Recurrent pregnancy loss

Dr. Vandana Bansal

MS, D.phil. (Gold Medalist), DGO, FCGP
Infertility & IVF Specialist & Advance Laparoscopic Surgeon

Director
Arpit Test Tube Baby Centre, Prayagraj
Jeevan Jyoti Hospital, Prayagraj (U.P.)
 INTRODUCTION

• The loss of pregnancy at any stage can be a devastating

experience
• Sensitivity is required in assessing and counselling couples with
recurrent miscarriage
• 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 being successful
 Definition

• A recurrent miscarriage ₌ recurrent pregnancy loss (RPL) is

3 or more consecutive, spontaneous pregnancy losses
(clinically recognized pregnancies) , under 20 week .

RPL-TYPES :
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

Am J Obstet Gynecol 2005;192:240–6

SUB TYPES :

• Preclinical pregnancy loss

• Clinical pregnancy loss
 Pre-embryonic
 Embryonic
 Foetal

• First trimester loss

• Second trimester loss
• Late foetal loss
1st trimester losses :
• PCOS (Polycystic ovary syndrome)
• APS (Antiphospholipid syndrome)
• Chromosomal abnormalities
• Endocrine disorders (untreated DM, thyroid disease)
• Uterine abnormalities
• Submucous fibroid
• Subseptate uterus

2nd trimester losses :

• Cervical incompetence
• Asherman syndrome (intrauterine synechiae)
• Bacterial vaginosis
• Uterine abnormalities
• Congenital – bicornuate, septate, subseptate, hypoplasia
• Myomas
• Thrombophilias
 Epidemiology
• 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 1 sporadic spontaneous
abortion
• 2% have 2 consecutive Spontaneous Abortion.

• 0.4-1% have 3 consecutive Spontaneous Abortion.

• Spontaneous successful pregnancy after 2 miscarriage is 80%

Lee Semin Reprod Med 2000;18(4):433-40

 Risk factors
Advanced maternal age :
12-19 year:13%
20 -24 year: 11%Risk factors
25-30 year: 12%
31-35 year: 15%
36-40 year: 25%
>40 year: 50%
BMJ 2000;320:1708–12.
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.
Confirmed association  Suspected association
Ionizing irradiation  Caffeine (> 300 mg/day)
Organic solvents  Cigarette smoking
Alcohol
(However, current evidence is insufficient to confirm this
Mercury
association)
Lead
(Gardella & Hill Semin Reprod Med
2000;18(4):407-424) Acta Obstet Gynecol Scand 2003;82:182–8.

obesity increases the risk of both sporadic and recurrent miscarriage.

(Fertil Steril 2010;94:290–5).
 AETIOLOG
Y
Only in 50 %, the cause can be determined
(Explained )
1. Genetic (embryonic and paLreeentSaelm)in Reprod Med 2000;18(4):433-40

2. Immunologic (autoimmune/alloimmune )
3. Anatomical Factors (Uterine )

4. Infectious causes .

5. Environmental

6. Endocrine

7. Hematologic disorders
 Genetic
• Advanced Maternal age α errors in meiosis .
• Oocytes ovulated earlier in life less prone to non
dysjunction
• Repetitive first trimester losses
• Anembryonic pregnancies
• History of malformations or mental retardation.
 Genetic
• 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
translocation. (BMJ 2006; 332:1012.)
– Inversion
– X chromosome mosaicsm
 Various Genetic Techniques
• Conventional Karyotyping
• Failure of tissue culture
• Doesn’t distinguish between maternal contamination and normal female fetus
• Fluorescene in situ hybridization (FISH)
• Limited use
• Uses probes for certain chromosomes
• Doesn’t necessarily detect chromosomal cause of the miscarriage
• Array based comparative genomic hybridization (Array
– CGH)
• Better and currently preferred technique
• Avoid limitations of Karyotyping and FISH
• New technique
• Next generation sequencing (NGS)
 Immune factors

Autoimmune : (directed to self)

Systemic Lupus Erythmatosus

Antiphospholipid Syndrome

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 antibodies.

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)
 Antiphospholipid syndrome

An Autoimmune disorder having specific clinical

& lab criteria:
Clinical features:
•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
Clinical Laboratory
Thrombosis ≥1 documented episodes of: ACA ACA of IgG and/or IgM isotype in
Arterial medium/high titre (> 40 IU) or
Venous and/or >99th percentile
Small vessel
thrombosis

Pregnancy ≥1 unexplained fetal deaths of ≥ 10 LA Detected

morbidity weeks POA
(morphologically normal fetus)

≥1 premature births of ≤ 34th week POA Anti- >99th percentile

d/t: beta2-
Severe PE or glycopro
Placental insufficiency (IUGR) tein
(morphologically normal neonate)

≥3 unexplained consecutive spontaneous * On 2 or more occasions

abortions < 10 week POA At least 12 weeks apart
Alloimmune :
Immune response to non-self components of pregnancy
•Cytotoxic antibodies
•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.
Hum Reprod
2005;20:1123–6.
T helper (Th1) immunodystrophism
A meta-analysis concluded that the available data are not consistent with associations
between cytokine polymorphisms and recurrent miscarriage. (Evidence level 2++)
 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
loss)
• Hemiuterus (unicornuate uterus)
• Bicornuate uterus
• Didelphic uteri
Diethylstilbestrol-linked condition
Acquired defects (eg, Asherman syndrome)
Incompetent cervix
Leiomyomas
Uterine polyps
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%.
Fertil Steril 1988; 49:944.
 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%.
• Most common.
• poorest reproductive outcome.
• Fetal survival with untreated cases 6 to 28
%
• The mechanism
– Not clearly understood
– Poor blood supply »»»
 Bicornuate Uterus
• 10% of anomalies
• Incomplete fusion of Uterine horns at level
of fundus
• Two separate but communicating
endometrial cavities
• Abortion rate 30%
• Preterm labour 20%
• Metroplasty .
 Unicornuate Uterus
• 20% of anomalies
• Agenesis or hypoplasia of one Mullerian duct
• May be alone or accompanied by Rudimentary
horn With presence / absence of cavity
Communicating / Non communicating
• Associated Renal anomalies occur in
40% patients Ipsilateral to hypoplastic horn
 Uterus Didelphys

• 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.
 Cervical incompetence
• Diagnosis is clinical, usually based on history
– Miscarriage
• 2nd-trimester miscarriage
• Subsequent miscarriages are usually earlier
• Preceded by spontaneous rupture of membranes
• Bulging membranes through the cervix prior to onset of
labour
• Painless and progressive cervical dilatation
• Fetus alive during miscarriage
– History of cervical surgery (cone biopsy, LLETZ)
 LEIOMYOMA
Unclear relationship between uterine leiomyomata
and RPL
• Submucous
• The mechanism -
– Their position
– Poor endometrial receptivity
– Degeneration with
increasing cytokine
production
 OTHER UTERINE CAUSES
• Endometrial polyps
• Intrauterine adhesions
– Curettage for pregnancy complications .
– Traumatize basalis layer  granulation
tissue
– Insufficient endometrium to support
fetoplacental growth
– Menstrual irregularities (hypomenorrhea,
amenorrhea), cyclic pelvic pain,
infertility.
 Endocrine factors
• Poorly controlled diabetes :
– (↑Blood glucose & HbA1c levels in 1st trimester) ↑
risk for loss.
– Miscarriage risk rises with the level of HbA1c
– Well-controlled No ↑ risk
• thyroid disease .
• Anti-thyroid antibodies have been linked to recurrent
miscarriage.
• Hyperprolactinemia
• Polycystic ovary syndrome (PCOS)
•Presence of at in
≥ 12 follicles least
each2ovary
of the(<10
following
mm (2-93mm
criteria:
in diameter)) and/or
– Polycystic
• Ovarian ovaries
volume > 10 cm 3

– 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).
 Infective agents

• No infectious agent has been proven to cause

recurrent pregnancy loss
• Certain infections have been associated with
spontaneous loss
– Toxoplasma Gondi, rubella, HSV, CMV, measles,
coxsackie
Lee Semin Reprod Med
2000;18(4):433-40

• Routine TORCH screening should be abandoned.

RCOG, 2011.
 Bacterial vaginosis
• Presence of BV in the first trimester
– Reported as a risk factor for 2nd-trimester miscarriage or
preterm delivery.
Best Pract Res Clin Obstet Gynaecol 2007;21:375–90.

• A RCT reported that treatment of BV early in the 2nd-

trimester with oral clindamycin significantly reduces the
incidence of second-trimester miscarriage and preterm
birth in the general population.
Lancet 2003;361:983–8.

• No data to assess the role of antibiotic therapy in women

with a previous second-trimester miscarriage.
 Hematologic disorders
Women with heritable or acquired thrombophilic
disorders have significantly increased risks of
loss
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
• hyperhomocysteinaemia
• prothrombin gene mutation
are established causes of systemic
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.
 MISCELLANEOUS
• Environmental chemicals
– Anesthetic gases
• Sporadic spontaneous loss
• No evidence of associations with RPL
• Personal habits
– Obesity »» ↑ Risk of Sporadic spontaneous
loss and RPL
– Smoking associated with ↑ Risk of
spontaneous loss
– Alcohol »» ↑ Risk of Sporadic spontaneous
loss.
– Caffeine associated with ↑ Risk of
spontaneous loss
Male factor :
•Advanced paternal age may be a risk factor for
miscarriage (at more advanced age than
females)
•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
 Idiopathic (Unexplained)
• 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
How and when to investigate?
Ideally after 3 losses but American Society of
reproductive medicine (ASRM 2008) Define as 2 consecutive
miscarriage
Earlier investigation/referral should be considered for special
cases:
Advanced maternal age (? How old)
Bad obstetric history (e.g. ectopic, IUD)
Medical disorders
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
chormosomal abnormality.
• 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:
• Hysteroscopy
• Laparoscopy
• 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.

Thrombophilias :
Women with second-trimester miscarriage should be
screened for inherited thrombophilias including factor V
Leiden, factor II (prothrombin) genemutation and protein S.
( 2++) Lancet 2003;361:901–8.
away from the acute event
when anticoagulation is discontinued
when the woman is not pregnant or on the combined
contraceptive pill.
 Endocrine factors
• PCOS screen
• Serum testosterone
• SHBG
• Fasting insulin and fasting glucose not recommended
• Thyroid Screen
• TSH and TPO antibodies is strongly recommended in
women with RPL
• Abnormal TSH and TPO antibody levels should be
followed up by T4 testing
Not useful
Imaging techniques for Uterine Anatomy
• All women with RPL should have Uterine anatomy assessment
• Preferred technique – Transvaginal 3D US (to differentiate septate
uterus and bicorporeal uterus with normal cervix)
• Sonohysterography (SHG) more accurate than HSG in diagnosing
uterine morphology
• In Mullerian uterine malformation, consider investigating kidney
and urinary tract
• MRI not first line option for uterine malformations in women with
RPL
Recurrent Pregnancy Loss Causes, Controversies and Treatment 2007
How to manage ?
Management
 Emotional aspect
 Lost of pregnancy – can be a devastating
traumatic experience
 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
the family
 May even lead to family problem @ divorce
 Sensitivity is required in assessing and
counselling couples
 Approach with sympathy and
understanding
 DO NOT blame, scold or make her feel at
fault
 Treatment - APS
• Pregnant women with APS should be treated with
low-dose aspirin plus heparin to prevent further
miscarriage. (B) (RCOG 2011)
• Aspirin 81 mg po/day .
• Subcutaneous unfractionated heparin 5000 - 10000
units/12 hours .
• Alternative: LMWH(e.g., enoxaparin 1mg/kg/day)
every 12 hours
potential advantages:
less heparin-induced thrombocytopenia .
administered once daily .
lower risk of heparin-induced
UFH vs LMWH vs Fondaparinux

14
Protocol for use of
Enoxaparin
Treatment guidelines for use of Anticoagulants in RPL: ESHRE 2017

• Recommendations
• For women who fulfil the laboratory criteria of APS and a history of
three or more pregnancy losses, we suggest administration with low
dose aspirin (75 to 100 mg/day) starting before conception and a
prophylactic dose heparin (UFH or LMWH) starting at date of a
positive pregnancy test, over no treatment
• The GDG suggests offering anticoagulant treatment for women with
two pregnancy losses and APS, only in the context of clinical research
RCOG Guidelines
Evidences
Evidences
 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 Abnormalities
Treatment
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.
Fibroids: myomectomy
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
way
.

(PROMISE,http://www.medscinet.net/promise)
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)

(RCOG 2011)
 PCOS
• Role of Metformin
– Previously prescribed to reduce risk of recurrent
miscarriage
– Insufficient evidence to evaluate the effect of
metformin supplementation
– 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
recurrent miscarriage
 Hypothyroidism
• Overt hypothyroidism arising before conception or during early
gestation should be treated with levothyroxine in women with
RPL
• In case of subclinical hypothyroidism (SCH), benefit vs risk should
be considered before starting the levothyroxine therapy
• In case of SCH and RPL, if pregnancy occurs, it is recommended
to check TSH in early gestation (7-9 weeks)
• In autoimmune hypothyroidism and RPL , TSH level should be
checked in early gestation (7-9 weeks) and hypothyroidism
should be treated with levothyroxine
Role of Progesterone and HCG in RPL

• There is insufficient evidence to recommend the use of

progesterone to improve live birth rate in women with RPL and
luteal phase insufficiency
• There is insufficient evidence to recommend the use of hCG to
improve live birth rate in women with RPL and luteal phase
insufficiency.
 Immunotherapy
Paternal cell immunisation
third-party donor leucocytes
trophoblast membranes and intravenous
immunoglobulin (IVIG)
»»»»previous unexplained recurrent miscarriage does
not improve the live birth rate . (A)
 Treatment Inherited thrombophilias
For heritable or acquired thrombophilia: heparin
anticoagulation

For elevated homocysteinemia without thrombosis

history (Supplementation with Vitamin B6, B12 and
folic acid)
(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
RCOG 2011
 Unexplained recurrent miscarriage
Preimplantation genetic screening with in
fertilisation treatment vitro women
in with
recurrent miscarriage does not unexplained
improve live birth rates.
(C)

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.) (Blood 2010;115:4162–7.)
 Role of Immunoglobulin in RPL
Mechanism of action is multiple, complex and not fully
understood
• Down regulation of Natural Killer (NK) cells
• Immunomodulator effects
• The F(ab’) dependant mechanism includes the killing of target cells by antibody
dependant cytotoxicity, blockade of cell – cell interactions, neutralization of
cytokines and autoantibodies, scavenging the anaphylotoxins C3a and C5a
• The Fc dependant mechanisms include the saturation of the neonatal Fc
receptor, the expansion of regulatory T cell populations, the modulation of
dendritic cell activation via FcΎ receptor III, modulation of activating and
inhibitory FcΎ receptor expression on innate immune effector cells and B cells
Effect of
intramuscular
immunoglobulin
in APA syndrome
Injection immunoglobulin in a dose of 2 ml
intramuscular of 16.5% strength every 21st day
until 36 weeks of pregnancy was given
 Take home message
• Recurrent Pregnancy Loss affects up to 5% of couples
• Approximately 40% of RPL is unexplained
• Investigations should include chromosomal screening
techniques, endocrine screening, anatomy screening,
autoimmune and anticoagulant screening
• Treatment options are limited and includes empirical
treatments such as anticoagulants,
immunomodulators, immunoglobulins
THANK YOU