Recurrent pregnancy loss

1. Recurrent
Pregnancy Loss
By
Ahmed Elbohoty MSc, MD, MRCOG, MIGSC
Assistant professor of Obstetrics and Gynecology
Ain Shams University

3. What I
am going
to discuss
Implantation and pregnancy
tolerance
Pregnancy loss (Definitions and
causes)
Management of of Explained
RPL
Explain possible causes of
unexplained RPL and the
available evidence to treat

4. Apposition
Adhesion/Invasion Implantation
Process of implantation

5. Immunological tolerance
Mor G et al., Nat Rev Immunol. 2017
Immunology Letters 162 (2014) 41–48
Dominance of TH2 over TH1
Dominance of Treg over T17
Uterine NK cells
Dendritic cells
Modify cytokines

6. Early Pregnancy loss
Pregnancy
Clinical
pregnancies
Failure is
miscarriage
Biochemical
pregnancy
Up to 60% of
general
population
not considered
as miscarriage
Chard T. Frequency of implantation and early pregnancy loss in natural cycles, Baillieres Clin
Obstet Gynaecol , 1991, vol. 5 (pg. 179-189)

7. 50% of sporadic 1st trimester miscarriages are
due to aneuoploid embryos
Rate of aneuploid oocytes Rate of miscarriage
Pellestor, 2005
Why does sporadic pregnancy loss happen?

8. Incidence of pregnancy loss
1st trimester
loss: 15 %
2nd trimester
loss: 1-2%
2 x 1st
trimester
losses : 2 %
3 x 1st trimester
losses :0.4 to 1 %

9. Recurrent pregnancy loss
definition?
The loss of three or more
consecutive pregnancies
(RCOG 2012)
1
Recurrent Pregnancy Loss
(RPL) the loss of two or
more pregnancies
(ASRM 2012; ESHRE 2017).
2

10. Prognosis
of live birth
next time
• Single sporadic miscarriage: 80%
• After 2 miscarriages: 70%
• After 3 miscarriages: 60%
• Cause can be found in only 60%.
• A previous live birth does not
preclude a woman developing
recurrent miscarriage

11. Etiology
• Age
• Chromosomal
• Immunological
• Thrombophilia related
• Anatomical
• Infection
• Hormonal
• Male (High DNA fragmentation) ?!
• Idiopathic: 40%

12. Age
• Advancing maternal age is associated with a decline in both the
number and quality of the remaining oocytes
• Advanced paternal age has also been identified as a risk factor
for miscarriage.
• The risk of miscarriage is highest among couples where the
woman is ≥35 years of age and the man ≥40 years of age.

13. Chromosomal

14. Numeric Chromosomal Abnormalities
1st Trimester
50%
2nd Trimester
15%
• Trisomies 13,18,21
3rd Trimester in
SB 5%
Live Births 0.6%

15. Chromosome
abnormalities
in early
spontaneous
miscarriages
Defect Frequency
Triploidy 10%
Tetraploidy 5%
Trisomy 30%
Turner syndrome
(45 X)
10%
Other 5%
Total 60%

16. Embryonic
chromosomal
abnormalities
In couples with recurrent
miscarriage: chromosomal
abnormalities of the embryo
account for 30–57% of
further miscarriages.
As the number of
miscarriages increases, the
risk of euploid pregnancy
loss increases.

17. Parental chromosomal rearrangements
• In approximately 2–5% of couples with recurrent miscarriage,
one of the partners carries a balanced structural chromosomal
anomaly (balanced reciprocal or Robertsonian translocation).
• Carriers of a balanced translocation are usually phenotypically
normal
• Their pregnancies are at increased risk of miscarriage and may
result in a live birth with unbalanced chromosomal
arrangement.
• The risk of miscarriage is influenced by the size and the genetic
content of the rearranged chromosomal segments.

18. Gametes
Zygote
Balanced reciprocal
translocation carrier
Sperm

19. Robertsonian translocation
(Translocation Down
syndrome)(Translocation
trisomy 14)
Sperm

20. Immunological

21. No benefit to measure

23. Antiphospholipid
syndrome
It is the most important treatable cause of
recurrent miscarriage.
Antiphospholipid antibodies are present in
15% of women with recurrent miscarriage
and less than 2% in low risk women.
In women with recurrent miscarriage
associated with antiphospholipid
antibodies, the live birth rate in pregnancies
with no pharmacological intervention has
been reported to be as low as 10%.

24. Mechanism
• Antiphospholipid antibodies cause pregnancy morbidity by
– inhibition of trophoblastic function and differentiation,
– activation of complement pathways at the maternal–fetal
interface resulting in a local inflammatory response
– in later pregnancy, thrombosis of the uteroplacental
vasculature.

27. Endocrine factors
• Systemic maternal endocrine disorders such as diabetes mellitus
and thyroid disease have been associated with miscarriage.
• There is association between thyroid dysfunction or thyroid
auto immunity and RPL.
• Women with diabetes who have high haemoglobin A1c levels in
the first trimester are at risk of miscarriage and fetal
malformation.
• Polycystic ovary syndrome (PCOS) has been linked to an
increased risk of miscarriage but the exact mechanism remains
unclear.

28. However
Well-controlled diabetes
mellitus is not a risk factor for
recurrent miscarriage, nor is
treated thyroid dysfunction.
The prevalence of diabetes
mellitus and thyroid
dysfunction in women who
suffer recurrent miscarriage is
similar to that reported in the
general population.

31. Prolactin
• Lower basal serum prolactin concentrations
were associated with an increased risk of
miscarriage in a subsequent pregnancy in
women with unexplained RM.
• Prolactin disorders are possibly associated
with PCOS, luteal phase deficiency, stress and
obesity, which further complicates studies
attempting to find a direct link between
prolactin and RPL.

32. Vitamin D
• Vitamin D deficiency was shown to be
associated with several obstetric and fetal
complications, but there is no report of an
association between vitamin D status and
miscarriage

33. Anatomical

34. Anatomical variations
• Congenital uterine malformation.
• Submucous fibroid
• Cervical incompetence
• Severe IU synechiae

35. Uterine anomalies
• Congenital uterine anomalies were present
in 4.3% (range from 2.7% to 16.7%) of the
general population of fertile women and in
12.6% (range from 1.8% to 37.6%) of
patients with recurrent pregnancy loss (2
or more consecutive losses)
• A high incidence of pregnancy loss
occurred in patients with
– septate (44.3% loss) (2nd trimester)
– bicornuate (36.0% loss)
– arcuate (25.7% loss) uteri (1st trimester)

36. These anomalies are often
detected at the time of
hysterosalpingography, and
can be more fully
characterized by either MRI
or 3-D ultrasound imaging.
A septate uterus is amenable
to hysteroscopic surgical
correction; there are no
surgically corrective options
for the unicornuate or
didelphic uterus.

37. • Septate uterus is most common
uterine abnormality associated
with RPL.
• Correction of septate defects in
particular may have beneficial
effects (live birth rate 83.2%)
and should be considered in
women with RPL.
• The primary limitation of these
data is the lack of randomized,
controlled therapeutic trials.

38. • The clinical management of pregnancy-loss patients with
Asherman syndrome/intrauterine synechiae, uterine fibroids,
and uterine polyps is also controversial, and there is no con-
clusive evidence that surgical treatment reduces the risk of
pregnancy loss.
• Because randomized trials in this area are lacking and difficult to
conduct, the general consensus is that surgical correction of
significant uterine cavity defects should be considered.
Other anatomical abnormalities

39. Cervical weakness
• Cervical weakness is a recognised
cause of second-trimester
miscarriage, but the true
incidence is unknown, since the
diagnosis is essentially a clinical
one.
• There is currently no satisfactory
objective test that can identify
women with cervical weakness in
the non-pregnant state.
• The diagnosis is usually based on
a history of second-trimester
miscarriage preceded by
spontaneous rupture of
membranes or painless cervical
dilatation.

40. Inherited Thrombophilias
• Factor V Leiden mutation
• Prothrombin mutation
• Protein C, Protein S and Antithrombin deficiency
• A positive test result was not associated with
improved outcomes for the couples based on the
lack of an effect of treatments on pregnancy
outcome

41. Environmental chemicals
exposure to occupational and environmental factors (heavy metals, pesticide, lack of
micronutrients) seems to be associated with an increased risk of pregnancy loss in women with
RPL.
Although exposure to possible hazardous substances should be avoided during pregnancy (for
all pregnant women), there are insufficient data to recommend protection against a certain
occupational or environmental factor in women with RPL

42. Personal habits
• Obesity
• Smoking
• Alcohol use
• Excessive caffeine
consumption??

43. • Couples with RPL should be informed that
excessive alcohol consumption is a possible
risk factor for pregnancy loss and proven risk
factor for fetal problems (Fetal alcohol
syndrome).
• Couples with RPL should be advised to limit
alcohol consumption.

44. • Couples with RPL should be informed that
maternal obesity or being significantly
underweight is associated with obstetric
complications and could have a negative
impact on their chances of a live birth and on
their general health.
• Striving for a healthy normal range BMI is
recommended.

45. Stress
• Stress is associated with RPL, but couples
should be informed that there is no evidence
that stress is a direct cause of pregnancy loss.

46. Infective agents
• Any severe infection that leads to bacteraemia or viraemia can cause
sporadic 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 woman.
• Toxoplasmosis, rubella, cytomegalovirus, herpes and listeria infections
do not fulfil these criteria and routine TORCH screening should be
abandoned.

47. Bacterial vaginosis
• Its presence in the first trimester of pregnancy has
been reported as a risk factor for second-trimester
miscarriage and preterm delivery but the evidence
for an association with first- trimester miscarriage is
inconsistent.
• A randomised placebo-controlled trial reported that
treatment of bacterial vaginosis early in the second
trimester with oral clindamycin significantly reduces
the incidence of second-trimester miscarriage and
preterm birth in the general population.

48. Chronic endometritis
• It is characterized by a plasma cell infiltrate in the
endometrium associated with a range of pathogenic
organisms.
• Its prevalence in women with RPL 7-58%
(depending on detection technique)
• Antibiotics were found to remove the endometritis
with an apparent improvement in live birth rate
(Cicinelli et al., 2014, McQueen et al., 2014).
However, this concept has not been tested in
randomized controlled trials.

49. management

50. Care setting
• Women with RPL should be looked after by a
health professional with the necessary skills and
expertise within a recurrent miscarriage clinic.

51. History
• Medical and family history could be used to tailor diagnostic investigations
in RPL.
• Age
• Life style
• Menstrual history: Irregular menstrual cycles may indicate endocrinopathy
• Obstetric history
– Gestational age
• Chromosomal and endocrine defects more common in 1st trimester
• Anatomic or immunological more common in 1st trimester
However there is significant overlap.
– Embryonic cardiac activity
• Chromosomal abnormality more common if Miscarriage occurs prior to detection of
embryonic cardiac activity
• Medical history: Venous or arterial thrombosis, DM, thyroid dysfunction
• Surgical: uterine surgeries (intrauterine adhesions)
• Family history
• Previous investigations and treatments

52. Physical examination
• BMI
• Signs of Endocrinopathy or chromosomal
abnormalities

53. investigations

54. Cytogenetic analysis
• It should be performed on products of
conception of the third and subsequent
consecutive miscarriage(s).
• It allows an informed prognosis for a future
pregnancy outcome to be given.
• Array CGH is the preferred technique
• NGS may be the preferred technique soon

56. APS screening
All women with recurrent first-
trimester miscarriage and all
women with one or more second-
trimester miscarriage should be
screened before pregnancy for
antiphospholipid antibodies.

57. Anatomical factors
All women with recurrent first-
trimester miscarriage and all
women with one or more
second-trimester miscarriages
should have a pelvic ultrasound
to assess uterine anatomy.
Suspected uterine anomalies
may require further
investigations to confirm the
diagnosis, using hysteroscopy,
laparoscopy or three-
dimensional pelvic ultrasound.

58. Uterine
assessment
• Ultrasound including
3D ultrasound
• Magnetic resonance
imaging
• Hysteroscopy
• Sonohysterography
• Hysterosalpingogra
m

59. All women with RPL should have an
assessment of the uterine anatomy.
• The preferred technique to evaluate the uterus is
transvaginal 3D US, which has a high sensitivity and
specificity, and can distinguish between septate uterus
and bicorporeal uterus with normal cervix
• Sonohysterography (SHG) is more accurate than HSG in
diagnosing uterine malformations. It can be used to
evaluate uterine morphology when 3D US is not
available, or when tubal patency has to be investigated.
• If a Müllerian uterine malformation is diagnosed,
further investigation (including investigation of the
kidneys and urinary tract) should be considered.

60. Some diagnostic tests, although not recommended
for all couples, can be relevant only in selected RPL
couples, for instance:
• Prolactin testing in women with clinical symptoms of hyperprolactinemia (oligo-
amenorrhea)
• HLA class II determination in women with secondary RPL after the birth of a boy
(Nielsen et al., 2009)
• Screening for inherited thrombophilias (specifically, factor V Leiden and the
prothrombin gene mutations, protein C, protein S, and antithrombin deficiencies)
may be clinically justified when a patient has a personal history of venous
thromboembolism in the setting of a non-recurrent risk factor (such as surgery) or
a first-degree relative with a known or suspected high-risk thrombophilia. (RCOG
recommended it for Women with second-trimester miscarriage however ASRM
denied)
• Sperm DNA fragmentation assessment can be more relevant in males with
unhealthy lifestyles (smoking, alcohol, excessive exercise, unhealthy body weight)
(indirect evidence from infertile couples)

61. HLA determination
• HLA determination in women with RPL is not
recommended in clinical practice. Only HLA
class II determination (HLADRB1*15:01 and
HLA-DQB1*05:01/05:2) could be considered in
Scandinavian women with secondary RPL after
the birth of a boy, for prognostic purposes.

65. • In the male partner, it is suggested to assess
life style factors (smoking, alcohol
consumption, exercise pattern, and body
weight).
• Assessing sperm DNA fragmentation in
couples with RPL can be considered for
explanatory purposes, based on indirect
evidence.

67. Treatment

68. Antiphospholipid syndrome
• Pregnant women with antiphospholipid syndrome should be
considered for treatment with low-dose aspirin plus heparin to
prevent further miscarriage.
• Treatment combination leads to a significant increase in the live
birth rate among women with antiphospholipid syndrome is
aspirin plus (Low-molecular-weight heparin or unfractionated
heparin). This treatment combination significantly reduces the
miscarriage rate by 54%
• Low-molecular-weight heparin is preffered it causes less
heparin-induced thrombocytopenia & can be administered once
daily and is associated with a lower risk of heparin-induced
osteoporosis.

69. Regimen
• 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.

70. Heparin side effects
Bleeding hypersensitivity reactions
heparin-induced thrombocytopenia
when used long term osteopenia and
vertebral fractures (loss of bone
mineral density at the lumbar spine
associated with low-dose long-term
heparin therapy is similar to that
which occurs physiologically during
normal pregnancy)

71. Pregnancies
associated
with
antiphospholi
pid antibodies
at high risk of
complications
during all
three
trimesters.
• Although aspirin plus heparin
treatment substantially
improves the live birth rate of
women with recurrent
miscarriage associated with
antiphospholipid antibodies,
these pregnancies remain at
high risk of complications during
all three trimesters, including
repeated miscarriage, pre-
eclampsia, fetal growth
restriction and preterm birth
this necessitates careful
antenatal surveillance.

72. The finding of an abnormal parental karyotype
should prompt referral to a clinical geneticist.
• Genetic counselling offers the couple a prognosis for the risk of future pregnancies
with an unbalanced chromosome complement and the opportunity for familial
chromosome studies.
• Reproductive options in couples with chromosomal rearrangements include
proceeding to a further natural pregnancy with or without a prenatal diagnosis
test, gamete donation and adoption.
• PGD has been proposed as a treatment option for translocation carriers.
• Since PGD necessitates that the couple undergo in vitro fertilisation to produce
embryos, couples with proven fertility need to be aware of the financial cost as
well as implantation and live birth rates per cycle following in vitro
fertilisation/preimplantation genetic diagnosis.
• Furthermore, they should be informed that they have a higher (50–70%) chance
of a healthy live birth in future untreated pregnancies following natural
conception than is currently achieved after preimplantation genetic diagnosis/in
vitro fertilisation (approximately 30%).

73. Congenital uterine malformations
• There is insufficient evidence to assess the effect of uterine
septum resection in women with recurrent miscarriage and
uterine septum to prevent further miscarriage.

74. Cervical weakness and cervical cerclage
• Cervical cerclage is associated with potential hazards
related to the surgery
• 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 25 mm or less is detected
by transvaginal scan before 24 weeks of gestation.
• Transabdominal cerclage has been advocated as a
treatment for second-trimester miscarriage and the
prevention of early preterm labour in selected women
with a previous failed transvaginal cerclage and/or a very
short and scarred cervix.

75. • Overt hypothyroidism arising before conception or during early gestation
should be treated with levothyroxine in women with RPL.
• There is conflicting evidence regarding treatment effect of levothyroxine for
women with subclinical hypothyroidism and RPL. Treatment of women with
SCH may reduce the risk of miscarriage, but the potential benefit of
treatment should be balanced against the risks.
• If women with subclinical hypothyroidism and RPL are pregnant again, TSH
level should be checked in early gestation (7-9 weeks AD), and
hypothyroidism should be treated with levothyroxine.
• If women with thyroid autoimmunity and RPL are pregnant again, TSH level
should be checked in early gestation (7-9 weeks AD), and hypothyroidism
should be treated with levothyroxine.
• There is insufficient evidence to support treatment with levothyroxine in
euthyroid women with thyroid antibodies and RPL outside a clinical trial.

76. Unexplained RPL
• When the diagnostic workup fails to show a
definitive cause.
• 40-50 % of RPL
(Stirrat, 1990; Stephenson, 1996; Stephenson and Kutteh, 2007; The Practice Committee of the
American Society for Reproductive Medicine, 2012)
Unexplained
RPL?
Chromosomal
Immunological
Endocrinology
Anatomy
Cervical
Insufficiency
infections

77. The cumulative incidence of conception is 86% after 24
months of which 65% resulted in a live birth.
Predicted percentage to get live birth on the next pregnancy
depends on:
• Age
• Number of previous miscarriages
Kaandorp et al., Time to conception and time to live birth in women with unexplained recurrent miscarriage S.P. Kaandorp
Human Reproduction, Vol.29, No.6 pp. 1146 –1152, 2014
Brigham, S.A., Conlon, C., and Farquharson, R.G. A longitudinal study of pregnancy outcome following idiopathic recurrent
miscarriage. Hum Reprod. 1999; 14: 2868–2871
Number of previous miscarriages
Age 2 3 4 5
20 -25 90 85 82 80
30-35 80 75 70 65
40 - 45 65 60 53 45
Prognosis of unexplained RPL:

78. Types of unexplained RPL
Type I Type II
Cause Occurred by chance Unknown underling
pathology
Age Old Young
No of pregnancy loss <3 >3
Presentation Early loss Loss of fetal heart beat
Karyotyping of
embryos
Aneuploid Euploid
Prognosis Good Poor
Saravelos SH, Li TC. Unexplained recurrent miscarriage: how can we explain it? Hum Reprod
2012 Jul;27(7):1882-6

79. Can we explain and treat the
couple with unexplained RPL ?

80. What could
be the cause
of
unexplained
RPL?
Saravelos SH, Regan L. Unexplained recurrent pregnancy loss. Obstet Gynecol Clin North Am
2014 Mar;41(1):157-66
Chance
Stress
Oocytes
Sperms
Endometrial
Embryos
Immunological
Thrombophilia
Dysbiosis

81. Psychological support
• Data from several non-RCTs and low quality RCTs have
suggested that attendance at a dedicated early pregnancy
clinic has a beneficial effect

82. The Egg: Diminished ovarian reserve.
Some women with unexplained RPL may suffer from
premature ovarian aging, leading to reduced oocyte
quality and quantity.
Larger prospective trials are warranted
Fertility Sterlity

83. The Sperm
• As the sperm DNA
damage is caused by
unhealthy lifestyles
(such as smoking,
obesity and excessive
exercise), clinicians
could make couples
aware of these risks
(ESHRE, 2017).
Fertility Sterility July 2019
Reproductive BioMedicine Online June 2019

84. Case series report: A total of 287 cycles of couples with idiopathic RPL
Is it a problem of embryos?
Idiopathic recurrent miscarriage is caused mostly by aneuploid
embryos (Hodes et al., . Fertility sterility 2012)
However, the frequency of normal
embryonic karyotypes significantly
increases with the number of previous
miscarriages (Ogasawara et al., 2010)
Retrospective analysis on
1309 women with history of
1st trimester miscarriages

85. Or the endometrium is over receptive ?
• Impaired decidualization predisposes to late
implantation of aneuoploid embryos
Molecular Human Reproduction, Volume 16, Issue 12, December 2010, Pages 886–895,
https://doi.org/10.1093/molehr/gaq079

86. Does selection of euploid
embryo solve the problem?

87. Retrospective Cohort study

89. Immunological
• No immunological biomarker can be used for
selecting couples with RPL for specific
treatments.
• Cytokine testing should not be used in women
with RPL in clinical practice
• There is insufficient evidence to recommend
natural killer (NK) cell testing of either
peripheral blood or endometrial tissue in
women with RPL
ESHRE 2017, Chao et al., 1995, Souza et al., 2002, Shakhar et al., 2006; Hadinedoushan et al.,
2007, Karami et al., 2012, Lee et al., 2013

90. Intravenous immunoglobulin
Immunotherapy for recurrent miscarriage (Review) 47 Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.

91. Paternal white cell immunization
Immunotherapy for recurrent miscarriage (Review) 47 Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.

92. Intralipid
• Intralipid does not improve live birth rates and is
not cost-effective

93. COSTS AND RISKS
Drug Cost Some known side effects or adverse events
Lipid Emulsion
e.g. Intralipid ©
Approx. £300 per infusion
in clinic setting
Hepatomegaly, jaundice, cholestasis, splenomegaly,
thrombocytopenia, leukopenia and fat overload
syndrome (<1% occurrence in clinical trials) (FDA,
2007)
Intravenous
Immunoglobulin
(IVIG)
Approx. £1500 per
infusion in clinic setting
Aseptic meningitis, renal failure, thromboembolism,
haemolytic reactions, anaphylactic reactions, lung
disease, enteritis, dermatologic disorders and
infectious diseases (Stiehm, 2013)
Corticosteroids
Net price 28-tablet pack
£1.86 (BNF, 2015)
Gastric ulceration, Cushing's syndrome, diabetes,
hypocalcaemia, osteoporosis, skin thinning, dry skin,
high blood sugar (BNF, 2015)
Anti-tumour
necrosis factor
(Anti-TNF)
Net price £352.14/40 mg
syringe (BNF, 2015)
Infection, lymphoma, demyelinating disease,
autoantibody induction, congestive heart failure,
injection site reactions, lupus-like syndrome
(Scheinfeld, 2004)
Granulocyte-
Colony Stimulating
Factor (G-CSF)
Net price 600 mcg/ml
£52.70, 0.5-ml prefilled
syringe (BNF, 2015)
Mucositis, splenic enlargement, hepatomegaly,
transient hypotension, epistaxis, urinary
abnormalities, osteoporosis, exacerbation of
rheumatoid arthritis, anaemia, pseudogout (BNF,
2015)

94. Uterine microbiota
& dysbiosis
• Uterine microbiota is
responsible for healthy
endometrial physiology
Benner et al., Human
reproduction update
2018)
• The endometrial microbiome in RPL is less
lactobacilli compared to parous fertile controls
(Vaughn etal., fertility sterility 2019)

95. Disturbance of Microbiota
• Altered immunologic response
• Chronic Endometritis
– method of detection is hysteroscopy and /or
immunohistochemistry
– Prevalence of 7-58 % among RPL patients
– Antibiotics were found to remove the endometritis with
an apparent improvement in live birth rate

96. RCT n = 836
Live birth rates were
similar in the two groups
(65.8 vs. 63.3%; RR 1.04,
95% CI 0.94–1.15).
RCT n = 700
Live birth rate was
higher during active
treatment (92%) than
placebo (77%)
Progesterone
NEJM 2016

97. 2
Progestogen for preventing miscarriage in women with recurrent
miscarriage of unclear etiology
Haas, David M; Hathaway, Taylor J; Ramsey, Patrick S
Cochrane Database of Systematic Reviews. Issue 10, 2018.

98. Aspirin and/or heparin for women with unexplained
recurrent miscarriage with or without inherited
thrombophilia (Review) 12 Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Heparin

99. Immunological response doesn’t
favor Heparin use

100. Conclusions
• Healthy life style and support should be offered to all the couples
with RPL.
• Management of APS increases the chances of LB.
• PGD for couples who are carrier for chromosomal translocation
decreases chances of recurrent miscarriage and abnormal child.
• Luteal start of vaginal progesterone showed improved pregnancy
success in women with unexplained RPL.
• PGS prolongs the time to get pregnant and doesn’t improve LB rates
for women with unexplained RPL.
• Immunological therapies showed to be not effective with a lot of
risks and side effects.
• More robust studies are needed to investigate the role of uterine
microbiome for healthy pregnancy.

101. There is a need to know more about RPL
3/26/20 elbohoty (101)
Thank you

102. References
• Justin Tan, Omur Taskin, Arianne Albert, Mohamed A. Bedaiwy . Association between sperm DNA fragmentation and
idiopathic recurrent pregnancy loss: a systematic review and meta-analysis. Reproductive BioMedicine Online 2019 38,
951-960DOI: (10.1016/j.rbmo.2018.12.029)
• Haas, David M; Hathaway, Taylor J; Ramsey, Patrick S. Progestogen for preventing miscarriage in women with
recurrent miscarriage of unclear etiology. Cochrane Database of Systematic Reviews. Issue 10, 2018.
• Robinson L, Gallos ID, Conner SJ, Rajkhowa M, Miller D, Lewis S, et al. The effect of sperm DNA fragmentation on
miscarriage rates: a systematic review and meta-analysis. Human Reproduction 2012 Oct 1;27(10):2908-17
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• ESHRE, 2017
• RCOG, 2012
• ASRM, 2012