Progesterone therapy to prevent premature birth: who, when,

Progesterone therapy to prevent premature birth: who, when, - Description

Professor Dilly OC Anumba. Chair in Obstetrics and Gynaecology. Consultant in Obstetrics and Fetomaternal Medicine. The University of Sheffield Medical School. Sheffield UK. Outline. Epidemiology of preterm birth (PTB). ID: 536159 Download Presentation

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Progesterone therapy to prevent premature birth: who, when,

Professor Dilly OC Anumba. Chair in Obstetrics and Gynaecology. Consultant in Obstetrics and Fetomaternal Medicine. The University of Sheffield Medical School. Sheffield UK. Outline. Epidemiology of preterm birth (PTB).

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Progesterone therapy to prevent premature birth: who, when,




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Presentation on theme: "Progesterone therapy to prevent premature birth: who, when,"— Presentation transcript:

Slide1

Progesterone therapy to prevent premature birth: who, when, why and how? 

Professor Dilly OC Anumba

Chair in Obstetrics and Gynaecology

Consultant in Obstetrics and Fetomaternal Medicine

The University of Sheffield Medical School

Sheffield UK

Slide2

Outline

Epidemiology of preterm birth (PTB)

Current management challenges with preterm birth

Predicting preterm birth

Progesterone therapy- who, when, why and how?

Future issues

Slide3

Global burden of prematurity - 2005

12.9 million preterm birthsAfrica and Asia: 10.9M (85%)Europe: 0.5MNorth America: 0.5MLatin America and the Caribbean: 0.9MReflects global health disparities

Bulletin of the

WHO, Beck et al

88 (1)

2010, 31-38

Slide4

Slide5

Rising preterm rates

Slide6

Obstetric

precursors of preterm birth

Goldenberg Lancet 2008; 371: 75–84

indications

Slide7

PrematurityPerinatal mortality/morbidity

Largest cause of perinatal death in non-anomalous fetuses (>70%)developmental delayvisual impairmentchronic lung diseasecerebral palsy<1500gm X10 more likely to be handicapped than >2500gm

Slide8

Trent Neonatal survey, Overall Disability at 30 Months for 314 Children Born at 22 -25 weeks

Wood et al. NEJM 343 378

.

Slide9

Cost of Preterm Birth

2005 PTB costs to US

$

26.2 billion, or $51,600 for every

infant

Medical care:

$16.9 billion (

65%).

Maternal delivery: $1.9

billion (

7%)

Early intervention services: $611

million (

2%)

special education services

$

1.1. billion (4

%) for

Lost

household and

labour

market

productivity $5.7

billion (

22%)

Average 1

st

year medical costs

10 times greater for preterm

($

32,325) than

term

infants ($3,325).

Source: Preterm

Birth: Causes, Consequences and Prevention, Institute of Medicine (2006)

Slide10

Key management challenges

Diagnosis - of aetiological subtype

Screening/prediction – general vs. selected high risk groups

Prevention

Primary – population focussed programmes

Secondary – care for those at high risk

Tertiary –

tocolytics

and neonatal management for threatened and actual preterm birth

Slide11

The accuracy of most of the tests purported

to be of value in prediction of spontaneous

preterm birth was disappointing. Likelihood

ratios as a measure of the tests’ ability to

predict all mothers who will develop preterm

birth spontaneously were particularly poor

.”

Slide12

Slide13

The uterine cervix has to remodel for birth

Slide14

Main challenge SPTBPrediction

Possible PTLCx <3cm

USS cervical length

Fetal fibronectin

“Factor(s) X”

Slide15

At risk prediction and 2

ry

prevention

Slide16

Progesterone in preterm birth prevention - background

Progesterone

receptor-modulation during pregnancyInitial evidence derived in early pregnancy from luteal phase support and IVF. Receptor enhanced to sustain pregnancyReceptor down-regulated to modulate pregnancy loss- mifepristone. In 2nd and 3rd trimesters, phase III trials demonstrate P supplementation prolongs gestationwomen with premature cervical shorteninghistory of idiopathic spontaneous PTB (Meis 2003 NEJM)

Slide17

Progesterone in preterm birth prevention- background

Progestins

reduce the rate of progressive cervical shorteningExposure to natural P reduces uterine contraction frequency.In contrast ex vivo clinical 17-OHPC associated with no change or increase in contraction frequency negating tocolysis as a potential mechanism for efficacy in PTB Increased fetal CNS blood flow after treatment with supplemental P - ? fetal or neonatal neuroprotection similar to early studies in adults.These differing pharmacodynamic observations suggest P agents must be assessed independently for safety.

Slide18

P effects in cervix and decidua

Progestins

alter

collagen

synthesis

limits

collagenolysis

alters

production of cytokines,

nitric oxide

, and

prostaglandins

limits apoptosis

P receptor antagonist

mifepristone impairs

decidual

function

trophoblast proliferation/functioning

accelerates cervical ripening

by enhancing

collagenolysis

Slide19

Slide20

17OH PC risk

O’Brien Am J Perinatol 2012;29:665–672.

The Kaplan-Meier curves from the study by Meis et aldemonstrating a crossover between groups suggesting a potential for 17-hydroxyprogesterone caproate (17-OHP) to act differently in different subpopulations including the potential the drug has both antagonistic (left side of the curves from 27 weeks) and agonist activity (right side of the curves).

Slide21

Progesterone receptor antagonism-miscarriage/previable pregnancy

Conflicting data for 17-OHPC

rhesus monkeys showed 100

% fetal loss rate with

exposure, not found in other

primate

species studies

Supports thesis of differences

in

response based

on

P receptor

genotype.

FDA concern about pregnancy loss from review of data

for 17-OHPC

for PTB prevention.

5 losses

prior

to viability in treatment

group in

Meis

et al

2003

vs

none

in women given

placebo, but non-significant difference.59

Slide22

Risks of 17-OHPC -miscarriage

Meiss

et al: 5 losses treated group

vs

0 controls, crossover in Kaplan Meier, unlike

Caritis

et al no difference

Coombs et al: triplets – 13 losses treated vs. 0 in placebo,

crossover in Kaplan

Meier

3 large RCTs showed no difference

Rouse et al

Coombs et al

Lim et al

Norman et al STOPPIT trial, non-significant increase in loss with natural P.

Slide23

P Receptor Antagonism Risk:Early Preterm Birth

?

Paradoxic

increase in PTB risk

Twin

trial

- reduction

in

pregnancy duration with

17-OHPC treatment

by survival analysis (

p

= 0.02)

Combs AJOG

2011;204:221, e1–e8

PTB reduced in most

phase III singleton trials

of natural

or synthetic

hormone.

Largest

trial

to date of 17-OHPC (n=657) with

a

short

cervix

– no increased

risk

of PTB.

Grobman

AJOG

2012;206(S1):S367

Slide24

Progesterone Receptor Antagonism Risk: Altered Fetal Growth

May alter fetal growth by impairing placentation

Fetal

growth

rates may differ to

differing

progestins

Most RCTs – no effect on fetal growth

Further study required

Slide25

Excess P Receptor Agonism: Altered Metabolism and Immune Response

Increased risk of gestational diabetes with

systemic 17-OHPC

(

Rebarber

Diabetes

Care 2007;30:2277–2280; Waters

Obstet

Gynecol

2009;114:45–49)

,

data conflicting

(

Gyamfi

Am J

Obstet

Gynecol

2009;201:392,

e1–e5)

Alteration of immune response

Anti-inflammatory

activity

vs

impaired

immunocompetency

Mice – higher rate of maternal death.

Symptomatic women/PPROM treated with

high-dose

progestins

- any risks.

Small trials no adverse

maternal or fetal

effects

Effect on fetal immune status unknown

Slide26

Dose and safety issues

Supplemental

natural hormone

PV or PR progesterone 90 or 200mg daily: likely within physiologic range, better safety profile than synthetic

progestins

.

IM 17-OHPC 250 mg weekly empiric

Safety

of

P may

vary

with pathophysiology/ time

of

treatment - further studies needed

eg

suspected infection

Slide27

Effect of vaginal progesterone on pretermbirth <33 weeks of gestation

Slide28

Twins and PTB prediction and treatment

Slide29

Effect of vaginal progesterone on preterm birth and perinatal outcomes in singleton and twin gestations

Slide30

Indications for progesterone for preterm birth prevention

Previous history of

recurrent

preterm birth – one or two?

Perhaps two but also for one if cervix shortening demonstrated serially

Unexplained mid-trimester miscarriage

Proven cervical shortening mid-trimester scan

< 25mm, ? 15mm, ?20mm

Combined with cerclage or as substitute?

When in doubt scan serially and demonstrate shortening

Slide31

Slide32

Timing of progesterone?

Unclear

Most trials from mid-trimester- 18 to 20

wks

Could pure progesterone be started earlier in first trimester since it has no antagonistic effects?

For how long?

Until 34, 36 weeks

Slide33

AN suspicion of cervical weakness

History of 2nd trimester miscarriage(s)Very preterm deliveriesPrevious failed cervical cerclage

Screen for infection/bacterial vaginosis at booking

Cervical length at 16-18wks

Normal cervical length/no funnelling1-2 weekly FU

Routine ANC

Cervical shortening and funnelling

? Cerclage, give progesterone

Follow-up

Normal cervical length at 24wks

Slide34

Previous preterm delivery

?1 preterm delivery <28 weeks2 previous preterm deliveries

Screen for infection/bacterial vaginosis at booking ?progesterone

Cervical length at 22wks + fFN assessment

Normal cervical length/no funnelling-ve fFN

Routine ANC

Cervical shortening and funnelling/+ve fFN , give progesterone

Cerclage, continue progesterone

Follow-up

Normal cervical length at 24-26wks

Slide35

Algorithm for use of progestogens in prevention of PTB – Berghella 2012 AJOG

Slide36

Summary/ Conclusion

RCTs indicate that:

Women

with singleton gestations,

no prior PTB

, and short

CL <20mm at 24 weeks - vaginal progesterone

,

90-mg

gel or 200-mg suppository,

associated

with reduction in PTB

and perinatal morbidity/mortality (Fonseca 2007).

Universal CL screening

of singleton gestations without prior PTB for the prevention of PTB

controversial. Some evidence of cost benefit potential

Singleton, prior

PTB 20-36

wks

- 17OHPC 250

mg

IM

wkly

,

from 16-20 until

36

wks

,

reasonable option

OR

vaginal P for the same pregnancy duration

Slide37

Summary/ Conclusion

In these women,

if

TV US CL

shortens

<25mm at 24

weeks, cervical cerclage may be offered.

Progestogens

not associated with prevention

of PTB in

women,

with or without a short

CL:

Multiple gestation

Preterm labour

Preterm

premature rupture of membranes.

Slide38

Future direction

Best formulation of P

Best dose

Best time to start

Best time to stop

Side effects and contraindications

Replace or supplement cerclage?

In preterm premature rupture of membranes

In recurrent mid-trimester miscarriage

Following LETTZ, congenital uterine malformations

Slide39