Recurrent pregnancy loss: causes and diagnosis, myths and facts (evidence based)

1. RPL: Myths and facts
evidence-based
Ali Bendary
Assistant Lecturer
Benha University Hospitals

5. Evidence-Based

12. Scope
• Definitions
• Incidence
• Candidates for
evaluation
• Causes
• History and Ex
• Investigations

13. Definition

14. • Miscarriage:
Spontaneous loss of clinically recognized
pregnancies before the fetus reaches
viability.
• Viability:
Includes all pregnancy losses from the time
of conception until 24 weeks of gestation.

15. ≥3
• Recurrent miscarriage
loss of three or more consecutive
pregnancies

16. Incidence

17. We support all mothers who are living childless life due to
miscarriage, stillbirth, neonatal death, as well as any other
form of child loss.

18. StirratGM.Recurrentmiscarriage.Lancet1990

20. Candidates for
evaluation

21. Relatively common, occurs in about 10-15% of clinically
recognized pregnancies under 20 weeks of gestation.
Stirrat GM. Recurrent miscarriage. Lancet 1990; 336:673.
• Should woman undergo extensive evaluation after
a single first trimester or early second trimester
spontaneous miscarriage?
• There is a general consensus that healthy women
should not undergo extensive evaluation after a
single spontaneous miscarriage. why?

22.  chemical pregnancies
 Ectopic and molar pregnancies
DO YOU REMEMBER THE DEFINITION?
Spontaneous loss of clinically recognized
pregnancies before the fetus reaches viability
not including
confirmed by
ultrasound
histopathologic evaluation

23. Q1
• A 37-year-old women is seen in clinic after her third
consecutive early pregnancy loss.
What is the most likely cause of recurrent
miscarriage?
a) Antiphospholipid syndrome
b) Cervical factors
c) Genetic causes
d) Genital infections
e) Uterine anatomical abnormality

24. Causes

25. • Epidemiological
• APLS
• Anatomic
• Genetic
• Endocrine
• Immune
• Infection
• Inherited
thrombophilia
• Male factor
• Psychological
• Unexplained

26. Clifford K et al., Future pregnancy outcome in unexplained recurrent first
trimester miscarriage. Hum Reprod 1997
Apreviouslivebirthdoesnot
precludeawomandeveloping
recurrentmiscarriage.

27. Q2
• Incidence of RPL in female patient 42 years
old
a) 15%
b) 35%
c) 50%
d) 75%
e) 90%

28. I.Epidemiologicalcauses

30. 12–19
years
20–24
years
25–29
years
30–34
years
35–39
years
40–44
years
≥45
years
13% 11% 12% 15% 25% 51% 93%
Nybo Anderson AM et al., Maternal age and fetal loss: population based register
linkage study. BMJ 2000
• Maternal age and number of previous miscarriages are
two independent risk factors for a further miscarriage.
1. Advancing maternal age is associated with a decline in
both the number and quality of the remaining oocytes.

31. N.B. Is advanced paternal age identified as a
risk factor for miscarriage?!
The risk of miscarriage is highest among
couples where
- woman ≥35 years of age
+
- man ≥40 years of age
de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors
for miscarriage; results of a multicentre European study. Hum Reprod 2002.

32. Q3
• A 39-year old woman has been referred with a history of 3
consecutive miscarriages. The first 2 miscarriages occurred
before 10 weeks and the third was at 12 weeks of gestation.
She has no significant medical history, and no uterine
abnormality were identified on a pelvic US scan.
What is the risk of miscarriage in the next pregnancy for this
woman?
a) <10%
b) 20%
c) 30%
d) 50%
e) 60%

33. Toth B et al., Recurrent miscarriage: current concepts in diagnosis and treatment. J
Reprod Immunol 2010;
previous miscarriages Miscarriage rate (%)
3 34/119 (29%)
4 13/49 (27%)
5 7/16 (44%)
≥ 6 9/17 (53%)
2. Previous reproductive history is an independent
predictor of future pregnancy outcome.

35. - Smoking, alcohol and caffeine consumption: a dose-
dependent manner.
- Anesthetic gases for theatre workers the evidence on
the effect of is conflicting.
- Obesity increases the risk of both sporadic and
recurrent miscarriage.
McGregor DG. Occupational exposure to trace concentrations of waste
anesthetic gases. Mayo Clin Proc 2000
Metwally M et al., Body mass index and risk of miscarriage in women with
recurrent miscarriage. Fertil Steril 2010
• Exposure to some environmental factors may
cause sporadic rather than recurrent miscarriage.

36. II.AntiPhophoLipid
Syndrome(APLS)

38. aPLsantibodies
• A heterogenous group of antibodies directed
against phospholipids and/or phospholipid
binding proteins.
• The commonest detected aPLs are:
- Anticardiolepin (aCL)
- Lupus anticoagulant (LA)

40. 1. aPL binding with phospholipids may interfere with
the coagulation cascade  pro-coagulant.
pathophysiology
The in Vivo mechanisms responsible for thrombosis and
fetal loss are uncertain,
But several pathways are suggested:
2. Annexin-V (anticoagulant on normal placental villi) is
↓ with aPL  placental thrombosis and infarction.

42. 3. aPL affect trophoblast differentiation, proliferation
and invasion  impaired implantation.

43. 4. in the mouse model, the mechanism of APLS
pregnancy loss is complement activation not
thrombosis.

44. Pregnancy
complications
↓
is related to
antibody titre,
especially IgG aCL Thrombosis
↓
is more strongly
associated with LA
than with aCL.

45. Q4
• A 28-year-old woman para 0+3 known to have
antiphospholipid syndrome who never took
treatment of her condition.
What is the possibility of live birth rate of her next
pregnancy without pharmacological intervention?
a) 10%
b) 30%
c) 50%
d) 70%
e) 90%

46. Incidence
of RPL
of SLE patients
- Most APS patients do not fulfill the
diagnostic criteria for SLE
- Most 1ry APLS do not progress to SLE
Rai RS et al., High prospective fetal loss rate in untreated pregnancies of women
with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 1995
In women with APLS + RPL
 LBR without ttt
10%
15%
30%

47. • of patient with thrombosis.
• of sever, early onset pre-eclampsia
(may develop as early as 15 weeks)
• Risk of FGR
• Risk of PTL in those with SLE, previous
thrombosis or late fetal death
30%
30%

48. TypesofAPLS
Occurs alone Associated with other
conditions, mainly SLE
1. Primary 2. Secondary

50. Presence of aPL
(either aCL &/or LA)
on 2 separate occasion
at least …. wks apart
RCOG 6 wks
ASRM 12 wks
• Anti-ß2GP1 are more
specific for APLS but
there is poor lab
standarization
1. Thrombosis (venous, arterial
, microcirculation)
2. Pregnancy morbidity i.e:
• ≥ 3 consecutive miscarriage
<10wks
• ≥ 1 fetal death >10wks
• ≥ 1 preterm birth <34wks
with normal fetal morphology
due to pre-eclampsia or
placental insufficiency.
Criteriafordiagnosis
(at least 1 lab & 1 clinical)
Clinical Laboratory

51. • Other clinical features:
- Autoimmune throbocytopnia (ITP),
hemolytic anemia
- Cerebral involvement: epilepsy, cerebral
infarction, chorea, migraine, transverse
myelitis.
- Heart valve involvement (particularly
mitral)
- Systemic and pulmonary hypertension.
- Leg ulcers.

52. APTT
dRVVT
LaboratorycriteriaforaPL
• LA requires 2 phospholipid-dependent coagulation
tests.
Addition of normal
plasma fails to correct
prolonged time
Addition of excess
phospholipid correct
prolonged time
Both
prolonged
• aCL measured using commercially avialable
enzyme-linked immunosorbent assay (ELISA) kits.

53. III.Anatomic

54. 1. CONGENITAL
2. ACQUIRED
3. CERVICAL WEAKNESS

55. 1. Congenital
• Prevalence of uterine anomalies
in recurrent miscarriage
• delivery rates of miscarriage and
preterm delivery in women with
untreated uterine anomalies
Salim R et al., A comparative study of the morphology of congenital uterine anomalies in
women with and without a history of recurrent first trimester miscarriage. Hum Reprod 2003
50%
12.6%

58. Incidence of pregnancy loss
septate bicornuate arcuate
44.3% loss 36.0% loss 25.7% loss
in particular Correction of septate
defects may have beneficial effects
live birth rate 83.2%
should be considered in women with RPL.
Grimbizis GF et al., Clinical implications of uterine malformations and
hysteroscopic treatment results. Hum Reprod Update 2001
More likely to
miscarry in 1st T
More likely to
miscarry in 2nd T

59. 2. Acquired

60. • The clinical management of pregnancy-loss
patients with Asherman syndrome, uterine
fibroids, and uterine polyps is also controversial
• There is no conclusive evidence that surgical
treatment reduces the risk of pregnancy loss.

61. • General consensus is:
surgical correction of significant uterine
cavity defects should be considered.

62. 3. Cervical weakness
History ?!
Ultrasound
?!
Pre-
pregnancy
diagnostic
tests ?!

63. History?!
• History-indicated cerclage should
be offered to women with
≥ 3 previous
PTL
and/or
2nd trimester losses.

64. Pre-pregnancydiagnostic
techniques?!

65. • aimed at diagnosing ‘cervical weakness’
include
- assessment of cervical resistance index
- hysterography
- insertion of cervical dilators.
in women with a history of PTL and/or 2nd
trimester loss
insufficient evidence to recommend the
use of these techniques
Pre-pregnancydiagnostic
techniques?!

66. TVUS between 16+0 and 24+0 weeks
reveals a cervical length < 25 mm.
+
history of spontaneous PTL or 2nd
trimester loss between 16+0 and 34+0
weeks of pregnancy
Offer a choice of either
prophylactic vaginal progesterone
or prophylactic cervical cerclage
Ultrasound?!

67. Ultrasound?!

68. Ultrasound?!

69. TVUS between 16+0 and 24+0 weeks reveals a
cervical length < 25 mm.
+
either
 P-PROM in a previous pregnancy or
 History of cervical trauma
Offer a choice of
prophylactic cervical cerclage

70. Q5
• A 20-year-old PG has an incidental finding of
cervical length of 20 mm at her routine routine 20-
week anomaly scan. She is asymptomatic and has no
significant past medical or surgical history.
What is the most appropriate management?
a) Abdominal cerculage
b) Cervical cerculage
c) Counsel the women that no further action is
required
d) Progesterone pessaries
e) Serial ultrasound scan to assess cervical length

71. cerclage is not recommended
• incidentally identified short cervix of 25 mm or less
without a history of spontaneous preterm delivery
or second-trimester loss?
• funnelling of the cervix (dilatation of the internal os
on ultrasound) in the absence of cervical shortening
to 25 mm or less?
cerclage is not recommended

74. Q6
• A 28-year-old nulliparous woman has had 2
consecutive miscarriage in the first trimester. She is
referred with a further incomplete miscarriage
What is the most appropriate genetic test to perform?
a) karyotype both partners.
b) Karyotype chorionic villus sample in next
pregnancy
c) Karyotype mother
d) Karyotype father
e) Karyotype products of conception

75. IV.Genetic

76. • There is a very high frequency of sporadic
karyotypic abnormalities (60%) in products
of conception
while
incidence of karyotypic abnormalities in the
parents is low.
Stephenson MD et al., Cytogenetic analysis of miscarriages from couples
with recurrent miscarriage: a case-control study. Hum Reprod 2002
60%

77. • 2–5% of couples with RPL , one of the
partners carries a balanced structural
chromosomal anomaly:
Stephenson MD, Sierra S. Reproductive outcomes in RPL associated with a parental
carrier of a structural chromosome rearrangement. Hum Reprod 2006
2-5%
- balanced
reciprocal
- Robertsonian
translocation

78. • Although carriers of a balanced translocation are
usually phenotypically normal
 their pregnancies are at ↑ risk of miscarriage,
CFMF and mental disability.

79. • Cytogenetic analysis should be performed on
products of conception (RCOG, class D)
• Parental peripheral blood karyotyping of both
partners should be performed in couples with RPL
(RCOG, class D)
• Testing of products of conception reports an
unbalanced structural chromosomal abnormality.
• The third and subsequent consecutive miscarriage(s)

80. V.Endocrine

81. 1. thyroid dysfunction:
• This is problematic given
the lack of consensus
regarding the definition
of a normal upper limit of TSH.
• Whereas TSH values of 4.0–5.0 mIU/L were once
considered normal,
a consensus is emerging that
TSH values > 2.5 mIU/L are outside the normal range.

82. • As long as thyroid-stimulating hormone (TSH)
levels are in the normal range
 there is insufficient evidence to recommend:
- Thyroxine (T4) testing
- Screening for anti-thyroid antibodies.
Abalovich M et al., Management of thyroid dysfunction during pregnancy and postpartum:
an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007

83. 2. Diabetes
• Well-controlled diabetes is not a risk factor for
RPL.
• Uncontrolled diabetes is associated with
increased pregnancy loss

84. 3. Polycystic ovary syndrome (PCOS)
has been linked to an increased risk of miscarriage but
the exact mechanism remains unclear.
- insulin resistance and hyperinsulinaemia
- hyperandrogenaemia.

85. 4. Hyperprolactinemia:
may be associated with recurrent pregnancy loss
through:
alterations in the hypothalamic-pituitary-ovarian axis
 Impaired folliculogenesis and oocyte maturation
 Short luteal phase.

86. • Normalization of prolactin levels with a dopamine
agonist improved subsequent pregnancy outcomes in
patients with recurrent pregnancy loss
Treated group untreated group
Live-birth rate 85.7% 52.4%
Hirahara F et al.,Hyperprolactinemic recurrent miscarriage and results of
randomized bromocriptine treatment trials. Fertil Steril 1998

87. 5. luteal phase defect:
• Problematic.
• The use of histologic and biochemical endpoints as
diagnostic criteria for endometrial dating are
unreliable
Coutifaris C et al., Histological dating of timed endometrial biopsy tissue
is not related to fertility status. Fertil Steril 2004
Therefore, routine endometrial biopsy for dating is
not recommended

88. VI.Immune

89. • Studies of
- Human leukocyte antigen (HLA) typing
- Embryotoxic factors
- Decidual cytokine profiles
- Blocking or antipaternal antibody levels
- HLA-G polymorphism
immunologic factors have produced inconsistent data that
generally have not been reproduced in more than one laboratory.
Proposed immuno-modulatory treatments for RPL in the setting of
one or more of these findings have not been proven effective.

90. VII.Infective

91. Q7
• From the following infective casues, which has
been strongly related to preterm labor and 2nd T
miscarriage?
a) Toxoplasmosis
b) Rubella
c) Listeria
d) CMV
e) Bacterial vaginosis

92. • Any severe infection that leads to bacteraemia or
viraemia can cause sporadic miscarriage.
• The role of infection in recurrent miscarriage is
unclear.

93. • For an infective agent to be implicated in the etiology of
RPL, it must be capable of:
- persisting in the genital tract
- avoiding detection
- must cause insufficient symptoms to disturb
the woman.
Toxoplasmosis, rubella, cytomegalovirus, herpes and listeria
infections do not fulfill these criteria
Routine TORCH screening should be abandoned
MacLean AB et al., Infection and pregnancy loss. London: RCOG Press; 2001

94. What about BACTERIAL VAGINOSIS ?!!

95. • The presence of bacterial vaginosis in the first
trimester of pregnancy has been reported as a risk
factor for 2nd T miscarriage and PTL.
• the evidence for an association with first trimester
miscarriage is inconsistent.
Leitich H, Kiss H. Asymptomatic bacterial vaginosis and intermediate flora as risk
factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2007

96. VIII.Inherited
Thromophilia

97. • inherited thrombophilias have been implicated as a
possible cause in
- Recurrent miscarriage
- Late pregnancy complications
The presumed mechanism being
thrombosis of the uteroplacental circulation

98. - prothrombin gene mutation 20210
- antithrombin III deficiency
- Factor V Leiden mutation
- deficiencies of protein C/S
- hyperhomocysteinaemia
- Methylenetetrahydrofolate mutation

99. • The association between thrombophilia and late
pregnancy loss has been consistently stronger than
for early pregnancy loss.
recurrent 1st T
fetal loss
recurrent 2nd T
fetal loss
factor V Leiden OR 2.01 OR 7.83
Prothrombin gene mutation OR 2.32 OR 2.56
Protein S deficiency OR 14
Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal
loss: a meta-analysis. Lancet 2003

100. • Women with 2nd T miscarriage should be
screened for inherited thrombophilias
including:
- Factor II (prothrombin) gene mutation
- Factor V Leiden
- protein S deficiency
(RCOG, class D)

101. IX.Malefactor

103. • Standard semen parameters, including sperm
morphology, do not appear to be predictive of
recurrent pregnancy loss.

104. • Abnormal DNA fragmentation may be seen in the
setting of
- advanced paternal age
- exogenous heat
- toxic exposures
- varicoceles

106. Benchaib M etal., Sperm deoxyribonucleic acid fragmentation as a prognostic
indicator of ART outcome. Fertil Steril 2007
• Currently, there are contradictory data
regarding a causal effect between pregnancy
loss and fragmentation of sperm DNA in IVF
cycles.

107. X.Psychologicalfactor

108. Recurrent
pregnancy loss
patients are prone
to:
- Anger
- Depression
- Anxiety
- grief and guilt.

109. • TLC was defined as:
- psychological support
- weekly medical and ultrasonographic
examinations
- instructions to avoid heavy work, travel, and
sexual activity.

110. A cohort of 158 couples with 3 consecutive pregnancy
losses and no otherwise identifiable etiology were
divided into 2 groups
One receiving routine care
during the next pregnancy
(n =42)
Live birth rate:
The other additionally
receiving tender-loving care
(TLC) (n =116)
Live birth rate
36% 85%
Sugiura-Ogasawara M et al., Depression as a potential causal factor in subsequent
miscarriage in recurrent spontaneous aborters. Hum Reprod 2002

111. XI.UnexplainedRPL

113. History
and
examination

114. History
Should include a description of:
- characteristics (eg, anembryonic pregnancy, live
embryo) of all previous pregnancies.
- Gestational age
RPL typically occurs at a similar gestational age in
consecutive pregnancies and the most common
causes of RPL vary by trimester.

115. As an example,
Miscarriage
related to
- chromosomal
- endocrine
defects
Losses
due to
- anatomic
- immunological
abnormalities
tends to occur
earlier in
gestation
than
However, there is significant overlap

116. Is there exposure to
environmental toxins, which
may be lethal to developing
embryos?
Has there been uterine
instrumentation, which may
have caused intrauterine
adhesions?
Additionalinformationtoconsider:
Is there a history of venous or
arterial thrombosis suggestive
of antiphospholipid syndrome?
What information is available
from previous laboratory,
pathology, and imaging
studies?
Are the menstrual cycles normal? Abnormalities
in cycle length may be due to endocrine
dysfunction. Is there galactorrhea, which also
suggests endocrine dysfunction
(hyperprolactinemia)?

117. Physical examination
• should include
- General physical assessment with attention to
signs of endocrinopathy (eg, hirsutism,
galactorrhea)
- Pelvic organ abnormalities (eg, uterine
malformation).

118. Mental health evaluation
RPL is a source of great stress for couples.
One study of 301 women with RPL reported:
- fourfold higher rates of depression (8.6 versus 2% in
women without RPL)
- doubling of severe stress (41 versus 23% in women
without RPL)
Kolte AM, Olsen LR, Mikkelsen EM, et al. Depression and emotional stress is
highly prevalent among women with recurrent pregnancy loss. Hum Reprod 2015

119. Investigations

127. Incidence of contributing causes to RPL

128. • Women should not undergo extensive evaluation
after a single first trimester or early second
trimester spontaneous miscarriage
• We evaluate women for recurrent pregnancy loss
(RPL) after three consecutive miscarriages.
• The history should include a description of
- gestational age (RPL typically occurs at a similar
gestational age)
- characteristics (eg, anembryonic pregnancy, live
embryo) of all previous pregnancies.

129. Additional testing depends upon the diagnosis suggested
by the history, physical examination, and laboratory results.
• Vaginal scan, 3D-TVUS, Sonohysterography or hyseroscopy for
assessment of uterine abnormalities
• Anticardiolipin antibody (IgG and IgM) titer and lupus
anticoagulant performed twice, six weeks apart
• Thyroid stimulating hormone (TSH), prolactin and HbA1C
• karyotype of the abortus and Parental karyotype if the above
examinations are normal.
The following tests are recommended for the initial
evaluation of women with RPL: