Implantation And Maintenance of pregnancy is a wonder of nature

1. Controversy and consensus
regarding management of
recurrent pregnancy loss
Prof. Rokeya Begum
Director
Surgiscope fertility center
&
Adviser
USTC
Bangladesh.

2. WELCOME TO PORT CITY
CHATTOGRAM

3. SURGISCOPE FERTILITY CENTER

4. Recurrent miscarriage is a complex condition
requiring consideration of multiple factors for
appropriate workup and management.
Miscarriage is defined as the spontaneous demise of
pregnancy before the foetus reaches viability
i,e 28 weeks of gestation.

5. Venn diagram of the responsibilities of
Reproductive Failure
Egg
80%
Sperm
10%
Uterus 10%

6. It should be noted that advances in neonatal care have
repeated in a smaller number of babies surviving
birth before 28 weeks of gestation and different
definitions apply in different countries.

7. Confirmation of pregnancy
A pregnancy in the definition is confirmed at least by either serum or urine
hCG i,e including non visualized pregnancy losses (biochemical pregnancy
losses and/or resolved and treated pregnancies of unknown locatioin).

8. In the non visualized pregnancy loss group, pregnancy losses after
gestational weeks 6 are included where an USG examination was only
done after complete expulsion of the embryo and trophoblast or no USG
was done after heavy bleeding it includes pregnancies that would have
been classified as clinical miscarriages in case an earlier ultrasound scan
had been done.
Ectopic and molar pregnancies early RPL
If identified as such ectopic and molar pregnancies should not be included
in the definition.

9. Implantation failure is also excluded from the definition
Pregnancy losses both after spontaneous conception and
after ART treatments should be included in the definition.

10. Implantation And Maintenance of
pregnancy is a wonder of nature
20% of all conceptions
Abort before 20 weeks
(Mostly before 12 weeks)
75% of miscarriages
Is due to a failure of
Implantation and initial
Vascularisation.

11. Live birth
30%
Miscarriage
10%
Post implantation
30%
Pre implantation
30%
Conception
Clinical
Pre -Clinical
The Tip of the ice berg.

12. Prevalance of RPL
1. Difficult
2. Pregnancy loss is any where between 5-15% depends on
different registries
3. RPL is (1-2%)

13. Definition of RPL
The Royal college of obstetricians and gynecologists defines RPL as three
or more consecutive pregnancy losses (RCOG 2016).
The American society of reproductive medicine practice committee defines
RPL as two or more pregnancy losses confirmed by ultrasound or
histology not necessarily consecutive (ASRM 2012).
ESHRE recommend the use of recurrent pregnancy loss to describe
repeated pregnancy demise after two or more pregnancy loss.
Recurrent miscarriage to describe cases where all pregnancy losses have
been confirmed as intrauterine miscarriage.

14. Type of RPL
Primary RPL is described as RPL without a previous ongoing
pregnancy (viable pregnancies) beyond 28 weeks of
gestation.
Secondary RPL is defined as an episode of RPL after one or
more previous pregnancies progressing beyond 28 weeks of
gestation.

15. Pregnancy loss is a significant negative life event and the
repetitive nature of RPL may intensify the grief
experienced
Clinicians and clinic should take the psychological needs
of couples when offering and organizing care for these
couple.
Counselling and management plan
Before trying to conceive couples and clinicians
attempt to find an explanation for their pregnancy losses
and a treatment that will prevent a recurrence especially
in cases with identifiable risk factors. Thus try to find
out cause.

16. Causes of recurrent Pregnancy Loss

17. Aetiology
Inherent defect
Environmental
factor
Psychological
causes
Environmental
causes
Smoking
Alcohol
consumption
Immunologic causes
Auto immune causes
Alloimmune causes
Endocrine causes
Untreated thyroid
dysfunction
Uncontrolled diabetes
mellitus
Luteal phase deficiency
Follicular phase defect.
Infections
causes
??
Genetic causes
Mendelian disorders
Genetic translocation.
Multifactorial disorders
Chromosomal inversion
Sex choromosome
Anatomic causes
Uterine mullerian
anomaly
Asherman syndrome
Incompetent cervix
Leiomyoma’s
Uterine polyp
Unknown
aetiology
40-50%

18. Risk factor analysis
The first visit after referral for RPL should allow time for the clinician to review the
patient’s history, which includes medical, obstetric and family history but also
information on life style of both the male and female partner.
Previous reproductive history.
1. Previous reproductive history is an independent predictor of future pregnancy
outcome.
2. The risk of a further miscarriage increases after each successive pregnancy loss
reaching approximately 40% after three consecutive pregnancy losses.
3. The prognosis worsens with increasing maternal age.
4. A previous live birth does not preclude a women developing recurrent miscarriage.

19. Gestational age is important.
5-7 weeks – genetic causes
8-10 weeks – Immunological causes
Mid trimester anatomical causes.

20. Child Adult
1:160 0.5-1%
live birth balanced translocation
Preconceptional
10% of spermatozoa
50% of
stimulated OVA
Zygote Embryo Fetus
50% of all 1st trimester abortions
5% in late trimester abortion, still birth
Genetic Causes

21. Karyotype is necessary of all cases of RRL
Yes/No

22. Prognosis based on parental Karyotypes
The Karyotype results from the parents provides prognostic information
for subsequent pregnancies.
Parents Karyotype Subsequent miscarriage
Reciprocal translocation 50-70%
Robertsonian translocation 30-50%
(Exception is translocation
to same chromosome)
Inversions 30%
Normal 30%

23. Recommendation
1.ASRM recommends parental Karyotype analysis as a balanced reciprocal or
Robertsonian translocation is present in about 2-5% of RPL couples thus could represent a
major prognostic factor.
2. ESHRE recommends testing only in couples at an increased risk evidenced by prior child
with congenital abnormalities offspring with unbalanced chromosomes or a translocation in
POC.
3. RCOG advises parental karyotype when an unbalanced structural chromosomes is found
in POC and referred of the couple for genetic counselling.
4. Recent studies have shown that parental karyotyping for all RPL couples is simply not
cost effective and that there is no overall difference in live birth rate when comparing pre
implantation genetic testing (PGT) to natural conception in those cases.
(Lews M. Lews M Reprod Biomed online 2018: 36 : 677-685)

24. Would you recommend regular genetic analysis of all abortus
Genetic etiology of conceptus
90% preimplantation and preembryonia (Post implantation, embryo not
visible on USG)
70% (Embryonic ) (embryo visible on USG and <10 week gestation)
50% Early foetal (10-13 weeks)
30% late foetal (14-19 weeks)
10% stillbirth 20 weeks

25. Genetic etiology of conceptus
Autosomal trimosmy – 62%
Multiple trimosmies – 4%
Autosomal monosomy – 1%
Monosomy X-11%
Triploicly – 12%
Tetraploidy – 1%
Segnantal delation /duplication – 4.6%
Single genic disorders
Polygenic / Multifactorial
Epigenic
Aneuploidy

26. The background risk of having 3 miscarriage
For women < 25yrs 0 -1.3%
for Women > 40yrs – 15%
100 times more likely

27. Numerical
Aneuploidy
Triploidy
Tetraploidy
Mosaic
Structural
Deletion
Ring chromosome
Duplication
Translocation
Insertion
Isochromosome
Autosomal
Down syndrome
Patan syndrome
Edward syndrome
Philadalphia
chromosome
Sex chromosomal
Turner klinefelter
Triple XXX syndrome
XYY syndrome
46 XX female
46 XX male
Fragile X syndrome
Chromosomal abnormalities

28. Types of test done in POC
Karyotype
FISH
Chromosomal microarray
Gene sequencing
1.Whole genom
2.Next generation
Karyotype – limitation
Non viable tissue
Culture failure rate for fresh tissue -14%
FISH – Fluorescence in situ hybridisation
FISH identifies specific neucleic acid sequence on interphase nuclei or
metaphase chromosome.
FISH provides option for simultaneous detection of one or more nucleic acid
sequence using different colour labelled probes.
CMA detects copy number variations (CNVS) in the entire genome with a much
higher resolution than conventional cytogenetics.

30. ESHRE
1. Genetic analysis of pregnancy tissue is not routine recommended but
it could be performed for explanatory purposes.
2 For genetic analysis of the pregnancy tissue, array CGH, is
recommended based on a reduced maternal contamination effect.
Single gene defects such as those associated with cystic fibrosis or
sickle cell disease are seldom associated with RPL.
Depending on the particular diagnosis
1. IVF with preimplanation genetic diagnosis
2. Use Donor gamete

31. Immunological factors
Auto immune (directed to self)
Systemic lupus Erythromatosus
Antiphospholipid antibody syndrome(APLA)
Alloimmune (directed to foreign issue/cells)
An abnormal maternal immune response to
foetal or placental antigen.

32. Antiphospholipid antibody syndrome(APLA)
Antiphospholipid antibodies are
1. Lupus anticoagulant
2. Anticardiolipin antibodies
3. Anti β2 glyco protein

33. Diagnostic criteria for APLA
Clinical Laboratory criteria
Recurrence loss < 10wk
Foetal death > 10wk
Venous thrombosis
Arterial thrombosis
Lupus anti coagulant
IgG anti CL (>99%)
IgM anti CL (>99%)
IgG anti β2 glyco protein
IgM anti β2 glyco protein
Miyakis etd. J Thromb Haemost 4:295-306. 2006

34. Epidemiology of APLA syndrome
1. Antiphospholipid antibodies are present in 15% of women with
recurrent miscarriage.
2. By comparison the prevalence of antiphospholipid antibodies in
women with a low risk obstetric history is less than 2%.
3.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%.

35. APA – clinical features
1. Pregnancy loss.
a) Tendency to miscarry at progressively lower gestational age.
b) Three or more unexplained consecutive miscarriage.
c) Unexplained death of a morphologically normal foetus at or
after 10 weeks.
d) Pre mature birth of morphologically normal neonate at or
before 34 weeks.

36. Mechanism of action
The mechanism by which
1. Antiphospholipid antibodies causes pregnancy loss includes inhibition of
trophoplastic function and differentiation.
2. Activation of complement pathways at the maternal foetal interface
resulting in a local inflammatory response.
3. In later pregnancy thrombosis of the uteroplacental vasculature.
4. In vitro studies have shown that the effect of antiphospholipid antibodies on
trophoblast function and complement activation is reversed by heparin.
Treatment regimes
1. Aspirin
2. Heparin / low nuclear weight heparin
Upto 34 weeks of pregnancy

37. Normally pregnancy is tolerated by maternal immune system through formation of
blocking antibodies
Couple that share similar type of HLA there is inadequate formation of blocking
antibodies in maternal environment
Diagnosis
HLA crossmatching between husband lymphocyte and wife serum
Not recommended routine
Costly
Treatment
1. Paternal white blood cell immunisation- no beneficial effect
2. Intravenous immunoglobulin (IVIG)-not evidence based
3. Intralipid -Reduce NK cell and TH 1cytokine activity
Alloimmune

38. Endocrine factors
Diabetes
Women with diabetes who have high HbAIC level in the first trimester are at risk of
miscarriage and fetal malformation.
PCOS
Spontaneous loss of foetus occurs in 40% women with PCOS.
The underlying causes may include
1.Obesity
2.Hyperinsulinaemia
3.Hyper androgen
4.Hyper homocysteinemia
5.High level at plasminogen activator inhibitor -1 factor
6 .Elevated level of luteiniting hormone (LH)
7.Poor endometrial receptivity.
Metformin continued
during pregnancy
prevent RPL.
(Jekub et al 2000)

39. Thyroid
The normal range of TSH in non pregnant reproductive aged women is 1.0-2.5 mlU/L
thyroid antibodies may precede the occurrence of hypothyroid disease.
Overt hypothyroidism is associated with infertility, recurrent miscarriages and adverse
pregnancy outcome.
15-25% of reproductive aged women have antithyroid antibodies.
The presence of thyroid autoantibodies is associated with RPL and premature delivery.
Screening for thyroid autoantibodies and treatment with thyroid hormone particularly
when TSH is >2.5 mlU/L.
Luteal phase defect( LPD) – luteal phase with progesterone
All guideline recommend against using progesterone in RPL but it is noted that
progesterone supplementation causes no harm .
Hyper prolactiamia

40. Thrombophilias
Women with second trimester miscarriage should be screened for
inherited thrombophilia’s including.
1. Factor V leiden mutation
2.Factor II (prothrombin) gene mutation
3. Protein S deficiency
Pre summed mechanism being thrombosis of uteroplacental circulation

41. Anatomical factors – uterine anomalies
1. The exact contribution that congenital uterine anomalies make to recurrent miscarriage
remain unclear since the prevalence and reproductive implication of uterine anomalies in
general population are unknown.
2. The reported prevalence of uterine anomalies in recurrent miscarriage population ranges
between 1.8 and 37.6%. This variability reflects the differences in the criteria and
techniques used for diagnosis and the fact that the available studies have included women
with two, three or more miscarriages in both the first and second trimester of pregnancy.
The prevalence of uterine malformations appears to be higher is women with second
trimester miscarriage compared with women who suffer first trimester miscarriage but this
may be related to the cervical weakness that is frequently associated with uterine
malformation.
It has been reported that women with arcuate uteri tends to miscarry more in the second
trimester while women with septate uteri are more likely to miscarry in first trimester.

42. Investigation of anatomical factor
The preferred method to evaluate the uterus is Transvaginal 3D USG which has a
high sensitivity and specificity and can distinguish between Septate uterus and
bicornuate uterus with normal cervix.
Suspected uterine anomaly may require further investigations to confirm the
diagnosis using hysteroscopy, laparoscopy or three dimensional pelvic
ultrasonography.
MRI is not recommend as first line option for assessment of uterus in women with
RPL.
All women with RPL should have 2D ultrasound to rule out adenomyosis

43. Other anatomical factors
1. Synaechae
2. Asherman
3. Polyp
4. Fibroid
5. Incompetance of OS

44. Cervical cerclage
Cervical cerclage is associated with potential hazards related to the surgery and
the risk of stimulating uterine contraction and hence should be considered only in
women who are likely to be benefited.
Women with a history of 2nd trimester miscarriage and suspected cervical
weakness who have not undergone a history indicated cerclage may offer serial
cervical sonographic surveillance.
In women with singletone pregnancy and history of one second trimester
miscarriage attributable to cervical factors an USG indicated cerclage should be
offered if a cervical length of 25mm or less is detected by Transvaginal scan
before 24 weeks of gestation.

45. Infection
Bacterial vaginosis.
Routine TROCH screening should be abandoned
Endometritis
Diagnosis by office hysteroscope.
Micropolyp with strawbery endometrium.
Plasma cells in histopathology.
Immuno histochemistry.

46. Male factor
There is lack of a consistent association between conventional semen parameters and
RPL.
The majority of recent studies addressing male factors and RPL have focused on male
genetic defeats.
These range from matter of the chromosomal deletion, chromatin integrity and DNA
damage.

47. Inter pretation of values in DFI Test
< 15% - Good
15-25 % - average fertility
>25% poor fertility
Significant DNA fragmentation beyond the threshold repairable by the oocyte may
contribute to poor blast development, implantation failure and miscarriage.
The effect of correcting elevated sperm DNA fragmentation :
Oral antioxidants, microfluidic sperm sorting and testicular sperm should be
investigated in a randomized controlled fashion before clinical evaluation.
At present, screening for sperm DNA fragmentation in RPL is not recommended by
ASRM.

48. Life style, Environmental and occupational factors
Confirmed association Suspected
Imaging radiation Caffeine > 300mg/day
Organic solvents
Alcohol
Mercury
lead Cigarette smooking.
Obesity increases the risk of both sporadic and recurrent miscarriage.
The evidence on the effect of anaesthetic gases for theatre worker is conflicting.

49. Tender love care(TCL) was defined as psychological support with
Weekly medical and ultrasonograghic exam
Instructions to avoid:
- Heavy work
- Travel
- Sexual activity
Difference in live births was significant
36% in control group
85% in TCL group
Evidence that significant improvement of subsequent pregnancy outcomes with
close monitoring and support at a dedicated recurrent pregnancy loss clinic.
Psychological factors

50. Unexplained
No apparent causative factor is identified in 50% cases.
The chance for a future successful pregnancy can exceed 50-60% depending on maternal
age and parity
Management
Post conception
1.Prophylactic aspirin
2.Prophylactic cervical cerclage
3.TLC
4.Steriod for pul monary maturity
5.Monitor closely near term
Preconception
1.Folic acid
2. Correct nutritional deficiencies
3.Prophylactic Doxycycline
4. Luteal support

51. Prognosis
1. The diagnosis can be quite devastating it can be helpful for the physician and patient
to keep in mind the relative high likelihood that the next pregnancy will be successful.
2. A particular individual prognosis will depend on both the underlying cause and the
number of prior losses.
3. Correction of endocrine disorders,APA,anatomical anomalies enjoy the highest
success rate approximately 60-90%.
4 Cytogenetic basis for loss experience a wide range of success(20-80%) that depends
on the type of abnormality present.
Prognosis for RPL is encouraging