Mechanical Environment Pregnancy With Short Cervix

In pregnancy the mother carries the growing fetus throughout gestation as her body prepares
for delivery. This maternal preparation includes anatomical, physiological, and biochemical
changes of the uterus, cervix, and ligaments that surround and support the uterus and cervix.
For a successful term delivery, the uterus, cervix and supporting ligaments must remodel in a
coordinated fashion to allow for adequate dilation and effacement of the cervix and delivery
of the fetus.

Preterm birth (PTB) is the leading cause of neonatal death. Premature babies that survive
face a significantly increased risk of long-term disabilities, such as mental retardation,
learning and behavioral problems, cerebral palsy, seizures, respiratory problems,
gastrointestinal problems and vision/hearing loss. PTB is also significant cost factor in
healthcare. In 2003, a study in the US approximated neonatal costs to be $224,400 for a
newborn that weighed 500-700g (extreme-severe preterm range) verse $1,000 at over 3,000g.
These costs increase exponentially with decreasing gestational age and weight. In 2007, an
Institute of Medicine report entitled "Preterm Birth" found that the 550,000 preemies born
each year in the U.S. cost $26 billion annually, mostly related to prolonged care in neonatal
intensive care units. The pathophysiology of PTB is multi-factorial and the degree of
severity spans a wide range, with pregnancy outcomes depending on a combination of
congenital, anatomical, obstetric, epidemiological, and biochemical factors. Because of these
confounding factors PTB rates in the US and around the world are on the rise and diagnostic
methods to identify high-risk women for PTB remain elusive.

Premature cervical remodeling which leads to softening/shortening of the cervix (i.e., a
mechanical failure of the cervix) is one of the leading contributors to the birth of a
severely preterm neonate. The true frequency and impact is unknown because diagnosing this
condition remains elusive and the biomechanical environment of pregnancy is unknown. The
pathophysiology is hypothesized to be multi-factorial leading to a common feature of a
structurally weak and excessively soft cervix that is unable to remain closed and to support
the fetus. Recently, it has been demonstrated that these preterm cervical changes may in some
cause premature cervical shortening as measured by transvaginal ultrasound imaging. When this
occurs, treatment with progesterone suppositories has been demonstrated to reduce the risk of
preterm delivery. However, this treatment is not effective in many cases; probably because a
short cervix is a late manifestation of the underlying biostructural alterations in the
uterus, cervix and supporting ligaments.

Many clinically-relevant advances in the field of orthopedics and gynecology (i.e., assessing
the causes of uterine prolapse have been attributed to the accurate biomechanical modeling of
the anatomy and tissue properties using finite element analysis (FEA). FEA is a computer
simulation that computes tissue stretch (i.e., tissue strain), tissue stress, and reaction
forces when external mechanical forces are applied to the system given the tissue's geometric
shape and mechanical properties. Lastly, directly measuring the mechanical stiffness of the
uterine cervix through use of a simple aspiration device has shown that in normal pregnancy
cervical tissue softens starting in the 1st trimester and continues until dilation. These
studies have also shown that using a simple mechanical aspirator applied to the end of the
cervix protruding into the vaginal canal has zero adverse effects on the patient, where the
measurement can be performed during a standard speculum exam.

The cervical pessary has been proposed as an additional option for treatment in pregnancies
with a short cervix. It offers additional theoretical benefits over the cerclage, in that it
does not require surgical intervention. Its proposed mechanisms of action include a) angling
the cervix toward the posterior, bringing the external os toward the sacrum, b) mechanically
closing the cervix with the constraining geometry of the device, and c) preserving the mucous
plug. These mechanisms of action involve lowering the mechanical stresses on the area of the
internal os, potentially modifying the release of the enzymes and inflammatory markers
involved in the preterm birth pathway. However, it is still unknown if the pessary relieves
the mechanical load on the cervix because a biomechanical investigation of its function has
not been performed. Therefore, the investigator plans to study a group of women with a short
cervix randomized in an existing trial: AAAR1353 - A Randomized Trial of Pessary in Singleton
Pregnancies with a Short Cervix (TOPS) in order to better understand the function and effect
of the cervical pessary on the biomechanical support of the cervix in addition to its effect
on its tissue properties and structural integrity. If a specific maternal utero-cervical
phenotype can be located, where the placement of the cervical pessary reduces the mechanical
load on the cervical internal os and therefore leads to a decreased incidence of preterm
birth, then a more personalized treatment may be possible for patients who fall within this
specific phenotype in the future.

For the substudy, a total of 36 women will be recruited and randomized through the existing
TOPS trial (18 randomized to Pessary and Progesterone and 18 randomized to progesterone
only). Obstetric and gynecologic history, age, race, body mass index, smoking history, and
outcome of the current pregnancy will be recorded for all patients.

Inclusion Criteria:

- Singleton gestation.

- Twin gestation reduced to singleton either spontaneously or therapeutically, is
not eligible unless the reduction occurred before 13 weeks 6 days project
gestational age.

- Higher order multifetal gestations reduced to singletons are not eligible.

- Gestational age at randomization between 16 weeks 0 days and 23 weeks 6 days based on
clinical information and evaluation of the earliest ultrasound as described in
Gestational Age.

- Cervical length on transvaginal examination of less than or equal to 20 mm within 10
days prior to randomization by a study certified sonographer. There is no lower
cervical length threshold.

Exclusion Criteria:

- Women who are ineligible for the TOPS trial.