Pilot Study to Evaluate a Prototype Electronic Uterine Inhibitor to Prevent Preterm Contractions

The preterm birth rate in the United states has been stubbornly stuck at 10.5% or higher
since the 1950's. The 2011 rate, 11.72%, is the most recent level available. That comes to
about a half a million preterm births per year in the United States alone.

Premature birth and the attendant complications are among the greatest health problems in the
world today and contribute to about 85% of all neonatal deaths, that is, deaths of infants
from the time of birth until1 month old.

During the past ten years, there has been developed a novel method to effectively and
objectively inhibit uterine contractility during the birthing process.

The method is nonpharmaceutical, and thus, avoids systemic side effects and has the potential
to be noninvasive and easy to master.

This method uses an electrical intervention (EI)/uterine pacemaker device that will allow for
rapid and reversible inhibition of preterm uterine contractions and preterm birth.

The following is a brief account of the electrical properties of the myometrium and why these
properties may be affected by electrical intervention (EI).

The contractile activity of the uterus is a direct consequence of the underlying electrical
activity in the myometrial cells. The sequence of contraction and relaxation of the
myometrium results from the cyclic depolarization and repolarization of the membranes of the
muscle cells.

The uterus at term has been shown to be myogenic just like the heart. The uterus will
contract spontaneously without neuronal control, like the heart, and form gap junctions
interconnecting the cells just like the syncytium of the heart. Also, both are excitable
tissues with similar current flows.

Electrical Intervention (EI) has successfully inhibited myometrial or uterine contractions in
many different species e.g. sheep, rabbit, rat, and human (in vitro). The EI was effective in
live animals when used on the uterus either directly attached or transvaginally.

The electrical pacemaker (Inch Inc., Brooklyn, NY) used in this work is a self-contained
portable device with integrated circuits, housed in a box about eight inches on all sides. EI
is delivered as 10-second bursts of bipolar, constant-current, square-wave pulses in 20% duty
cycles. A 20% duty cycle consists of a pulse of current at the given amperage lasting 20% of
the cycle, followed by a period without current for the remaining 80% of the cycle. The
number of cycles per second defines the frequency in Hertz (Hz). Because the duty cycle is
constant at 20%, a 10-second burst always delivers current for a total of 2 seconds, with the
frequency determining the length and number of individual pulses, in milliseconds (msec),
during the burst.

Participants were enrolled beginning in February 2005. IRB approval was in place at New York
Downtown Hospital, Manhattan, NY, from inception until March 2013, when it ceased to be a
study site. During the study period at Downtown Hospital, 3 participants overall were
enrolled and studied. St. Luke's Roosevelt Hospital Center, Manhattan, NY, became a study
site when it received IRB approval in January 2010 and at present is the only study site, and
has continuing IRB approval. While under IRB approval, 5 patients have been enrolled and
studied at St. Luke's and Roosevelt. Each participant has given written informed consent. To
date, 53 women have been recruited overall, and 8 have given informed consent and been
studied.

Those studied are females 18 years old or older, between 24-34 weeks gestation, have a
reassuring fetal heart rate (FHR) tracing, and in preterm labor as defined by the American
College of Obstetrics and Gynecology (ACOG). The participants must have persistent uterine
contractions, with 4 every 20 minutes or 8 every 60 minutes, and any one or more of the
following: documented cervical change, > 1 cm cervical dilation, or > 80% cervical
effacement. The exclusion criteria are the same as for most tocolytic therapy; most
importantly, premature rupture of the membranes (PROM), and additionally, severe
preeclampsia, severe abruption placenta, chorioamnionitis, fetal death, fetal anomaly
incompatible with life, severe fetal growth restriction or estimated fetal weight (EFW) <5%,
mature fetal lung studies, maternal cardiac arrhythmias, a permanent cardiac pacemaker, a
fetal cardiac arrhythmia, or any other contraindication for tocolysis.

The women have a pacemaker electrode placed vaginally. A 5 (1.67mm) or 6 (2.00mm) French
electrode catheter with distal 4x2mm platinum alloy rings 5mm apart (C. R. Bard, Inc.,
Lowell, MA, USA) is manually placed into the posterior vaginal fornix next to the external
cervical os. The catheter's proximal end is taped to the patient's thigh and its connecting
cable attached to the pacemaker, which can generate a weak bipolar electrical current (0-20
mA, 0-50 msec/pulse, 50 Hz). In the study, the EI current is increased slowly, as needed, up
to a maximum of 17 mA.

The human study begins immediately after placing the catheter and lasts 60 minutes; FHR,
uterine contraction timing, and subjective contraction amplitude are monitored during the
entire study. The first 20 minutes are the control contraction period (C1). The second 20
minutes are the EI period, with a 10-second burst of current administered just prior to each
expected contraction; expected contractions are determined by the timing of the C1
contractions and/or by the rise of the subjective tocodynamometer tracing above baseline
levels. The third 20 minutes is the post-intervention control contraction period (C2). The
contraction intervals, the times between contraction peaks (P-P), were measured in minutes
for C1, EI, and C2. All statistical analyses for the human study have been performed using
Statistical Analysis System (SAS) software (SAS Institute Inc., Cary, NC, USA) Version 9.2.
For each period, C1, E1, and C2, the mean minutes between contractions are estimated, using
the mixed-model analysis of variance (ANOVA) to account for both within-subject and
between-subject variability. Pairwise differences between mixed-model ANOVA means and
corresponding p-values testing for difference from zero were estimated. All hypothesis
testing is performed at the 0.05 level of significance.

Inclusion Criteria:

- Pending preterm birth

- vaginal birth

Exclusion Criteria:

- disease disorders including but not limited to thyroid, liver disease, HIV, diabetes
or drug addiction

- using a permanent cardiac pacemaker

- have malignancies that are currently being treated or recurrent