Recurrent pregnancy loss

Dr. LaxmiShrikhande
MD;FICOG;FICMU
Director-Shrikhande Fertility Clinic, Nagpur
President Menopause Society, Nagpur
National Corresponding Editor-The Journal of Obstetrics & Gynecology of India
Senior Vice President FOGSI 2012
Vice Chairperson Indian College OB /GY
Governing Council member ICOG 2012-2017
Governing Council Member ISAR 2014-2019
Governing Council Member IAGE for 3 terms
Patron-Vidarbha Chapter ISOPARB
Chairperson-HIV/AIDS Committee, FOGSI (2007-09)
Received Best Committee Award of FOGSI
Received Bharat excellence Award for women’s health
President Nagpur OB/GY Society 2005-06
Associate member of RCOG
Member of European Society of Human Reproduction
Visited 96 FOGSI Societies as invited faculty
Delivered 3 orations
Publications-Thirteen National & seven International
Presented Papers in FIGO, AICOG, SAFOG, AICC-RCOG conferences
Conducted adolescent health programme for more than 15,000 adolescent girls

Recurrent Pregnancy loss
DR LAXMI SHRIKHANDE
NAGPUR

Introduction
Emotionally traumatic, similar to stillbirth or neonatal death
Primary / secondary / Tertiary
Primary RPL- refers to multiple losses in a woman with no previous viable infants,
secondary RPL refers to multiple losses in a woman who has already had a pregnancy beyond 20
gestational weeks
Tertiary RPL refers to multiple pregnancy losses between normal pregnancies
◦Better prognosis with secondary and Tertiary
Terminology for pregnancy loss prior to viability : a consensus statement from the ESHRE early pregnancy special interest group.
Hum Reprod 2015;30(3):495-498
Nomenclature for pregnancy outcomes : time for a change. Obstet Gynecol 2011 ; 118(6): 1402-1408

RPL – basic facts
1% of women have recurrent miscarriages
A majority of women do not have an identifiable cause
At least 70% of women have a successful pregnancy
outcome in the subsequent pregnancy
ACOG Practice Bulletin No.24, 2001
RCOG GreenTop Guideline No.17, 2003

Why is studying RPL difficult?
More than one factor may exist in the same couple
Lacunae in literature
◦ Differences in definitions, evaluation protocols
◦ Variations in treatment regimens even with the same drug
◦ Randomized trials need to be very large to prove statistical and
clinically significant differences

Women with H/O 2 previous spontaneous abortions
Has come for preconception counselling
Will you start investigating ?

Recurrent Miscarriage
Recurrent Miscarriage Definitions
◦ 3 or more consecutive pregnancy losses (UK)1
◦ 2 or more consecutive pregnancy losses (USA)2
◦ Miscarriage as loss of fetus weighing ≤ 500g, which would
normally be at 20-22 complete weeks of gestation (WHO)3
1. Royal College of Obstetricians and Gynaecologists 2011. The Investigation and Treatment of Couples with
Recurrent First-trimester and Second-trimester Miscarriage, [Guideline no. 17]. London, UK.
2. 2. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2008; 90(5 Suppl): S60.
3. 3. Pokale YS. Int. Res. J. Medical Sci. 2015;3(9):13-19

How you will proceed further ?

Diagnostic Work-Up in Recurrent
Miscarriage?

Pathogenesis & Diagnostic Work-Up in Recurrent Miscarriage (RM)
Heterogeneous condition
Pathogenesis is multifactorial, complex and poorly
understood
Standard investigative protocol fails to identify
specific cause in 50% of cases
Walch KT & Huber JC. Best Practice & Research Clinical Obstetrics and Gynaecology. 2008; Vol. 22, No. 2, pp. 375–389. Pokale YS. Int. Res. J.
Medical Sci. 2015;3(9):13-19

What are the possible causes of RPL

Possible Causes of Miscarriage
Paternal Factor
Abnormal embryo
 Structural anomalies incompatible with life1
 Chromosomal abnormalities: trisomy, polyploidy, monosomy X, structural abnormalities
of individual chromosomes2
Hostile maternal environment
 Uterine abnormalities: congenital anomalies, adhesions, leiomyoma2
 Infection: bacterial vaginosis, toxoplasmosis, listeriosis, chlamydia, gonorrhea, rubella2
 Chronic maternal disease: poorly controlled diabetes, celiac disease2
 Immune dysfunction: antiphospholipid antibody syndrome2 and thyroid autoimmunity1
 Endocrine: failure of proper progesterone concentration, thyroid hormone levels3
1. Larsen EC et al. BMC Medicine 2013; 11: 154-65. 2. Griebel CP et al. Am Fam Physician 2005;1; 72(7): 1243-50.3. Zhang HX et al. Clin Exp Obstet Gynecol 2014; 41(2): 182-5.

Etiology
Established causes of recurrent miscarriage include
 immunological (20-50%),
endocrine (17-20%),
anatomical (12-16%),
genetic (5%), and
infection (0.5-1.5%).

Evaluation
It includes taking
history,
physical examination and
appropriate investigations which differ with the trimester though there is an
overlap.1
1) Evaluation and management of recurrent early pregnancy loss.
Stephenson M, Kutteh W.Clin Obstet Gynecol. 2007 Mar;50(1):132-45.

History
Gestational age of the loss. Chromosomal & endocrine earlier than anatomic or immunological causes
Irregular menstrual cycles or galactorrhoea suggestive of possible Endocrine dysfunction/ Hyperprolactinemia
Consanguinity/ family h/o congenital abnormalities/early losses - Genetic
Uterine instrumentation- possible intrauterine adhesions
Exposure to exogenous agents like bisphenol A and concurrent noxious agents is difficult to recall, document and
to measure the toxin dose.
Radiation and Chemotherapeutic agents, chemicals.
Alcohol and caffeine intake are toxic to the embryo in a dose-dependent manner.
Cigarette smoking,
H/o thrombosis - APLA
PCOS
Information from previous laboratory, pathology, and imaging studies

Examination
General-Signs of endocrinopathy (hirsutism, galactorrhea, thyroid)
Systemic
Gynec
TVS

Which tests to order ?
Eyes can’t see what mind doesn’t know
From History and examination you should draw your further course of action

Investigations recommended for recurrent miscarriages
Investigation Recommendation If required
Genetic - Karyotype Parental and fetal
Anatomical Two-dimensional/
three-dimensional
ultrasonography and
sonohysterography
Hysteroscopy, laparoscopy, or
magnetic resonance imaging
Thrombophilia Acquired APS Inherited
Infection Chlamydia, Endometrial
biopsy and culture
Immunological Antinuclear antibody
Endocrine Thyroid -TSH, Antibodies Prolactin,HbA1C
Male factor Sperm DNA fragmentation
index

Male factor-
Some studies suggest that DNA fragmentation is increased with RPL,
especially in the in vitro fertilization setting.
The ASRM guidelines state that routine sperm DNA fragmentation
indexing is not indicated because of the weak evidence, but
 the ESHRE guidelines state that this can be done to provide an
explanation for RPL.

Evidence
Further compelling reasons for testing sperm DNA come from its strong
associations with miscarriage.
A systematic review and meta-analysis (16) of 16 cohort studies (2969 couples),
14 of which were prospective studies which examined the effect of sperm DNA
damage on miscarriage rates was performed.
The meta-analysis showed a significant increase in miscarriage in patients with
high DNA damage compared with those with low DNA damage
(Risk Ratio (RR)= 2.16 [1.54, 3.03], P <0.00001).

Recurrent Miscarriage-Maternal causes
Recommended Investigations to Search for Causes (UK)1
1. Royal College of Obstetricians and Gynaecologists 2011. The Investigation and Treatment of Couples with
Recurrent First-trimester and Second-trimester Miscarriage, [Guideline no. 17]. London, UK.
Antiphospholipid antibodies Karyotyping
Anatomical factors Thrombophilias

Antiphospholipid Antibody Syndrome
and
RPL

A number of antibodies have been studied
The antibodies with the greatest significance and association with
obstetric events are
Lupus anticoagulant (LA)
Anticardiolipin antibodies (ACL IgG and ACL IgM)
Others such as β2glycoprotein-I, antiphosphatidylserine antibodies,
annexin, etc may not be obstetrically significant
Which antibodies ?

•5 – 20% of women with recurrent miscarriages have antiphospholipid
antibodies
MacLean AS et al, BJOG 1994
Rai RS et al, Hum Reproduction 1995
Balasch J et al, Hum Reproduction 1996
Incidence

•Based on clinical and laboratory criteria
•One obstetric or thrombotic criteria and one laboratory criteria should be
present to diagnose PAPS
•Other autoimmune disease has to be ruled out to make the diagnosis of PAPS
Wilson A et al, International Consensus statement on APS,
Arthritis Rheumatol 1999
Diagnosis of PAPS

Three or more consecutive spontaneous abortion before
the 10th week of gestation
One or more unexplained fetal death at or beyond the 10th
week of gestation
Severe preeclampsia or placental insufficiency (IUGR)
necessitating birth before the 34th week of gestation
Obstetric Criteria

•Anticardiolipin antibody IgG or IgM isotype in medium to high titers
by standardized ELISA assay
•Lupus anticoagulant present
•A positive test has to be repeated on at least one more occasion six
weeks apart to fulfill the laboratory criteria
Laboratory Criteria

Usually an over diagnosed syndrome
Not meeting clinical and the strict laboratory criteria
Not repeating the laboratory test at 6 weeks
Non standardized ELISA for ACL antibodies
Inter laboratory variations for phospholipid dependent coagulation
tests used for screening for lupus anticoagulant
Pitfalls in diagnosis of PAPS

Improperly collected and processed samples
Temporal and trimester wise fluctuations
VDRL positive patients who may or may not have syphilis
General infections and inflammations
Coagulopathies and anticoagulant medication users (including
aspirin, heparin)
False results in PAPS

Avoid early pregnancy loss
Normalize placental and fetal circulations to prevent early
birth from obstetric complications such as preeclampsia and
growth restriction
Prevent maternal vascular thrombosis in pregnancy and
postpartum
Goals for treating PAPS

Women with PAPS
without a history of
thrombotic events
(most women with RPL)
Women with PAPS with
history of thrombotic
events (past or present)
Prophylactic therapies
such as aspirin, heparin in
pregnancy and 6 to 8
weeks postpartum
Full anticoagulation with
heparin (or warfarin) in
pregnancy and postpartum

Recent meta analysis shows that the combination of
Aspirin + Heparin is better than Aspirin alone in
achieving live births in women with recurrent
pregnancy loss and antiphospholipid antibodies
Aspirin alone v/s Aspirin + Heparin
Mak A et al, Rheumatology (Oxford) 2010

•There is controversy as to whether LMW Heparin is effective in
preventing recurrent pregnancy loss
•Consider costs, convenience and compliance before initiating
therapy
•Therapy should be started when fetal cardiac activity is
demonstrated and continued throughout pregnancy and postpartum
•Heparin in prophylactic doses needs to be stopped for about 24
hours around the time of labor and delivery
Clinical Tips for using Heparin

Heparin in prophylactic doses should not be monitored and does
not require monitoring by coagulation parameters
Do a platelet count at 3 days, 1 week and bimonthly when the
patient is on heparin
Standard doses
Unfractionated heparin – 5000 units sc bd
Enoxaparin – 40 mg sc daily or in two doses
Clinical Tips for using Heparin

•Steroid therapy should be avoided for PAPS because it significantly
increases morbidity (hypertension, diabetes, preterm births) without
any demonstrable benefit
•Immunoglobulin therapy is experimental and not for clinical use at
present
What not to do for PAPS

Antiphospholipid Syndrome: Intravenous
Immunoglobulin therapy
Triolo G, et al. Arthritis Rheum 2003:
Low-molecular-weight heparin + aspirin - Higher rate of live births
than those treated with intravenous immunoglobulin (RR 2.28)
Dendrinos S et al. Int J Gynaecol Obstet 2009:
Low-molecular-weight heparin + aspirin resulted in a higher live birth
rate than intravenous immunoglobulin (OR 1.80)
https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf

Uterine anomalies : How Common ?
General population 6.3%
Infertile women 7.6%
Women with reproductive failure 16.1%
Saravelos H et al, Hum Rep Update 2008

Which anomaly ?
General Infertile Recurrent
Miscarriage
Hypoplastic 0 0.7 0
Unicornuate 0.03 0.4 0.4
Didelphys 0.03 0.2 0.1
Bicornuate 0.3 0.8 1
Septate 2 3.5 5
Arcuate 4.9 1.9 12.2
T shaped 0 0 0.6
Saravelos H et al, Hum Rep Update 2008

Uterine anomalies
Most common anomaly is a septate or subseptate
uterus
Others: T-shaped uterus, fibroids, intrauterine
adhesions
Jurkovic D et al, BJOG 1997

Possible Mechanisms
Small cavity, less suitable areas for implantation
Vascular compromise
Mechanical constraints of space
Cervical incompetence

Diagnosis of uterine anomalies
Hysteroscopy with laparoscopy is the gold standard
Sonosalpingography and 3D ultrasound have more than
90% accuracy
Hysteroscopy is the only one which allows a “see-and-
treat” approach

Key points-anatomical factors
RPL may be due to anatomical causes
Hysteroscopic surgery is the modality of choice for treating
most cases
Postoperative measures to prevent intrauterine adhesion
formation should be taken
Anatomical causes are a potentially rewarding etiology to
diagnose and treat

Cervix
Most neglected part of obstetric sonography !!

Incidence
It is estimated that cervical incompetence will complicate
anywhere from 0.5% to 2% of all pregnancies
CI is responsible for approximately 15% of habitual
immature deliveries between 16 and 28 weeks of gestation

Etiology
Idiopathic -In most cases
Known causes include
- Congenital weakness as Mullerian abnormalities (cervical hypoplasia)
 -In utero DES (diethylstilbestrol) exposure
 -Traumatic abnormalities (prior surgical or obstetric trauma)
 -Connective tissue abnormalities (Ehlers-Danlos syndrome).

DIAGNOSIS OF CI
History of painless repeated mid trimester spontaneous
miscarriage or premature delivery
Manual estimations
Ability to introduce a number 8 Hegar dilator through the
internal os when patient is not pregnant.
Hysterosalpingogram demonstrating cervical funneling.
Clinical evidence of extensive obstetric or surgical trauma to
cervix.

Transabdominal Sonography
Fails to visualise the cervix in a high
proportion of cases and in particular those
with a short cervix.
Successful visualisation requires a full
bladder which falsely increases cervical
length.

The best approach for
measurement of cervical length is
by Transvaginal Sonography.
Technique

1. Empties her bladder
2. Lithotomy position.
3. The ultrasound probe is introduced in the vagina and directed in the
anterior fornix.
4. Avoid undue pressure on the cervix, which may artificially increase
the length.
5. A sagittal view of the cervix is obtained and the endocervical mucosa
is used as a guide to the true position of the internal os.
Transvaginal Sonography

Sonographic criteria for Cervical incompetence
1. Cervical length shortening to a length below 5th centile
(20 mms) before 24 weeks
1. Funneling of the internal os at least 30% of the total
length of cervix - (funnel + residual length), observed
spontaneously or after Fundal pressure

--the shorter the cervix ,
--the earlier in gestational age at which the shortening
occurs,
Higher the risk.
--
Key Points

Emergency cerclage
Reserved for patients without classical features of
incompetence
Success rate lower
Higher incidence of infection
Prolonged hospital stay

Immunotherapy
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 rate.
Porter TF et al. Cochrane Database Syst Rev 2006:
◦ Provides no significant beneficial effect over placebo in preventing
further miscarriage
Harrison RF. Eur J Obstet Gynecol Reprod Biol 1992;47:175–9.
Quenby S, Farquharson RGFertil Steril 1994;62:708–10.

Inherited thrombophilias
Insufficient evidence to evaluate effect of heparin in pregnancy to
prevent miscarriage in women with recurrent first-trimester
miscarriage associated with inherited thrombophilia
Heparin therapy during pregnancy may improve live birth rate of
women with second-trimester miscarriage associated with inherited
thrombophilias
Harrison RF. Eur J Obstet Gynecol Reprod Biol 1992;47:175–9.
Quenby S, Farquharson RGFertil Steril 1994;62:708–10.

Endocrinal factors
Luteal phase defects
Thyroid replacement therapy
Optimizing HBA1c levels
Correct hyperprolactinaemia
Polycystic ovaries ? metformin

What are the available guidelines
for Use of Progestogens in RM ?

FOGSI - Good Clinical Practice Recommendations: Use of Progestogens in
Early Pregnancy
Recurrent Miscarriage
• Dydrogesterone: 10 mg BD till 20 weeks of pregnancy
http://www.fogsi.org/fogsi-gcpr/. Accessed on 12th Jan 2016
Oral Route
Vaginal Route
• Micronized Progesterone: 400 mg/day vaginally till 20
weeks of pregnancy

How to Choose Progestogens?
The Patient’s choice ?The Doctor’s Choice ?

Doctor’s Choice
•Evidence based
•Efficacy
•Safety & Side effects
•Results

Patient’s Choice
Convenience
Ease
Cost
Result

What is the safety aspect of
Progestogens Use in RM?

Early Pregnancy
Safety of Progestogens
Available evidence strongly supports safety of progesterone when used in pregnancy (based on
available clinical data on vaginal progesterone & dydrogesterone)

Early Pregnancy
Safety of Progestogens
Progesterone should be used with caution in patients with cardiovascular diseases & in patients
with impaired liver function & cholestasis

Dydrogesterone vs. Micronized
Progesterone
Dydrogesterone Compared with Micronized Progesterone
Selective for the progesterone receptor (and thus avoiding other receptor related side-effects)1-3
Dydrogesterone vs oral micronized progesterone
◦ Better oral bioavailability1,2
◦ Requires a 10–20 times lower oral dose1,2
Oral micronized progesterone is associated with a risk of cholestasis in pregnancy4
Vaginal micronized progesterone is also metabolized in the liver5
These differences translate into clinical benefits6-8
1.Schindler AE, et al. Maturitas. 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009; 65S: S3-S11.
3. Rižner TL, et al. Steroids. 2011;76(6):607-615; 4. Utrogestan 200mg oral capsules. SPC. UK October 2013;
5.. Utrogestan 200mg vaginal capsules. SPC. UK October 2013; 6. Patki A, et al. Gynecol Endocrinol. 2007; 23(Suppl 1): 68-726;
7. Ganesh A, et al. Fertility and Sterility. 2011;95(6):1961-1965. 8. Chakravarty BN, et al. J Steroid Biochem Mol Biol. 2005; 97(5):416-420.

Mostly sporadic ; 80% losses in 1st 12 wks
50-70% due to chromosomal anomalies
◦ Autosomal trisomy 50-60%
◦ 13,16,18,21,others
◦ Monosomy X-20%
◦ Triploidy –15%
◦ Tetraploidy-5%
◦ balanced translocation-3-5%
Spontaneous Miscarriage
Parental Karyotypes normal Minimal recurrence risk

Karyotype of the abortus
( fetal/placental tissue)
Peripheral blood Karyotyping of the parents in all couples
with RM

Whether we should do POC
karyotype????

 No definite recommendations for routinely
obtaining abortus karyotype (ACOG 2001)
 Karyotype analysis of abortus tissue for couples with a subsequent
second or third pregnancy loss (Hogge, et al 2003)
 If abortus is aneuploid, maternal cause is excluded (ACOG, 2001)
 If POC karyotype not possible, do parental karyotype

Normal
Abnormal (trisomy or chromosomal rearrangement)
Both requires parental karyotype
Direct parental karyotype is more cost effective

Genetic
Fetal POC
Karyotype
Euploid-
RPL
workup
Unbalanced
translocation or
inversion-Parental
Karyotype ,offer
PGD
Aneuploid-No
further
evaluation,
consider PGD

Side Effects to Embryo
PGD/PGS is an invasive procedure that requires a serious consideration,
One of the risks of PGD includes damage to the embryo during the biopsy
procedure (which in turn destroys the embryo as a whole)
Another risk is cryopreservation where the embryo is stored in a frozen state
and thawed later for the procedure.
About 20% of the thawed embryos do not survive.[31][32]
 There has been a study indicating a biopsied embryo has a less rate of surviving
cryopreservation.
"Reduced survival after human embryo biopsy and subsequent cryopreservation".
Human Reproduction vol.14 no.11 pp.2833-2837.

Ethical issues
The technique can be used for prenatal sex discernment of the embryo, and
thus potentially can be used to select embryos of one sex in preference of the
other in the context of "family balancing".
PGD allows discrimination against those with disabilities
PGD has the potential to screen for genetic issues unrelated to medical
necessity such as intelligence and beauty, and against negative traits such as
disabilities.
The prospect of a "designer baby" is closely related to the PGD technique,
creating a fear that increasing frequency of genetic screening will move toward a
modern eugenics movement.

Policy and legality
In India, Ministry of Family Health and Welfare, regulates the concept under -
"The Pre-Conception and Prenatal Diagnostic Techniques (Prohibition of Sex
Selection) Act, 1994".
The Act was further been revised after 1994 and necessary amendment were
made are updated timely on the official website of the Indian Government
dedicated for the cause.
ahttp://www.pndt.gov.in/

Unexplained Recurrent
Miscarriage

Unexplained Recurrent Miscarriage
Aspirin alone or in combination with heparin is being prescribed
for women with unexplained RM, with the aim of improving
pregnancy outcome
◦ 2 RCTs reported that neither of these interventions improves
live birth rate among women with unexplained RM
https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf

Unexplained RPL
50% of RPL remain unexplained
Prognosis is still good
◦>50 % live birth even without intervention

Unexplained RPL - Pregnancy Issues
Increased risk of :
○IUGR
○Preterm labor
No increased risk of:
○PIH
○GDM

Conclusion
RPL is an important reproductive health issue. Various etiologies have identified
over the years and successful therapeutic strategies implemented.
A full workup can be initiated following two consecutive losses to identify
treatable causes that include uterine abnormalities, APS, endocrine diseases,
and balanced translocations.
Lifestyle modifications should also be implemented to improve reproductive
prognosis. However, almost half of the cases remain unexplained, for which
various treatments are continuously being developed.
Regardless of the cause, a thorough follow up with an important psychological
support can help most couples achieve a successful live birth

Dr. Laxmi Shrikhande
Shrikhande Hospital & research Centre
Ph-96234 59766 / shrikhandedrlaxmi@gmail.com

Recurrent pregnancy loss

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