A Randomized Trial of Pessary in Singleton Pregnancies With a Short Cervix

While cervical length is one of the most powerful predictors of subsequent preterm birth, the
best treatment to reduce subsequent preterm birth remains unknown. This study is a randomized
trial of women who have a singleton pregnancy and a short cervical length on transvaginal
ultrasound as determined by a study-certified sonographer. It is being conducted at 12
clinical centers across the country and the recruitment target is enrollment of 850 pregnant
women. Participants will be randomized to 1) Arabin pessary or 2) usual care as per by local
hospital protocol. Pessary is a promising low-cost, non-surgical intervention that appears to
be well-tolerated. The pessary will be placed by obstetric providers trained in appropriate
placement of the Arabin pessary. The primary outcome of the study is delivery or fetal death
prior to 37 weeks 0 days gestational age.

In the literature, there are two large trials that have produced conflicting results (M Goya
et al, 2012, K Nicolaides et al, 2016). Thus, the results of an adequately powered and
appropriately conducted trial from the United States will be important in determining whether
pessary is a useful intervention for the prevention of subsequent preterm birth in women with
singleton gestation.

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.

- 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:

- Cervical dilation (internal os) 3 cm or greater on digital examination or evidence of
prolapsed membranes beyond the external cervical os either at the time of the
qualifying cervical ultrasound examination or at a cervical exam immediately before
randomization.

- Fetal anomaly or imminent fetal demise. This includes lethal anomalies, or anomalies
that may lead to early delivery or increased risk of neonatal death e.g.,
gastroschisis, spina bifida, serious karyotypic abnormalities. An ultrasound
examination from 14 weeks 0 days to 23 weeks 6 days by project Estimated Date of
Confinement (EDC) must be performed prior to randomization to evaluate the fetus for
anomalies.

- Previous spontaneous preterm birth between 16 weeks 0 days and 36 weeks 6 days. This
includes induction for pPROM in a prior pregnancy.

- Planned treatment with intramuscular 17-α hydroxy-progesterone caproate.

- Placenta previa, because of risk of bleeding and high potential for indicated preterm
birth. A low lying placenta is acceptable.

- Active vaginal bleeding greater than spotting at the time of randomization, because of
potential exacerbation due to pessary placement.

- Symptomatic, untreated vaginal or cervical infection because of potential exacerbation
due to pessary placement. Patients may be treated and if subsequently asymptomatic,
randomized. However, if it is more than 10 days since the cervical length measurement,
a new cervical length measurement must be obtained.

- Active, unhealed herpetic lesion on labia minora, vagina, or cervix due to the
potential for significant patient discomfort or increasing genital tract viral spread.
Once lesion(s) heal and the patient is asymptomatic, she may be randomized. History of
herpes is not an exclusion.

- Rupture of membranes due to likelihood of pregnancy loss and preterm delivery as well
as the risk of ascending infection which could be increased with pessary placement.

- More than six contractions per hour reported or documented prior to randomization. It
is not necessary to place the patient on a tocodynamometer.

- Known major Mullerian anomaly of the uterus (specifically bicornuate, unicornuate, or
uterine septum not resected) due to increased risk of preterm delivery which is
unlikely to be affected by progesterone.

- Any fetal/maternal condition which would require invasive in-utero assessment or
treatment, for example significant red cell antigen sensitization or neonatal
alloimmune thrombocytopenia.

- Major maternal medical illness associated with increased risk for adverse pregnancy
outcome or indicated preterm birth (treated hypertension requiring more than one
agent, treatment for diabetes prior to pregnancy, chronic renal insufficiency defined
by creatinine >1.4 mg/dL, carcinoma of the breast, conditions treated with chronic
oral glucocorticoid therapy). Lupus, uncontrolled thyroid disease, and New York Heart
Association(NYHA) stage II or greater cardiac disease are also excluded. Patients with
seizure disorders, HIV, and other medical conditions not specifically associated with
an increased risk of indicated preterm birth are not excluded. Prior cervical
cone/LOOP/Loop Electrocautery Excision Procedure (LEEP) is not an exclusion criterion.

- Planned cerclage or cerclage already in place since it would preclude placement of a
pessary.

- Planned indicated delivery prior to 37 weeks.

- Allergy to silicone.

- Participation in another interventional study that influences gestational age at
delivery or neonatal morbidity or mortality.

- Participation in this trial in a previous pregnancy. Patients who were screened in a
previous pregnancy, but not randomized, may be included.

- Prenatal care or delivery planned elsewhere unless the study visits can be made as
scheduled and complete outcome information can be obtained.