Progesterone therapy to prevent premature birth

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
• Epidemiology of preterm birth (PTB)
• Current management challenges with
preterm birth
– Predicting preterm birth
• Progesterone therapy- who, when, why and
• Future issues
Global burden of prematurity - 2005
• 12.9 million preterm
– Africa and Asia: 10.9M
– Europe: 0.5M
– North America: 0.5M
– Latin America and the
Caribbean: 0.9M
• Reflects global health
Proportion of global
preterm birth
Bulletin of the WHO, Beck et al 88 (1) 2010, 31-38
Europe Others
& North
Rising preterm rates
Obstetric precursors of preterm birth
Goldenberg Lancet 2008; 371: 75–84
Perinatal mortality/morbidity
• Largest cause of perinatal death in nonanomalous fetuses (>70%)
• developmental delay
• visual impairment
• chronic lung disease
• cerebral palsy
• <1500gm X10 more likely to be handicapped than
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 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 1st year medical costs 10 times greater
for preterm ($32,325) than term infants
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 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.”
The uterine cervix has to remodel for birth
Main challenge SPTB
Possible PTL
Cx <3cm
USS cervical
“Factor(s) X”
At risk prediction and 2ry prevention
• Ultrasound
• Fetal fibronectin
• Others
• Progesterone
• Cerclage
• Antimicrobials
High risk
Women with
symptoms of
labour, cervix
< 3cm
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 lossmifepristone.
• 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 preventionbackground
• 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
– limits apoptosis
• P receptor antagonist mifepristone impairs
– decidual function
– trophoblast proliferation/functioning
– accelerates cervical ripening by enhancing
17OH PC risk
The Kaplan-Meier curves from the study by Meis et al
demonstrating a crossover between groups suggesting a potential for 17hydroxyprogesterone 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).
• O’Brien Am J Perinatol 2012;29:665–672.
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
• 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
• Fetal growth rates may differ to differing
• 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 17OHPC (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 preterm
birth <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
• 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
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
• For how long?
• Until 34, 36 weeks
AN suspicion of cervical weakness
History of 2nd trimester miscarriage(s)
Very preterm deliveries
Previous failed cervical cerclage
Screen for infection/bacterial vaginosis at booking
Cervical length at 16-18wks
Normal cervical length/no funnelling
1-2 weekly FU
Normal cervical length at 24wks
Routine ANC
Cervical shortening and funnelling
? Cerclage, give progesterone
Previous preterm delivery
?1 preterm delivery <28 weeks
2 previous preterm deliveries
Screen for infection/bacterial vaginosis at booking ?progesterone
Cervical length at 22wks + fFN assessment
Normal cervical length/no funnelling
-ve fFN
Cervical shortening and funnelling/
+ve fFN , give progesterone
Normal cervical length at 24-26wks
Cerclage, continue progesterone
Routine ANC
Algorithm for use of
progestogens in
prevention of PTB –
Berghella 2012 AJOG
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
• 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

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