Preterm birth is a global problem, with a prevalence of 8 to
12% depending on location.
Several large trials and systematic reviews have shown
progestogens to be effective in preventing or delaying preterm birth in
selected high risk women with a singleton pregnancy (including those with a
short cervix or previous preterm birth).
However, the OPPTIMUM study results presented recently at the Society for
Maternal and Fetal Medicine (SMFM)
36th
Annual pregnancy meeting at Atlanta
Georgia in
February, 2016 have shown that vaginal progesterone confers no obstetrical or
neonatal benefit, and no long-term benefit with respect to cognitive and
neurosensory outcomes in children when used to prevent preterm birth.
The findings from OPPTIMUM – the largest trial to date looking at
progesterone for the prevention of preterm birth – have important implications for
current practice. Vaginal progesterone is not currently approved for the
prevention of preterm birth in the United States, but is commonly used
off label for this purpose.
The OPPTIMUM study is a randomized double blind placebo
controlled trial recruited over 1,228 women around UK to test
whether giving natural progesterone daily from 22 to 34 weeks of gestation is a
cost-effective way to reduce the likelihood of preterm birth. It also aims to look whether compared to
placebo, vaginal progesterone:
- improve obstetric outcome by
lengthening pregnancy and thus reducing the incidence of preterm delivery
(before 34 weeks gestation)?
- improve neonatal outcome by
reducing a composite of death and major morbidity?
- lead to improved childhood
cognitive and neurosensory outcomes at two years?
- represent cost effective
management for women at high risk of preterm delivery?
Dr.
Jane Norman, MD, from the University
of Edinburgh in the United Kingdom said “We saw no
significant effect of vaginal progesterone on obstetrical, neonatal, or
childhood outcomes, this was true even for women with a cervix of 25 mm or
less, and "we found no evidence of benefit in any identifiable
subgroups."
A
Cochrane meta-analysis
in 2013 assessed
the role of both the vaginal and intramuscular form of progesterone in
preventing PTB (
Cochrane Database Syst Rev.
2013;7:CD004947).
Progesterone was shown to prevent preterm births, reduce perinatal mortality,
reduce the incidence of birthweight below 2500 g, and reduce neonatal
deaths. In women with a short cervix, progesterone was shown to reduce preterm
births, but did not affect the other parameters.
But
there has been little information about the long-term risk this may have on
children Dr Norman explained. "We felt we needed to look at the long-term
effects. We cannot assume that things with short-term benefit will not have
long-term harm," she added.
The
study recruited 1228 women with singleton pregnancies at risk for preterm birth
because of a positive fetal fibronectin test, a history of spontaneous preterm
birth at 34 weeks of gestation or earlier, or a cervical length 25 mm or
less.
About
618 women were randomized to receive 200 mg of natural vaginal progesterone
starting at 22-24 weeks and continuing to 34 weeks, compared with 600 women who
received placebo.
The
primary obstetric outcome was delivery <34 weeks of gestation, the primary
neonatal outcome is a composite of death or two markers of neonatal morbidity (brain
injury or bronchopulmonary dysplasia); and the primary childhood outcome is
developmental status at two years. A formal economic evaluation was also a key
part of the study.
It
was seen that progesterone had no significant effect on either the obstetric or
childhood outcomes. It also had no significant effect on any components of the
primary outcome, including fetal death or live-born delivery before 34 weeks.
“A
secondary analysis looking at the individual components of the composite
neonatal outcomes showed that progesterone reduced the risk of brain injury and
neonatal death, but not bronchopulmonary dysplasia.” Dr. Norman said.
“We
were really surprised that we didn’t show that progesterone prevented preterm
birth, and we became concerned that perhaps our cutoff of 34 weeks was just the
wrong time to choose a cutoff,” Dr. Norman said, noting that a post hoc
survival curve analysis was performed to look at the trajectory to delivery,
and a “very marginal benefit” was seen with progesterone, but the difference
was not statistically significant.
On
subgroup analysis it was seen that in women with a short cervix, no evidence
was seen that progesterone was more or less effective than in women with a
longer cervix. Other subgroups studied included fibronectin-positive and
fibronectin-negative women and women with a history of preterm birth.
Progesterone was no more or less effective in any of these subgroups.
“OPPTIMUM
is the largest trial of progesterone to prevent preterm birth, and after
adjusting for multiple comparisons as we planned, we did not disprove the null
hypothesis that progesterone doesn’t prevent preterm birth, it doesn’t reduce
adverse neonatal outcomes, and it doesn’t have a beneficial effect on childhood
outcomes,” Dr. Norman said, concluding that “there is a remaining unmet need
for a safe and effective agent to prevent preterm birth.”
Further
it was commented at the Society for
Maternal and Fetal Medicine (SMFM) conference by Mary D'Alton, MD, the
William C. Rappleye Professor of Obstetrics and Gynecology at the Columbia
University Medical Center in New York Citythat that the results should not be
extrapolated to 17-hydroxyprogesterone, which was not part of this analysis.
This
certainly gives pause around vaginal progesterone," said Mary D'Alton, MD,
the William C. Rappleye Professor of Obstetrics and Gynecology at the Columbia University
Medical Center
in New York City.
But she said she would not advise a change in practice before seeing the final
published results.
The
US Food and Drug Administration has not approved vaginal progesterone for the
prevention of preterm birth in women with a short cervix.
