Recurrent Miscarriage Guidelines

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Recurrent MiscarriageGuidelines

• Dr Muhammad El Hennawy
• Ob/gyn specialist
• Rass el barr central hospital and
• dumyat specialised hospital
• Dumyatt EGYPT
• www.geocities.com/mmhennawy

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Definition

• A recurrent miscarriage is 3 or more
  consecutive, spontaneous pregnancy losses, under
  20 week gestation from the last menstrual period
  , by the same partner.

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• Primary recurrent pregnancy loss" refers to
  couples that have never had a live birth,
• while "secondary RPL" refers to those who have
  had repetitive losses following a successful
  pregnancy

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• a woman who had a miscarriage,instead of getting
  sympathy and support, is made to feel that it is
  somehow her fault
• It is all too common to find recurrent
  miscarriges leading to divorce

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Terminology

• The medical term 'spontaneous abortion' should be
  replaced with the term 'miscarriage'
• Other names recurrent pregnancy loss (RPL),
• habitual abortions ,
• habitual miscarriages,
• recurrent abortions ,
• recurrent miscarriages.

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Incidence

• 1015 of all clinically recognised pregnancies
  end in a miscarriage
• the theoretical risk of three consecutive
  pregnancy losses that expected by chance alone is
  0.34.
• This incidence is greater than that expected by
  chance alone---Recurrent miscarriage affects 1
  of all women ---Hence, only a proportion of women
  presenting with recurrent miscarriage will have a
  persistent underlying cause for their pregnancy
  losses

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Risk factors

• Advanced maternal age
• adversely affects ovarian function, giving
  rise to a decline in the number of good quality
  oocytes, resulting in chromosomally abnormal
  conceptions that rarely develop further.
• . previous number of miscarriages

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possible causes

• Recurrent miscarriage is a heterogeneous
  condition that has many possible causes more
  than one contributory factor may underlie the
  recurrent pregnancy losses.
• each may have had a different cause.

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Recurent Miscarriage
Explained
Un-explained
Genetic factors
Infective agents
Endocrine
Enviromental factors
Anatomical factors
Immune factors
Inhereted Thrombophilic defect
Bacterial Vaginosis
Body
Cervix
C I
APS
Uterine anomalies
Paternal karyotyping
Cytogenetic Of miscarriage
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Investigations and treatmentsRecent information
indicates that women should look into RPL testing
after two losses when it used to be common to
wait until three. This is especially important
for women in their 30s and 40s
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Diagnosis and investigation

• EPAUs should use and develop diagnostic and
  therapeutic algorithms of care.
• In particular, these should include management
  of 'suspected ectopic pregnancy' (including serum
  hCG) and the 'indeterminate' ultrasound scan.
• EPAUs should have access to transvaginal
  ultrasound with staff appropriately trained in
  its use.
• Non-sensitised rhesus (Rh) negative women should
  receive anti-D immunoglobulin in the following
  situations ectopic pregnancy, all miscarriages
  over 12 weeks (including threatened), all
  miscarriages where the uterus is evacuated, and
  for threatened miscarriages under 12 weeks when
  bleeding is heavy or associated with pain.

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Genetic factors
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• 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.
• 35 of couples with recurrent miscarriage, one
  of the partners carries a balanced structural
  chromosomal anomaly
• 510 chance of a pregnancy with an unbalanced
  translocation.

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• In all couples with a history of recurrent
  miscarriage cytogenetic analysis of the products
  of conception should be performed if the next
  pregnancy fails.
• an abnormal embryo, which is incompatible with
  life, e.g. chromosomal abnormalities or
  structural malformations.
• If the karyotype of the miscarried pregnancy is
  abnormal, there is a better prognosis in the next
  pregnancy
• Cytogenetic testing is an expensive tool and
  should be reserved for patients who have
  undergone treatment in the index pregnancy or
  have been participants in a research trial

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Fetal chromosomal abnormalities

• This may be due to abnormalities in the egg,
  sperm or both. The  most common chromosomal
  defects are
• Trisomy
• Monosomy 
• Polyploidy

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• 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 , HOW?

• It is A display of an individuals chromosome
  pairs.
• Process Sample of cells is taken, usually blood
  cells.
• 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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Anatomical factors

• One in six to ten women with recurrent
  miscarriages has a structural defect like uterine
  septum or adhesions

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• Hysterosalpingogram (HSG)
• two dimensional pelvic ultrasound with (or
  without) Sonohysterography
• 3D Ultrasound
• Laparoscopy
• Hysteroscopy

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• 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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Congenital anomalies

• an abnormal or irregularly shaped uterus.
• Sometimes the uterus has an extra wall down its
  centre, which makes it look as if it is divided
  into
• two (bicornuate or septate uterus)
• a septate uterus Where as a partial septum
  increases the risk to 60-75 a total septum
  carries a risk for loss of up to 90.
• Today a relatively simple surgical procedure
  can remove a uterine septum
• or it may have only developed one half
  (unicornuate uterus).
• It is not clear if such problems cause recurrent
  miscarriage,

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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.
  It is less clear whether fibroids in the wall of
  the uterus cause reproductive problems

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scar tissue in the uterus

• scar tissue in the uterus which may hinder
  implantation or growth of the fetus.

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Hysterosalpingography

• 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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Hysterosonography

• Hysterosonography provides a sensitive and
  specific screening tool for evaluating the
  uterine cavity and it could be an accurate
  alternative to HSG in screening for uterine
  abnormalities

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Ultrasound

• It is sometimes possible to see abnormalities
  inside the uterus at the time of a scan,
  especially a
• vaginal scan. A scan will also enable the ovaries
  to be examined at the same time. Occasionally
• polycystic ovaries are diagnosed by ultrasound
  scan (see above).
• Some units will offer a scan and an examination
  of the inside of the uterus at the same time -
  saline
• installation sonography (SIS). A small plastic
  tube is passed through the cervix and a
  water-like
• solution injected through it. The scan can
  determine whether there is any abnormality inside
  the
• uterus.

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All women with recurrent miscarriage should have
a pelvic ultrasound to assess uterine anatomy and
morphology

• Two dimensional pelvic ultrasound assessment of
  the uterine cavity with (or without)
  Sonohysterography

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three-dimensional ultrasound

• The diagnostic value of three-dimensional
  ultrasound has been explored and appears
  promising.
• Since three-dimensional ultrasound offer both
  diagnosis and classification of uterine
  malformation its use may obviate the need for
  diagnostic hysteroscopy and laparoscopy.

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Hysteroscopy

• This investigation, performed under general
  anaesthetic, examines the inside of the uterus
  with a thin
• telescope (3-5 mm in diameter) . By inserting
  this telescope through the cervix and into the
  uterus,
• the doctor can see the shape of the uterus and
  examine its lining.

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Cervical weakness
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• Cervical cerclage is associated with potential
  hazards related to the surgery and the risk of
  stimulating uterine contractions and hence should
  only be considered in women who are likely to
  benefit.
• Cervical weakness is often over-diagnosed as a
  cause of mid-trimester miscarriage.
• The diagnosis 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
• Transabdominal cerclage has been advocated as a
  treatment for second-trimester miscarriage and
  the prevention of early preterm labour in
  selected women with previous failed transvaginal
  cerclage and/or a very short and scarred cervix

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Endocrine factors
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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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There is insufficient evidence to evaluate the
effect of progesterone supplementation in
pregnancy to prevent a miscarriage

• hormonal treatments for luteal phase deficiency
  concluded that the benefits are uncertain the low
  progesterone levels that have been reported in
  early pregnancy loss may reflect a pregnancy that
  has already failed. Exogenous progesterone
  supplementation should only be used in the
  context of randomised controlled trials.
• Progesterone doesn't prevent miscarriages.
  Miscarriages happen for many reasons,
• but lack of progesterone as a cause for
  miscarriage is not proven. The low progesterone
  levels found in pregnancies which go on to become
  miscarriages is a sign that the pregnancy is
  already failing

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There is insufficient evidence to evaluate the
effect of human chorionic gonadotrophin (hCG) in
pregnancy to prevent miscarriage.

• early pregnancy hCG supplementation failed to
  show any benefit in pregnancy outcome

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Prepregnancy suppression of high luteinising
hormone (LH) concentration among ovulatory women
with recurrent miscarriage and polycystic ovaries
who hypersecrete LH does not improve the live
birth rate

• the outcome of pregnancy without pituitary
  suppression is similar to that of patients
  without raised LH.

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Polycystic ovary morphology itself does not
predict an increased risk of future pregnancy
loss among ovulatory women with a history of
recurrent miscarriage who conceive spontaneously.

• pelvic ultrasound criteria, is significantly
  higher among women with recurrent miscarriage
  (41) when compared with the general population
  (22).
• However, despite this high prevalence,
  polycystic ovary morphology itself does not
  predict an increased risk of future pregnancy
  loss among ovulatory women with a history of
  recurrent miscarriage who conceive spontaneously.

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

• One in ten women with recurrent miscarriages show
  evidence of auto immune factors on investigation
• As much as 40 percent of unexplained infertility
  may be the result of immune problems, as are as
  many as 80 percent of "unexplained" pregnancy
  losses. Unfortunately for couples with
  immunological problems, their chances of
  recurrent loss increase with each successive
  pregnancy.

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Antithyroid antibodies

• Routine screening for thyroid antibodies in women
  with recurrent miscarriage is not recommended.

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Antiphospholipid syndrome

• To diagnose APS it is mandatory that the patient
  should have two positive tests at least six weeks
  apart for either lupus anticoagulant or
  anticardiolipin (aCL) antibodies of IgG and/or
  IgM class present in medium or high titre.
• Adverse pregnancy outcomes include
• (a) three or more consecutive miscarriages before
  ten weeks of gestation,
• (b) one or more morphologically normal fetal
  deaths after the tenth week of gestation and
• (c) one or more preterm births before the 34th
  week of gestation due to severe pre-eclampsia,
  eclampsia or placental insufficiency.

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• Currently there is no reliable evidence to show
  that steroids improve the live birth rate of
  women with recurrent miscarriage associated with
  aPL when compared with other treatment
  modalities their use may provoke significant
  maternal and fetal morbidity.
• In women with a history of recurrent miscarriage
  and aPL, future live birth rate is significantly
  improved when a combination therapy of aspirin
  plus heparin is prescribed.
• Pregnancies associated with aPL treated with
  aspirin and heparin remain at high risk of
  complications during all three trimesters.

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Alloimmune factors

• Immunotherapy, including paternal cell
  immunisation, third-party donor leucocytes,
  trophoblast membranes and intravenous
  immunoglobulin (IVIG), in women with previous
  unexplained recurrent miscarriage does not
  improve the live birth rate

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Infective agents
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• 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 fulfil these criteria and
  routine TORCH screening should be abandone

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• 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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Group B Streptococcus

• Pre and Post-conceptional, broad-spectrum
  intravenous antibiotic therapy was used in
  patients with multiple miscarriages
• Although this is a relatively small series and
  does not establish a cause and effect
  relationship between Group B Streptococcus and
  habitual abortions, the beneficial effects of
  antibiotic therapy is unquestionable

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Inherited thrombophilic defects
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• Inherited thrombophilic defects,
• including activated protein C resistance (most
  commonly due to factor V Leiden gene mutation),
  deficiencies of protein C/S and antithrombin III,
  hyperhomocysteinaemia and prothrombin gene
  mutation,
• are established causes of systemic thrombosis

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

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Unexplained recurrent miscarriage

• In about half the women in the research studies,
  no cause could be found, so no specific treatment
  could be given.
• However, this group responded very well to a
  programme which removed as many stress factors as
  possible from their lives, resulting in an 80
  success rate with the subsequent pregnancy

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Women with unexplained recurrent miscarriage have
an excellent prognosis for future pregnancy
outcome without pharmacological intervention if
offered supportive care alone in the setting of a
dedicated early pregnancy assessment unit. After
all these investigations 50 of recurrent
aborters will be found to have no abnormalities
and these should be attributed to chromosomal
defect in the conceptus.
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According to the American College of
Obstetricians and Gynecologists

• cultures for bacteria and viruses
• glucose tolerance testing
• thyroid tests
• antibodies to infectious agents
• antithyroid antibodies
• paternal human leukocyte antigen status, or
  maternal antiparental antibodies
• are not beneficial and, therefore,
• are not recommended in the evaluation of
  otherwise normal women with recurrent pregnancy
  loss.

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Things unlikely to cause recurrent miscarriage

• Retroversion - or backward tilting of the uterus.
  
• Infection - such as toxoplasmosis, listeria,
  brucella, chlamydia, herpes simplex and
  cytomegalovirus.
• Endocrine or metabolic disease - hypothyroidism
  (underactive thyroid), diabetes mellitus, Crohn's
  disease, sickle cell or endometriosis.
• Occupational exposures - very little reliable
  evidence exists for things such as herbicide
  spraying, electromagnetic fields, chemical
  inhalation, anaesthetic gases or VDU usage.
• Not resting enough - bedrest doesn't alter
  whether you miscarry or not. Nor does working
  when you're pregnant, exercise, making love or
  flying.

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Management

• Miscarriages, like infertility, is a problem of a
  couple and they should be seen together. The
  majority can be reassuared.
• most cases, neither a woman nor her doctor can do
  anything to prevent a miscarriage

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Controversies surrounding treatment for pregnancy
loss

• Evidence-based medicine (EBM) has not succeeded
  in giving patients and physicians the data they
  need to choose (or not choose) a therapy in the
  field of pregnancy loss

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If any of the above tests should come back
indicating an underlying reason for the problem

• treatment is direced at the cause
• eg genetic counselling,
• removal of fibroids,
• cervical stitch

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If all of the above have been excluded

• (as they will do in most cases), the diagnosis is
  recurrent miscarriage of unknown cause
• the use of empirical treatment in women with
  unexplained recurrent miscarriage is unnecessary
  and should be resisted
• for both partners to be as healthy as possible
  before she conceive (avoid drugs, alcohol,
  chemicals, etc) and to get any other medical
  conditions under control.
• The only intervention to have demonstrated
  benefit is serial ultrasound scans in the early
  months of pregnancy.
• It is certainly not unreasonable to expect this
  psychological support to improve outcome given
  the close interaction between the higher areas of
  the mind and the delicately balanced hormonal
  system.
• Education and reassuarance with these good
  statistical odds
• Education about smoking, alcohol and drug abuse
  is also important

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Psychological support

• The value of psychological support in improving
  pregnancy outcome has not been tested in the form
  of a randomised controlled trial. However, data
  from several non-randomised studies8688 have
  suggested that attendance at a dedicated early
  pregnancy clinic has a beneficial effect,
  although the mechanism is unclear
• All professionals should be aware of the
  psychological sequelae associated with
  miscarriage and should provide support and
  follow-up, as well as access to formal
  counselling when necessary.

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Emprical treatment

• the use of empirical treatment in women with
  unexplained recurrent miscarriage is unnecessary
  and should be resisted
• BUT
• Some doctors give treatment like
• Low dose asprin
• Subcutaneous hepaein
• Folic acid
• Progesterone
• Solcoseryl(increase oxygen supply)
• Nitroglycerin (increase implantation by increase
  uterine blood flow)
• tocolytic

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Treatment of miscarriage

• Surgical uterine evacuation for miscarriage
  should be performed using suction curettage.
• All at risk women undergoing surgical uterine
  evacuation for miscarriage should be screened for
  Chlamydia trachomatis.
• Medical and expectant methods are also effective
  in the management of confirmed miscarriage.
• Medical and expectant management should be
  offered only in units where patients have access
  to 24-hour telephone advice and immediate
  admission can be arranged.
• Tissue obtained at the time of miscarriage should
  be examined histologically to confirm pregnancy
  and to exclude ectopic pregnancy or gestational
  trophoblastic disease.

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Fate

• A woman who has suffered a single sporadic
  miscarriage has an 80 chance and a woman with
  three consecutive miscarriages a 60 chance of
  her next pregnancy being successful