Throughout this detailed description, patient and subject will be used interchangeably.
Patients presenting to either an acute care setting (Woman's Hospital Assessment Center) or
outpatient clinic setting with concerns for rupture of membranes will be clinically evaluated
by an obstetrician (including private physicians, resident faculty and resident physicians).
Exam findings including either/or 1) visualization of amniotic fluid passing from the
cervical canal and pooling in the vagina via sterile speculum examination, 2) a basic pH
(i.e., positive nitrazine) test of vaginal fluid, 3) arborization (ferning) of dried vaginal
fluid identified via microscopic examination by the examining physician, or 4) an amniotic
fluid index (AFI) of less than 4cm between 18 0/7 and 22 6/7 weeks gestation are to be
diagnostic of previable, preterm premature rupture of membranes (PPROM). Eighteen weeks
gestational was arbitrarily chosen as the lower limit of gestational ages included based on
review of currently available retrospective studies on previable PPROM. If patient meets all
inclusion and exclusion criteria as listed above specimens to be collected at the time of
diagnosis include a catheterized urinalysis with reflex urine culture if indicated, wet prep
(i.e., vaginitis panel), group B strep DNA recto-vaginal swab, complete blood count and PCR
testing for gonorrhea, chlamydia and trichomonas via endocervical swab. An ultrasound to
determine amniotic fluid index (AFI) should also be performed at this time (either by
radiology or Maternal-Fetal Medicine). These will be collected according to current standard
of care practices for preterm prelabor rupture of membranes. Patient will then be admitted to
the Woman's Hospital Labor and Delivery unit for a 24-hour observation period. Acetaminophen
and ibuprofen will be withheld during this 24-hour observation period in order to ensure that
no signs or symptoms of underlying infection or preterm labor are masked. A repeat complete
blood count will be performed the morning of hospital day 2, and repeat AFI on hospital day 2
to be performed with full obstetric ultrasound by Maternal Fetal medicine physicians.
If, during the 24-hour observation period, the subject is without signs of chorioamnionitis,
preterm labor, or placental abruption with vaginal bleeding as determined by the MFM staff,
and if patient continues to meet both inclusion and exclusion criteria, subject will then be
offered enrollment in the study. The consenting process will be performed by the MFM staff
physicians or by Felicia LeMoine, MD, or Kaitlyn Taylor, MD, the co-investigators. The
consenting process will be performed within the patient's private hospital room (designated
at the time of admission). Once the subject as agreed to voluntary participation and
in-formed consent has been signed, the subject will then be assigned an individual study
identifier that includes the study acronym OAPPPROM patient initials, and unique number
(randomly generated using the sample () function in R statistical software). All blood
samples and specimens collected prior to admission, at admission and future blood samples and
specimens will be available to the treating physician and reported within the patient's chart
as is current standard practice. The samples and specimens will also be referenced using the
patient's unique identifier for the sake of research data collection. The enrolled subjects
will then be randomized using a computer-generated sample without replacement from the
patient ID numbers into either the control (no antibiotics) or treatment (antibiotics) arm.
Following the 24-hour observation period and randomization, those subjects enrolled into the
treatment (antibiotics) arm of the study will be thoroughly counseled on the risks and
adverse side effects associated with the use of azithromycin and amoxicillin and which of
those side effects should prompt emergency evaluation at Woman's Hospital Assessment Center
or the nearest emergency department with obstetrical care. The subjects of the treatment arm
will also receive the first dose of antibiotics while in the hospital to ensure no immediate
adverse effects.
Both arms of the study will receive, at the time of discharge, a "Patient Information
Pamphlet" along with a thermometer to take home. All subjects will be instructed on proper
methods to measure body temperature with the thermometer. All subjects will be thoroughly
counseled on symptoms or findings which should prompt immediately follow-up at Woman's
Hospital or the nearest emergency department with obstetrical care. Such symptoms include,
but are not limited to, vaginal bleeding, fevers, chills, purulent vaginal discharge,
contractions, pelvic pain or cramping, abdominal pain or cramping, or any other concerns.
Subjects will be counseled on avoidance of sexual intercourse and avoidance of overt
exertion, yet, strict bed rest will not be advised. Subjects will be instructed to keep the
"Patient Information Pamphlet" with them at all times while enrolled in this study. If
patient either reports a lost or misplaced pamphlet at any point during the study or presents
to any scheduled follow up appointment in the MFM clinic without the pamphlet, the patient
will be provided with a new copy. The pamphlet includes a daily temperature log, an
adverse/side effect log, and emergency contact information for key figures involved in this
study. The pamphlet also includes a table in which dates and findings (i.e., EGA, maternal
heart rate, fetal heart rate, maternal blood pressure, maternal temperature, and AFI) from
follow-up MFM appointments are to be logged. The initial MFM follow-up appointment will be
scheduled prior to discharge from the hospital for all subjects enrolled. Documentation of
scheduled time and date will be noted on patient's discharge paperwork. Follow-up for both
arms of the study will be scheduled within the MFM outpatient clinic weekly until subjects
either reach 23 0/7 weeks gestation or show signs of change in clinical condition. Weekly
follow-up visits will consist of vital signs (maternal heart rate, maternal blood pressure,
temperature and weight), a physical examination of subject, an obstetric ultrasound to assess
fetal well-being, calculate amniotic fluid index, and determine fetal heart rate, and weekly
complete blood counts (lab draws). Patients will also be instructed to bring the antibiotic
pill bottles the initial follow up appointment. The number of pills remaining will be counted
to assess degree of antibiotic compliance. The results of these assessments, along with a
copy of the "Patient Information Pamphlet", will be made at each follow up visit and stored
within a data collection sheet. Each patient will be assigned an individual data collection
sheet which will be marked with the patient's medical record number and unique subject
identifier (determined as mentioned above).
All of the data collection sheets will be stored within a secure research binder. This binder
will be kept secure in a locked desk drawer, within a locked office (MFM office located at
100 Woman's Way, Baton Rouge, LA 70817), when not in use. Access to study data will only be
granted to Robert Clifton Moore, MD, Felicia LeMoine, MD, and Kaitlyn Taylor, MD during the
study period. Following completion of the study, a final Excel spreadsheet will be created
which will include all data previously collected, including the patient's unique identifier
but excluding the patient's medical record number (de-identified). The final, compiled
spreadsheet with de-identified data will be made available to Andrew Chapple, PhD for final
data analysis. Upon completion of finalized data spreadsheet, the hard copies contained
within the designated research binder will be disposed of in a secured, locked shred bin on
Woman's Hospital campus. The spreadsheet will be encrypted and stored on an
password-protected and encrypted laptop, property of the investigator Felicia LeMoine, MD.
The spreadsheet will not be stored or saved onto any of the various, available internet
storage services (i.e., DropBox, Google Drive, etc.)
If at any point during the study, subjects of either arm show signs of infection (fever,
rigors, chills, pain), labor, abruption (vaginal bleeding), or fetal distress, subjects will
be admitted to Woman's Hospital for induction of labor/delivery as recommended per
established standards of care. Delivering physician will be either the patient's primary
obstetrician or MFM specialist if subject received prenatal care at facility outside of
Woman's Hospital.
If subject and the fetus show signs of continued stability with no adverse events/side
effects, signs of chorioamnionitis, infection, labor, or placental abruption, from the time
of rupture until 23 0/7 weeks gestation, the subject will be readmitted to Woman's Hospital's
Labor and Delivery Unit at 23 0/7 for continued inpatient management until delivery. At the
time of readmission, both treatment and control arms will receive fetal neuroprotective
magnesium sulfate (6 gram loading dose, 6g in 100mL in-fused over 15- 20 minutes, followed by
maintenance dose of 2g/hour at rate of 50mls/hr of 20g/500mL for a minimum of 12 hours),
betamethasone course for fetal lung maturity (12mg intramuscular admin-istered every 24 hours
for total of two doses), and latency antibiotics (a single dose of azithromycin 1g orally
with 48-hour course of ampicillin 2g intravenously every 6 hours followed by amoxicillin
500mg orally every 9 hours for 5 days) as guided by current standard of care practices.
Duration of treatment with magnesium sulfate will be standardized to a total of 12 hours on
readmission and a plan for restart of medication if delivery is felt to imminent and at a
gestational age of less than 34 weeks. While subjects are receiving magnesium sulfate,
routine evaluations to assess for signs of magnesium toxicity will be performed as is
outlined in the hospital policy regarding magnesium administration in pregnancy. Briefly this
includes monitoring for signs and symptoms of magnesium overdose and therapy with calcium
gluconate as need for magnesium toxicity.
Other orders to be instituted at the time of readmission include a repeat culture of urine,
complete blood cell count, Maternal Fetal Medicine consultation, fetal ultrasound, regular
diet, IV with saline lock, bed rest with bathroom privileges and fetal non-stress testing
twice per day. Obstetric ultra-sounds will be repeated by the Maternal-Fetal medicine
specialists within 24 hours of readmission and at least once every 7 days till delivery is
indicated.
A rescue course of betamethasone (single dose of 12mg intramuscularly) will be administered
if the subject does not deliver within 14 days of completion of the initial 2-dose course of
betamethasone and if delivery is suspected within the next seven days.
Delivery following readmission will be at the discretion of the attending obstetrician in
regards to evidence of maternal or fetal infection, labor, non-reassuring fetal assessment or
placental abruption in addition to any other standard indication for delivery (ie.,
pre-eclampsia) or if patient reaches 34 0/7 weeks gestational age. Route of delivery will be
determined by routine obstetrical indications.
All investigational products (study drugs) will be stored under appropriate storage
conditions in a secure area according to local regulations. The investigator is responsible
for ensuring that it is dispensed only to study subjects and only from official study sites
by authorized personnel, as dictated by local regulations. The investigator is responsible
for ensuring that the investigational product is stored under the appropriate environmental
conditions (temperature, light, and humidity), as noted in the product labeling. Labels will
be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory
guidelines for labeling.