17OHP for Reduction of Neonatal Morbidity Due to Preterm Birth (PTB) in Twin and Triplet Pregnancies

Prematurity is a leading cause of neonatal morbidity and mortality in the USA. Nationally,
12% of all babies deliver before term and 3% deliver before 32 wks gestational age (GA).
Recent studies suggest that 17OHP and other progesterone derivatives may reduce the rate of
preterm birth among women with a history of prior preterm birth. However, it has not been
demonstrated that this reduction in preterm birth is accompanied by a clinically significant
reduction in neonatal complications. Further, most women who deliver preterm have no history
of a prior preterm birth. Little is known about whether progesterone treatment is effective
in women with other risk factors for preterm birth such as multiple gestation. The proposed
study will assess the role of 17OHP in women with twin or triplet pregnancies and will
assess the impact on neonatal health, not merely the impact on gestational age at delivery.
Prior studies were not designed to be large enough to have statistical power to assess
effects on neonatal morbidity.

In the 6 trials combined in the Goldstein meta-analysis, only 279 women were treated with
17OHP and only 73 women had a preterm delivery. The NICHD study presented by Meis
approximately doubles the world-wide experience, with 306 women under treatment, of whom 73
delivered prior to 35 wks. Yet, this study was not designed to have power to show a
reduction in neonatal complications but only a reduction in preterm birth rates.

The present study is the first to be specifically designed to have adequate power to test
whether 17OHP reduces neonatal morbidity among women with one of two specific risk factors
for preterm birth.

Inclusion Criteria:

1. Gestational age (GA) 15-23w0d gestational age at the time of recruitment

2. GA 16w0dk to 23w6d at the time of randomization and initiation of injections

3. Maternal age 18 years or older

4. One of these risk factors for spontaneous preterm birth:

1. Twins in current pregnancy, dichorionic placentation

2. Triplets in current pregnancy, trichorionic placentation

5. Intact membranes

6. Patient has had at least one detailed 2nd-trimester ultrasound examination
documenting placentation, chorionicity, fetal number, fetal size, amniotic fluid
volumes, and fetal anatomy. (This examination must comply with minimum standards such
as those published by the American Institute of Ultrasound in Medicine, American
College of Radiology, or American College of Obstetricians & Gynecologists It is NOT
mandatory that this examination be performed at the research-study center.)

7. Investigator believes patient will be reliable with follow-up visits and believes
that delivery data and neonatal data are likely to be available.

Exclusion Criteria:

1. Symptomatic uterine contractions in current pregnancy

2. Contraindication to interventions intended to prolong the pregnancy (including lethal
fetal anomalies, amnionitis, preeclampsia, severe oligohydramnios, severe growth
delay, fetal death appears imminent or inevitable)

3. Risk factors for major neonatal morbidity unrelated to preterm delivery (such as
monochorionic placentation in multiple gestation, major malformations, certain
medication exposures)

4. Preexisting maternal medical condition that might be worsened by progesterone
therapy, including: asthma requiring medications, renal insufficiency, seizure
disorder, ischemic heart disease, active cholecystitis, impaired liver function,
history of thromboembolic disorder, history of breast cancer, history of major
depression requiring hospitalization.

5. Preexisting maternal medical condition associated with a high risk of preterm
delivery including: refractory hypertension, diabetes with nephropathy or
retinopathy, renal insufficiency, active systemic lupus erythematosus. Note that a
history of prior preterm birth is NOT an exclusion.

6. Use of progesterone or progesterone-derivative medication after 15 weeks gestation in
current pregnancy.

7. Allergy to 17OHP or oil vehicle.

8. Placement of emergent cerclage (defined as one placed after the occurrence of
cervical change such as dilation, funneling, or effacement) with this pregnancy.
Prophylactic cerclage is NOT an exclusion (defined as one placed before any cervical
change, for example, because of a history of cervical incompetence, or because of a
prior cervical procedure such as LEEP or cone biopsy).