Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial

The rate of preterm birth has steadily increased in the United States over the past 10 years.
This increase is driven in part by the rising rate of late preterm birth, defined as those
births occurring between 34 and 36 weeks. Late preterm infants experience a higher rate of
readmission than their term counterparts, and these infants are more likely to suffer
complications such as respiratory distress, kernicterus, feeding difficulties, and
hypoglycemia. Late preterm infants also have a higher mortality for all causes when compared
to term infants. The use of antenatal corticosteroids has been shown to be beneficial in
women at risk for preterm delivery prior to 34 weeks but has not been evaluated in those
likely to deliver in the late preterm period. If shown to reduce the need for respiratory
support and thus to decrease the rate of special care nursery admissions and improve
short-term outcomes, the public health and economic impact will be considerate.This protocol
describes a randomized placebo controlled trial to evaluate whether antenatal corticosteroids
can decrease the rate of neonatal respiratory support, thus decreasing the rate of neonatal
intensive care unit (NICU) admissions and improving short-term outcomes in the late preterm
infant.

Two follow-up studies will be conducted concurrently. The first follow-up study will examine
if the positive effects of betamethasone on lung function will persist in children at 6 years
of age of mothers randomized to betamethasone with an expected late preterm delivery.
Neonatal respiratory morbidity is associated with an increased risk of adverse childhood
respiratory disease. Thus it is quite plausible that the effect of betamethasone, in reducing
neonatal morbidity, particularly TTN, will translate into improved respiratory morbidity in
early childhood.The primary outcome is childhood respiratory disease defined by a composite
outcome of abnormal pulmonary function test (PFT) measured by spirometry, physician diagnosis
of asthma, or other respiratory illnesses with medication.

The second follow-up study will examine whether late preterm antenatal betamethasone
treatment is associated with long-term neurocognitive functioning, and whether there are any
long-term consequences of what is believed to be transient neonatal hypoglycemia. Cognitive
function will be measured by the Differential Ability Scales 2nd Edition (DAS-II) core
components of the general conceptual ability (GCA) that includes verbal ability, non-verbal
reasoning ability and spatial ability. The primary outcome is defined as a GCA score of <85
(1 standard deviation below the mean) at 6 years of age or greater.

Inclusion Criteria:

Singleton Pregnancy. A twin pregnancy reduced to singleton (either spontaneously or
therapeutically) before 14,0 weeks by project gestational age is acceptable

Gestational age at randomization between 34,0 weeks and 36,5 weeks confirmed by study
criteria

High probability of delivery in the late preterm period (any one of the following):

- Membrane rupture as defined by the occurrence of any two of the following: pooling of
fluid in the vaginal vault, positive Nitrazine test, ferning of vaginal fluid,
positive AmniSure test; or any one of the following: indigo carmine pooling in the
vagina after amnioinfustion, visible leakage of amniotic fluid from the cervix

or

- Preterm labor with intact membranes. Preterm labor is defined as at least 6 regular
uterine contractions in an observation period of no more than 60 minutes and at least
one of the following: cervix greater than or equal to 3cm dilated or at least 75%
effaced

or

- Planned delivery by induction of labor or cesarean section in no less than 24 hours
and no more than 7 days, as deemed necessary by the provider. An induction must be
scheduled to start by 36,5 weeks at the latest, whereas a cesarean delivery must be
scheduled by 36,6 weeks at the latest. Therefore the latest gestational age for
randomization is 36,4 weeks for a planned induction. The planned delivery may be for
any indication, such as the following: prior myomectomy, prior classical cesarean,
intrauterine growth restriction (IUGR), oligohydramnios, preeclampsia, nonreassuring
fetal heart rate tracing warranting delivery, abruption, placenta previa

Exclusion Criteria:

1. Any prior antenatal corticosteroid course during the pregnancy because of potential
contamination of the placebo group

2. Candidate for stress dose corticosteroids because of chronic steroid therapy to
prevent suppression of adrenal gland, because of potential contamination of the
placebo group

3. Twin gestation reduced to a singleton gestation at or after 14 weeks 0 days by project
gestational age either spontaneously or therapeutically

4. Fetal demise, or known major fetal anomaly, including cardiac anomaly and hydrops

5. Maternal contraindication to betamethasone: hypersensitivity reaction to any
components of the medication, idiopathic thromboycytopenic purpura, systemal fungal
infection in case of exacerbation by betamethasone, use of amphotericin B due to the
possibility of heart failure with concomitant betamethasone

6. Pre-gestational diabetes - exclude if the patient was on medication (insulin,
glyburide) prior to pregnancy

7. Delivery expected within 12 hours of randomization, because of insufficient time of
corticosteroids to confer benefit, including any of the following:

A. Rupture of Membranes (ROM) does not satisfy protocol criteria - exclude if the
patient being evaluated for Preterm Premature Rupture of Membranes (pPROM), does not
have preterm labor or planned delivery and does not satisfy the spontaneous membrane
rupture criteria (any 2 of: positive Nitrazine test, pooling of fluid in the vaginal
vault test or ferning of vaginal fluid; or indigo carmine pooling in the vagina after
amnioinfusion; or visible leakage of amniotic fluid from the cervix) B. Rupture of the
membranes in the presence of more than 6 contractions per hour or cervical dilation of
3 cm or more, unless oxytocin was withheld for at least 12 hours (other induction
agents allowed) C. Chorioamnionitis - exclude if patient is diagnosed with
chorioamnionitis D. Cervical dilation ≥ 8 cm E. Evidence of non-reassuring fetal
status requiring immediate delivery

8. Participation in another interventional study that influences neonatal morbidity and
mortality

9. Participation in this trial in a previous pregnancy

10. Delivery at a non-network hospital

11. At 36, 0 weeks to 36, 5 weeks and quota for 36 weeks already met. To ensure there is
an adequate proportion of women presenting at 34 to 35 weeks of gestation, enrollment
will be restricted so that no more than 50% of the women in the trial present at 36
weeks.