Role of new progesterone congener in repeated pregnancy loss

1. ROLE OF IMMUNOMODULATORS IN
MANAGEMENT OF RECURRENT
PREGNANCY LOSS

2. DR. NIRANJAN CHAVAN
MD, FCPS, DGO, MICOG, DICOG, FICOG, DFP,
DIPLOMA IN ENDOSCOPY (USA)
Professorand Unit Chief, L.T.M.M.C& L.T.M.G.H,Sion Hospital
JointTreasurer,FOGSI (2021-2024)
Vice President,MOGS (2021-2022)
MemberOncologyCommittee,SAFOG(2020-2022)
Dean AGOG & Chief ContentDirector,HIGHGRAD & FEMAS Courses
Editor-in-Chief,FEMAS & JGOG Journal
47 publicationsin nationaland internationaljournal with 50 citations.
NationalCo-Ordinator,FOGSIMedical Disordersin PregnancyCommittee (2019-2021)
Chair & Convener,FOGSI Cell Violence AgainstDoctors (2015-16)
Member,OncologyCommitteeAOFOG(2013-2015)
Co-Ordinatorof 11 batches of MUHS recognizedCertificateCourse of B.I.M.I.Eat L.T.M.G.H(2010-
16)
Member,ManagingCommitteeIAGE(2013-17),(2018-20)
EditorialBoard, EuropeanJournalof Gynaec.Oncology(Italy)
Course Co-Ordinatorof 3 batchesof AdvancedMinimalAccess GynaecSurgery(AMAS)at LTMGH
(2018-19)

3. “………I recall nothing which in times past has caused me more anxiety
and doubt,
or
in regard to which I have found it more difficult to get any satisfactory
rules from books,
than the treatment of
Abortion.”
- T. G. Thomas (1908)

4. RECURRENT PREGNANCY LOSS
• Recurrent pregnancy loss is defined as 3 or
more clinically recognized pregnancy losses
before 20wks from LMP.
• Primary recurrent pregnancy loss refers to
couples that have never had a live birth.
• Secondary recurrent pregnancy loss refers
to those who have had repetitive losses
following a successful pregnancy.
• Recurrent miscarriage affects 0.5–2% of
pregnant women.

5. AETIOLOGY
• Embryonic Genetic abnormalities 60-80%
• Parenteral Genetic Factors 2-5%
• Anatomic Factors 12-16%
• Endocrine Factors 17-20%
• Infectious Factors 7-56%
• Immunologic Factors 12-15%

6. EMBRYONIC GENETIC FACTORS
• Spontaneous miscarriage occurs in 10–15% of
clinically recognized pregnancies.
• Around 40% of miscarriages in recurrent
miscarriage patients are chromosomally abnormal.
• Major underlying cause being embryonic aneuploidy.
• Meiotic chromosome segregation errors in oocytes
account form the majority of embryonic aneuploidies
.
• Miscarriage is strongly influenced by female age.
• Risk of having 3 miscarriages for women <25 yrs is
around 0.13% but 100 times more likely (~13%) if
> 40yrs.

7. PARENTERAL GENETIC FACTORS
• 2–5% of repeated miscarriage couples compared
with 0.7% of the general population have:
• Structural chromosomal abnormalities, most
commonly (~85%)
• Balanced translocations (reciprocal
translocations (~60%) and
• Robertsonian translocations (~40%))
• Parental karyotyping is recommended by the ASRM
and the DGGG/OEGGG/SGGG
• The RCOG proposed selective karyotyping
depending on whether an unbalanced arrangement is
found in the products of conception.
Hennessy M et al. Reprod Biomed Online. 2021;42(6):1146-1171.

8. • Patients with chromosomal abnormalities should be referred for genetic
counselling.
• Preimplantation Genetic Testing (PGT) is not routinely advised since the
likelihood of a pregnancy with an unbalanced karyotype surviving into the second
trimester is low (0.8% in one study) and overall livebirth rates have not been
shown to be higher with IVF/PGT compared with natural conception.
• However, PGT in couples with structural chromosomal defects might reduce the
number of miscarriages experienced prior to a successful live birth, but this
requires further evaluation.
Hennessy M et al. Reprod Biomed Online. 2021;42(6):1146-1171.

9. ANATOMIC FACTORS
• Congenital (6.2%)
• Septate
• Bicornuate
• Unicornuate
• Didelphys
• Arcuate defects
• Acquired (13.3%)
• Fibroids,
• Polyps And
• Adhesions

10. • Diagnosis :
 An assessment of uterine anatomy is
therefore recommended for patients
with repeated miscarriage.
 2-D ultrasonography with or without
saline infusion (sonohysterography)
usually constitutes first-line
investigations.
 The Thessaloniki ESHRE/ESGE
consensus group recommended 3-D
ultrasonography for investigating
uterine anomalies in high-risk patients,
and
 MRI and endoscopic examinations
for suspected complex malformations
or diagnostic difficulties.

11. ENDOCRINE FACTORS
• While miscarriage is increased with overt
hypothyroidism, the association between
subclinical hypothyroidism (SCH) and pregnancy
loss is less clear.
• Using an upper limit of 4–5 mIU/L for TSH, the
prevalence of sub clinical hypothyroidism in
women of reproductive age is 4–8%.
• Pre-pregnancy TSH threshold of 2.5 mIU/L found
no association with increased miscarriage.
• American Thyroid Association give a strong
recommendation for thyroxine use with combined
autoimmunity and TSH >4 mIU/L and a weak
recommendation to consider thyroxine with
autoimmunity and TSH >2.5 mIU/L.
Homer HA. Aust N Z J Obstet Gynaecol. 2019;59(1):36-44.

12. • Although PCOS has been associated with increased miscarriage risk (related to
hyperinsulinaemia / hyperandrogenaemia) there is a lack of clear evidence that
PCOS predisposes to repeated miscarriage.
• Meta-analysis found that metformin, an insulin-sensitising drug often used in
PCOS patients, did not reduce miscarriage in PCOS.
• A single small RCT (N=46) considered of low quality found that bromocriptine
treatment in recurrent miscarriage patients with hyperprolactinaemia
significantly reduced miscarriage rates.
• Larger trials to clarify the potential benefit of dopamine agonists in RM patients
with idiopathic hyperprolactinaemia.
Homer HA. Aust N Z J Obstet Gynaecol. 2019;59(1):36-44.

13. INFECTIOUS FACTORS
• Embryo-fetal infections have been reported to cause recurrent
spontaneous abortions (RSAs) at a rate lower than 4%.
• The possible mechanisms include production of toxic metabolic
byproducts, fetal or placental infection, chronic endometrial infection, and
chorio-amnionitis.
• Viruses appear to be the most frequently involved pathogens, since some
of them can produce chronic or recurrent maternal infection.
• Cytomegalovirus,
• Parvovirus
• Bacteria include :Chlamydia trachomatis, Ureaplasma urealyticum and
Mycoplasma hominis
• Bacterial Vaginosis may also be implicated in RPL.
• Nigro G, Mazzocco M, Mattia E, Di Renzo GC, Carta G, Anceschi MM. Role of the
infections in recurrent spontaneous abortion. J Matern Fetal Neonatal Med.
2011;24(8):983-989. doi:10.3109/14767058.2010.547963

14. • Although a definitive relationship between
recurrently active infections and RPL is still
lacking, mostly due to difficulties in
demonstrating the pathogenic role of each
individual isolated pathogen, diagnosis and
therapy of RPL-related infections should be
attempted.
• The diagnosis of infectious agents as a
possible cause of RPL might lead to a
therapeutic approach with antiviral drugs and
antibiotics or using immunoglobulins, which
can display both anti-infective neutralizing
and immunomodulating properties.
• Nigro G, Mazzocco M, Mattia E, Di Renzo GC, Carta G, Anceschi MM. Role of the
infections in recurrent spontaneous abortion. J Matern Fetal Neonatal Med.
2011;24(8):983-989. doi:10.3109/14767058.2010.547963

15. IMMUNOLOGICAL FACTORS
AFFECTING PREGNANCY
Pregnancy causes natural
IMMUNOMODULATION by:
• Causing an enhancement in humoral
immune response.
• A decrease in cell mediated immunity.
• A reduction in cell mediated autoimmune
response.
• Downregulation of Th1 responses.
• Upregulation of Th2 responses.

16. IMMUNE FACTORS IN
RECURRENT PREGNANCY LOSS
• Th1 is a pro inflammatory cytokine that has many
cytotoxic and tissue-damaging capabilities .
• Women with recurrent spontaneous miscarriage
(RSM) have a greater bias towards a Th1-type or
pro-inflammatory cytokine profile as compared to
women with healthy pregnancy.
• Whereas women with healthy pregnancy have
decreased Th1 cytokines and increased Th2
cytokines.
Thus, there is an increased pro-inflammatory
cytokine bias in unexplained recurrent
miscarriage

17. The relationship of cytokines, progesterone, other
immune factors and cells with miscarriage.
NK cells- Natural Killer

18. MECHANISM OF CYTOKINE ACTION
IN REPEATED PREGNANCY LOSS
• NK cells, like activated Th1 cells, could release
cytokines deleterious to trophoblast, its
increased activity in blood/uterus is linked to
miscarriage.
• Th1 cytokines also convert NK cells into
lymphokine-activated killer (LAK) cells.
• Systemic levels of LAK-like cells correlate
with high miscarriage rates.
• Th1-dominated response detrimental to early
placental differentiation & embryonic
development.
Raghupathy R. Current Medicine Research and Practice. 2016 Nov 1;6(6):233-9.

19. • Inflammatory Th1 cytokines- TNF-α and IFN-g
causes
• apoptosis of trophoblast cells and thus
directly damage “conceptus” and
• also inhibits secretion of GM-CSF from
uterine epithelium.
• Cytokines activate coagulation mechanisms leads
to vasculitis affecting blood supply to the
implanted embryo, a process that they have
termed ‘‘cytokine-triggered vascular auto-
amputation’’
Raghupathy R. Current Medicine Research and Practice. 2016 Nov 1;6(6):233-9.

20. PROGESTERONE
• Progesterone absolutely indispensable for
establishment of the receptive endometrium.
• Now it is also recognized as contributing
immunologically to sustenance of pregnancy by
interacting with maternal immune system.
• Studies demonstrated immunosuppressive
properties of progesterone.
Kumar A. Immunomodulation in recurrent miscarriage. J Obstet Gynaecol India. 2014;64(3):165-168.

21. • Progesterone has been shown to
• suppress activation and proliferation of
lymphocytes.
• decrease oxidative burst of monocytes.
• prolong survival of allografts when
administered locally.

22. ROUTES OF ADMINISTRATION
• Injectable-Intramuscular and Subcutaneous injections used.
• Adverse effects include Injection site pain, may cause skin irritation,
inflammatory reactions, and abscess formation
• Vaginal - Transvaginal use of progesterone can cause discharge, vaginal
irritation in some patients & also discomfort while administration
• Oral - Oral administration is the easiest route of administration, and
generally the most acceptable route for the patient.

23. ORAL PROGESTERONE
• Oral Micronized Progesterone
• Oral Dydrogesterone

24. Oral dydrogesterone
Approved in Recurrent Pregnancy
Loss, Luteal Phase Defect and
other progesterone deficiencies.
28% bioavailability.
Minimizes unwanted effects &
activation of other unwanted
receptors
Major metabolite DHD conducive
to success of pregnancy.
DHD induced Nitric Oxide
synthesis improves endometrial
receptivity & pregnancy outcomes.
Micronized progesterone
Approved only for secondary
amenorrhea.
<5% bioavailability.
Metabolites can cause dizziness &
drowsiness.
Major metabolites may adversely
affect pregnancy outcomes.
Major metabolites may affect
normal progesterone action.

25. DYDROGESTERONE
• Dydrogesterone is metabolized to 20[α]-
dihydrodydrogesterone (DHD); thus in
circulation dydrogesterone is actually present
as DHD.
• This metabolite also inhibits production of the
pro-inflammatory cytokines IFN-g and TNF-α
and upregulates production of the anti-
inflammatory cytokine IL-4 showing that this
metabolite retains immunomodulatory effects
of parent molecule dydrogesterone.

26. DYDROGESTERONE
• Dydrogesterone Modulating Cytokine
effects via inducing a protein called
Progesterone-Induced Blocking Factor
(PIBF).
• PIBF induces a Th2-dominant cytokine
response, by facilitating production of IL-4
and IL-10, thus altering Th1/Th2 balance in
favor of pregnancy

27. DYDROGESTERONE
• Dydrogesterone is superior as it has
• Longer biologic half-life,
• Improved bioavailability
• Dydrogesterone retains immunomodulatory
activity even after it is converted to its
major metabolite after oral administration.
• Dydrogesterone-treated women with
unexplained recurrent pregnancy loss had
fewer miscarriages.
• Therapy with dydrogesterone in threatened
abortion led to a significantly higher rate of
continuing pregnancy success.
Zakia M Ibrahim. W J Gynecol Women’s Health. 3(3): 2020. WJGWH.MS.ID.000567.

28. • BJOG;2005 Aug;112(8):1096-101

29. STUDY
• Controlled prospective, clinical
study conducted in a maternity
hospital and a university-based
immunology laboratory.
• Cytokine production in the
presence and absence of
progesterone and dydrogesterone
in 30 women with unexplained
RSM.
RESULT
• Dydrogesterone significantly inhibited the
production of the Th1 cytokines IFN-γ
(P= 0.0001) and TNF-α (P= 0.005) and
induced an increase in the levels of the
Th2 cytokines IL-4 (P= 0.03) and IL-6
(P= 0.017) resulting in a substantial shift
in the ratio of Th1/Th2 cytokines.
• Dydrogesterone inhibits the
production of the Th1 cytokines
IFN-γ and TNF-α from
lymphocytes and up-regulates the
production of the Th2 cytokines
IL-4 and IL-6, inducing a Th1 to
Th2 cytokine shift

30. • Fertil Steril 2014 Nov;102(5):1357-1363.e3

31. STUDY
• Double-blind, randomized, placebo-controlled study.
• Sample size : 540 cases.
• The patients were randomly assigned to orally take 2 tablets of 10-
mg dydrogesterone or placebo daily from the time of enrollment
to 20 weeks of gestation.
• Dydrogesterone 20 mg/day from confirmation of pregnancy to 20
weeks of gestation.
• Women with either a history of idiopathic recurrent pregnancy
loss (RPL), or no history of miscarriage.

32. RESULT
• There was a statistically significant decrease in the number of
miscarriages in the dydrogesterone group (6.9%) compared with the
placebo group (16.8%, P=.004). Further, the mean gestational age at
delivery (excluding those aborted before 20 weeks of gestation) increased
significantly in the dydrogesterone group (38.0 ± 2.0 weeks) compared
with the placebo group (37.2 ± 2.4 weeks; P=.002).
• The study supports the use of dydrogesterone in women with
recurrent abortions to improve pregnancy outcome, such as a
reduction in abortions and improved gestational age and baby
weight at delivery.
• However, these outcomes were not modulated by Th1 and Th2
cytokine production

34. DOSE
• FOGSI Position Statement on the Use of
Progestogens (2015), under the guidance of
GCPR In charge, Dr Sanjay Gupte, in the
FOGSI Presidential tenure of Dr Prakash
Trivedi (2015) and Dr Suchitra Pandit
(2014), in women with recurrent pregnancy
loss:
• Dydrogesterone: 10mg BID from
confirmation of pregnancy till 20 weeks of
pregnancy.

35. CONCLUSION
• Dydrogesterone has immunomodulatory capability.
• Useful in the treatment of threatened abortion via modulating cytokine profile
and causing shift in Th1/Th2 ratio for Th2 predominance and more
specifically via decreasing level of Th1 markers as IF-γ
• Oral dydrogesterone has been shown to be more effective than micronized
vaginal progesterone in luteal phase support.
• Dydrogesterone & Micronized Progesterone yielded similar rates of
successful pregnancies, Dydrogesterone had a higher tolerability by patients.
• Well-established safety profile of dydrogesterone & fact that it is
administered orally make it an attractive candidate for immunomodulation in
pregnancy complications.

37. THANK YOU