MANAGEMENT OF RECURRENT

PREGNANCY LOSS
 RECURRENT PREGNANCY LOSS

• The definition of recurrent pregnancy loss (RPL) has long

been debated and differs among international societies
• ESHRE & RCOG
• RPL refers to three consecutive pregnancy losses, including
non- visualized ones. However, according to the
• ASRM
• Defined as two or more clinical pregnancy losses (documented
by ultrasonography or histopathologic examination), but not
necessarily consecutive

El Hachem H et al.  Int J Womens Health. 2017;9:331-345

 RECURRENT PREGNANCY LOSS

• It is appropriate to remember that human

reproduction is an extremely inefficient process

• RPL occurs in up to 3% of reproductive age couples

• In 50% of cases, no obvious pathology can be

identified

Curr Opin Obstet Gynecol 2020, 32:371–379

ETIOLOGY
 RPL IN RELATION TO FEMALE AGE

Age group (years) Spontaneous

miscarriage (%)
20-24 11
25-29 12
30-34 15
35-39 25
40-44 51

• The risk of having a miscarriage is strongly influenced by female age

• The background risk of having three miscarriages for women<25

years is around 0.13% but 100 times more likely (~13%) if over 40.6

Aust N Z J Obstet Gynaecol 2018; 1–9

 GENETIC FACTORS 

• Around 40% of miscarriages in RM patients are

chromosomally abnormal

• Combined parental and embryonic factors provide

an explanation in >90% of RM patients.

Rev Obstet Gynecol. 2009;2(2):76-83

 PREVALENCE OF ABNORMAL RESULTS

Abnormalities n %

Parental chromosomal abnormality 492 5.5

Uterine structural defects 506 17.6

Lupus anticoagulant 523 2.5

Anticardiolipin antibodies 537 14.7

Aust N Z J Obstet Gynaecol 2018; 1–9

 ETIOLOGY GENETIC FACTORS

• Balanced translocation most

common
• Reciprocal (60%) or
Robertsonian (40%)
• 25-50% risk of pregnancy loss
• May eventually produce
normal offspring
 PARENTAL KARYOTYPING

• It is not predictive of a subsequent miscarriage

• Routine karyotyping of couples with recurrent

miscarriage is no recommended

• Cytogenetic analysis may be performed on products

of conception to avoid unnecessary evaluation and
treatment
Curr Opin Obstet Gynecol 2020, 32:371–379
 ANATOMICAL DEFECTS

• Estimated prevalence is about 16.7% in RPL patients

as compared with 6.7% in the general population

• 1.0% to 16.9% chance of having an arcuate uterus

• Hysteroscopy and laparoscopy can be considered in

evaluating congenital uterine anomalies

Curr Opin Obstet Gynecol 2020, 32:371–379

 ANTIPHOSPHOLIPID SYNDROME (APS)

• The generally accepted prevalence of APS in women with RPL

to be 5%–20%

• It should be part of the initial workup in patients with RPL

• Treatment considered are aspirin, unfractionated heparin,

LMWH, corticosteroids, intravenous immunoglobulins (IVIg),
and combinations of the above

Curr Opin Obstet Gynecol 2020, 32:371–379

 ENDOCRINE FACTORS

Hyperprolactinemia
• results in impaired folliculogenesis and anovulation
• Treatment of the underlying cause restores normal fertility.

Hypothyroidism
• Serum thyroid-stimulating hormone (TSH) threshold to define
subclinical hypothyroidism is >2.5 mIU/L

Polycystic ovarian syndrome (PCOS)

• Increases risk of miscarriage

Curr Opin Obstet Gynecol 2020, 32:371–379

 ENDOCRINE FACTORS

Luteal Phase Defect

• results in inadequate follicular growth, dysovulation, poor corpus
luteum function, and abnormal endometrial response and receptivity
• Progesterone supplementation is widely consider treatment

Curr Opin Obstet Gynecol 2020, 32:371–379

 INHERITED THROMBOPHILIAS

• Increases the risk of venous thromboembolism, secondary to a genetic

alteration of a functional protein in the coagulation cascade
• These include
• Factor V Leiden (FVL)
• Prothrombin gene (PT G20210A) mutation
• Protein C and protein S deficiency (PSD)
• Antithrombin III (ATIII) deficiency, and
• Methyltetrahydrofolate reductase (MTHFR) mutation
• The association with RPL remains controversial
•  It is therefore not recommended to test or treat women with RPL for
inherited
Curr Opin Obstet Gynecol 2020, 32:371–379
 MISCELLANEOUS

• Obesity
• Smoking
• Excessive caffeine consumption (>300 mg/day, or the equivalent of
two cups)
• Excessive alcohol intake, and
• Cocaine
• Psychological factors
• such as grief and depression, hopelessness, guilt, anxiety, and anger toward the
partner, friends, or the treating physician
• International societies recommend offering supportive care in dedicated clinics
for couples with RPL
Curr Opin Obstet Gynecol 2020, 32:371–379
 MISCELLANEOUS

• Male factor
• Trend toward repeated miscarriages with abnormal sperm (<
4% normal forms, sperm chromosome aneuploidy)
• ICSI
• Paternal HLA sharing not risk factor for RPL
• Advanced paternal age may be a risk factor for miscarriage (at
more advanced age than females)
• Infection
• Listeria, Toxoplasma, CMV, and primary genital herpes
• Cause sporadic loss, but not RPL
https://www.google.co.in/url?url=https://www.dshs.state.tx.us/genetics/ppt/
GeneticsforNursesinPediatricDisciplines.ppt&rct=j&frm=1&q=&esrc=s&sa=U&ei=PX78U_ONM8ihugTKnIGYBw&ved=0CEEQFjAIOAo&usg=AFQjCNH42tq_JIy7
 CANDIDATES FOR EVALUATION 

• Evaluate and Rx ≥ 2 or 3 consecutive losses

• Most have good prognosis for a successful pregnancy, even

when no diagnosis or treatment

• The minimum workup:

• Complete medical, surgical, genetic, and family history
• Physical examination
• Both partners should also be questioned about the modifiable
lifestyle factors, such a smoking, alcohol use, and nutritional habits
 PHYSICAL EXAMINATION

• General physical

• Signs of endocrinopathy (hirsutism, galactorrhea,

thyroid)

• Pelvic organ abnormalities (uterine malformation,

cervical laceration)

Curr Opin Obstet Gynecol 2020, 32:371–379

 LABORATORY EVALUATION 

• Complete blood count

• Fasting serum glucose (or HbA1c) and

• Prolactin level

• Serum TSH

• Antibodies for APS (lupus anticoagulant, anticardiolipin antibodies,

and anti-β II glycoprotein I antibodies)

• Others …. Vitamin D status

Curr Opin Obstet Gynecol 2020, 32:371–379
 UTERINE EXAMINATION

• Transvaginal 3D ultrasound

• Antral follicle count

• Uterine cavity should be further explored

• Sonohysterography
• Hysterosalpingography
• Hysteroscopy
• Pelvic MRI can be helpful in complicated cases of anatomic
defects
Curr Opin Obstet Gynecol 2020, 32:371–379
 UTERINE ASSESSMENT

• ESHRE prefers 3D-transvaginal ultrasound to assess the

uterine cavity

• ASRM accepts sonohysterography, hysteroscopy, and/or

hysterosalpingography as suitable methods

• RCOG suggests a pelvic ultrasound on all women with

RPL followed by hysteroscopy or 3D ultrasonography if a
uterine anomaly is suspected
Curr Opin Obstet Gynecol 2020, 32:371–379
 MALE FACTOR

Sperm DNA fragmentation (SDF)

• Meta‑analysis have showed significant increase in miscarriage in patients

with high DNA damage compared with those with low DNA damage

• It seems reasonable to offer SDF testing to couples with otherwise

unexplained RPL

• Ordering SDF could be useful and could help strengthen the decision to
pursue lifestyle modifications.

Int J Womens Health. 2017;9:331-345 https://doi.org/10.2147/IJWH.S100817

 TENDER LOVING CARE (TLC) AND
LIFESTYLE ADVICE

• RPL cause tremendous psychological impact

• Couples should be offered appropriate emotional

support and reassurance

• Lifestyle modification and stress reduction should be

emphasized

Int J Womens Health. 2017;9:331-345 https://doi.org/10.2147/IJWH.S100817

 ETIOLOGIES OF RPL – DIAGNOSIS AND
TREATMENT

Int J Womens Health. 2017;9:331-345

SUMMARY OF THE CURRENT GUIDELINES FROM RCOG, ASRM AND
ESHRE WITH THE NEW PROPOSED ALGORITHM FOR THE
EVALUATION OF RPL

Curr Opin Obstet Gynecol 2020, 32:371–379

SUMMARY OF THE CURRENT GUIDELINES FROM RCOG, ASRM AND
ESHRE WITH THE NEW PROPOSED ALGORITHM FOR THE
EVALUATION OF RPL

Curr Opin Obstet Gynecol 2020, 32:371–379

 SUMMARY OF RPL MANAGEMENT
Supported by currently available evidence and
Condition Notes
expert opinion
Unfractionated heparin and low-dose • Further investigation required for LMWH and
APS
aspirin • non-criteria APS

Uterine septum Hysteroscopic resection • RCT evidence awaited

Submucous fibroids, polyps and

Hysteroscopic resection • RCT evidence awaited
adhesions
Structural chromosomal • Lack of evidence that IVF with PGT improves
Genetic counselling
rearrangements • chances of livebirth
Thyroxine treatment for TSH > 4 mIU/L ± • Consider thyroxine for TSH > 2.5 mIU/L + anti-thyroid
Thyroid function
anti-thyroid antibodies • antibodies
• Lack of standardised diagnostic criteria for
Inherited thrombophilia Screening is not recommended
• specific immunological conditions
Treatment for immune factors is not recommended • Consider synthetic versus natural, time of
Unexplained RM
Progesterone likely to be beneficial • commencement and duration of use
• Provides a strong indication of likelihood of
• finding a parental abnormality and helpful in
Embryonic chromosomal Karyotyping of products of conception is • providing an explanation for couples
Abnormalities informative
• Lack of evidence that IVF with PGT increases
• chances of livebirth
• Patients find dedicated RM clinics with regular
Psychological support Tender loving care (TLC)
• ultrasound scanning very helpful
 SUMMARY

• The management of unexplained miscarriage is a challenge

• A full workup can be initiated following two consecutive

losses to identify treatable causes

• Lifestyle modifications should also be implemented to

improve reproductive prognosis

• Almost 50% of the cases remain unexplained

• Regardless of the cause, a thorough follow-up with an

important psychological support can help most couples
achieve a successful live birth.
THANK YOU