FOGSI WorkshopPreventing Early Pregnancy Loss (EPL)

The Cocktail Therapy

Dr. Suchitra Pandit Dr. Ritu Joshi Dr. Shailesh Kore Dr. Kedar Ganla President Vice -President Chairperson National Coordinator

Workshop supported by Unconditional Educational Grant by

Alloimmune Background in

Early Pregnancy Loss (EPL)

Dr Rajesh Gajbhiye Nagpur

Introduction

• About 50% of pregnancies are lost after conception

• About 15 % are lost after clinically detectable pregnancies

• Causes are not known in more than 50% of cases of RPL

• Such large unexplained causes has fuelled interest in immunological causes.

Pregnancy is a semi-graft 50% of the antigens

are foreign

Immunomodulation during pregnancy

Embryo / Fetal antigens produce two types of antibodies:

• T Helper I Cell response

• T Helper II Cell response

Immune reaction during pregnancy

Fetus withPaternalantigens

T helper 1cell response

Abortion ofThe Fetus

T helper 2cell response

Protection of The Fetus

Embryo / Fetus

T helper 1 cell response activated

Tumor Necrosis Factor άInterleukin2

Natural killer Cells

Lymphokine Activated Killer Cells

Abortion of Fetus

Cascade Reaction

Secreted molecules that regulate the intensity and duration of the immune response by exerting a variety of effects on lymphocytes and other immune cells

Cytokines are the messengers of the Immune System (Th1 : TNFα, Il-2, Th2 : IL-4, IL-10)

just as Hormones are the messengers of the Endocrine System

What are Cytokines ?

Th-1 cytokines trigger thrombotic / inflammatory processes at the maternal uteroplacental blood vessels by activation of vascular endothelial cell procoagulant.

Th-2 cytokine inhibit Th-1 induced tissue destruction by monocytes.

TNF-β is supposed to suppress the growth of trophoblasts by inducing apoptotic changes in these cells.

Cytokines and TNF- β

Luteal phase of young healthy women is associated with decline in Interleukin 2 levels

Hormone Metab. Res. 2001: 33; 348-53.

Luteal phase in healthy non pregnant women

Decrease in IL-2 blood levels. Decrease in intracellular IL-2 containing lymphocytes. Seen as a start of immune suppression necessary for

embryo nidation. Could also be the cause of premenstrual infections seen

in young women.

Role of Interleukin in the Luteal Phase

Embryo protective Immunomodulation

- How is this brought about?

Normal Pregnancy

Progesterone(P) Receptor Activation

Blocks Cascade Reaction, Shift to Th type 2

Embryo Protective Immunomodulation

Protection of Embryo / Fetus

Progesterone Induced Blocking Factor(PIBF)

Embryo Protective Immunomodulation – What is it?

Raghupathy et al., (2000): Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion. Hum. Reprod. 15(3); 713-18.

3 Positive responses

T helper 2 cell response NK Activity

Asymmetric Antibodies

No binding with Antigen

No activation of Complement Cascade

Protection of Fetus

Protective Cytokines

IL 3IL 4IL 5IL 6

IL 10IL 13

Progesterone

PIBF Th2

Normally Progressing Pregnancy

Progesterone-induced Blocking Factor (PIBF) Link between the Endocrine and Immune System

Progesterone

PIBF Th1Miscarriage

Ru 486

Progesterone

PIBF+anti-PIBF

Th1Miscarriage

Szekeres - Bartho J et al. Int Immunopharm 2001; 1:1037-1048.

Increased Th1 Cytokine Response in Women with RSA Losses & with Multiple Implantation

Failures after IVF

Kwak -Kim JY et al. Hum Reprod. 2003 Apr;18(4):767-73.

Control, n = 21

RSA, n = 26

IVF failure, no Hx SA, n = 14

Comparison of Th1/Th2 cytokine producing CD3+/CD8– (T helper) cell ratios

** p < 0.01 * p < 0.05

0

10

20

30

40

50

60

70

IFNγ / IL-4 IFNγ / IL-10 TNFα / IL-4 TNFα / IL-10

*

**

***

*

20

40

60

80

100

120

140

160

7-19 20-29 30-37 38-41

Weeks of gestation

PIB

F c

once

ntr

atio

n (

ng/m

l)

Normal pregnancy

Miscarriage / Preterm labour

<41 L

PIBF Concentrations in Normal and High Risk

Pregnancies

Polgar B et al. Biol Reprod 2004; 71:1699-1705.

* p<0.05*

*

*

P-receptors in Pregnancy Lymphocytes

Activation

γ/δPR+

P PP P

PIBFPIBF

+

Szekeres-Bartho J et al. Int Immunopharm 2001; 1:10371-1048.

γ/δ

Natural Killer Cell Activity

Th2 / Th1 +

Normally Progressing Pregnancy

Decidual NK cells

• Decidual NK Cells appear to be mainly involved in alloimmune abortion.

• Under influence of Th1 cytokines they damage the trophoblasts.

• Patients who abort have increased NK cell activity and NK cells of CD3,CD 56,CD 16 types.

Immunomodulation during pregnancy

Molecules like dydrogesterone inhibit the cytokines through PIBF, thereby enhancing chances of successful pregnancy.

(Rajraghupati – Abstract World Congress. Hong Kong, Dec 2-5, 2001).

No other progesterone has so far been experimented on this aspect of immunomodulation

IMMUNOLOGIC FACTORS

Autoimmune Alloimmune (directed to self) (directed to foreign

tissues/cells)

-Systemic Lupus Erythmatosus An abnormalmaternal -Antiphospholipid Syndrome immune response to fetal or placental antigen.

Autoimmune• Systemic Lupus Erythmatosus (SLE) -Risk for loss is 20%,mostly in 2nd and 3rd trimester of pregnancy and associated with antiphospholipid antibodies.

• Antiphospholipid syndrome (APA)– 5 - 15 % of womenwith RPL may have APA APA likely induce microthrombi at placentation site.

Altered vascularity affects developing embryo, induces abortion

Antiphospholipid syndrome – An Autoimmune disorder having specific clinical & lab

criteria. --Sapporo criteria

Diagnosis requires at least one of each. CLINICAL 1) Thrombolic events-arterial,venous,small

vessel 2)Pregnancy loss- ≥3 losses at <10wks

gestation, fetal death after 10wks,premature birth at <34wks associated with severe preeclampsia or placental insufficiency.

LABORATORY 1) Lupus Anticoagulant 2) Anticardiolipin antibodies(IgG or IgM)

Any lab test results must be observed on at least 2 separate occasions 6 wks apart.

(An International Consensus Conference held in Sapporo in 1998)

• Recent metaanalysis 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

Mak A et al, Rheumatology (Oxford) 2010

23

Aspirin alone v/s Aspirin + Heparin

• 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

24

• Heparin in prophylactic doses NEED not be monitored and does not require monitoring by coagulation parameters

• Standard doses– Unfractionated heparin – 5000 units sc bd

– Enoxaparin – 40 mg sc daily or in two doses

25

• Meta analysis• Heparin with Aspirin imroved live birth• 25-75%• In 20-30% loss ,inspite of therapy• Alt treatment glucocoticids or IVIG• IVIG is no more effective than aspirin and

Heparin in pts of APS

Alloimmune mechanism Normally pregnancy(foreign tissue graft) is

tolerated by the maternal immune system through formation of antigen blocking antibodies.

Felt that in couples that share similar types of HLA, there is inadequate formation of blocking antibodies in the maternal environment.

Therefore the maternal immune system mounts an immune response to the implanting pregnancy and a spontaneous abortion occurs.

Alloimmune mechanism

Although previous studies have concluded that there was a higher degree of HLA sharing in couples with recurrent abortion, multiple recent studies have not confirmed this.

Multiple investigators have attempted to modulate the immune response using

1) paternal WBC immunization2) IV Immunoglobulin 3) donor seminal plasma vaginal

suppositories

NONE HAVE BEEN SHOWN TO BE BENIFICIAL

ALLOIMMUNITY DIAGNOSIS

HLA Typing-HLA sharing-Insufficient antigenic stimulus• Antipaternal antibodies- absence

maternal unreponsiveness• Husband’s lymphocytes + wife’s serum to find antibodiesNone of the above test Diagnostic

• In practice study of Peripheral blood NK cells is used.

• NK cell markers -Immunotherapy

Immunologic Factors -Treatment

• Immunostimulating Therapies-Leukocyte Immunization

• Immunosuppressive Therapies

Immunostimulating Therapies-Leukocyte Immunization

– stimulation of the maternal immune system using alloantigens on either paternal or pooled donor leukocytes

– a number of reports support possible mechanism for potential therapeutic value

– however, there is no credible clinical or laboratory method to identify a specific individual who may benefit from such therapy

– leukocyte immunization also poses significant risk to both the mother and her fetus • graft-versus-host disease, severe intrauterine growth

retardation, and autoimmune and isoimmune complications

TREATMENT

Acive immunisation-Transfusion of husband’s lymphocytesPure suspension of husband’s

lymphocytes [ 300ml of blood = 10ml of suspension ]Inject 5ml IV, 1 ml subcu and 1ml

intradermal

• Effective presentation of paternally derived antigen and regulate maternal response through suppression of NK cell activity

• Increases Th2 type immune response• Cochrane review 2006 doesnot support this

therapy.• ASRM it has higher side effects and marginal

benefits

Intravenous immunoglobulinPassive immuisation

• Mechanism– Blockage of allogenic cytotoxic reactions– Suppresses NK cell activity

• disadvantage– expensive, invasive, and time-consuming, requiring

multiple intravenous infusions over the course of pregnancy

• side effects – nausea, headache, myalgias, hypotension, anaphylaxis

• 0.5 g/Kg body weight IVIG started at 5 wks• Followed by 0.35g/kg every 3 weeks until 24

weeks.• Only therapeutic solution increased activity of

NK Cells• When used as homogenous group not

effective in various meta-analysis but in properly selected pts beneficial.

FUTURE

• Cytokines GM-CSF9Granulocyte macrophage colony stimulating Factor)

• TGF-b

• In addition to immunotherapy hormonal support (Progesterone and HCG) has been used to improve the live birth rate in recurrent abortion by modulating balance between Th1 and Th2 cytokines.

Progesterone

• Mechanism– inhibits Th1 immunity – shift from Th1-to Th2 type responses

• administered – intramuscularly – intravaginally • may increase local, intrauterine concentration• averting any adverse systemic side effects

Progesterone favours the development of human T helper cells producing Th2-type cytokines and promotes IL – 4 production.

Piccinni MP, Gindizi MG et.al , J. Immunal 1995; 155 : 128-133

Progesterone inhibits in vitro embryotoxic Th1 cytokine production in trophoblast in women with recurrent pregnancy loss

Choi BC, Polgar K et. Al Hum. Reprod 2000; 15 (supp 1) 46-59

Hormonal Immunomodulation

Progesterone

Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage.

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 & IL-6 inducing Th1 to Th2 cytokine shift.

Raj Raghupathy et. al BJOG 112; 1 – 6 2005

Hormonal Immunomodulation

Progestogens in Implantation in ART Cycles

• LPD & implantation failure results from abnormal serum E2:P ratio or abnormal E2:P receptor ratios

• Mitigate the deleterious effects of hyper estrogenism on endometrial development

Effective Luteal Phase

Means:

• Effective secretory endometrial preparation “Firm” implantation

• Effective endometrial immunomodulation to prevent embryonic rejection

Effective Luteal phase

Both these immunophysiological functions are carried out primarily by Progesterone backed up by estrogen.

Estrogen induces nuclear progesterone receptors

Progesterone then acting through its own receptor produces a mediator protein known as progesterone induced blocking factor (PIBF).

Luteal phase defect (LPD)

• LPD is the failure of the uterine lining to be in the right phase at the right time

• May be due to inadequate progesterone production by corpus luteum

• Or inadequate response of endometrium to the normally circulating level of progesterone.

Incidence of LPD:

26.5% in infertile women (Sahmay et al; Fert. Menopausal Stud. 1995;40 (6) : 316-321).

45% in patient suffering from recurrent miscarriage(Daya et al; Am.J. Obst. Gyn. 1988;158 : 225-232).

Cause of LPD in Non ART cycles

Poor follicular phase inadequate Luteal phase.

Premature LH Stimulation of immature granulose cells.

Abnormal patterns of LH secretion in the Luteal phase

Decreased endometrial nuclear progesterone receptors

Can also be found with normal levels of progesterone

Attenuated “LH” & “FSH” ovulatory surge

Causes of LPD in ART cycles

• CC INDUCTION

Antiesterogenic to endometrium

Reduced endometrial progesterone receptor production

• ART

Long downregulation resulting in LPD (Smitz, Devroey 1988)

Use of Antagonist Supraphysiological level of E2 – Leutolytic

Multiple puncture of follicles – damage to granulosa cells.

• Diagnosis• Sreum progesterone level less than

10ng/ml in midluteal phase.• 3 estimation between day 5-8 should be

30ng/ml.• Out of phase endometrium – Histological lags 2days behind menstrual

datesNot used now a days

• USG Doppler• CL high resistence flow• Ovarian RI is similar in both ovaries

Newer tests

PIBF measurements

Treatment for LPD

Progesterone supplementation

given in suspected cases or empirically

Prevents 33% miscarriages

Reduces 28% to 6% along with follicular maturing drugs

• HCG supplementation-majority have PCOS and LPD

Progestogens for Luteal phase support in ART cycles

• Needs to be given daily basis either oral, vaginal, IM routes

• Neutralize the negative effects of hyper estrogenism on endometrial development

• Immunosuppressive effect facilitating implantation (Immunomodulation)

HCG for Luteal phase support in ART cycles

• Frequent dosing intervals of 3 - 4 days

• Increases incidence of OHSS

• HCG increases Luteal E2 to undesirable levels, upsetting E2 : P ratio

• HCG is good for luteal support

• Natural micronised progesterone is drug of choice for LPD

• Vaginal route is preferred over others.

• Chochrane review –IVIG is ineffective

• In poor prognosis patients in whom other treatments have failed and in properly selected patients IVIG has been found to improve birth rate.

• If immunotherapy fails and embryo is karyotypically normal then Surrogacy is advised.

• Many questions to be answered

• Many stages of maternal immune response remain unclarified

• Available diagnostic methods can only provide indirect marker

• Results must be interpreted with caution

• Appropriate immnointervention be admisnistered.

Thanks to YOU - For being wonderful audience

EPL Team - who conceptualized and created this program - Team Lead by

• Dr . Suchitra N. Pandit - President FOGSI• Dr. Ritu Joshi - Vice President FOGSI • Dr. Shailesh Kore - Chairperson Genetic & Fetal Medicine

Committee, FOGSI• Contributors - Dr . Nozer Sheriar, Dr. Kedar Ganla, Dr. Ameet Patki, Dr. Sarita Bhalerao, Dr. Parikshit Tank, Dr. Bhaskar Pal,

Dr. Bharti Dhorepatil, Dr. Atul Ganatra, Dr. Kalyani Ingle Dr. Ameya Purandare, Dr. Kundan Ingle, and all the Doctor Speakers.

Acknowledgement

For supporting the program with unconditional educational grant For organizing and managing the program across the country

-

Thankyou

Outline

• Basic facts

• Levels

• Treatment of low progesterone levels

• Role of progesterone in pregnancy

• Role of progesterone in ART

• Conclusion

Basic facts:

Progesterone support in pregnancy has been in use for nearly 60 years, dating back to the 1940s.

Its initial use was in patients who had habitual spontaneous abortion caused by Luteal phase deficiency (LPD).This is due to a failure of the function of the corpus luteum in the production of progesterone ,which is indispensable during the first seven weeks of pregnancy.

Symmetric Antibodies

Exact alignment between binding surfaces of the paternal antigens and maternal antibodies causes activation of the

complement cascade

Abortion of the fetus

Von Wolff et al., (2000): Regulated expression of cytokines in human endometrium throughout the menstrual cycle: dysregulation in habitual abortion. Mol. Hum. Reprod. 6; 626-34.

Basic facts:

Surgical removal of the corpus luteum during this period of time results in pregnancy loss and progesterone replacement can help maintain the pregnancy.

There is evidence of support in the concept that progesterone given in early pregnancy may be useful in some women with recurrent miscarriage and that the measurement of serum progesterone levels in early pregnancy can be an adjunctive marker for the further assessment of pathologic pregnancies.

Levels

Progesterone levels are based on her menstrual cycle and in the stage of pregnancy.

Before Pregnancy Prior to ovulation: Progesterone levels tend to be < 2 ng/ml After Ovulation: > 5 ng/ml

In Pregnancy Progesterone levels rise with pregnancy. This can often indicate the health of a pregnancy. First Trimester: 9-47 ng/ml Second Trimester: 17-147 ng/ml Third Trimester: 55-200 ng/ml

Progesterone

HCG

Menses Ovulation Implantation

FSH

2 4 6 8 10 12 14 16 18 20Days

4 6 8 10 12 14Weeks

LH

Progesterone in the Luteal Phase and Pregnancy

Speroff L et al. Clinical Gyn Endo and Infert 1999; 6: 235.

Progesterone levels in Pregnancy

Maintenance of Early Pregnancy

Syncytiotrophoblast

Cytotrophoblast

Amniotic

cavity

Yolk sac

Chorioniccavity

hCG

Lacunarnetwork

Progesterone

Regulation ofprostaglandin

production

VDGF-VEGFreceptors

Angiogenesis

Progesterone

Bloodvessels

Endometrialgland

Decidualizedendometrial stroma

Suppressormacrophage

Chorion

Maternal bloodsinusoid

Facilitationof immunetolerance

Corpus luteum of ovary

Decreasedcomplement

activity

Altered antigenpresenttaion

(HLA-G)

Regulation ofleukocyte traffic by

cytokines and chemokines

Indoleamine2,3-dioxygenase

Norwitz et al., N Engl J Med. 2001; 345(19):1400-8.

Schindler AE et al. Maturitas 2003; 46SI:S7-S16.

NaturalFound in nature

SyntheticStructurally related to

progesterone or testosterone

Classification of Progestogens

17α-hydroxyprogesterone

19-nortestosterone

•Medroxyprogesterone acetate (MPA)• Megestrol acetate• Cyproterone acetate

GONANES• Norgestrel•Norgestimate•Gestodene

19-norprogesterone

• Trimegestone ESTRANES• Norethisterone = Norethindrone acetate (NETA)• Allylestrenol

• Progesterone

STEROIDSSTEROIDS

Retro progesterone Dydrogesterone

Progestogen Progestogenic Estrogenic Androgenic Glucocorticoid

Dydrogesterone + − − −

Progesterone + − − +

Cyproterone acetate

+ − − +

MPA + − ± +

Norethisterone + + + −

Schindler AE et al. Maturitas 2003; 46SI:S7-S16.

Biological Activities of the Progestogens

• Brain is sensitive to progesterone during critical periods of development and maturation

• Dramatic sex differences in progesterone receptor (PR) expression, in which males express higher levels of PR than females in specific regions, suggest PR may play an important role in the sexual differentiation of brain and behavior.

Wagner CK, Endocrinology 2008 June;149(6):2743-9

Progesterone and Fetal Brain development

315 ICSI and 94 recipients on donor oocyte program were included in

the trial. 89 patients were at risk of OHSS (E2 > 2000 pg/ml)

All were matched for Demographic factors including age, social status,

infertility factors and years of infertility.

All patients underwent

long term down regulation with GnRHa for a minimum of 10 days.

Controlled ovarian stimulation with Gonadotropins

Recipients on the donor oocyte program were started on Tab.

Progynova (estradiol valerate) in an increasing dose from day of

stimulation of the Donor.

Re Genesis – Pilot Study (Phase I) 2002-04

Patients on any other protocol were excluded from the study.

All patients received 600 mg of micronized progesterone (utrogestan) vaginally from day of oocyte retrieval.

In addition, patients were randomized to either receive Dydrogesterone 20 mg or placebo daily from the day of embryo transfer till serum β hCG which if more than 50 mIU/ ml, the treatment was continued.

A USG was done to confirm a viable pregnancy after 3 weeks.

Only intrauterine viable pregnancies were considered as positive for pregnancy.

Re Genesis – Pilot Study (Phase I) 2002-04

ICSI Patients: 315

Treatment with Dydrogesterone 112 (35.5%)

Treatment with no Dydrogesterone 203 (64.4%)

Pregnancy Rate

With Dydrogesterone 37 (33.03%)

With no Dydrogesterone 48 (23.64%)

Results: I

P value NS

Patients at risk of OHSS : 89

Treatment with Dydrogesterone 57 (64.04%)

Treatment with no Dydrogesterone

32 (35.95%)

Pregnancy Rate

With Dydrogesterone 21 (36.84%)

With no Dydrogesterone 09 (28.12%)

Results: II

P value NS

Recipient on Donor Oocyte Program : 94

Treatment with Dydrogesterone 49 (52.12%)

Treatment with no Dydrogesterone 45 (47.87%)

Pregnancy Rate

With Dydrogesterone 21 (42.85%)

With no Dydrogesterone 07 (15.55%)

Results: III

P < 0.001 Chi. Square test

450 ICSI and 120 recipients on donor oocyte program were included

in the trial. 105 patients were at risk of OHSS (E2 > 2000 pg/ml)

All were matched for Demographic factors including age, social

status, infertility factors and years of infertility.

All patients underwent long term down regulation with GnRHa for a minimum of 10

days. Controlled ovarian stimulation with Gonadotropins

Recipients on the donor oocyte program were started on Tab.

Progynova (estradiol valerate) in an increasing dose from day of

stimulation of the Donor.

Re Genesis – (Phase II) 2004-06

Patients on any other protocol were excluded from the study.

Patients were randomized to either receive 600 mg daily of micronized progesterone (utrogestan) vaginally or Dydrogesterone 30 mg daily from day of oocyte retrieval.

Serum β hCG was tested 14 days from embryo transfer and if more than 50 mIU/ ml, the treatment was continued.

A USG was done to confirm a viable pregnancy after 3 weeks.

Only intrauterine viable pregnancies were considered as positive for pregnancy.

Re Genesis – (Phase II) 2004- 05

ICSI : 450 Patients

Treatment with Dydrogesterone 248 pts [55.1%]

Treatment with Micronised Progesterone

202 pts [44.9%]

Pregnancy Rate

With Dydrogesterone 97 [*39.1%]

With Micronised 54 [26.7%]

Results - I

• By Chi Square Test * P<0.01 Significant

At risk of OHSS – 105 Patients

Treatment with Dydrogesterone 60 [57.13%]

Treatment with Micronised Progesterone

45 [42.8%]

Pregnancy Rate

With Dydrogesterone 25 [*41.6%]

With Micronised Progesterone 16 [35.5%]

Results - II

• By Chi Square Test * P<0.01 Significant

Donor oocyte program – 120 Patients

Treatment with Dydrogesterone 58 [48.3%]

Treatment with Micronised Progesterone

62 [51.6%]

Pregnancy Rate

With Dydrogesterone 28 [*48.2%]

With Micronised Progesterone 21 [33.8%]

Results - III

• By Chi Square Test * P<0.001 Significant

Paper presented at …

• Five National conferences in India

• Teaching Universities in China Egypt and Vietnam

This paper is published in Gynecological Endocrinology, October 2007; 2(S1): 68-72

Functions of progesterone

Converts the endometrium to its secretory shape to prepare uterus for implantation.

Affects the vaginal epithelium and cervical mucus , making it thick to un-penetrable sperm.

During implantation & pregnancy ,progesterone appears to decrease the maternal immune response to allow for acceptance of pregnancy.

Decreases contractility of uterine smooth muscle.

Inhibits lactation during pregnancy. Fall in the levels following delivery is one of the triggers for milk production.

Drop in progesterone is possibly one step that facilitates the onset of labor.

Treatment for low progesterone levels

Low progesterone levels are associated with increased risk of miscarriage in the first trimester. There are many forms of treatment or supplementation that help to increase and maintain the production of progesterone. The treatment options listed below are generally followed for the first trimester of pregnancy. Dosages vary based on specific need or deficiency.

Intra-muscular progesterone injections- self administered for the first trimester of pregnancy

Oral progesterone capsules (standard or sustained release) progesterone vaginal pressaries HCG- Human chorionic gonadotropin

Routes of administration

• Intramuscular (painful, low patient compliance)

• Vaginal (very effective, available as pessaries, gel, effervescent tablets)

• Oral (Micronised progesterone not effective due to the hepatic first bypass )

Shedding of the zona pellucida

Orientation

Apposition

Attachment

Adhesion

Implantation

Role of Progestins in the Treatment of Threatened

and Habitual Abortion

Spontaneous abortion occurs in

approximately 15% of all clinically

recognized pregnancies but up to

45% after 3 consecutive miscarriages

Speroff L et al. Clinical Gyn Endo and Infert 1999; 6:1043-1044.

Progestogens for preventing miscarriage

No evidence for routine use

However in women with recurrent miscarriages of 3 or more , statistically significant decrease rate in miscarriage compared to placebo or no treatment.

No statistical difference between route of administration (oral, IM, vaginal)

Cochrane Database Reviews 2008 Issue 2 Haas DM, Ramsay PS

Adverse effects

Cramps, abdominal pain, skeletal pain, headaches Diarrhoea, nausea, vomiting Breast enlargement, joint pains Thirst, increased appetite, drowsiness, excessive urination at

night. Mood swings, emotional instability, abnormal crying, insomnia,

sleep disorders. Plays an important role in the signaling of insulin release &

pancreatic function, affect susceptibility to diabetes. Women with high levels of progesterone during pregnancy are

likely to develop abnormalities

Immunomodulation during pregnancy

If T helper I cell response is activated it produces harmful

cytokines and fetus is rejected.

Interferon's and progesterone for establishment and

Interferon's (IFNs) Type I and /or Type II are important in establishing uterine receptitivity to implantation in mammals.

Uterine receptivity to implantation is progesterone dependent. Hence IFNs and progesterone activate complimentary cell signaling pathways to modulate expression of genes for attachment of trophectoderm to uterine luminal and superficial glandular epithelia .

Repmed Biol 2008 Nov:8 (3);179-211

maintenance of pregnancy, interactions among novel cell signaling pathways

• Selection Criteria for Review : 59 randomized controlled trials

of luteal phase support after ART treatment

• Objectives /Conclusions1) Does luteal phase support after assisted reproduction increases the

pregnancy rate? - Yes

(2) What is the optimal hormone for luteal phase support? - hCG does not provide better results than progesterone and is associated with a greater risk of OHSS when used with GnRHa

(3) What is the optimal route of progesterone administration? - This has not yet been established

Luteal Phase Support in Assisted Reproduction Cycles

(Cochrane Review)

Daya S, Gunby J. Cochrane Review 2004; Issue 3.

• Natural miracle known as immunological paradox of pregnancy.

APAS

• Treatment1. Low Molecular weight Heparin

– 3000 IU subcut twice a day– Expensive treatment

1. Un-fractionated Heparin is better option2. Low dose Aspirin 3. Steroids? Mainly for anti nuclear antibodies

– 10 – 20 mg prednisolone / day

Immunosuppressive Therapies

– To antiphospholipid antibodies and to inappropriate cellular immunity toward the implanting fetus

• intravenous immunoglobulin

• progesterone