur in patients
  having laboratory evidence for antibodies against
  phospholipids or phospholipid-binding protein
  cofactors in their blood.

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antiphospholipid syndrome

• Antiphospholipid antibodies are a family of
  approximately 20 antibodies directed against
  negatively charged phospholipid binding proteins.
• only the lupus anticoagulant and anticardiolipin
  antibodies (IgG and IgM subclass, but not IgA)
  have been shown to be of clinical significance.

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PRINCIPAL PATHOGENIC MECHANISMS MEDIATED BY (APL
)

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Sapporo criteria

• An International Consensus Conference held in
  Sapporo in 1998 clinical criteria of (APAS )
• thrombosis, one or more confirmed episodes of
  venous, arterial, or small vessels disease .
• pregnancy criteria

• one or more unexplained fetal deaths after ten
  weeks of pregnancy.
• one or more preeclampsia or placental
  insufficiencies occurring before 34 weeks .
• three or more unexplained consecutive
  spontaneous abortions less than 10 weeks.

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OBSTETRICAL AND FETAL MANIFESTATIONS IN THE
COHORT OF 1,000 APS PATIENTS ENROLLED BY THE
EUROPEAN APL FORUM

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Inherited Thrombophilia
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Inherited Thrombophilia

• three important inherited thrombophilias
• mutation in factor V causing Resistance to
  activated protein C (responsible of 2030 of
  venous thromboembolism events.)
• mutation in prothrombin (guanine 20210 adenine )
• mutation in methylenetetrahydrofolate reductase
  (MTHFR) (cytosine 677 thymine (C677T) ) The
  mutation is responsible for reduced MTHFR
  activity and is the most frequent cause of mild
  hyperhomocysteinemia and can be found in 515 of
  the population.

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factor V Leiden(A506G) mutation

• present in 3-8 of the general population ,
  (heterozygotes) have a seven fold increased risk
  for thrombosis compared to the general population
  whereas homozygotes have an eighty fold increase.
  
• It has been linked with an increased risk for
  venous thromboembolism due to Resistance to
  activated protein C and is responsible of 2030
  of venous thromboembolism events

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prothrombin (G20210A) mutation

• A change of G to A at position 20210 in
  prothrombin (prothrombin 20210A) elevates
  baseline prothrombin levels and thrombin
  formation.

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MTHFR (C677T) mutation

• responsible for reduced MTHFR activity results in
  decreased synthesis of 5-methyltetrahydrofolate,
  the primary methyl donor in the conversion of
  homocysteine to methionine and the resulting
  increase in plasma homocysteine concentrations
• ( Hyperhomocysteinemia ) is a risk factor for
  thrombosis
• Dietary restriction of folate and vitamin B12
  remains the most common cause.

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MTHFR (C677T) mutation

• A homozygous (MTHFR) mutation, present in 1-4 of
  the general population, is associated with a
  three fold increased risk for DVT or PE, as well
  as preeclampsia and placental abruption.

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Protein S deficiency

• Protein S deficiency (PSD), present in up to 2
  of the general population.
• is found in approximately 15 of individuals with
  a DVT or PE .
• is found in 6 of women with obstetrical
  complications including a relatively high risk
  for stillbirth.

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Thank you