Recurrent pregnancy loss
Kamel Mohamed Ibrahim
M.B.B.CH – MSC ain shams University maternity hospital
Specialist in fetomaternal medicine
Member of Egyptian fertility society
Member of Egyptian association of Gynelaparoscopists
• The loss of pregnancy at any stage can be a
sensitivity is required in assessing and
• A woman who has suffered a single sporadic
miscarriage has an 80% chance and a
woman with three consecutive miscarriages
a 40-60% chance of her next pregnancy
Our Learning Objectives
• Identify possible causes of early pregnancy
• Outline basic evaluation for recurrent
pregnancy loss (RPL).
• Review current treatment approaches for
• Miscarriage is defined as the spontaneous loss of
pregnancy before the fetus reaches viability.
• A recurrent miscarriage ₌ recurrent pregnancy loss
(RPL) is 3 or more consecutive, spontaneous
pregnancy losses (clinically recognized pregnancies) ,
under 20 week .
Am J Obstet Gynecol 2005;192:240–6
SUB TYPES :
All pregnancy losses, no viable pregnancy
Viable pregnancy followed by pregnancy losses
Pregnancy losses interspersed with viable pregnancie
•Primary recurrent pregnancy loss" refers to
couples that have never had a live birth,
•“Secondary RPL" refers to those who have had
repetitive losses following a successful pregnancy
• 50% of all conceptions fail (most unrecognized)
• 13-15% of recognized pregnancies are lost, 90 % of
these before 12-14 weeks
• 10-20% of pregnant women have 1sporadic
• 2% have 2 consecutive Spontaneous Abortion.
• 0.4-1% have 3 consecutive Spontaneous Abortion.
• Spontaneous successful pregnancy after 2miscarriage is 80%
Lee Semin Reprod Med 2000;18(4):433-40
Advanced maternal age :
20 -24 year: 11%Risk factors
25-30 year: 12%
31-35 year: 15%
36-40 year: 25%
>40 year: 50%
Previous miscarriage :
↑ up to 40% after 3 consecutive pregnancy losses &
prognosis worsens ѐ↑maternal age.
Recurrent Pregnancy Loss 2007
Environmental Risk Factors:
The evidence on the effect of environmental risk factors
is based mainly on data studying women with sporadic rather
than recurrent miscarriage.
Caffeine (> 300 mg/day)
(However, current evidence is insufficient to confirm this
(Gardella & Hill Semin Reprod Med 2000;18(4):407-424)
Acta Obstet Gynecol Scand 2003;82:182–8.
Working with or using video display terminals does not increase the
risk of miscarriage.
(J Am Med Womens Assoc 2000;55:84–8, 105.)
The evidence on the effect of anaesthetic gases for theatre workers is
(Mayo Clin Proc 2000;75:273–7).
obesity increases the risk of both sporadic and recurrent miscarriage.
(Fertil Steril 2010;94:290–5).
Only in 50 %, the cause can be determined
Lee Semin Reprod Med 2000;18(4):433-40
1. Genetic (embryonic and parental )
2. Immunologic (autoimmune/alloimmune )
3. Anatomical Factors (Uterine )
4. Infectious causes .
7. Hematologic disorders
• Advanced Maternal age α errors in meiosis .
• Oocytes ovulated earlier in life less prone to non
• Repetitive first trimester losses
• Anembryonic pregnancies
• History of malformations or mental retardation.
• Embryonic chromosomal abnormalities :
account for 30–57% of further miscarriages.
(Hum Reprod 2002;17:446–51)
– gametogenic error (^ with maternal age) .
– Recurrent aneuploidy
– Euploid abortion
• Parental chromosomal abnormality 3-5% :
The risk of miscarriage is influenced by the size and the
genetic content of the rearranged chromosomal segments.
– most commonly a balanced reciprocal or Robertsonian
(BMJ 2006; 332:1012.)
– X chromosome mosaicsm
Autoimmune : (directed to self)
Systemic Lupus Erythmatosus
Alloimmune :(directed to foreign tissues/cells)
An abnormal maternal immune response to fetal
or placental antigen.
Systemic Lupus Erythmatosus (SLE) :
-Risk for loss is 20%,mostly in 2nd and 3rd
trimester of pregnancy and associated with
Antiphospholipid syndrome (APA) :
5 - 15 % of women with RPL may have APA .
inhibition of trophoblastic function and differentiation.
Am J Obstet Gynecol 2005;192:23–30.
activation of complement pathways at the maternal-fetal interface
resulting in a local inflammatory response .( Lupus 2003;12:535–8.)
in later pregnancy, thrombosis of the uteroplacental vasculature .
(Am J Obstet Gynecol 1993;169:1403–6)
An Autoimmune disorder having specific clinical & lab
•Vascular thrombosis or
•Loss of fetus at or after 10 weeks or
•Preterm delivery at or before 34 weeks or
•3 or more consecutive SAB before 10 weeks
Laboratory features :
•Anti-cardiolipin (aCL) antibodies: IgG or IgM at moderate or
high levels on 2 or more occasions at least 12 weeks apart
•Lupus anticoagulant (LA) antibodies: detected on 2 or more
occasions at least 12 weeks apart
Diagnosed by Revised Sapporo classification (2006):
At least one clinical criteria and one laboratory criteria
≥1 documented episodes of:
Small vessel thrombosis
ACA of IgG and/or IgM isotype in
medium/high titre (> 40 IU) or
≥1 unexplained fetal deaths of ≥ 10
(morphologically normal fetus)
≥1 premature births of ≤ 34th week POA
Severe PE or
Placental insufficiency (IUGR)
(morphologically normal neonate)
≥3 unexplained consecutive spontaneous
abortions < 10 week POA
* On 2 or more occasions
At least 12 weeks apart
Immune response to non-self components of pregnancy
•Absence of maternal blocking antibodies
•Inappropriate sharing of HLA
•Disturbances in natural killer cell function and distribution.
Porter Semin Reprod Med 2000;18(4):393-400
Natural killer cells:
There is no clear evidence that altered peripheral blood
NK cells are related to recurrent miscarriage.
T helper (Th1) immunodystrophism
Hum Reprod 2005;20:1123–6.
A meta-analysisconcluded that the available data are not consistent with associations between
cytokine polymorphisms and recurrent miscarriage. (Evidence level
Anatomical Factors (Uterine )
Uterine anomalies : prevalence of uterine anomalies in recurrent
miscarriage populations ranges between 1.8% and 37.6%
Hum Reprod 2003;18:162–6.
• Uterine septum (the anomaly most commonly associated with pregnancy
• Hemiuterus (unicornuate uterus)
• Bicornuate uterus
• Didelphic uteri
Acquired defects (eg, Asherman syndrome)
Defective endometrial receptivity
the role of uterine anomalies in recurrent miscarriage will remain debatable.
untreated uterine anomalies let women experience high rates of miscarriage
and preterm delivery, with a term delivery rate of only 50%.
Hum Reprod Update 2001;7:161–74.
• 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
• Most common.
• poorest reproductive outcome.
• Fetal survival with untreated cases 6 to 28
• The mechanism
– Not clearly understood
– Poor blood supply
• 10% of anomalies
• Incomplete fusion of Uterine horns at level of
• Two separate but communicating endometrial
• Abortion rate 30%
• Preterm labour 20%
• Metroplasty .
• 20% of anomalies
• Agenesis or hypoplasia of one Mullerian duct
• May be alone or accompanied by Rudimentary horn
With presence / absence of cavity Communicating /
• Associated Renal anomalies occur in
40% patients Ipsilateral to hypoplastic horn
• Least common anomaly -5-7%
• associated with a miscarriage rate of 20.9% and a
preterm delivery rate of 24.4%
Hum Reprod 2003; 18:162–6.
• Diagnosis is clinical, usually based on history
Subsequent miscarriages are usually earlier
Preceded by spontaneous rupture of membranes
Bulging membranes through the cervix prior to onset of
• Painless and progressive cervical dilatation
• Fetus alive during miscarriage
– History of cervical surgery (cone biopsy, LLETZ)
Unclear relationship between uterine leiomyomata
• The mechanism – Their position
– Poor endometrial receptivity
– Degeneration with increasing
OTHER UTERINE CAUSES
• Endometrial polyps
• Intrauterine adhesions
– Curettage for pregnancy complications .
– Traumatize basalis layer granulation
– Insufficient endometrium to support
– Menstrual irregularities (hypomenorrhea,
amenorrhea), cyclic pelvic pain, infertility.
Poorly controlled diabetes :
– (↑Blood glucose & HbA1c levels in 1st trimester)
risk for loss.
– Miscarriage risk rises with the level of HbA1c
No ↑ risk
thyroid disease .
Anti-thyroid antibodies have been linked to recurrent miscarriage.
Polycystic ovary syndrome (PCOS)
Presence of at least 2 of the following 3 criteria:
≥ 12 follicles in each ovary (<10 mm (2-9 mm in diameter)) and/or
Ovarian volume > 10 cm3
Oligomenorrhea and/or anovulation
Clinical and/or biochemical hyperandrogenism
• The increased risk of miscarriage in women
with PCOS has been recently attributed to
insulin resistance,hyperinsulinaemia and
hyperandrogenaemia. (Hum Reprod 2000;15:612–5.)
• An elevated free androgen index appears to
be a prognostic factor for a subsequent
miscarriage in women with recurrent
miscarriage. (Hum Reprod 2008;23:797–802).
• No infectious agent has been proven to cause
recurrent pregnancy loss
• Certain infections have been associated with
– Toxoplasma Gondi, rubella, HSV, CMV, measles, coxsackie
Lee Semin Reprod Med 2000;18(4):433-40
• Routine TORCH screening should be abandoned.
• Presence of BV in the first trimester
– Reported as a risk factor for 2nd-trimester miscarriage or
Best Pract Res Clin Obstet Gynaecol 2007;21:375–90.
• A RCT reported that treatment of BV early in the 2ndtrimester with oral clindamycin significantly reduces the
incidence of second-trimester miscarriage and preterm
birth in the general population.
• No data to assess the role of antibiotic therapy in women
with a previous second-trimester miscarriage.
Women with heritable or acquired thrombophilic
disorders have significantly increased risks of pregnancy
Kutteh Semin Reprod Med 2006;24(1):54-65
Inherited thrombophilic defects :
Activated protein C resistance (most commonly due to factor V
Leiden gene mutation).
deficiencies of protein C/S and antithrombin III
prothrombin gene mutation
are established causes of systemic thrombosis
Carriers of factor V Leiden or prothrombin gene
mutation have double the risk of experiencing
recurrent miscarriage compared with women
without these thrombophilic mutations.
Arch Intern Med 2004;164:558–63.
• Environmental chemicals
– Anesthetic gases
• Sporadic spontaneous loss
• No evidence of associations with RPL
• Personal habits
– Obesity »» ↑ Risk of Sporadic spontaneous loss and
– Smoking associated with ↑ Risk of spontaneous loss
– Alcohol »» ↑ Risk of Sporadic spontaneous loss.
– Caffeine associated with ↑ Risk of spontaneous loss
– does not ↑ sporadic or RPL
Male factor :
•Advanced paternal age may be a risk factor for
miscarriage (at more advanced age than
•Paternal HLA sharing not risk factor for RPL.
•Aside from cytogenetic abnormalities, male
factor contribution to RPL unknown
Hill ASRM 2002 Course 6 p.56
• More than 50% of couples with RPL have no
explanation despite extensive evaluation(s)
• Informative and sympathetic counseling appears to
play an important role
Lee Semin Reprod Med 2000;18(4):433-40
Detailed history :
personal history : Age-<16y, >35
Pattern of losses and if a live embryo or fetus was present
Exposure to environmental,toxins or drugs
Known gynecological or obstetrical infections
Features associated with APS
OBH : GA<^6 w, 6-8w,
FHR+/Past Surgical & Medical history: renal, look for autoimmune disease
(SLE) , D&C , Previous diagnostic tests and treatments
Family history : thrombophilia, birth defects, Consanguinity,RPL
– General physical exam
Features of PCOS
Features of SLE
Features of thyroid diseases
– Pelvic exam
–Any features of genital tract infection,
Ideally after 3 losses but American Society of
reproductive medicine (ASRM 2008) Define as 2 consecutive
Earlier investigation/referral should be considered for special
Advanced maternal age (? How old)
Bad obstetric history (e.g. ectopic, IUD)
History of infertility, known family history.
Patient request due to social reasons
How to Investigate ?
Investigate commoner and treatable causes first
Do not order a blind screen
• Antiphospholipid antibodies : ( Grade D)
– Anticardiolipin antibodies (ACA) & Lupus anticoagulant
2 +ve tests (12 weeks apart )
• Karyotyping : (Grade D )
– Should be performed on products of conception (POC)of the
3rd and subsequent consecutive miscarriages
– Parenteral karyotyping of both partners should be performed
when testing of POC reports an unbalanced structural
• Pelvic ultrasound – assess uterine anatomy : (√ )
– HSG can also be used as an initial screening test
– Suspected uterine anomalies may require further
investigations to confirm diagnosis:
• 3D ultrasound
• 2D ultrasound scanning and/or HSG can be used as an
initial screening test. Combined hysteroscopy and
laparoscopy and possibly 3D ultrasound scanning should be
used for definitive diagnosis. (3)
Hum Reprod Update 2008;14:415–29.
Women with second-trimester miscarriage should be
screened for inherited thrombophilias including factor V
Leiden, factor II (prothrombin) genemutation and protein S.
away from the acute event
when anticoagulation is discontinued
when the woman is not pregnant or on the combined
• PCOS screen
– Serum testosterone
• Screening for diabetes, thyroid disorders is only
indicated if there is clinical suspicion. Not recommended
as a routine test.
Recurrent Pregnancy Loss Causes, Controversies and Treatment 2007
Lost of pregnancy – can be a devastating
Can lead to anxiety, stress & depression
Instead of getting sympathy and support,
often made to feel that it is somehow her fault
Under intense pressure to provide a child for
May even lead to family problem @ divorce
Sensitivity is required in assessing and
Approach with sympathy and understanding
DO NOT blame, scold or make her feel at
Treatment - APS
• Pregnant women with APS should be treated with
low-dose aspirin plus heparin to prevent further
• Aspirin 81 mg po/day .
• Subcutaneous unfractionated heparin 5000 - 10000
units/12 hours .
• Alternative: LMWH(e.g., enoxaparin 1mg/kg/day)
every 12 hours
less heparin-induced thrombocytopenia .
administered once daily .
lower risk of heparin-induced osteoporosis. (RCOG 2011)
Neither corticosteroids nor intravenous immunoglobulin
therapy improve the live birth rate of women with recurrent
miscarriage associated with APS. (A)
Management: Genetic Losses
Abnormal parental karyotype should be referred to
a geneticist. (D)
Genetic counselling »» Reproductive options »»» a further
natural pregnancy with or without a prenatal diagnosis
test, gamete donation and adoption.
Preimplantation Genetic Diagnosis (PGD) : proposed
as a treatment option for translocation carriers
Hum Fertil (Camb) 2001;4:168–71.
Uterine septum: Hysteroscopy septal resection and
temporary intrauterine device.
Intrauterine adhesions : hysteroscopic division and
temporary intrauterine device: postoperative course of
cyclic estrogen and progesterone therapy.
In women with a singleton pregnancy and a history of one
second-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 . (B) RCOG 2011
Management : Endocrine factors
There is insufficient evidence to evaluate the effect of
progesterone supplementation in pregnancy to
prevent a miscarriage (RCOG 2011)
However newer evidences is coming up as large
multicentre study PROMISE is currently on the
There is insufficient evidence to evaluate the effect of
human chorionic gonadotrophin supplementation in
pregnancy to prevent a miscarriage in women with
recurrent miscarriage. (B)
Suppression of high luteinising hormone levels among
ovulatory women with recurrent miscarriage and
polycystic ovaries does not improve the live birth rate. (A)
• Role of Metformin
– Previously prescribed to reduce risk of recurrent
– Insufficient evidence to evaluate the effect of
– Recent meta-analysis of 17 RCTs - metformin has
no effect on sporadic miscarriage risk
– Uncontrolled small studies (no RCTs) – associated
with reduction in miscarriage rate in women with
Paternal cell immunisation
third-party donor leucocytes
trophoblast membranes and intravenous
»»»»previous unexplained recurrent miscarriage does
not improve the live birth rate . (A)
Treatment Inherited thrombophilias
For heritable or acquired thrombophilia: heparin
For elevated homocysteinemia without thrombosis
history (Supplementation with Vitamin B6, B12 and
(Heparin anticoagulation for history of thrombosis)
Heparin therapy during pregnancy may improve the live
birth rate of women with second-trimester miscarriage
associated with inherited thrombophilias. (A)
Management – Unexplained RM
• 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. (B)
• 75% chance of a eventual live birth in subsequent
pregnancy However, prognosis worsens with:
• Increasing maternal age
• Number of previous miscarriages
the use of empirical treatment in unexplained recurrent
miscarriage is unnecessary and should be resisted
Unexplained recurrent miscarriage
Preimplantation genetic screening with in vitro
fertilisation treatment in women with unexplained
recurrent miscarriage does not improve live birth rates.
Two recent randomised controlled trials reported that
neither of (Aspirin alone or in combination with heparin)
improves the live birth rate among women with
unexplained recurrent miscarriage.
(N Engl J Med 2010;362:1586–96.)
• Paternal cell immunisation, third-party donor
leucocytes, trophoblast membranes
• and intravenous immunoglobulin in women
with previous unexplained recurrent
• miscarriage does not improve the live birth