RCT of Vaginal Progesterone in Women With Threatened Preterm Labor (PROTO)

• Proportion of women who have preterm birth <35 weeks [ Time Frame: At birth ] [ Designated as safety issue: No ]
• Proportion of women who have a preterm birth at <37 weeks [ Time Frame: At birth ] [ Designated as safety issue: No ]
• Maternal hospital length of stay (days) [ Time Frame: Time of discharge from hospital ] [ Designated as safety issue: No ]
• Proportion of women who have hospital admission for premature labor [ Time Frame: After birth ] [ Designated as safety issue: No ]
• Maternal compliance with treatment [ Time Frame: At time of birth ] [ Designated as safety issue: No ]
  Diary self-report of treatment use
• Neonatal hospital length of stay (days) [ Time Frame: At time of discharge from hospital ] [ Designated as safety issue: No ]
• Neonatal morbidity [ Time Frame: Up to 28 days after birth ] [ Designated as safety issue: No ]
  Respiratory distress syndrome (type 1), intraventricular hemorrhage, chronic lung disease, periventricular leukomalacia,necrotising eneterocolitis, retinopathy of prematurity
• Number of days of assisted ventilation (neonate) [ Time Frame: Up to 28 days after birth ] [ Designated as safety issue: No ]
• Number of days of supplemental oxygen (for neonate) [ Time Frame: Up to 28 days after birth ] [ Designated as safety issue: No ]
• Birth weight (grams) [ Time Frame: At time of birth ] [ Designated as safety issue: No ]
• Neonatal survival to discharge home (yes/no) [ Time Frame: During 28 days after birth ] [ Designated as safety issue: No ]
• Adverse events (maternal or neonate) [ Time Frame: Up to 28 days after birth ] [ Designated as safety issue: Yes ]

Prematurity remains the most important single factor in perinatal morbidity and mortality. Unfortunately, the rate of premature delivery is increasing in Canada and is especially high in Alberta with 7.5% of pregnancies ending before 37 weeks gestation. Despite years of research into the causes of spontaneous preterm labor, few effective treatments have been identified. Progesterone is one candidate treatment. The purpose of this study is to investigate whether progesterone can prolong pregnancy in women who have symptoms of preterm labor.

Pregnant women who have symptoms of premature labor will be invited to take part in the study if they are between 22 to 24 weeks pregnant. If they agree to join the study, they will be randomly allocated to either take progesterone 200mg each day via the vagina until 36 weeks, or to take a placebo preparation. Neither the women nor their clinician will know which group they are in.

Women and their babies will be followed until 28 days after the birth, to find out about the length of the pregnancy, any adverse events that might occur (none have been reported in previous trials), and to look at whether women have taken the treatment.

When the study is complete, the results for the progesterone group will be compared to the placebo group. If progesterone is found to be useful in helping to prolong pregnancy, then this will be a possible treatment to help mothers in the future.

• Drug: Vaginal progesterone
  Capsules of 200mg micronised progesterone suspended in sunflower oil. One capsule inserted vaginally per day from time of randomisation to gestational age 35(+6)weeks or delivery (if sooner).
  Other Name: Utrogestan
• Drug: Placebo
  Capsules of placebo (sunflower oil). One capsule inserted vaginally per day from time of randomisation to gestational age 35(+6)weeks or delivery (if sooner).

• Experimental: Vaginal progesterone
  Intervention: Drug: Vaginal progesterone
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Women with symptomatic premature contractions successfully arrested for at least 12 hours with tocolytics.
• Women with symptoms suggestive of early preterm labor whose contractions resolve without tocolysis but are fetal fibronectin positive.
• Gestational age 23(+0)-32(+6) weeks.
• Consent to taking part in the study.

Exclusion Criteria:

• Placenta previa
• Preterm premature rupture of membranes at presentation
• Pre-existing hypertension will be excluded in order to reduce the likelihood of iatrogenic preterm delivery within the study women
• Known major fetal anomaly detected on ultrasound
• Multiple pregnancy
• Maternal seizure disorder
• Active or history of thromboembolic disease
• Maternal liver disease
• Known or suspected breast malignancy or pathology
• Known or suspected progesterone-dependent neoplasia
• Plans to move to another city during pregnancy
• Previous participation in a progesterone trial during this pregnancy
• Known sensitivity to progesterone