Role of Dydrogesterone in repeated pregnancy loss

Role of new progesterone congener in repeated pregnancy loss

1. ROLE OF IMMUNOMODULATORS IN MANAGEMENT OF RECURRENT PREGNANCY LOSS

2. “……… 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 )

3. 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.

4. 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%

5. 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.

6. 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.

7. 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.

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

9. 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.

10. 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.

11. 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.

12. 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

13. 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

14. 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.

15. 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

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

17. 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.

18. 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.

19. 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.

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

21. 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.

22. Oral progesterone Oral Micronized Progesterone Oral Dydrogesterone

23. 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.

24. 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 .

25. 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

26. 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.

27. BJOG; 2005 Aug;112(8):1096-101

28. 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

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

30. 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.

31. 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

32. 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.

33. 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.

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