Treatment for Miscarriages: It’s long overdue

Dr Nurulhuda SamsudinO&G Dept

Getting the Definition Right

• Miscarriage is pregnancy loss before 22 weeks’ gestation based on the LMP or if gestation age is unknown, it is the loss of an embryo or a fetus of less than 500g.

Miscarriage: Why Does It Matter?

• It is the most prevalent complication in pregnancy, affecting 1 in 4 pregnancies.

• Psychological Morbidity; Level of distress has been shown to be equivalent to stillbirth

at term.

• Physical Morbidity; Vaginal bleed. Infection. Surgical or medical evacuation and its associated morbidities.

Even if the pregnancy survives > 22 weeks

Threatened miscarriage is associated with:• Increased rate of antepartum

haemorrhage.• PROM.• Preterm delivery.• IUGR.

Can We Help Our Patient?

• Complete miscarriage.• Septic miscarriage.• Inevitable miscarriage.• Threatened miscarriage.• History of Recurrent miscarriage.

The Question Is ……

History of recurrent miscarriageThreatened Miscarriage

Miscarriage

PREVENTABLE?

Pregnancy Continues

Late Complications

THREATENED MISCARRIAGE

Therapeutic Strategies for Management of Threatened Miscarriage

Proposed treatment include:• Bed rest.• HCG injection.• Progestagen.

Bed Rest

• The hypothesis:Hard work and hard physical activity during pregnancy are associated with miscarriage, bed rest might reduce the risk.

(Lapple 1990).

• The fact:Most of the causes of miscarriage are not related to physical activity.

Aleman A, 2005

In Addition…

• Bed rest may increase the likelihood of thromboembolic events. (Kovacevich 2000)

• Muscle atrophy and symptoms of musculoskeletal and cardiovascular deconditioning. (Maloni1993; Maloni 2002)

• May be stressful and costly for women and their family. (Crowther 1995; Gupton 1997; Maloni 2001; May1994)

• May induce self blame feelings in case of failure to comply to the prescribed treatment of bed rest.

Role of hCG?

• Human chorionic gonadotrophin (hCG) is secreted by the syncytiotrophoblast.

• It promotes the corpus luteum to secrete progesterone and helps in maintaining the pregnancy.

Objective of Meta-analysis:To assess the effectiveness of hCG in the treatment of

threatened miscarriage compared to placebo, no treatment of any other intervention.

There was no statistically significant difference in the incidence of miscarriage between hCG and 'no hCG' (placebo or no treatment) groups. (Risk ratio (RR) 0.66; 95% CI 0.42 to 1.05)

Deevaselvan et al, Cochrane 2010

Role of Progestagens

• Progestational agents have been prescribed since 1950s to prevent miscarriages.

• The progestagens are one of the five major classes of steroid hormones which binds to progesterone receptor:

• 2 types of Progestagens:- Natural Progesterone.- Synthetic form/Progestin.

The main sites of progesterone biosynthesis are:• The ovaries and the adrenal cortices in non-pregnant.• The ovaries in early pregnancy followed by the placenta.

Pro – Gestagens = Pro - Pregnancy

Physiological role of Progestagens in maintaining pregnancy:• Enhances implantation by: Inhibiting endometrial proliferation. Promoting differential of the endometrium. Immunomodulatory Effecct:

Affect cytokines balance. Inhibit natural K cells activities at the fetomaternal interface. Promoting the synthesis of Progesterone Induced Blocking Factors

(PIBF) by lymphocytes, favouring production of pregnancy protecting antidodies.

• Prevent myometrial contactility.• Prevent cervical dilatation.

Progesterone & Modulation of Immune Response

Potential Link Between the Endocrine and Immune Systems

Progesterone stimulates the production of progesterone-induced blocking factor (PIBF) and induces via the cytokines a T-helper 2 response1,2

Progesterone

CD-8 + T cell

PIBF

Th2

1. Szekeres-Bartho J, Wegmann TG. J Reprod Immunol 1996; 31(1-2): 81-95.2. Szekeres-Bartho J. Int Rev Immunol 2002; 21(6): 471-495.

PIBF Link Between the Endocrine and Immune System

Progesterone

PIBF Th2Normally Progressing Pregnancy

Progesterone

PIBF Th1Miscarriage

Mifepristone

Progesterone

PIBF+anti-PIBF

Th1Miscarriage

Adapted from: Szekeres-Bartho J, et al. Int Immunopharmacol 2001; 1(6): 1037-1048.

Adapted from: Raghupathy R, et al. BJOG 2005; 112(8): 1096-1101.

Further substantiated by…..

• Leutectomy prior to 7 weeks causes miscarriage.

• Low progesterone levels have been linked to increase risk of first trimester miscarriage.

• Progesterone antagonist (mifepristone) has been successfully used in induction of abortion.

Studies on Progestagen in The Prevention of Threatened Miscarriage: The Challenges.

• Various type of progestagens have been utilised:• Oral progestagens: Dydrogesterone.

- Good safety and tolerability profile.- Structurally similar to natural progesterone.- Good oral bioavailabity.- No androgenic effects on the fetus.

• Vaginal progesterone – Micronized progesterone.

• Various dosages .• Various Methodology.• Small size of the studies.

Wahabi 2011

Progestagen vs Placebo or No Treatment in Threatened MiscarriageOutcome: Miscarriage

Wahabi, 2011.

The Author concluded:

• Progestagen treatment reduced the risk of miscarriage by 47%, CI 21% to 65%.

• In the subgroup:• Women treated with vaginal progesterone, the result was not

significant.• Women treated with dydrogesterone, the result was significant.

“ The result of the SR should be approached with caution due to poor methodological quality of some of the included trials and small number of participants”

A Systemic Review of Dydrogesterone for The Treatment of Threatened Miscarriage

Carp, Gynacological Endocrinology,2012.

There was statistically significant reduction in OR for miscarriage after treatment.11% absolute reduction in miscarriage rate.

The Fetus Survived Miscarriage, What Next?

Wahabi,2011

The Issues

• Who should we treat?• What’s the standard regime?• What are current expert bodies

recommendations?

Who Should We Treat?

• The likelihood of miscarriage after detection of fetal heartbeat is 9% with a range of 3.4% - 19.2%.

• Prospective data indicate that the presence of any of three risk factors (fetal bradycardia, discrepancy between gestational sac and crown to rump length, and discrepancy between menstrual and sonographic age by more than one week) increases the rate of abortion from 6% when none are present to 84% when all three are present.

• Single serum progesterone measurement of at least 25 ng/ml carries a 97% likelihood for viable intrauterine pregnancy. However progesterone secretion is pulsatile.

• Therefore, the diagnosis & treatment with progestagen is empirical.

What’s the Standard Regime?

El Zibdeh, 2009

Pandian,2009

Omar,2005

• Route; oral vs vaginal?

• The only progestagen extensive studied with respect to immunomodulation effect is dydrogesterone.

What’s the Standard Regime?

Current Opinion by Expert Body

• The guideline development group (GDG) agreed that the most important outcomes were;

The rate of term pregnancy Miscarriage and pregnancy rate

beyond 20 weeks of gestation.

• The group had hoped that there would be evidence regarding long-term outcomes of progesterone use, but none was reported in the included studies.

Current Recommendation by Authoritative Body

• Overall, the GDG felt that the evidence was insufficient to recommend the use of progesterone or dydrogesterone.

• This was partly because: There was no demonstrated significant difference in the rate of

term birth. but mainly because of concern about the lack of long-term safety

data.

• The group felt strongly that further, high quality studies investigating both the efficacy and safety of progesterone and progestogens were needed, and decided that this was a priority area for research.

Enter the PRISM trial

• The primary aim of the PRISM trial is: To test the hypothesis that in women presenting with vaginal bleeding in the first trimester,

progesterone (400 mg vaginal capsules, twice daily), started as soon as possible after a scan has demonstrated a visible intrauterine gestation sac, and continued to 16 completed weeks of gestation, compared with placebo, increases maternities with live births beyond 34 completed weeks by at least 5%.

Additional secondary aims are: To test the hypothesis that progesterone improves other pregnancy and neonatal

outcomes, including gestation at birth and survival at 28 days of neonatal life. To test the hypothesis that progesterone, compared with placebo, is not associated with

substantial adverse effects to the mother or the neonate, including chromosomal anomalies in the newborn.

To explore differential or subgroup effects of progesterone in prognostic subgroups, including age, fetal heart activity, gestation at presentation, amount of bleeding and body mass index.

To perform a cost-effectiveness analysis.

• Closing Jan 2016

RECURENT MISCARRIAGES & PROGESTERONE

Causes of Recurrent Miscarriages

• Antiphospholipids syndrome.• Uterine structural abnormality. • Parenteral chormosomal rearrangements.• Thrombophilia.• Infection.

• Unexplained: Immunological problems.

Treat accordingly

What do Expert Bodies say?

Enter the PROMISE trial• The PROMISE: PROgesterone in early MIScarriage Test the hypothesis that in women with unexplained recurrent miscarriages,

progesterone (400mg pessaries, twice daily), started as soon as possible after a positive pregnancy test (at < 6 weeks gestation) and continued to 12 weeks of gestation, compared to placebo, increases live births beyond 24 completed weeks of pregnancy by at least 10%.

• Secondary aims To test the hypothesis that progesterone improves various pregnancy and

neonatal outcomes. To test the hypothesis that progesterone, compared to placebo, does not

incur substantial adverse effects to the mother or the neonate. To explore differential or subgroup effects of progesterone in various

prognostic subgroups. To perform an economic evaluation for cost-effectiveness.

In the meanwhile…..Progestagen for Treatment of Threatened Miscarriage: To give or Not to Give?

• Patient will demand treatment which is risk free & decreases the chance of miscarriage.

• Counselling is essential:• Progestagen reduce the rate of miscarriage.• No increase in congenital abnormalities.• Lack of long term safety data.

• At the end of the day, the patient will make the informed choice.

• Watchout for PRISM and PROMISE.

Thank you……..