Progesterone therapy to prevent premature birth: who, when, why

and how?

Professor Dilly OC AnumbaChair in Obstetrics and Gynaecology

Consultant in Obstetrics and Fetomaternal MedicineThe University of Sheffield Medical School

Sheffield UK

Outline• Epidemiology of preterm birth (PTB)• Current management challenges with

preterm birth– Predicting preterm birth

• Progesterone therapy- who, when, why and how?

• Future issues

Global burden of prematurity - 2005• 12.9 million preterm

births– Africa and Asia: 10.9M

(85%)– Europe: 0.5M– North America: 0.5M– Latin America and the

Caribbean: 0.9M• Reflects global health

disparities

Africa

Asia

Europe & North Americ

a

Others0%

10%20%30%40%50%60%

Proportion of global preterm birth

Bulletin of the WHO, Beck et al 88 (1) 2010, 31-38

Rising preterm rates

Obstetric precursors of preterm birth Goldenberg Lancet 2008; 371: 75–84

indications

PrematurityPerinatal mortality/morbidity

• Largest cause of perinatal death in non-anomalous fetuses (>70%)

• developmental delay• visual impairment• chronic lung disease• cerebral palsy• <1500gm X10 more likely to be handicapped than

>2500gm

Trent Neonatal survey, Overall Disability at 30 Months for 314 Children Born at 22 -25 weeks Wood et al. NEJM 343 378.

Cost of Preterm Birth2005 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 1st 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)

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

The accuracy of most of the tests purportedto be of value in prediction of spontaneouspreterm birth was disappointing. Likelihoodratios as a measure of the tests’ ability topredict all mothers who will develop pretermbirth spontaneously were particularly poor.”

The uterine cervix has to remodel for birth

Main challenge SPTBPrediction

Possible PTLCx <3cm

USS cervical length

Fetal fibronectin“Factor(s)

X”

Prediction

• Ultrasound cervix

• Fetal fibronectin• Others

Prevention

• Progesterone• Cerclage• Antimicrobials

High risk asymptomatic women

Women with symptoms of preterm labour, cervix < 3cm

At risk prediction and 2ry prevention

Progesterone in preterm birth prevention - background

Progesterone receptor-modulation during pregnancy• Initial evidence derived in early pregnancy from luteal phase

support and IVF. • Receptor enhanced to sustain pregnancy• Receptor down-regulated to modulate pregnancy loss-

mifepristone. • In 2nd and 3rd trimesters, phase III trials demonstrate P

supplementation prolongs gestation– women with premature cervical shortening– history of idiopathic spontaneous PTB (Meis 2003 NEJM)

Progesterone in preterm birth prevention- background

• Progestins reduce the rate of progressive cervical shortening• Exposure 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.

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

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).

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

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.

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

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

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

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

Effect of vaginal progesterone on pretermbirth <33 weeks of gestation

Twins and PTB prediction and treatment

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

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

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

AN suspicion of cervical weaknessHistory 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

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

Algorithm for use of progestogens in

prevention of PTB – Berghella 2012 AJOG

Summary/ ConclusionRCTs 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

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.

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