Miscarriage

Treating Threatened Miscarriage – What does the evidence say?

WHAT IS MISCARRIAGE?

• 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.

So why does it matter?

WHY DOES IT MATTER?

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. After a miscarriage 30%–50% of women experience anxiety symptoms and 10%–15%

experience depressive symptoms, , which commonly persist up to 4 months (3).

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

• Mortality

• Socio-economic effect.

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 in Preventing Miscarriage?

• 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 and no treatment of any other intervention.Size ofstudy

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 Effect:

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 antibodies.

• Prevent myometrial contactility.• Prevent cervical dilatation.

A fetus is a semi-allograft

Immunology Revisited

Figure 2 CD4+T cells can differentiate into type 1 (Th1) or type 2 (Th2) helper cells.

J C Warning et al. Reproduction 2011;141:715-724© 2011 Society for Reproduction and Fertility

Favourable for Pregnacy

PIBF and the Th1-Th2 balance

• Progesterone- induced blocking factor (PIBF) is an immunomodulatory molecule secreted by lymphocytes.

PIBF

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.

• Micronized Progesterone

• Vaginal progesterone – Micronized progesterone.• IM Progestagen-

• Hydorxyprogesteron caproate.• 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

What Do We Know So Far?

• Dydrogesterone significantly reduce risk of miscarriage.

• Progesterone and dydrogesterone are safe in pregnancy.

• Small studies.

The Issues

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

recommendations?• Should we treat?

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 indicates that the presence of any of these 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

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.

• Still recruiting.

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.

Result of PROMISE trial

Result of PROMISE trial

• N=826

Series10

102030405060708090

100Rate of live birth

PlaceboProgesterone

• Rate difference, 2.5 percentage points; 95% CI, −4.0 to 9.0

• There were no significant between-group differences in the rate of adverse events

Is there light at the end of the tunnel?

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:• Progesterone/Dydrogesterone 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.

• Geller PA, Kerns D, Klier CM. Anxiety following miscarriage and the subsequent pregnancy: A review of the literature and future directions. Journal of Psychosomatic Research 2004;56: 35–45.

Thank you……..