Progesterone Supplementation to

Reduce Preterm Birth Recurrence

Ana Tobiasz, MD
November 18, 2016
• No financial disclosures
 Objectives
• Explain how progesterone supplementation has
been demonstrated to reduce the recurrence of
preterm birth in certain women.
• Describe the women whose birth outcomes are
most likely to be improved by progesterone
supplementation.
• Suggest strategies for obtaining access to
progesterone supplementation for women whose
birth outcomes are likely to be improved by this
medication.
 Scope of the problem
• 11% of births in the United States occur prior
to 37 weeks gestation (Schoen, et al., 2015).
– 70% are considered spontaneous preterm birth
(i.e. not medically indicated)
• Preterm birth rate increased more than 20%
from 1990‐2006
• Predominant cause of perinatal mortality in
the US
• Increased risks throughout childhood
 Risk factors
• Strongest risk factors is a history of a prior
preterm birth (1.5‐2 fold increased risk)
– Number of prior preterm births
– Gestational age at the prior delivery
• Short cervical length (less than 25 mm before
24 weeks)
• Smoking
• Maternal chronic illness
• Vaginal bleeding
• Urinary tract infections
• Genital tract infections
• Periodontal disease

– Treatment for any of these has not demonstrated

a decreased risk, however
• Low pre‐pregnancy weight (BMI <20)
• Substance abuse
• Short interpregnancy interval (less than 18‐23
months)
• Preterm labor is treated as if it were a single
condition
• The reality is that there are multiple pathologic
processes

Romero, Science, 2014.

 Current tools
• Modifiable risk factors
• Progesterone supplementation
• Cerclage
 Progestogens
• Encompassing term for natural progesterone,
pharmacologic agents that are identical to
endogenous progesterone, and synthetic
progestins that are similar
• Oral, vaginal, or injection forms
• Role in uterine quiescence reported in 1950’s
• Mechanism of action is not exactly known
– Anti‐inflammatory effects
– Local increase in progesterone counteracting a
functional decrease in progesterone that may lead to
preterm birth
43 women with mostly singleton gestation
History of prior preterm birth or >1 spontaneous abortion
17‐OHPC started at the initiation of prenatal care
Significant reduction in preterm birth and perinatology mortality
Randomized trial
Singleton gestation and prior spontaneous preterm birth at 20‐36 6/7 weeks
17P 250 mg IM weekly starting at 16‐20 6/7 weeks

NEJM, 2003.
• 2011: FDA approves Makena
(hydroxyprogesterone caproate) injection for
the prevention of preterm birth in women
with a history of one or more prior
spontaneous preterm births
• Randomized controlled trial
• 55 obstetric clinical in the Netherlands
• Women with multiple gestations randomized
• 250mg 17OHP or placebo
• 16‐20 weeks gestation through 36 weeks
• Primary outcome: adverse neonatal outcome
• Secondary outcome: Gestational age at delivery and delivery
before 28, 32, and 37 weeks

Lim, et al. Ob & Gyn, 2011

• 671 women
• No difference in the primary outcome
• No difference in gestational age at delivery
– 35.4 in treatment group, 35.7 in placebo group
• Conclusion: 17‐OHP does not prevent
neonatal morbidity or preterm birth in
multiple pregnancies
• Retrospective secondary analysis
• Singleton gestation, history of at least 1 prior PTB, 16‐
26.9 weeks gestation
• Two groups according to timing of treatment initiation:
16‐20.9 weeks and 21‐26.9 weeks
• Primary outcome was incidence of recurrent preterm
birth
• Secondary analysis of a randomized controlled trial
• Women with ≥1 prior SPTB <37 weeks
• Daily omega‐3 supplementation or placebo
• All women received 17‐OHP
• Women classified as a responder vs nonresponder
• Difference in delivery gestational age
• Responders=pregnancy extending ≥3 weeks later compared to
earliest prior PTB
AJOG, 2016.
Vaginal progesterone
• Randomized controlled trial
• Women presenting for routine anatomic survey at 20‐25 weeks
gestation
• Option of transvaginal ultrasound cervical length measurement
• Women with cervical length ≤15 mm randomized
• Primary outcome: spontaneous delivery before 34 weeks
• Treatment with vaginal micronized
progesterone (200 mg daily) vs placebo
• Associated with a 44% decrease in
spontaneous preterm birth at <34 weeks with
cervical length of 15 mm or less at 20‐25
weeks and no prior preterm birth

Fonseca, 2007, NEJM

• Randomized controlled trial
• Women between 19 and 23 6/7 weeks
• Transvaginal cervical length between 10 and 20 mm
• Singleton gestation
• Asymptomatic
• Randomized to vaginal progesterone or placebo starting at 20 to
23 6/7 weeks
• Primary outcome: preterm birth prior to 33 weeks
• Vaginal progesterone gel (90 mg daily)
• 45% decrease in spontaneous preterm birth at
less than 33 weeks with a cervical length of
10‐20.9 mm at 19‐24 weeks
• Meta‐analysis of RCTs comparing vaginal progesterone
to placebo or not treatment
• Women with a singleton gestation
• Mid‐trimester cervical length ≤25 mm
• Primary outcome: preterm birth ≤34 weeks or fetal
death
• 5 trials including 974 women
• Significant reduction in risk of preterm birth
<34 weeks with the use of vaginal
progesterone in women with a cervical length
<25 mm
– 90‐100 mg/day and 200 mg/day
 SMFM and ACOG recommendations
• Vaginal progesterone recommended as an
option to reduce risk of preterm birth
– Asymptomatic women
– Singleton gestation
– No prior preterm birth
– Incidentally identified short cervical length <20
mm before 24 weeks gestation
 Summary
• History of prior spontaneous preterm birth
– Offer 17‐OHP starting at 16‐24 weeks

• No history of prior spontaneous preterm birth

– Offer vaginal progesterone if cervical length < 20
mm before 24 weeks gestation
 Objective
• Suggest strategies for obtaining access to
progesterone supplementation for women
whose birth outcomes are likely to be
improved by this medication.
• Identifying patients that qualify
• Referring for treatment
• Access to medications
• Improving insurance coverage
– Vaginal progesterone not covered by Tenncare
– 17‐OHP not covered by Arkansas Medicaid
 Thank you
• Questions?