Recurrent miscarriage- dr.alajami

dr. Mohamed Alajami
Higher Studies in Obs.Gyne- MD
Lecturer in HAMA University
Recurrent Miscarriage

Investigation and Treatment of Recurrent
Miscarriage
dr. Mohamed Alajami
IS A HARD JOURNEY

 Miscarriage is the spontaneous loss of pregnancy before the fetal
viability.
 all pregnancy losses from the time of conception until 24w.
 ectopic and molar pregnancies are not included.
 Recurrent miscarriage is the loss of three or more
consecutive pregnancies.
 affects 1% of couples trying to conceive
 > 2 (ASRM, 2008)
INTRODUCTION
dr. Mohamed Alajami

1. Epidemiological factors
2. Antiphospholipid syndrome
3. Genetic factors (25%)
4. Anatomical factors ( 10%)
5. Endocrine factors (5%)
6. Immune factors
7. Infective agents
8. Inherited thrombophilic defects
causes of recurrent miscarriage
dr. Mohamed Alajami

1. Advancing maternal age
2. Advanced paternal age
3. number of previous miscarriages
4. obesity
5. environmental risk factors
 Maternal cigarette smoking
 Caffeine consumption
 Heavy alcohol consumption
 The effect of anesthetic gases for theatre workers is conflicting
Epidemiological factors
dr. Mohamed Alajami

֎ Maternal age :
 Advancing maternal age is associated with a decline in both
the number and quality of the remaining oocytes .
 The age-related risk of miscarriage in recognized pregnancies:
• 12–19 years, 13%
• 25–29 years, 12%
• 35–39 years,25%
• ≥45 years,93%.
֎ The risk of miscarriage is highest among couples where the
woman is ≥35 years of age and the man ≥40 years of age
dr. Mohamed Alajami
• 20–24 years, 11%
• 30–34 years, 15%
• 40–44 years,51%

֎ Previous reproductive history is an independent predictor of future
pregnancy outcome.
 The risk of a further miscarriage increases after each successive
pregnancy loss.
• ~ 40% after three consecutive pregnancy losses,
 prognosis worsens with increasing maternal age.
 A previous live birth does not preclude a woman developing
recurrent miscarriage.
dr. Mohamed Alajami

 Antiphospholipid syndrome:
 is the most important treatable cause of recurrent miscarriage.
 Antiphospholipid syndrome is the association between
antiphospholipid antibodies – lupus anticoagulant,
anticardiolipin antibodies and anti-B2 glycoprotein-I antibodies –
and adverse pregnancy outcome or vascular thrombosis.
antiphospholipid syndrome
dr. Mohamed Alajami

 Adverse pregnancy outcomes :
1. > 3 consecutive miscarriages before 10 weeks of gestation
2. > 1 morphologically normal fetal losses after the 10th week
3. > 1 preterm births before the 34th week owing to placental
disease.
dr. Mohamed Alajami

 Antiphospholipid antibodies
 15% of women with recurrent miscarriage.
 < 2% of women with a low-risk obstetric history.
 In recurrent miscarriage associated with antiphospholipid
antibodies, the live birth rate in pregnancies with no drug
intervention ~ low as 10%.
dr. Mohamed Alajami

 The mechanisms by which antiphospholipid antibodies cause
pregnancy morbidity include:
1. inhibition of trophoblastic function and differentiation
2. activation of complement pathways at the maternal–fetal
interface resulting in a local inflammatory response
3. in later pregnancy, thrombosis of the uteroplacental Vasculature
 the effect of antiphospholipid antibodies on trophoblast function
and complement activation is reversed by heparin
dr. Mohamed Alajami

 Parental chromosomal rearrangements
 ~ 2–5% of recurrent miscarriage, one of the partners carries a balanced
structural chromosomal anomaly
• mostly a balanced reciprocal or Robertsonian translocation.
 carriers of a balanced translocation
 usually phenotypically normal,
 their pregnancies are at increased risk of unbalanced chromosomal
arrangement.
• miscarriage (influenced by the size and the genetic content of the
rearranged chromosomal segments)
• multiple congenital malformation and/or mental disability
Genetic factors
dr. Mohamed Alajami

Genetic factors
dr. Mohamed Alajami

Genetic factors
dr. Mohamed Alajami
Reciprocal translocations

Genetic factors
dr. Mohamed Alajami
Balanced Translocation
Unbalanced Translocation

 Embryonic chromosomal abnormalities:
 In couples with recurrent miscarriage, chromosomal
abnormalities of the embryo is 30–57% of further miscarriages.
 increases with advancing maternal age.
 as the number of miscarriages increases, the risk of euploid
pregnancy loss increases.
Genetic factors
dr. Mohamed Alajami

 Congenital uterine malformations
 debatable role (1.8-37.6%??).
 higher in second-trimester miscarriages
 may be related to the cervical weakness that is associated.
• arcuate uteri tend miscarry more in the second trimester
• septate uteri miscarry in the first trimester
 Submucous fibroid
 Severe IU synechiae
Anatomical factors
dr. Mohamed Alajami

 Cervical weakness
 cause second-trimester miscarriage
 true incidence is unknown, since the diagnosis is essentially a
clinical one.
 There is currently no satisfactory objective test
 The diagnosis is usually based on
• history of second-trimester miscarriage preceded by
spontaneous rupture of membranes or painless cervical
dilatation.
Anatomical factors
dr. Mohamed Alajami

 Uncontrolled diabetes mellitus & Uncontrolled thyroid disease
 high HbA1c in 1st trimester
 Anti-thyroid antibodies??
 PCOS
 insulin resistance, hyperinsulinemia and hyperandrogenemia
 elevated free androgen index is a prognostic factor for a
subsequent miscarriage in recurrent miscarriage.
Endocrine factors
dr. Mohamed Alajami

 No clear evidence support
 the hypothesis of human leucocyte antigen incompatibility
between couples,
 the absence of maternal leucocytotoxic antibodies
 the absence of maternal blocking antibodies
 No clear evidence that altered peripheral blood NK cells are
related to recurrent miscarriage.
 Natural killer (NK) cells are found in peripheral blood and the
uterine mucosa.
 They are different phenotypically and functionally.
Immune factors
dr. Mohamed Alajami

 uNK cells may play a role in
 trophoblastic invasion
 angiogenesis
 being an important component of the local maternal immune
response to pathogens.
 This remains a research field.
Immune factors
dr. Mohamed Alajami

 Cytokines are immune molecules that control both immune and
other cells.
 Cytokine responses are generally characterised either as
 T-helper-1 (Th-1) type,
 production of the pro-inflammatory cytokines
• interleukin 2,
• interferon
• tumour necrosis factor alpha (TNF ),
• T-helper-2 (Th-2) type,
 production of the anti-inflammatory cytokines
• interleukins 4,6 and 10.
Immune factors
dr. Mohamed Alajami

 Cytokines:
 normal pregnancy might be the result of a predominantly Th-2
cytokine response
 women with recurrent miscarriage have a bias towards mounting
aTh-1 cytokine response.
Immune factors
dr. Mohamed Alajami

 Any severe infection that leads to bacteraemia or viraemia can
cause sporadic miscarriage
 The role of infection in recurrent miscarriage is unclear.
 infective agent implicated in repeated pregnancy loss, must be:
1. capable of persisting in the genital tract
2. avoiding detection
3. or must cause insufficient symptoms to disturb the woman
 Toxoplasmosis, rubella, cytomegalovirus, herpes and listeria
infections do not fulfil these criteria
Infective agents
dr. Mohamed Alajami

 Routine TORCH screening should be abandoned
 bacterial vaginosis in the first trimester of pregnancy is:
 a risk factor for second-trimester miscarriage and preterm
delivery,
 not association with first trimester miscarriage.
 Treatment early in 2-nd trimester with oral clindamycin
reduces the 2-nd trimester miscarriage and preterm birth in
the general population.
 No role of antibiotic therapy in women with a previous second-
trimester miscarriage.
Infective agents
dr. Mohamed Alajami

Ꚛ Both inherited and acquired thrombophilias cause systemic
thrombosis
Ꚛ Inherited thrombophilias cause recurrent miscarriage and late
pregnancy complications (thrombosis of the uteroplacental
circulation)
1. activated protein C resistance (most commonly due to factor V Leiden
mutation)
2. deficiencies of protein C/S
3. antithrombin III,
4. Hyperhomocysteinaemia
5. prothrombin gene mutation
dr. Mohamed Alajami
Inherited thrombophilic defects

Ꚛ the association between inherited thrombophilias and fetal loss
varies according to type of fetal loss and type of thrombophilia.
Ꚛ The association between thrombophilia and late pregnancy loss
has been consistently stronger than for early pregnancy loss.
Ꚛ carriers of factor V Leiden or prothrombin gene mutation have
double the risk of experiencing recurrent Miscarriage
Ꚛ The data on the outcome of untreated pregnancies in women with
hereditary thrombophilias are ?
dr. Mohamed Alajami
Inherited thrombophilic defects

 Epidemiological factors
 Herbicide spraying.
 Electromagnetic field
 Radiation
 Exposure to solvents, heavy metals & industrial chemicals
 Anatomic
• Mild IU adhesions.
• Subserous fibroid
• Arcuate uterus
• RVF
dr. Mohamed Alajami
Doubtful causes
 Endocrine
1. Endometriosis.
2. Inadequate luteal phase
3. Hyperprolactinemia

 Infections
 Toxoplasmosis.
 CMV
 C. trachomatis
 Mycoplasma
 HSV & L. monocytogenes.
 Immunologic
• Alloimmune
• Antithyroid antibodies
dr. Mohamed Alajami
Doubtful causes

֎ History
֎ Physical examination
֎ Recommended investigations
EVALUATION of RM
dr. Mohamed Alajami

֎ Obstetric:
 Gestational age
• Chromosomal and endocrine defects: 1st TM
• Anatomic or immunological: 2nd TM
• There is significant overlap.
 Embryonic/fetal cardiac activity
• chromosomal abnormality: RM prior to detection of
embryonic cardiac activity
HISTORY
dr. Mohamed Alajami

֎ Surgical:
 uterine instrumentation (intrauterine adhesions)
֎ Menstrual:
 Irregular menstrual cycles (endocrine dysfunction).
 Galactorrhea (hyperprolactinemia)
֎ Family:
֎ Eenvironmental (toxins)
֎ Venous or arterial thrombosis (APA synd)
֎ Previous laboratory, pathology, and imaging
HISTORY
dr. Mohamed Alajami

֎ Signs of endocrinopathy
 Hirsutism
 Galactorrhea
֎ Pelvic organ abnormalities
 uterine malformation
 cervical laceration
Physical examination
dr. Mohamed Alajami

© Antiphospholipid antibodies
© Karyotyping
© Anatomical factors:
 pelvic ultrasound
 Hysteroscopy
 laparoscopy
 3D pelvic ultrasound
© Thrombophilias:
• factor V Leiden,
• factor II (prothrombin) gene mutation and
• protein S.
Recommended investigations
dr. Mohamed Alajami

 All women with recurrent first-trimester miscarriage
 all women with one or more second-trimester
miscarriage
֎ should be screened before pregnancy for
antiphospholipid antibodies.
Antiphospholipid antibodies
dr. Mohamed Alajami

֎ To diagnose antiphospholipid syndrome it is mandatory
that the woman has two positive tests at least 12 weeks
apart for either lupus anticoagulant or anticardiolipin
antibodies of IgG and/or IgM class present in a medium
or high titre
֎ Transient positivity secondary to infections may be found
dr. Mohamed Alajami

֎ Women with second-trimester miscarriage should be screened for
inherited thrombophilias including:
 factor V Leiden
 factor II (prothrombin) gene mutation
 protein S.
dr. Mohamed Alajami

 Cytogenetic analysis should be performed on products of
conception of the third and subsequent consecutive
miscarriage(s).
 Parental peripheral blood karyotyping of both partners should be
performed in couples with recurrent miscarriage where testing of
products of conception reports an unbalanced structural
chromosomal abnormality.
Karyotyping
dr. Mohamed Alajami

 sporadic fetal chromosome abnormality is the most common cause
of any single miscarriage
 the risk of miscarriage as a result of fetal aneuploidy decreases
with an increasing number of pregnancy losses
 If the karyotype of the miscarried pregnancy is abnormal, there is a
better prognosis for the next pregnancy
Karyotyping
dr. Mohamed Alajami

 couples with balanced translocations:
 low risk (0.8%) of pregnancies with an unbalanced karyotype
surviving into the second trimester
 chance of having a healthy child is 83%.
 Routine karyotyping of couples with recurrent miscarriage cannot
be justified.
 Selective parental karyotyping is more appropriate when an
unbalanced chromosome abnormality is identified in the products
of conception.
Karyotyping
dr. Mohamed Alajami

 All women with recurrent first-trimester miscarriage and all
women with one or more second-trimester miscarriages should
have a pelvic ultrasound /or hysterosalpingography to assess
uterine anatomy.
 Suspected uterine anomalies may require further investigations to
confirm the diagnosis, using hysteroscopy, laparoscopy or three-
dimensional pelvic ultrasound.
 The value of MRI undetermined.
Anatomical factors
dr. Mohamed Alajami

 TSH
1. clinical manifestations
2. personal history of thyroid disease.
3. asymptomatic for subclinical hypothyroidism
 Thyroid peroxidase (TPO) antibodies (Controversial)
Endocrine
dr. Mohamed Alajami
[Negro et al, 2010]
[Chen et al, 2011; Thangaratinam et al, 2012]

֎ Women with recurrent miscarriage should be referred to a
specialist clinic.
Treatment options for RM
dr. Mohamed Alajami

 Pregnant women with antiphospholipid syndrome should be
considered for treatment with low-dose aspirin plus heparin to
prevent further miscarriage.
 No difference in between unfractionated heparin and low-
molecular-weight heparin when combined with aspirin.
dr. Mohamed Alajami
Antiphospholipid syndrome

 Heparin does not cross the placenta and hence there is no
potential to cause fetal haemorrhage or teratogenicity.
 Heparin can be associated with maternal complications including
 Bleeding
 hypersensitivity reactions
 heparin-induced thrombocytopenia
 osteopenia and vertebral fractureswhen used long term
dr. Mohamed Alajami

 Low-molecular-weight heparin
 causes less heparin-induced thrombocytopenia
 administered once daily
 lower risk of heparin-induced
dr. Mohamed Alajami

 Pregnancies with antiphospholipid antibodies treated with aspirin
and heparin remain at high risk of complications during all three
trimesters.
 repeated miscarriage
 pre-eclampsia
 fetal growth restriction
 preterm birth
dr. Mohamed Alajami

 low-dose aspirin plus heparin:
 reduces the miscarriage rate by 54%
 No difference between unfractionated heparin and low-
molecular-weight heparin when combined with aspirin
 Low dose Aspirin
• no adverse fetal outcomes
dr. Mohamed Alajami

®Pregnancies with antiphospholipid antibodies treated with aspirin
 Neither corticosteroids nor intravenous immunoglobulin
therapy improve the live birth rate of women
 their use may provoke significant maternal and fetal morbidity
dr. Mohamed Alajami

® Abnormal parental karyotype should referred to a clinical
geneticist.
® Preimplantation genetic diagnosis is a treatment option for
translocation carriers ( IVF )
® Preimplantation genetic screening with IVF treatment in women
with unexplained recurrent miscarriage does not improve live
birth rates
dr. Mohamed Alajami
Genetic factors

 Congenital uterine malformations:
 insufficient evidence to assess the effect of uterine septum
resection in women with recurrent miscarriage and uterine
septum to prevent further miscarriage
 Open uterine surgery is associated with
 postoperative infertility and
 risk of uterine scar rupture during pregnancy.
 These are less occur after transcervical hysteroscopic resection of
uterine septae.
Anatomical factors
dr. Mohamed Alajami

 Cervical weakness and cervical cerclage:
 risk of stimulating uterine contractions
 No conclusive evidence that prophylactic cerclage reduces the risk
of pregnancy loss and preterm delivery in women at risk of
preterm birth or mid-trimester loss owing to cervical factors.
 The benefit most marked in women with > 3 second-trimester
miscarriages or preterm births.
 no significant improvement in perinatal survival.
Anatomical factors
dr. Mohamed Alajami

 a history of 2nd-trimester miscarriage and suspected cervical
weakness who have not undergone a history-indicated cerclage
may be offered serial cervical sonographic surveillance
 singleton pregnancy and a history of one 2nd-trimester
miscarriage attributable to cervical factors, an ultrasound-indicated
cerclage should be offered if a cervical length of 25mm or less is
detected by transvaginal scan before 24 weeks of gestation.
Anatomical factors
dr. Mohamed Alajami

 Transabdominal cerclage in a previous failed transvaginal cerclage
and/or a very short and scarred cervix.
 perform transabdominal cerclage before pregnancy or during
pregnancy remains uncertain.
Anatomical factors
dr. Mohamed Alajami

 Congenital uterine malformations
 uterine septum hysteroscopic resection
 Submucosal fibroid
 Hysteroscopic myomectomy
 Severe IU adhesions
 Hysteroscopic surgery
 Cervical incompetence
 indications of Cervical cerclage:
• > 1 of 2nd TM or PTL before 24 w. +TVS: cervix < 25 mm
• > 3 previous PTL and/or 2nd TM.
Anatomical factors
dr. Mohamed Alajami

 effect of progesterone supplementation in pregnancy to prevent
a miscarriage in women with recurrent miscarriage ??
 effect of human chorionic gonadotrophin supplementation in
pregnancy to prevent a miscarriage in women with recurrent
miscarriage ??
 Suppression of high luteinising hormone levels among ovulatory
women with recurrent miscarriage and polycystic ovaries does
not improve the live birth rate.
 Pre-pregnancy pituitary suppression of luteinising hormone does
not improve the live birth rate.
Endocrine
dr. Mohamed Alajami

 Effect of metformin supplementation in pregnancy to prevent a
miscarriage in women with recurrent miscarriage??
 The increased risk of miscarriage in PCOS because of insulin
resistance and hyperinsulinaemia.
 metformin, in women with PCOS and infertility has no effect on
the miscarriage risk.
Endocrine
dr. Mohamed Alajami

 Euthyroid women with high serum thyroid peroxidase antibody
(50 mcg daily levothyroxine) decreased miscarriage and PTL rate.
 Hyperprolactinemia:
 Bromocriptine higher rate of successful pregnancy.
 Treatment of hyperprolactinemia and RM, even in the absence
of overt hypogonadism is recommend
Endocrine
dr. Mohamed Alajami

© Paternal cell immunization, third-party donor leucocytes,
trophoblast membranes and intravenous immunoglobulin in
women with previous unexplained recurrent miscarriage does not
improve the live birth rate.
© serious adverse effects:
 transfusion reaction
 anaphylactic shock
 hepatitis
 Lymphoma
dr. Mohamed Alajami
Immunotherapy
 granulomatous disease as TB
 demyelinating disease
 congestive heart failure
 syndromes similar to systemic lupus
erythematosus.

© Heparin in pregnancy to prevent a miscarriage in women with
recurrent first-trimester miscarriage associated with inherited
thrombophilia???.
© Heparin therapy during pregnancy may improve the live birth rate of
women with second-trimester miscarriage associated with inherited
thrombophilias.
dr. Mohamed Alajami
Inherited thrombophilias

© Women with known heritable thrombophilia are at an increased
risk of venous thromboembolism.
© The efficacy of thromboprophylaxis by heparin during pregnancy in
women with recurrent first-trimester miscarriage who have inherited
thrombophilias may improve the live birth rate.
© The efficacy of the low-molecular-weight heparin enoxaparin for
the treatment of women with a history of a single late miscarriage
after 10 weeks of gestation who have inherited thrombophilias .
 The live birth rate of women treated with enoxaparin was 86%
compared with 29% in women taking low-dose aspirin alone.
dr. Mohamed Alajami
Inherited thrombophilias

֎ unexplained RM have an excellent prognosis for future pregnancy
outcome without pharmacological intervention if offered
supportive care alone.
 successful future pregnancy with supportive care alone ~ 75%.
 prognosis worsens with increasing maternal age and the
number of previous miscarriages
dr. Mohamed Alajami
Unexplained RM

֎ Psychological support has a beneficial effect, although the
mechanism is unclear.
֎ Aspirin alone or in combination with heparin doesn't improves
the live birth rate among women with unexplained recurrent
miscarriage.
֎ The use of empirical treatment is unnecessary and should be
resisted
dr. Mohamed Alajami
Unexplained RM

֎ Lifestyle modification
 Stop tobacco products, alcohol
 Caffeine reduction
 Reduction BMI (for obese women)
 Bed rest (unnecessary and will not affect outcome)
֎ Progesterone (controversial)
֎ Aspirin alone or in combination with heparin (No improvement)
dr. Mohamed Alajami
Unexplained RM

֎ Combination therapy: (before and during pregnancy)
 folate (5 mg every second day)
 aspirin (100 mg/day)
 with prednisone (20 mg/day)
 progesterone (20 mg/day)
֎ Human chorionic gonadotropin
 insufficient evidence
 During early gestation may be useful in preventing miscarriage
{endogenous hCG plays critical role in the establishment of pregnancy }.
dr. Mohamed Alajami
Unexplained RM

֎ Human menopausal gonadotropin:
 observational study: effective for tt of endometrial defects in
women with RPL. [Li et al, 2001]
 Mechanism: correction of a luteal phase defect stimulation of a
thicker endometrium: better implantation site.
 Clinical experience supports the efficacy of this treatment
dr. Mohamed Alajami
Unexplained RM
(Tulandi et al, 2013)

 Dose
 Progesterone vaginal Supp 200 mg three times daily
 Progesterone vaginal gel 90 mg once daily
 Micronized oral progesterone (dydrogesterone) 100 mg
orally, two to three tablets per day
 Duration
 Start: 3 days after the LH surge {not to inhibit ovulation}
 Continue: until 10 w {placental progesterone production fully
functional}
Cochrane SR, 2011) +[Carp, 2012 MA]
Progesterone
dr. Mohamed Alajami
2015 European Progestin Club Guidelines

 controversial
 natural progesterone vaginal pessaries 400 mg 12-h until 12 w
(Munawar et al, 2012)
Progesterone
dr. Mohamed Alajami

© After two or three consecutive miscarriages
1. Pelvic US (or HSG or Sonohysterography)
2. Antiphospholipid antibodies
3. TSH ±thyroid peroxidase antibodies
4. Factor V Leiden, factor II (prothrombin) gene mutation and protein
S.
5. If the above examinations are normal: karyotype of the abortus:
unbalanced structural chromosomal abnormality: Parental
karyotype
Recommended investigations
dr. Mohamed Alajami

1. Uterine septum, submucous fibroid, severe IU adhesions:
Hysteroscopic surgery.
2. Cervical incompetence: cervical cerclage
3. PCOS: Metformin.
4. Subclinical hypothyroidism: Eltroxin
5. Positive APA: Low dose aspirin & heparin.
6. Inherited thrombophilias: Heparin
7. Karyotyping abnormalities: Clinical geneticist.
8. Unexplained: Reassurance
Treatment
dr. Mohamed Alajami

 The role of uterine NK cells and cytokines in recurrent miscarriage.
 The role of uterine septum resection in women with recurrent
miscarriage and septate uterus.
 Thromboprophylaxis in women with thrombophilia and recurrent
first-trimester miscarriage.
 Progesterone treatment in women with unexplained recurrent
miscarriage.
 Metformin treatment in women with recurrent miscarriage and
insulin resistance.
Recommendations for future research
dr. Mohamed Alajami

Recurrent miscarriage- dr.alajami

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