A Review of the Potential Therapeutic Application
of Vagus Nerve Stimulation During Childbirth
By
Tanya Enderli
A thesis submitted to the College of Engineering at
Florida Institute of Technology
in partial fulfillment of the requirements
for the degree of
Master of Science
In
Biomedical Engineering
Melbourne, Florida
March, 2017
We the undersigned committee hereby recommend
that the attached document be accepted as fulfilling in
part the requirements for the degree of
Master of Science of Biomedical Engineering.
“A Review of the Potential Therapeutic Application
of Vagus Nerve Stimulation During Childbirth,”
a thesis by Tanya Enderli
____________________________________
T. A. Conway, Ph.D.
Professor and Head, Biomedical Engineering
Committee Chair
____________________________________
M. Kaya, Ph.D.
Assistant Professor, Biomedical Engineering
____________________________________
K. Nunes Bruhn, Ph.D.
Assistant Professor, Biological Sciences
Abstract
Title: A Review of the Potential Therapeutic Application of Vagus Nerve
Stimulation During Childbirth
Author: Tanya Enderli
Principle Advisor: T. A. Conway, Ph.D.
The goal of this research is to show that transcutaneous Vagus nerve stimulation
(tVNS) should be investigated as a possible modality for increasing endogenous
release of oxytocin during childbirth. There have been many great advances made
in the practice of modern obstetrics in the last century. The 1900s saw the
discovery, isolation, and subsequent widespread use of the hormone oxytocin as an
agent to prevent postpartum hemorrhage and to initiate or quicken labor during
childbirth. There are significant risks to the fetus when synthetic oxytocin is used.
While the medical administration of oxytocin during labor was being popularized,
there was also research being conducted on its physiologic mechanism in labor. A
popular idea is that uterine contractions initiate a positive feedback mechanism by
triggering a neural pathway that stimulates the release of oxytocin from the
iii
pituitary gland, and that the oxytocin then strengthens the contractions which leads
to more oxytocin being released, and so on. The use of labor analgesia also became
widely used in the 1900s, and by midcentury methods had been described for
administering analgesics into the epidural space of the spinal cord. Currently, the
epidural is considered the gold standard in labor analgesia. However, there is some
evidence that epidural analgesia may inhibit the oxytocin release mechanism by
blocking the neural input needed to stimulate it, as women who have had an
epidural tend to require synthetic oxytocin infusion more often than women who
have not. Research on women with complete spinal cord injury has shown that the
Vagus nerves provide an alternate neural pathway from the female reproductive
system to the area in the brain that stimulates oxytocin release. It has also been
shown that electrical stimulation of the Vagus nerve increases plasma oxytocin
levels. Implantable VNS systems are impractical for a single use in pregnant
women and may be why VNS has not been explored in obstetrics. However, if a
noninvasive transcutaneous method is found to elicit the same response as
traditional VNS then it might provide a clinically relevant alternative to using
synthetic oxytocin during labor.
iv
Table of Contents
Table of Contents .....................................................................................................v
List of Figures ........................................................................................................ vii
List of Tables .......................................................................................................... ix
List of Abbreviations ...............................................................................................x
Acknowledgement ................................................................................................. xii
Chapter 1 Introduction ............................................................................................1
1.1 Background of the Study .......................................................................................... 1
1.2 Problem Statement .................................................................................................... 4
1.3 Objectives of the Study ............................................................................................. 6
1.4 Limitations of the Study ........................................................................................... 7
Chapter 2 Anatomy Review ....................................................................................9
2.1 Primary Anatomical Structures of Birth ................................................................ 9
Chapter 3 Review of Childbirth Process ..............................................................13
3.1 Overview of Parturition .......................................................................................... 13
3.2 The First Stage of Labor ......................................................................................... 14
3.3 The Second Stage of Labor ..................................................................................... 15
3.4 The Third Stage of Labor ....................................................................................... 15
3.5 Birth by Cesarean Section ...................................................................................... 16
Chapter 4 Nervous System Review .......................................................................17
4.1 Nervous System Overview ...................................................................................... 17
4.2 The Spinal Cord ...................................................................................................... 21
4.3 The Autonomic Nervous System ............................................................................ 22
Chapter 5 Innervation of Female Reproductive System ....................................26
5.1 Background and History ........................................................................................ 26
5.2 Sensory Nerves......................................................................................................... 28
5.3 Motor Nerves ........................................................................................................... 30
Chapter 6 Endocrine System Involvement in Parturition .................................34
6.1 Background and History ........................................................................................ 34
6.2 Hormones of the Posterior Pituitary ..................................................................... 36
6.3 Hormones of the Anterior Pituitary ...................................................................... 38
6.4 Hormones of the Adrenal Glands .......................................................................... 41
6.5 Endocrine Role in Initiation of Labor ................................................................... 42
v
Chapter 7 Oxytocin: A Closer Look .....................................................................44
7.1 Endogenous Oxytocin Release in Labor ................................................................ 44
7.2 Pharmacologic Use of Oxytocin in Labor ............................................................. 50
Chapter 8 Epidural Analgesia: Uses and Effects ................................................53
8.1 Background and History of Epidural Use ............................................................. 53
8.2 Nerves Blocked by Epidural Analgesia ................................................................. 54
8.3 Effect of Epidural Analgesia on Labor.................................................................. 57
Chapter 9 Studies on the Female Sexual Response .............................................58
9.1 Oxytocin Release During Orgasm.......................................................................... 58
9.2 Orgasm in Women with Complete Spinal Cord Injury ....................................... 59
9.3 Orgasm During Childbirth ..................................................................................... 63
Chapter 10 Vagus Nerve Stimulation ...................................................................66
10.1 Overview of Vagus Nerve Stimulation ................................................................ 66
10.2 Methods of Vagus Nerve Stimulation .................................................................. 68
Chapter 11 Discussion ...........................................................................................74
11.1 Motivation for This Research ............................................................................... 74
11.2 Transcutaneous Vagus Nerve Stimulation .......................................................... 82
References ...............................................................................................................89
vi
List of Figures
Figure 1 – Sixteenth Century Drawing of Female Reproductive System ................ 10
Figure 2 – Modern Drawing of Female Reproductive System ................................ 11
Figure 3 – Spinal nerve roots exiting the CNS ........................................................ 19
Figure 4 – Motor and Sensory Distribution of the Cranial Nerves to the Brain ...... 20
Figure 5 – Diagram of Cross Section of Spinal Cord .............................................. 21
Figure 6 – Sympathetic Nervous System ................................................................. 23
Figure 7 – Parasympathetic Nervous System........................................................... 24
Figure 8 – Diagram Showing Neural Projections of PVN, SON, and Arcuate Nuclei
From Hypothalamus to Pituitary Gland ................................................................... 25
Figure 9 – Innervation of the Female Reproductive System.................................... 29
Figure 10 - Neuropathways of Parturition ............................................................... 31
Figure 11 – Nerve Pathways for Labor Pain ............................................................ 33
Figure 12 – Diagram Showing 1930s Understanding of Pituitary Involvement in
Female Reproductive System................................................................................... 35
Figure 13 – The Hypothalamic-Pituitary Portal System and Vasculature ............... 38
Figure 14 – Biosynthesis of Noradrenaline and Adrenaline from Dopamine .......... 42
Figure 15 – Graph Showing Higher Plasma Oxytocin Levels in Pregnant Women
Not at Risk for Developing PPD than in Women Who Are at Risk for PPD .......... 46
vii
Figure 16 – Vasopressin and Oxytocin Release in Hypothalamic and
Extrahypothalamic Sites........................................................................................... 48
Figure 17 – Diagram of the Ferguson Reflex........................................................... 49
Figure 18 – Schematic Of Sensory Input During Labor .......................................... 55
Figure 19 – Mean Plasma Oxytocin Levels at Baseline, Early, Middle, and Late
Stages of Self Stimulation, During Orgasm, and 2 and 5 Minutes Post-Orgasm in
Men and Women ...................................................................................................... 59
Figure 20 – Hypothetical Alternative Reproductive System Afferent Pathway
Mediated by the Vagus Nerve .................................................................................. 60
Figure 21 – MRI and fMRI Evidence of Activation of PVN During Orgasm in
Woman With Complete SCI .................................................................................... 62
Figure 22 – fMRI Images Showing NTS Activation ............................................... 62
Figure 23 – Diagram Showing the Neural Connection Between the Vagus Nerve
and PVN Through the DVN..................................................................................... 63
Figure 24 – Diagram of Left Ear, Lateral View ....................................................... 71
Figure 25 – Diagrams of Lateral and Medial Surfaces of External Ear and
Associated Innervation and Vasculature .................................................................. 72
Figure 26 – The NET-1000 and NET-2000 CES units ............................................ 81
Figure 27 – The NEMOS Device for tVNS ............................................................. 82
Figure 28 - The Alpha-Stim 100 unit and earclip electrodes ................................... 85
viii
List of Tables
Table 1 – Duration of Second Stage of Labor in Minutes .......................................14
Table 2 – Comparison of Technical Details Between the NET-2000 and AlphaStim Devices ............................................................................................................86
ix
List of Abbreviations
ABVN
Auricular Branch of the Vagus Nerve
ACTH
Adrenocorticotropic Hormone
ATN
Auriculotemporal Nerve
BBB
Blood-Brain Barrier
CA
Catecholamines
CNS
Central Nervous System
CES
Cranial Electrotherapy Stimulator
CSS
Cervical Self-Stimulation
CRH
Corticotropin Releasing Hormone
DVN
Dorsal Vagal Nucleus
FDA
Food and Drug Administration
fMRI
Functional Magnetic Resonance Imaging
GAN
Great Auricular Nerve
IU
International Units
LON
Lesser Occipital Nerve
MRI
Magnetic Results Imaging
NTS
Nucleus Tractus Solitarii
PET
Positron Emission Tomographic
x
PMA
Premarket Approval
PPD
Postpartum Depression
PNS
Peripheral Nervous System
PVN
Paraventricular Nucleus
SCI
Spinal Cord Injury
SON
Supra-Optic Nucleus
STA
Superficial Temporal Artery
TENS
Transcutaneous Electrical Nerve Stimulator
TRH
Thyrotropin Releasing Hormone
tVNS
Transcutaneous Vagus Nerve Stimulation
VIP
Vascular Intestinal Peptide
VNS
Vagus Nerve Stimulation
xi
Acknowledgement
I would like to begin by thanking my advisor and mentor, Dr. T. A. Conway of the
Biomedical Engineering department at Florida Tech. Dr. Conway was always
available to guide me in the direction I needed to go but at the same time gave me
freedom to explore my own ideas and be creative. I learned more than I ever could
have dreamed under his advisement.
I would also like to thank Dr. Nunes of the Biology department and Dr. Kaya of the
Biomedical Engineering department both for being on my thesis committee and for
their willingness to offer advice when I came to them with questions related to their
areas of expertise. I would have been lost without their input.
Finally, I would like to express my sincere appreciation to my family, friends, and
massage clients for supporting me through my collegiate experience and for
willingly serving as a sounding board for my ideas throughout this research. I am
deeply grateful for all the encouragement and constructive criticism that helped me
finish this project.
xii
1
Chapter 1
Introduction
1.1 Background of the Study
One of the most important, although in many ways poorly understood, events in
human life is birth. A baby can be delivered either vaginally or by cesarean section,
a surgical incision made directly into the uterus through the abdomen (Posner,
Jones, Dy, & Black, 2013). There is a risk of morbidities or mortalities occurring in
either mother or child for both methods of delivery (Posner et al., 2013), but the
American College of Obstetricians and Gynecologists recommends vaginal
delivery unless there are medical indications for cesarean (ACOG, 2013). Labor
that lasts much longer than usual is referred to as labor dystocia, and can indicate
the need for cesarean (Barber et al., 2011; Posner et al., 2013). Endogenous, or
internal, oxytocin release is associated with a positive feedback mechanism called
the Ferguson reflex where sensory input from uterine contractions stimulates the
posterior pituitary gland to release oxytocin which then stimulates stronger
contractions (Ferguson, 1941). Therefore, if labor dystocia is caused by insufficient
uterine contractions, then synthetic oxytocin may be used to stimulate stronger
contractions and thus prompt the progression of labor (Posner et al., 2013).
2
In normal childbirth, one of the issues of greatest clinical significance is the
management of labor pain, as the majority of women experience moderate to severe
pain during labor (Posner et al., 2013). There are several pharmaceutical treatments
available to mothers in labor, but the current gold standard in pain control during
labor is epidural analgesia (Posner et al., 2013). There has been some controversy
about whether epidural analgesia affects the Ferguson reflex (Saunders et al.,
1989), but when the nerves that convey the sensations that control the reflex are
considered it is possible that it does (Goodfellow, Hull, Swaab, Dogterom, & Buijs,
1983). Actually, epidural analgesia use is associated with a longer labor
(Alexander, Lucas, Ramin, McIntire, & Leveno, 1998; Leighton & Halpern, 2002b;
Posner et al., 2013), and this may contribute to the higher rate of synthetic oxytocin
infusions required for women who have received an epidural (Goodfellow et al.,
1983; Leighton & Halpern, 2002a, 2002b; Zhang, Klebanoff, & DerSimonian,
1999).
Some evidence exists that indicates that oxytocin promotes mother-child bonding
(Feldman, Weller, Zagoory-Sharon, & Levine, 2007; Skrundz, Bolten, Nast,
Hellhammer, & Meinlschmidt, 2011), but oxytocin is not known to cross the blood
brain barrier (Altemus et al., 2004; Landgraf & Neumann, 2004; Skalkidou,
Hellgren, Comasco, Sylvén, & Poromaa, 2012). Therefore, oxytocin that is not
released by the pituitary gland, which includes synthetic oxytocin administered
3
during labor, is not believed to act on the brain (Altemus et al., 2004). Also, while
the risks of using synthetic oxytocin are not generally life-threatening to the
mother, there are some side effects related to its use that can be quite dangerous to
the fetus (Posner et al., 2013). Another potential downside when comparing
synthetic oxytocin administration to endogenous oxytocin release is that oxytocin is
generally infused at a constant rate whereas oxytocin release from the pituitary
gland occurs in a pulsatile manner (Simpson, 2011).
Recently, the Vagus nerve has been found to innervate the cervix of women
(Komisaruk, Beyer-Flores, & Whipple, 2006; Komisaruk et al., 2004). In studies
conducted on women with complete spinal cord injury (SCI) above the level of
sensory input from the reproductive system it was found that cervical stimulation
activated the area of the brainstem where Vagus nerve fibers enter, and if the
woman reached orgasm it was also seen that the part of the brain that stimulates
oxytocin release from the posterior pituitary was activated (Komisaruk et al.,
2004). Research has also shown that electrical Vagus nerve stimulation (VNS)
results in an increase of blood flow, indicating activation, to this region (Henry et
al., 1998; Narayanan et al., 2002). However, there have not yet been any studies to
determine if there is a potential clinical application of VNS to increase oxytocin
release during labor.
4
1.2 Problem Statement
The current state of the art in labor pain management is epidural analgesia, which
essentially functions as a nerve block for input from the reproductive organs to the
spinal cord and brain (Posner et al., 2013). While the blocking of sensory input
does produce analgesia, there is some evidence suggesting that women who receive
epidural analgesia are more likely to require an infusion of synthetic oxytocin
during labor (Alexander et al., 1998; Goodfellow et al., 1983; Leighton & Halpern,
2002a, 2002b; Zhang et al., 1999). The importance of oxytocin in childbirth cannot
be understated, as it has a well-documented role in inducing uterine contractions
(Caldeyro‐Barcia & Poseiro, 1959; Dale, 1906; Den Hertog, De Groot, & Van
Dongen, 2001; Ferguson, 1941; Magon & Kalra, 2011; Posner et al., 2013).
Therefore, if medical interventions to control pain cause the blockage of the main
pathway by which sensory input regulates endogenous oxytocin release, then any
possible alternate nerve pathways should be assessed to determine their efficacy in
stimulating this release.
It is now well established that VNS is an effective treatment for epileptic seizures
(George et al., 1995; Woodbury & Woodbury, 1990; Zabara, 1992) and depression
(Bajbouj et al., 2010; Christmas, Steele, Tolomeo, Eljamel, & Matthews, 2013;
Daban, Martinez-Aran, Cruz, & Vieta, 2008; Eljamel, 2015). The VNS systems
5
that are currently approved by the Food and Drug Administration (FDA) consist of
a device implanted under the skin with lead wires running from the device to the
branch of the Vagus nerve in the neck (Howland, 2014). The invasive surgical
implantation of a medical device to assess if it stimulates the release of oxytocin in
childbirth would clearly be a laughable topic if it were to be presented to any
Institutional Review Board, especially given the ready availability of synthetic
oxytocin that can be used instead. However, it has been found that there is a branch
of the Vagus nerve that extends to the external ear (Ellrich, 2011; Frangos, Ellrich,
& Komisaruk, 2015; Howland, 2014), and that electrical stimulation to the skin
over these nerves results in a response in the brain that is similar to direct VNS
(Frangos et al., 2015; Kraus et al., 2013).
This method, called transcutaneous Vagus nerve stimulation (tVNS), has not been
approved by the FDA, although tVNS systems have been approved of and are in
use in Europe. However, tVNS is considered safe and well tolerated (Busch et al.,
2013; Lehtimäki et al., 2013; Stefan et al., 2012), and tVNS of the Vagus branch in
the external ear has even been performed using cranial electrotherapy stimulator
(CES) units (Hein et al., 2013; Howland, 2014), which have been approved by the
FDA for treating anxiety, depression, and insomnia. Given the fact that VNS has
been shown to activate the region of the brain that stimulates oxytocin release and
that tVNS offers a noninvasive alternative to implanted VNS systems, the goal of
6
this research is to present an argument for the potential application of tVNS in
labor for increasing endogenous oxytocin release.
1.3 Objectives of the Study
This study will identify the anatomical structures, neural pathways, and endocrine
factors relevant to childbirth. The development of the current understanding of each
of these will be discussed throughout the review. A specific focus will be placed on
the nervous system to establish the currently accepted understanding of sensory
transmission during childbirth. The literature review will highlight medical
interventions currently used in obstetrics as well as potential impacts they might
have on the childbirth process.
Another goal of this study is to identify key points that need to be researched in
order to determine the feasibility of using tVNS for increasing oxytocin release
during childbirth. This will include a discussion on the lack of empirical data
showing the safety of using VNS during pregnancy due to the exclusion of
pregnant women from VNS studies. It will also propose which preliminary studies
should be conducted in healthy humans to properly develop the technology before
performing any trials on pregnant women.
7
1.4 Limitations of the Study
Currently, there is no evidence directly showing the involvement of the Vagus
nerve in human labor and delivery. The lack of scientific evidence means that the
entire concept of this thesis is theoretical. Functional magnetic resonance imaging
studies on the female sexual response have shown that the Vagus nerves directly
innervate the female reproductive system and facilitate orgasm in women with
complete SCI (Komisaruk et al., 2004). Therefore, it has been assumed that the
Vagus nerve might also play a role in facilitating the mechanical process of labor
and delivery.
With the understanding that there is no published data on using VNS in any form as
an application in labor and delivery nor any known laboratory research currently
being conducted for this application, the argument presented in this thesis is
therefore limited to a literature review of the physiology of the female reproductive
system in both sexual response and childbirth, the involvement of the nervous and
endocrine systems during labor and delivery, any medical interventions that might
affect the role of these systems, the applications, methods, and effects of VNS, and
any relevant research pertaining to childbirth as the basis for the reasoning behind
the research goal. Every effort has been made to synthesize this research into a
8
logical argument, and discussions are presented in cases where the literature has
been found to be contradictory of itself.
9
Chapter 2
Anatomy Review
2.1 Primary Anatomical Structures of Birth
It is well understood that to learn about labor and birth one must first know the
parts that comprise the female reproductive system and what functions they
perform in this process. Indeed, the first few chapters of one of the earliest
published compilations of conventional knowledge on midwifery consist of a
description of what the muscles and membranes of the body are followed by a
detailed review of the anatomical structures of the female reproductive system (see
Figure 1) (Hobby, 2009). The same format was used over 100 years later in one of
the first textbooks on obstetric medicine, which begins with a comprehensive
overview of the anatomy of the female reproductive system before listing the
contents of the book itself (Mauriceau, 1697). Modern textbooks tend to follow the
same format of reviewing female reproductive anatomy before presenting any other
content (see Figure 2) (Dewhurst & Edmonds, 2007; Posner et al., 2013; Pritchard
& MacDonald, 1976; Schumann, 1937), or may give a brief history of obstetrics
followed by a review of the anatomy involved in childbirth (Bookmiller & Bowen,
1954), but it appears that in presenting any approach to childbirth authors feel that
10
it is first necessary to inform the reader of the relevant anatomy and physiology
involved.
Figure 1 – Sixteenth Century Drawing of Female Reproductive System
(Hobby, 2009)
11
Figure 2 – Modern Drawing of Female Reproductive System (Pritchard &
MacDonald, 1976)
Anatomical terminology has changed over the centuries and the current
understanding of the female reproductive system is much more complex than it was
in the formative years of obstetric medicine, but little has changed in regards to
agreement about the gross anatomical structures involved in childbirth.
12
Specifically, the uterus, cervix, and vagina are the main parts of the reproductive
system that accomplish parturition, or birth, and thus comprise the birth canal
(Schumann, 1937). It was known at least as early as the sixteenth century that the
fetus is enclosed in the uterus during gestation and that the cervix, a narrow passage
connecting the vagina to the uterus, remains tightly closed during pregnancy but
during childbirth dilates many times its normal size until it is large enough to
accommodate the passing of the fetus’ head out of the uterus and through the
vagina for delivery (Hobby, 2009).
13
Chapter 3
Review of Childbirth Process
3.1 Overview of Parturition
Parturition is a complex event with many physiological and anatomical changes
occurring over a relatively short time. The whole process is broken down into three
stages of labor (Posner et al., 2013). Parturients are categorized as either nulliparas,
if they have not given birth before, or multiparas, if they have (Posner et al., 2013).
By the start of labor the cervix should be ripe, which is defined as soft, shorter than
1.3 cm in length, easily admits a finger and is dilatable (Posner et al., 2013).
The period between onset of labor and full cervical dilation is the first stage of
labor, and generally lasts between six to eighteen hours for nulliparas and two to
ten hours for multiparas (Posner et al., 2013). The second stage of labor begins
when the cervix is fully dilated and lasts until the baby is born, and the third stage
of labor is the period between the expulsion of the baby from the birth canal and
the delivery of the placenta (Posner et al., 2013).
The duration of the second stage of labor is largely dependent on parity and
whether or not the mother received epidural analgesia, a nerve block for labor pain
(Posner et al., 2013). Multiparous women with two or more previous births tend to
14
labor a quarter of the time as nulliparas, and women who have received epidurals
tend to labor almost twice as long as women of the same parity who have not (see
Table 1) (Posner et al., 2013). The duration of the third stage of labor is considered
abnormal if it takes longer than thirty minutes (Posner et al., 2013).
Table 1 – Duration of Second Stage of Labor in Minutes (Posner et al., 2013)
3.2 The First Stage of Labor
The first stage of labor consists of three main phases: the latent phase, the active
phase, and the descent of the presenting part (Posner et al., 2013). The latent phase
begins with the mother feeling strong, regular contractions of the uterus that
progressively get stronger and more coordinated (Posner et al., 2013). Also during
this time the cervix is becoming softer, pliable, and elastic (Posner et al., 2013).
The active phase begins when the cervix is dilated between 3 to 4 cm for nulliparas
15
and 4 to 5 cm for multiparas, and during this phase cervical dilation continues until
it reaches about 10 cm, or full dilation (Posner et al., 2013). The descent of the
presenting part refers to the descent of the fetus through the birth canal, and while it
begins in the latent phase it mostly occurs when the cervix reaches full dilation and
progresses into the second stage of labor (Posner et al., 2013).
3.3 The Second Stage of Labor
There are two separate phases in the second stage of labor, passive and active
(Posner et al., 2013). In the passive stage, the cervix is fully dilated but the fetal
head has not reached the pelvic floor and expulsive efforts have not yet begun
(Posner et al., 2013). Once the fetal head is at the level of the pelvic floor or lower
the active phase begins, in which the mother engages in pushing (Posner et al.,
2013). As the mother pushes, the contractions push the baby lower in the birth
canal until the head emerges from the vagina (Posner et al., 2013). After the birth of
the head one final push delivers the shoulders, and generally the rest of the body
then slides out without effort (Posner et al., 2013). After the baby is delivered, the
umbilical cord is clamped and the second stage of labor ends (Posner et al., 2013).
3.4 The Third Stage of Labor
The third stage has two parts: separation of the placenta from the uterine wall and
expulsion of the placenta through the birth canal (Posner et al., 2013). Placental
16
separation usually occurs within five minutes of the end of the second stage of
labor (Posner et al., 2013). Expulsion of the placental is done by tractioning the
cord while applying pressure to the uterus just above the symphysis pubis of the
pelvis, a technique referred to as the Brandt-Andrews maneuver (Posner et al.,
2013). The delivery of the placenta ends the third stage of labor, and thus
completes the birth.
3.5 Birth by Cesarean Section
Cesarean section is a form of delivery where the fetus is removed from the uterus
through a surgical incision in the abdomen (Posner et al., 2013). Current cesarean
rates are between 25-30 percent (Posner et al., 2013), although the World Health
Organization has suggested that the rate should be between 10-15 percent (WHO,
2015). There are a number of indications for cesarean section, such as fetopelvic
disproportion, where the fetal head is too large to pass through the birth canal,
malpresentation or malposition of the fetus, labor dystocia, or labor that lasts much
longer than usual, previous cesarean surgery, and fetal distress (Posner et al., 2013).
The fetal mortality rate in cesarean procedures is higher than that of vaginal
delivery, but that is primarily attributable to the conditions for which the cesarean
was indicated (Posner et al., 2013).
17
Chapter 4
Nervous System Review
4.1 Nervous System Overview
The nervous system consists of a central nervous system (CNS) and a peripheral
nervous system (PNS). The CNS includes the brain and spinal cord (Nathan, 1997),
and the PNS is comprised of the cranial, spinal, and autonomic nerves ("Nervous
System," 2016). The brain has several major divisions, including the cerebrum,
basal nuclei, mid-brain, pons, cerebellum, and medulla oblongata ("Brain," 2010),
and the spinal cord is a cylindrical structure that is continuous with the medulla
oblongata and extends through the spinal column to give off the spinal nerves of
the PNS ("Spinal cord," 2010).
These nerves include eight cervical nerves (C1-C8), twelve thoracic nerves (T1T12), five lumbar nerves (L1-L5), five sacral nerves (S1-S5), and a coccygeal
nerve (Co) (See Figure 3) (Netter, 2014). At about the level of L1 the spinal cord
starts to branch out and separate into a bundle of the remaining spinal nerves,
referred to as the cauda equina (Netter, 2014). The brain and spinal cord are
protected by a sheath of three layers of tissue called the dura mater, arachnoid
mater, and pia mater that collectively are referred to as the dural sac (Netter, 2014).
18
This sac also encases much of the cauda equina, but it terminates at about the level
of S3 (Netter, 2014). There are also twelve cranial nerves, and with the exception
of the hypoglossal nerve, or the twelfth cranial nerve, they all directly innervate the
brain without any fibers passing through the spinal cord (See Figure 4) (Netter,
2014).
19
Figure 3 – Spinal nerve roots exiting the CNS (Netter, 2014)
20
Figure 4 – Motor and Sensory Distribution of the Cranial Nerves to the
Brain (Netter, 2014)
21
4.2 The Spinal Cord
The spinal contains both white matter, which contains mostly myelinated neurons,
and gray matter, comprised mainly of nonmyelinated neurons, arranged such that
the gray matter has a shape somewhat like a butterfly and is surrounded by white
matter (See Figure 5) (Nathan, 1997; Netter, 2014). Spinal nerves terminate and
originate in the grey matter, with afferent, or sensory, input entering through the
posterior portion, or dorsal horn, and efferent, or motor, output exiting through the
anterior portion, or ventral horn (Nathan, 1997; Netter, 2014). The gray matter has
been further compartmentalized into ten subunits, called laminae, that correspond
to localized differences in cellular structure (Rexed, 1952). These subunits,
commonly referred to as Rexed laminae, were first described based on anatomical
findings in the cat, but have been used as a model to describe human anatomy and
physiology, as well (Bonica, 1979; Schoenen, 1982).
Figure 5 – Diagram of Cross Section of Spinal Cord (Nathan, 1997)
22
4.3 The Autonomic Nervous System
Autonomic nerves are not under voluntary control, and can be further broken down
into the sympathetic and parasympathetic nervous systems (See Figure 6 and
Figure 7) ("Nervous System," 2016). However, the autonomic nerves are not
entirely separate from the cranial or spinal nerves. Sympathetic input to the CNS is
relayed first to sympathetic nerve ganglion and then to the spinal nerves via
structures called white and gray ramus communicans (Netter, 2014).
Parasympathetic nerves at the spinal nerve level, on the other hand, do not have
rami communicans; rather they connect directly to the spinal nerves (Netter, 2014).
Interestingly, a few of the cranial nerves, including the oculomotor, facial,
glossopharyngeal, and Vagus nerves, are, in fact, part of the parasympathetic
nervous system (Netter, 2014). Also, it has been established that emotions can
influence the autonomic nervous system ("Nervous System," 2016). The
sympathetic system tends to be activated by negative feelings such as rage and fear
whereas the parasympathetic system regulates bodily functions while one is relaxed
and peaceful (Nathan, 1997).
23
Figure 6 – Sympathetic Nervous System (Netter, 2014)
24
Figure 7 – Parasympathetic Nervous System (Netter, 2014)
There are many substructures within the primary divisions of the brain that have
specialized functions. One of these is the hypothalamus, which is found in the basal
nuclei of the brain ("Brain," 2010). The hypothalamus is believed to be the
structure that regulates the autonomic nervous system, and is the site that controls
primitive physical and emotional behavior ("Hypothalamus," 2010). It also has
25
centers that regulate metabolism, sleep, body temperature, and sexual function
("Hypothalamus," 2010). The primary nervous structures of the hypothalamus
include the paraventricular, posterior, dorsomedial, supra-optic, ventromedial,
arcuate, and mammillary body nuclei (Netter, 2014). Of these, it is the
paraventricular nucleus (PVN), supra-optic nucleus (SON), and arcuate, or
infundibular, nucleus which have neurons that project into the pituitary gland via
the pituitary stalk, or infundibulum (See Figure 8) (Netter, 2014). The pituitary
gland, while connected to the hypothalamus, is actually part of the endocrine
system ("Pituitary gland," 2010). Endocrine involvement in parturition is discussed
in Chapter 6.
Figure 8 – Diagram Showing Neural Projections of PVN, SON, and Arcuate
Nuclei From Hypothalamus to Pituitary Gland (Netter, 2014)
26
Chapter 5
Innervation of Female
Reproductive System
5.1 Background and History
The modern idea that the brain oversees voluntary motion and interpretation of
sensory information was first proposed in a scientific sense by Galen (130 – 210
A.D.), whose experiments with nerves allowed him to identify both that there are
separate nerve roots now known as the afferent and efferent nerves, and that
damage to the spinal cord results in partial or total loss of their function (Riese,
1959). Regarding childbirth, Galen believed that labor was caused by the head of
the fetus stimulating the nerves of the cervix and lower uterus as it began its
descent through the birth canal, a possibility still accepted by modern medicine as a
potential cause of the onset of labor (Schumann, 1937).
The nerves of the uterus, referred to as the womb, were described by Mauriceau as
originating from the “sixth pair of the brain” and the spinal cord (Mauriceau, 1697).
At the time, the sixth pair of nerves was used to describe the three cranial nerves
now known as the glossopharyngeal, Vagus, and accessory nerves (Swanson,
2014). These are the ninth, tenth, and eleventh cranial nerves, respectively, but it is
27
only the Vagus nerve that has fibers that project inferior to, or below, the shoulder
line in the human (See Figure 3) (Netter, 2014). As mentioned previously, the
Vagus nerve is also one of the cranial nerves that comprises the parasympathetic
nervous system (Netter, 2014). Interestingly, Mauriceau attributed the shared
innervation of the sixth pair of nerves between the stomach and womb to nausea
experienced during pregnancy and even suggested that vomiting during childbirth
hastens delivery (Mauriceau, 1697). It does not appear that any modern research
has been done to determine if there is any truth to that claim, but there are cases not
related to childbirth where emesis can be induced or ceased by modifying Vagus
nerve function (Lang, 1999).
Modern anatomy and obstetric textbooks do not acknowledge that the female
reproductive system is directly innervated by the Vagus nerve. Some claim that
labor is regulated exclusively by the sympathetic nervous system and spinal nerves
(Pritchard & MacDonald, 1976; Schumann, 1937). Others only mention the
parasympathetic system in discussions on topics not directly related to childbirth
such as urinary incontinence (Dewhurst & Edmonds, 2007) Moreover, some
textbooks do not even mention the nerves of the reproductive system except in
discussing what nerves to apply a block to in labor analgesia and anesthesia (Posner
et al., 2013; Pritchard & MacDonald, 1976). It was previously suggested that
parasympathetic nerves may have afferent fibers that extend to the uterus (Moir,
28
1939; Robertson & Guttmann, 1963), and it is now shown in anatomy books that
both afferent and efferent parasympathetic fibers do indeed innervate the lower
uterus, cervix, and upper vagina (Netter, 2014). However, the pathway for this is
believed to be associated only with the sacral spinal nerves and not the Vagus nerve
(Moir, 1939; Netter, 2014). More recently, it has been shown that women with
complete spinal cord injury above the level of T10, meaning that they receive no
sensory input from the reproductive system through the CNS, are capable of
experiencing an orgasm through mechanical stimulation of the vagina and cervix,
presumably modulated by afferent Vagus nerve fibers extending from these
structures (Komisaruk et al., 2004).
5.2 Sensory Nerves
Generally speaking, afferent nerve fibers of the female reproductive system include
the pudendal, pelvic splanchnic, and hypogastric nerve bundles, which innervate
the vagina, cervix, and uterus, respectively (See Figure 9) (Netter, 2014), although
the afferent innervation of the cervix has been disputed (Bonica, 1979; Bonica &
Chadwick, 1989; Komisaruk et al., 2004). Interestingly, sensory information from
both the pudendal and pelvic splanchnic nerves enter the CNS through the second,
third, and fourth spinal nerves of the sacrum, and the pelvic splanchnic nerves are
also the route that parasympathetic nerve fibers follow to enter the spinal cord
29
(Netter, 2014). Aferent input from the hypogastric nerve enters the sympathetic
ganglia of the L2 and L3, and then travels through the ganglia to enter the spinal
cord through T11 and T12 (Netter, 2014).
Figure 9 – Innervation of the Female Reproductive System (Netter, 2014)
30
5.3 Motor Nerves
Motor impulses to the female reproductive system are under both autonomic and
voluntary control, but there is a discrepancy between the texts on what spinal
nerves give rise to the efferent fibers that innervate uterus. It is stated in Williams
Obstetrics that during labor motor impulses are transmitted by T7 and T8
(Pritchard & MacDonald, 1976), but in the Atlas of Human Anatomy it is shown
that sympathetic motor fibers extend from the T11 and T12 to the uterus,
parasympathetic motor fibers travel through the pelvic splanchnic nerves to the
cervix and upper vagina, and motor fibers under voluntary control extend to the
lower vagina and external female anatomy through the pudendal nerve (See Figure
10) (Netter, 2014). Both the pelvic splanchnic and pudendal nerves extend from
S2-S4 (Netter, 2014).
31
Figure 10 - Neuropathways of Parturition (Netter, 2014)5.4 Nerves That
Transmit Pain During Labor
It has been reported throughout the last few decades that the nerves that transmit
pain during childbirth include T10-L1 in the first stage of labor and S2-S4 in the
32
second stage (Bonica, 1970, 1979; Bonica & Chadwick, 1989; Brownridge, 1995;
Nicolls, Corke, & Ostheimer, 1981; Pritchard & MacDonald, 1976). This is in
direct conflict with the Atlas of Human Anatomy, which states that the pain from
uterine contractions are transmitted through a number of nerves in the abdomen and
pelvis and enter the CNS via T11 and T12, and that pain from cervical dilation and
the upper vagina is conducted through the pelvic splanchnic nerves to S2-S4
(Netter, 2014). In fact, it has been noted that research has concluded that labor pain
from cervical dilation is transmitted by T10-L1 and not S2-S4 as reported in
anatomy books (See Figure 11) (Bonica, 1979; Bonica & Chadwick, 1989), and
from this it has been assumed that the parasympathetic nervous system is not
involved in transmitting pain signals during parturition (Brownridge, 1995;
Rowlands & Permezel, 1998). Also, it has been suggested that the descent of the
fetal head through the birth canal may cause pain to be referred through L2-S1
(Bonica, 1979; Brownridge, 1995).
33
Figure 11 – Nerve Pathways for Labor Pain (Bonica & Chadwick, 1989)
34
Chapter 6
Endocrine System Involvement in
Parturition
6.1 Background and History
Towards the end of the nineteenth century, there was a rapid expansion of
knowledge about the glands that secrete hormones, or chemical signals that are
produced to effect the function of the organ it targets (Kleine & Rossmanith, 2016).
Hormones are transported to the target organ through the bloodstream in what is
known as the endocrine process (Kleine & Rossmanith, 2016). In childbirth, the
primary hormones released are oxytocin, beta-endorphin, adrenaline and
noradrenaline, and prolactin (Buckley, 2005). There is also a possible role of the
hormones estrogen and progesterone in parturition, but their involvement is not
well understood (Posner et al., 2013).
By the 1930s, the extent of knowledge regarding the role of the endocrine system
on the reproductive system was limited to a few hormones secreted from the
pituitary gland (See Figure 12) and the observation that the size of the thyroid,
parathyroid, and adrenals increase during pregnancy (Schumann, 1937). It was
known that the posterior pituitary had a pressor, or blood pressure-raising, effect on
35
the circulatory system, a water-retention effect on the kidneys, and an oxytocic
action on the uterus while the anterior pituitary produced hormones for growth,
metabolism, follicle ripening, milk production, and luteinization (preparation of
uterus for pregnancy) (Schumann, 1937). While the pressor and antidiuretic effect
of posterior pituitary extract had been described previously and are now attributed
to the hormone vasopressin (Kleine & Rossmanith, 2016), the so-called oxytocic
effect was discovered by Sir Henry Dale in 1906 when he noted that pituitary
extract had a strong contractile effect on the uterus of a cat (Dale, 1906; Kleine &
Rossmanith, 2016). This substance was named oxytocin, meaning “swift birth” in
Greek (Magon & Kalra, 2011).
Figure 12 – Diagram Showing 1930s Understanding of Pituitary Involvement
in Female Reproductive System (Schumann, 1937)
36
6.2 Hormones of the Posterior Pituitary
One of the places oxytocin receptors can be found in the body is on the uterus, and
towards the end of pregnancy the number of uterine oxytocin receptors increases
significantly so that by the start of labor there are 300 times the number of
receptors found in the nonpregnant uterus (Tenore, 2003). The increased number of
receptors increases uterine sensitivity to oxytocin, and oxytocin is believed to
increase the excitability of the uterine muscle and thus causes it to contract (Posner
et al., 2013). Endogenous oxytocin release can be stimulated by cervical dilation,
sexual intercourse, emotional reactions, suckling, and certain drugs such as
acetylcholine (Posner et al., 2013)
The origin of posterior pituitary hormones has not been well understood until the
last several decades. In 1951, it was proposed that the posterior pituitary functions
as a place to store, but not produce, vasopressin and oxytocin as had previously
been believed (Bargmann & Scharrer, 1951; Kleine & Rossmanith, 2016; Scharrer
& Scharrer, 1954). It was theorized that in the brain these hormones are produced
by the PVN and SON of the hypothalamus, and then transported via a portal system
to be stored in the posterior pituitary gland (Bargmann & Scharrer, 1951; Scharrer
& Scharrer, 1954). This was substantiated in 1975 (Daniel & Prichard, 1975), and
the hypothalamic-pituitary, or hypophyseal, portal system is now the accepted
37
model of posterior pituitary hormone release into the bloodstream (See Figure 13)
(Kleine & Rossmanith, 2016). Interestingly, while the pituitary gland is continuous
with the brain it actually sits outside the blood-brain barrier (BBB) (Nussey &
Whitehead, 2001), a highly selective transport system that limits the passage of
circulatory molecules to only those required by the brain to function properly
(Montenegro & Juarez, 2012)
38
Figure 13 – The Hypothalamic-Pituitary Portal System and Vasculature
(Netter, 2014)
6.3 Hormones of the Anterior Pituitary
Unlike the posterior pituitary, the anterior pituitary is capable of producing
hormones in addition to storing them, but in order to release them the portal system
must deliver hypothalamic-releasing hormones from the hypothalamus to receptors
39
on the anterior pituitary (Kleine & Rossmanith, 2016). There are four different
hypothalamic-releasing hormones that affect the release of various anterior
pituitary hormones (Kleine & Rossmanith, 2016). Of these, the ones involved in
releasing hormones associated with childbirth are corticotropin releasing hormone
(CRH) and thyrotropin releasing hormone (TRH) (Kleine & Rossmanith, 2016). A
nonpregnant woman not under stress normally has CRH levels around 10-20 pg/ml,
but a woman at full term pregnancy or in labor generally has a peak concentration
between 1000-10,000 pg/ml, a level normally only reached in periods of stress
(McLean & Smith, 2001). However, the stress response results in only a brief
period of elevated CRH whereas in late term pregnancy and labor these levels are
relatively constant (McLean & Smith, 2001).
Two of the pituitary hormones CRH stimulates the release of are beta-endorphin
and adrenocorticotropic hormone (ACTH), which are both derived from the
anterior pituitary hormone precursor proopiomelanocortin (Kleine & Rossmanith,
2016). Beta-endorphin is an endogenous analgesic, or pain suppressor, and ACTH
acts on the adrenal glands (Kleine & Rossmanith, 2016). The adrenals are located
on top of the kidneys, and when stimulated they glucocorticoids,
mineralocorticoids, and the hormone adrenaline (Kleine & Rossmanith, 2016).
Interestingly, animal studies have shown that there is a chance that oxytocin may
also be associated with ACTH release during labor (Campbell et al., 1987; Link,
40
Dayanithi, Föhr, & Gratzl, 1992; Matthews, 1999), and therefore could be partially
responsible for the adrenal response in parturition (Campbell et al., 1987; Gimpl &
Fahrenholz, 2001). In fact, both human and rat studies have found oxytocin in the
adrenal glands at much higher concentrations than in the plasma (Ang & Jenkins,
1984), and oxytocin is also known to enhance the effects of CRH (Gimpl &
Fahrenholz, 2001).
Prolactin, another anterior pituitary hormone, is regulated by dopamine and is
stimulated by TRH, oxytocin, vasoactive intestinal peptide (VIP), an intestinal
neurotransmitter and neuromodulator, and possibly by a yet unidentified
hypothalamic-releasing hormone (Kleine & Rossmanith, 2016). Interestingly, the
lactotropic pituitary cells, which dopamine functions to suppress, release prolactin
without stimulation if dopamine levels are low (Kleine & Rossmanith, 2016). Also,
dopamine can inhibit prolactin release that is stimulated by the hypothalamic
releasing hormone TRH, but not oxytocin or VIP (Kleine & Rossmanith, 2016).
While prolactin has no mechanical role in childbirth, it does regulate milk
production and helps to promote the mother-child bond (Buckley, 2005; Kleine &
Rossmanith, 2016). Also, it has been shown that that prolactin stimulates the
release of oxytocin and vasopressin in rats (Vega et al., 2010). However, at present
there is no evidence that this also occurs in humans.
41
6.4 Hormones of the Adrenal Glands
Adrenaline and noradrenaline, as well as dopamine, are collectively referred to as
the catecholamines (CA), or amino acid derived hormones (Kleine & Rossmanith,
2016). In fact, adrenaline is derived from noradrenaline, which is derived from
dopamine (See Figure 14) (Kleine & Rossmanith, 2016). Noradrenaline and
adrenaline control the sympathetic response to stress, such as increasing heart rate,
constricting blood vessels, and increasing glucose availability (Kleine &
Rossmanith, 2016). The primary difference between noradrenaline and adrenaline
is that noradrenaline functions as a neurotransmitter that acts through nerve
synapses while adrenaline is released into and acts through the circulatory system
(Kleine & Rossmanith, 2016). It should be noted that increased levels of
adrenaline and noradrenaline are normal during labor and help provide the energy
needed for the final fetal expulsion efforts by the mother, but if the levels get too
high due to maternal stress or discomfort they can interfere with oxytocin release
(Buckley, 2005). When there are high levels of both oxytocin and CA the uterus
will produce a few extremely strong contractions resulting in a quick birth, referred
to as the fetus ejection reflex (Buckley, 2005; Odent, 1987).
42
Figure 14 – Biosynthesis of Noradrenaline and Adrenaline from Dopamine
(Kleine & Rossmanith, 2016)
6.5 Endocrine Role in Initiation of Labor
It cannot be definitively stated what initiates labor in humans. It has long been
assumed that the fetus, not the mother, is responsible for the start of labor, and
while this is well documented in sheep there is also evidence that this occurs in
primates and may also be the case in humans (Challis, Matthews, Gibb, & Lye,
2000). Animal studies have shown that the fetus and placenta may release
hormones that act on the maternal endocrine system to trigger the start of labor
(Challis et al., 2000; Posner et al., 2013). There is some evidence that suggests
43
prostaglandin may play a role in the onset of labor (Challis et al., 2000; Posner et
al., 2013; Tenore, 2003).
Prostaglandins are similar to hormones in that they are chemical messengers, but
they have a more localized action and are primarily made by immune cells so they
are not considered part of the endocrine system (Kleine & Rossmanith, 2016).
Prostaglandins, as well as synthetic oxytocin, are used as pharmacological agents to
induce labor (Posner et al., 2013; Tenore, 2003). Interestingly, endogenous
oxytocin is not believed to be able to induce labor (Posner et al., 2013; Pritchard &
MacDonald, 1976). It has been suggested that prostaglandin plays a major role in
parturition (O'Brien, 1995), but at present knowledge of its function is limited to
cervical ripening (Nair, Verma, & Singh, 2017). Although the exact role of
oxytocin in childbirth is still being discovered, there is already an abundance of
information available on its use in labor induction and augmentation.
44
Chapter 7
Oxytocin: A Closer Look
7.1 Endogenous Oxytocin Release in Labor
It was first proposed in 1961 that oxytocin is released from the posterior pituitary
during delivery as a result of a sympathetic nervous response activated by
stretching of the lower birth canal (Goodfellow et al., 1983). Subsequently,
multiple teams of researchers measured increased plasma oxytocin levels during
labor that peaked in the second stage (Coch, Brovetto, Cabot, Fielitz, & CaldeyroBarcia, 1965; Dawood, Raghavan, Pociask, & Fuchs, 1978; Goodfellow et al.,
1983; Leake, Weitzman, Glatz, & Fisher, 1979). Evidence of this has also been
shown in the rat, where it has been found that the amount of oxytocin stored in the
posterior pituitary gland increases by 50% during pregnancy but is temporarily
depleted postpartum, or following birth (Blanks & Thornton, 2003). Another
interesting finding is that endogenous oxytocin has a pulsatile release profile, and
that during labor and delivery the frequency and duration of the pulses increases
(Fuchs et al., 1991).
There is also some evidence that the fetus may play a role in releasing oxytocin
during parturition (Goodfellow et al., 1983). It has been shown that umbilical cord
45
blood from babies delivered vaginally has a significantly higher oxytocin
concentration than from babies delivered by cesarean section (De Geest, Thiery,
Piron-Possuyt, & Driessche, 1985). Some researchers have even theorized that the
synthesis of mRNA encoding oxytocin within the uterus late in pregnancy may
have a local hormonal effect that could be important in parturition (Mitchell, Fang,
& Wong, 1998). Much more research needs to be done to learn the full extent of
the involvement of these different endogenous sources of oxytocin release during
parturition.
Besides the known effect of oxytocin to stimulate uterine contractions, it has also
been found that plasma oxytocin levels during pregnancy have an effect on motherchild bonding and postpartum depression (PPD) (Feldman et al., 2007; Skrundz et
al., 2011). Indeed, it has been reported that plasma oxytocin levels during
pregnancy are negatively associated with the risk of developing PPD (See Figure
15), a condition that affects nearly one in five women after childbirth (Skrundz et
al., 2011). One important point to note is that oxytocin does not cross the BBB
(Altemus et al., 2004; Landgraf & Neumann, 2004; Skalkidou et al., 2012), so
peripherally released oxytocin is not believed to act on the CNS (Altemus et al.,
2004). However, peripheral oxytocin levels taken from plasma samples have been
found to be significantly higher than CNS oxytocin levels measured from samples
of cerebrospinal fluid in pregnant women compared to nonpregnant women
46
(Altemus et al., 2004; Skalkidou et al., 2012). Interestingly, it has also been noted
that PPD is associated with a marked decrease in hypothalamic-pituitary activity
(Tsigos & Chrousos, 2002).
Figure 15 – Graph Showing Higher Plasma Oxytocin Levels in Pregnant
Women Not at Risk for Developing PPD than in Women Who Are at
Risk for PPD (Skrundz et al., 2011)
It does not appear that any research has yet been done to determine if there is a
significant difference in CNS levels of oxytocin between pregnant women who are
47
at risk and not at risk for experiencing PPD. There has, however, been research
published that women who suffered from a traumatic childhood, a group known to
be vulnerable to depression, had significantly lower CNS levels of oxytocin than
women who did not (Heim et al., 2009). The exact relationship between CNS
oxytocin levels and depression, if there is one, remains to be seen (Altemus et al.,
2004; Heim et al., 2009). Regardless, the BBB limits the oxytocin, as well as
vasopressin, that is released in the CNS to the hypothalamic nuclei, and thus it is
believed that it is these neurons that contribute to the emotional response of the
brain to these hormones (See Figure 16) (Landgraf & Neumann, 2004).
48
Figure 16 – Vasopressin and Oxytocin Release in Hypothalamic and
Extrahypothalamic Sites (Landgraf & Neumann, 2004)
Interestingly, both the PVN and SON have oxytocin receptors, and thus oxytocin
released from these structures binds to them and stimulates further oxytocin release
creating a positive feedback loop (Carson, Guastella, Taylor, & McGregor, 2013).
During labor, it is believed that the first contractions of the uterus trigger a release
of oxytocin from the PVN and SON which then binds to receptors both in the
uterus and hypothalamus, and thus causes stronger contractions and greater
oxytocin release, respectively (Carson et al., 2013; Neumann, Douglas, Pittman,
49
Russell, & Landgraf, 1996). However, evidence of this is currently limited to
results of animal studies (Armstrong & Hatton, 2006; Kimura et al., 2003;
Neumann et al., 1996), although the release of oxytocin during parturition is well
known and is referred to as the Ferguson reflex (See Figure 17) (Carson et al.,
2013; Ferguson, 1941). While Ferguson’s research was conducted on cats and
rabbits, it has been demonstrated in humans, as well (Vasicka, Kumaresan, Han, &
Kumaresan, 1978).
Figure 17 – Diagram of the Ferguson Reflex (Everett, 1964)
50
7.2 Pharmacologic Use of Oxytocin in Labor
Although oxytocin is not believed to be directly responsible for the initiation of
parturition, it has been used in the management of labor for many years. In 1909, it
was reported that posterior pituitary extract was effective in treating post-partum
hemorrhage (Theobald, Graham, Campbell, Gange, & Driscoll, 1948), and because
of this it remains current practice to administer 10 IU (International Units), or about
17 μg, of oxytocin via intramuscular injection during the third stage of labor
(Posner et al., 2013). Oxytocin was isolated in 1926 (Kleine & Rossmanith, 2016),
and by 1927 it had been used to treat prolonged labor (Theobald et al., 1948).
However, the method of administration was not standardized until a slow drip
intravenous method was developed in 1948 (Moir, 1964; Theobald et al., 1948),
and prior to that there was a general fear of using oxytocin during labor due to a
number of cases where women died after being given too large of a dose (Moir,
1964).
There are still some notable risks and side effects for using synthetic oxytocin,
including tachysystole, or more than five contractions in ten minutes over a thirty
minute period, uterine rupture, cervical and vaginal lacerations from the baby
passing through too quickly, water intoxication, and premature separation of the
placenta (Posner et al., 2013). Additionally, there is the possibility of loss of uterine
51
tone and postpartum hemorrhage after the oxytocin infusion is stopped (Posner et
al., 2013). Oxytocin can also have damaging effects on the fetus, including loss of
oxygen supply caused by contractions that last too long or are too hard or frequent,
being forced through a pelvis that is too small for its head, and abnormal heart rate
patterns (Posner et al., 2013). In fact, one of the indications for monitoring the fetal
heart rate during labor is the use of synthetic oxytocin (Posner et al., 2013).
Currently, all medically administered forms of oxytocin are synthetic, and the
preferred method of delivery is intravenous infusion (Posner et al., 2013). It is
recommended that the dosage of synthetic oxytocin for labor augmentation be kept
at a minimum, and therefore the infusion is generally started at a rate of 1 mU/min
(1.7 pg/min) and increased gradually until regular uterine contractions are achieved
(Posner et al., 2013). Generally doses of less than 10 mU/min are adequate to
induce contractions, and for safety the maximum dose should not exceed 20
mU/min (Posner et al., 2013). In comparison, oxytocin secreted by the fetus and
maternal posterior pituitary gland during the first stage of spontaneous, or noninduced, labor has a combined concentration between 5-7 mU/min (Simpson,
2011).
Also, it has been noted that while endogenous oxytocin is released in a pulsatile
manner the infusion of synthetic oxytocin is generally administered at a continuous
52
rate (Simpson, 2011). The pulsatile nature of endogenous oxytocin release is
believed to create a greater effect on uterine contractions with a lower amount of
hormone than is required to get the same effect with synthetic oxytocin (Rooks,
2009). This has been demonstrated in an oxytocin challenge test, or pre-labor
screening of the fetal heart rate during contractions utilizing pulsatile versus
continuous oxytocin infusion, although notably the pulsatile method did take longer
to produce the same strength of contractions as the continuous infusion (Perales et
al., 1994).
Limited research has been done to determine if there is an advantage to using
pulsatile instead of continuous oxytocin infusion during labor, but the data reported
is inconsistent in terms of length of delivery and fetal morbidity (Cummiske, Gall,
& Dawood, 1989; Tribe, Crawshaw, Seed, Shennan, & Baker, 2012). It has been
proposed that a systematic review be performed to clarify any difference in safety
or efficacy between pulsatile and continuous oxytocin infusion in labor (Kendrick
& Neilson, 2015). There has been at least one review done to compare the safety
and efficacy of high dose versus low dose oxytocin infusion in labor augmentation,
but the authors excluded studies that used a pulsatile oxytocin delivery method
(Wei, Luo, Qi, Xu, & Fraser, 2010).
53
Chapter 8
Epidural Analgesia: Uses and Effects
8.1 Background and History of Epidural Use
There has been some controversy in the past regarding the use of analgesics in
labor. A number of physicians were initially skeptical of the idea after it was first
reported that the use of ether, an anesthetic, was successful at relieving labor pain
(Bookmiller & Bowen, 1954). There was also opposition from members of the
clergy, whose resistance was largely due to the bible passage in the book of
Genesis which, in reference to childbirth, states “In sorrow thou shalt bring forth
children.” (Bookmiller & Bowen, 1954). Regardless, the use of labor analgesics
persisted, and it is now widely considered inhumane to not offer pain relief during
labor. This philosophy may contribute to the widespread use of labor analgesics, as
a 2008 study of almost two million vaginal births across 27 states found that
epidural and spinal anesthesia was used in 61 percent of all cases (Osterman &
Martin, 2011).
Continuous caudal analgesia, a method of blocking pain by injecting an analgesic
into the area just outside of the dural sac (See Figure 3), or epidural space, of the
sacrum, was first described for use in labor almost halfway through the twentieth
54
century (Galley & Peel, 1944). This procedure focused on delivering an analgesic
that would migrate through the space until it reached the level of L1, but it was
specified that it should not go above that point or it could block the motor fibers
supplying the upper segment of the uterus and affect contractions (Galley & Peel,
1944). It was later noted, however, that uterine contractions are largely controlled
by hormones and that epidural blocks up to and including T2 do not interfere with
uterine contractions, although blocks should not paralyze the voluntary muscles of
the abdomen (Bromage, 1961).
8.2 Nerves Blocked by Epidural Analgesia
While the caudal method was effective at relieving childbirth pain, one of the
disadvantages of its use was that it only blocked pain transmitted by S2-S4 in the
second stage of labor (Bonica, 1970; Bromage, 1961). Instead, it was proposed that
a more effective method is the lumbar epidural method in which the infusion needle
is inserted into the L2 or L3 epidural space (Bromage, 1961). This method allows
input to T11 and T12 to be blocked during the first stage of labor and S2-S4 to be
blocked during the second stage (See Figure 18) (Bromage, 1961). It was specified
that the patient be lying down when the epidural analgesics were administered
during the first stage of labor so that the analgesic would only affect the upper
thoracic nerves, and during the second stage another dose should be given with the
55
patient sitting upright so that gravity could help the analgesic migrate through the
spinal canal to reach the sacral nerves (Bromage, 1961). In current practice it
appears that the patient can either be side lying or sitting during either stage of
labor to receive an infusion of epidural analgesia (Posner et al., 2013).
Figure 18 – Schematic Of Sensory Input During Labor (Bromage, 1961)
As mentioned previously, in the 1960s it was believed that epidural analgesia
below T2 had no effect on uterine contractions produced by hormone release
(Bromage, 1961). However, this has remained a controversial topic in obstetrics,
and in fact there is even an inconsistency in reports from the same author. In 1970,
John J. Bonica published an article comparing caudal to lumbar epidural anesthesia
and concluded that one of the advantages of using a lumbar epidural during the first
56
stage of labor was that the Ferguson reflex, a significant posterior pituitary release
of oxytocin during parturition, would not be blocked because the block would not
affect S2-S4 (Bonica, 1970). However, the Ferguson reflex is believed to be caused
by sensory input from the cervix as it dilates (Ferguson, 1941), and Bonica later
asserted that the nerve supply to the cervix is provided by T10-L1 rather than S2S4 (Bonica, 1979; Bonica & Chadwick, 1989).
It appears that the discrepancy this created in regards to the Ferguson reflex was not
addressed. In fact, when the details of the findings of the cervical sensory pathway
were reported only sympathetic pathways were mentioned (Bonica & Chadwick,
1989), and thus it has led some researchers to conclude that the parasympathetic
nervous system, which the Ferguson reflex is associated with, is not involved in
cervical labor pain (Brownridge, 1995; Rowlands & Permezel, 1998). The
Ferguson reflex is still associated with the parasympathetic innervation of S2-S4
when the cervix is fully dilated (May & Leighton, 2007). However, the second
stage of labor begins when the cervix reaches full dilation (Posner et al., 2013), and
that is when the epidural block is applied to S2-S4 (Bonica, 1970; Bromage, 1961;
May & Leighton, 2007).
57
8.3 Effect of Epidural Analgesia on Labor
Interestingly, it has been found that women who have received an epidural exhibit a
lower level of uterine activity during labor than women who have not (Alexander et
al., 1998; Bates, Helm, Duncan, & Edmonds, 1985), and the duration of the second
stage is notably longer in women who have versus have not had an epidural (See
Table 1) (Alexander et al., 1998; Cheng, Shaffer, Nicholson, & Caughey, 2014;
Leighton & Halpern, 2002b; Posner et al., 2013). The duration of the first stage of
labor might also be increased by epidurals (Alexander et al., 1998), although claims
have been made that it does not (Leighton & Halpern, 2002b; Posner et al., 2013).
Also, there have been some studies that have associated epidural use with an
increased risk of requiring oxytocin for labor augmentation (Alexander et al., 1998;
Goodfellow et al., 1983; Leighton & Halpern, 2002a, 2002b; Zhang et al., 1999),
and in fact some research has shown that women who receive epidural analgesia
have decreased plasma oxytocin levels during childbirth compared to controls
(Rahm, Hallgren, Högberg, Hurtig, & Odlind, 2002). It has even been reported that
the use of epidural analgesia decreases uterine activity following labor induction
with oxytocin (Alexander et al., 1998). It is unclear if the increased need for
synthetic oxytocin with epidural analgesia is due to a blockage of the Ferguson
reflex (Saunders et al., 1989), but given the nerves that the epidural blocks it is
possible (Goodfellow et al., 1983).
58
Chapter 9
Studies on the Female Sexual Response
9.1 Oxytocin Release During Orgasm
Since the 1960s, there has been a growing body of knowledge on the
neuroendocrine effect of the human sexual response. In 1987, it was shown in both
men and women that plasma oxytocin levels increase during sexual arousal
(Carmichael et al., 1987). After a single orgasm oxytocin levels peaked in females
but continued to rise in males (See Figure 19) (Carmichael et al., 1987). It was
concluded that the secretion pattern of oxytocin might coincide with smooth muscle
contractions of the reproductive system during orgasm (Carmichael et al., 1987).
Interestingly, it had been written years earlier that oxytocin might be released
during the female sexual response and was noted that uterine contractions
following sexual activity in nonpregnant women occur more often during the
premenstrual phase, when the uterine tissue is most sensitive to oxytocin (Lloyd,
1964). It was also suggested that this could be a variation of the Ferguson reflex
found in parturition (Everett, 1964).
59
Figure 19 – Mean Plasma Oxytocin Levels at Baseline, Early, Middle, and
Late Stages of Self Stimulation (SS), During Orgasm (OO), and 2 and
5 Minutes Post-Orgasm in Men (♂) and Women (♀) (Carmichael et
al., 1987)
9.2 Orgasm in Women with Complete Spinal
Cord Injury
One of the most recent discoveries in research on female sexuality is the ability of
women with complete SCI above the level of sensory input from the reproductive
system, believed to be T10 (Berard, 1989), to experience an orgasm. This
phenomenon had been mentioned as early as 1975 (Cole, 1975), and subsequent
reports of orgasm in women with complete SCI above the level of T9 followed
(Kettl et al., 1991; Sipski & Alexander, 1993; Sipski, Alexander, & Rosen, 1995;
60
Whipple, Gerdes, & Komisaruk, 1996). It was shown in 1990 that the uterus of the
rat is innervated by the Vagus nerve (Ortega-Villalobos et al., 1990), and it was
later reported that it innervates the cervix, as well (Collins, Lin, Berthoud, &
Papka, 1999). In a study published in 1997 it was suggested that the Vagus nerve
might also provide an afferent pathway for genital sensation in humans
(Komisaruk, Gerdes, & Whipple, 1997). It was hypothesized that this pathway
might be responsible for the pain-attenuating effects produced by vaginocervical
self-stimulation (See Figure 20) (Komisaruk & Sansone, 2003).
Figure 20 – Hypothetical Alternative Reproductive System Afferent Pathway
Mediated by the Vagus Nerve (Komisaruk & Sansone, 2003)
61
Later, functional magnetic resonance imaging (fMRI) was used to show that the
PVN of the hypothalamus is activated at the time orgasm is reported by women
with complete SCI above T10 using cervical self-stimulation (CSS) (See Figure 21)
(Komisaruk et al., 2004). It was stated that this activation is consistent with prior
reports that oxytocin is released occurring during orgasm (Carmichael et al., 1987),
as the PVN releases oxytocin from the posterior pituitary gland (Cross & Wakerley,
1977). In addition to the PVN, the Nucleus Tractus Solitarii (NTS) of the medulla
oblongata, where the Vagus nerves project into the CNS, is also activated during
CSS (See Figure 22) (Komisaruk et al., 2004). Vagal afferent fibers enter the NTS
via the dorsal vagal nucleus (DVN) (Netter, 2014), and a direct pathway extends
from the DVN to the PVN (See Figure 23) (Palkovits, 1999). Thus, the fMRI
studies of orgasm in women with complete SCI provides evidence of a genital
sensory pathway facilitated by the Vagus nerves (Komisaruk et al., 2006;
Komisaruk et al., 2004).
62
Figure 21 – MRI and fMRI Evidence of Activation of PVN During Orgasm in
Woman With Complete SCI (Komisaruk et al., 2004)
Figure 22 – fMRI Images Showing NTS Activation (arrows) During CSS
(Komisaruk et al., 2004)
63
Figure 23 – Diagram Showing the Neural Connection Between the Vagus
Nerve (X) and Paraventricular Nucleus (PVN) Through the Dorsal
Vagal Nucleus (DVN) (Palkovits, 1999)
9.3 Orgasm During Childbirth
Perhaps one of the greatest paradoxes in childbirth is that it can be a pleasurable,
and in some cases orgasmic, experience (Caffrey, 2014; Harel, 2007; Komisaruk &
Whipple, 2011; Komisaruk, Whipple, & Nasserzadeh, 2009; Mayberry & Daniel,
2015; Postel, 2013). The possibility of this experience, termed birthgasm, has led to
the development of a birth model referred to as Orgasmic Birth™, which consists
64
of a documentary film and book focused on describing pleasurable birth
experiences and how to have one (Davis & Pascali-Bonaro, 2010; Pascali-Bonaro,
2009). Like other birthing methods that utilize relaxation and breathing techniques
to reduce pain during labor (Bradley, 2008; Mongan, 2015), the Orgasmic Birth
concept also focuses on empowering the expectant mother by teaching her to
channel her pain and turn it into pleasure (Davis & Pascali-Bonaro, 2010; PascaliBonaro, 2009). One point worth noting is that models such as Orgasmic Birth tend
to advocate a natural birth, which generally refers to a birth that occurs at home or
in a midwife-assisted setting, rather than a medicalized birth that takes place in a
hospital in the care of an obstetrician (Brubaker & Dillaway, 2009).
Data showing the efficacy of these methods in improving birth outcomes is
questionable. For example, a comparison report on a method called
HypnoBirthing® showed excellent outcomes in areas such as synthetic oxytocin
infusion, episiotomy, and epidural rates compared to a national sample
(Swencionis, Litman Rendell, Dolce, Massry, & Mongan, 2012). A major
limitation of the study was that the HypnoBirthing data was collected from all
HypnoBirthing parents who completed an optional online survey (Swencionis et
al., 2012), but the data it was compared to had been adjusted to represent an
accurate national profile based on age, ethnicity, parity, and birth method and
attendant (Declercq, Sakala, Corry, & Applebaum, 2006). Overall, it appears that
65
there has been no solid empirical research conducted on the effectiveness of
Orgasmic Birth or any other natural birth method. However, recent research
conducted in a single hospital showed that mothers whose labors were attended by
a midwife had almost half the cesarean rate of deliveries attended by a physician
(Nijagal, Kuppermann, Nakagawa, & Cheng, 2015).
Although the success of Orgasmic Birth in producing a pleasurable childbirth
experience is largely based on anecdotal evidence, it does highlight the importance
in addressing the connection between childbirth and female sexuality. There are
some authors who believe that the medicalization of childbirth has taken the
intimacy and privacy out of the experience (Buckley, 2010; Mayberry & Daniel,
2015; Tew, 1998). There may also be a psychological explanation for the
separation of sexuality and childbirth, as the personal experience of both might be
influenced by culturally ingrained expectations in the individual of what should be
felt or thought during the experience (Mayberry & Daniel, 2015; Wiederman,
2005). Regardless, the nerves that convey sensory input from the reproductive
system to the CNS in the female sexual response are the same ones that transmit
pain during childbirth (Giuliano, Rampin, & Allard, 2002; Netter, 2014), and while
the Vagus nerves used to only be considered very likely to be involved in the
female sexual response (Giuliano et al., 2002) there is now fMRI evidence to show
that they are (Komisaruk et al., 2004).
66
Chapter 10
Vagus Nerve Stimulation
10.1 Overview of Vagus Nerve Stimulation
Electrical stimulation of the Vagus Nerve, referred to as Vagus nerve stimulation
(VNS), is a FDA approved neurostimulation method (Kotagal, 2011). In 1997,
VNS was approved for use in partial epilepsy (Kotagal, 2011), where seizures are
localized in one area of the brain ("epilepsy," 2016), although the mechanism by
which it reduces seizures is not yet known (McLachlan, 1997). Interestingly,
positron emission tomographic (PET) studies have found that blood flow in the
hypothalamus increases significantly both when the maximum or threshold level of
stimulation is applied (Henry et al., 1998), and fMRI studies also showed increased
blood flow in the hypothalamus with VNS being applied at 30 second rotating on
and off intervals (Narayanan et al., 2002).
Originally, VNS clinical trials were only performed using patients twelve years of
age and up, but its off label use has shown it to be effective in treating epilepsy in
younger patients, as well (Kotagal, 2011). In fact, it has been shown that children
under the age of twelve respond better to VNS implantation than children aged
twelve or above do (Alexopoulos, Kotagal, Loddenkemper, Hammel, & Bingaman,
67
2006). The safety of electrical stimulation in pregnancy has not been evaluated, and
pregnant women have therefore been excluded from enrollment in studies that
utilize it (Husain, Stegman, & Trevino, 2005; Sand et al., 1995). While this means
that no data exists on the safety or efficacy of any electrical stimulation therapy in
the pregnant population, there is case study evidence from a single patient who got
pregnant and delivered a baby while receiving VNS that indicated that it was safe
for both the patient and her baby (Husain et al., 2005). As an aside, the woman
received an epidural during labor but it was not mentioned if she required synthetic
oxytocin (Husain et al., 2005).
In addition to preventing seizures, VNS has also been found to improve the mood
in epileptic patients that receive it (Elger, Hoppe, Falkai, Rush, & Elger, 2000). It
has subsequently been approved by the FDA as a treatment for treatment-resistant
major depression (Cristancho, Cristancho, Baltuch, Thase, & O'Reardon, 2011),
and studies have found that in this group VNS has a response rate around forty
percent after one year (Cristancho et al., 2011; Schlaepfer et al., 2008) and up to
fifty percent after two years (Bajbouj et al., 2010). Researchers have also
investigated the potential use of VNS in treating a variety of pathologies such as
schizophrenia (Hasan et al., 2015), heart failure (De Ferrari et al., 2011), and
migraine and cluster headaches (Mauskop, 2005).
68
Previously, research has also been conducted on the potential application of VNS
as an analgesic (Komisaruk et al., 2006; Maixner & Randich, 1984; T. Ness,
Fillingim, Randich, Backensto, & Faught, 2000; T. J. Ness, Randich, Fillingim,
Faught, & Backensto, 2001; Randich & Gebhart, 1992). Interestingly, in rats
vaginocervical stimulation has been shown to modulate pain following transection
of all known genitospinal nerves with Vagus nerves left intact, but after the Vagus
nerves were transected in the same rats this analgesic effect was diminished
(Cueva-Rolón et al., 1996; Komisaruk et al., 2006; Komisaruk et al., 1996). Animal
models are also revealing the potential role of VNS in treating intestinal
inflammation (de Jonge et al., 2005; Han, Fink, & Delude, 2003; The et al., 2007;
Van Der Zanden, Boeckxstaens, & De Jonge, 2009) and improving recovery from
neurological injury (Ay, Napadow, & Ay, 2015; Ay, Sorensen, & Ay, 2011; Sun,
Baker, Hiraki, & Greenberg, 2012). Clearly, there is a diverse range of conditions
VNS can be applied to, but pregnancy does not appear to be one that has yet been
seriously considered.
10.2 Methods of Vagus Nerve Stimulation
When VNS was approved by the FDA for treatment of partial epilepsy, the devices
used in studies consisted of a surgically implanted stimulator with lead wires to left
69
branch of the Vagus nerve that passes through the neck (Henry et al., 1998;
Howland, 2014; Narayanan et al., 2002; Schachter & Saper, 1998). Left VNS was
also used later in the treatment of depression (Berry et al., 2013; Daban et al., 2008;
Howland, 2014). The use of right Vagus nerve stimulation has generally been
avoided due to the potential risk of unwanted cardiac side effects (Howland, 2014).
However, there have been VNS devices designed for and implanted into the right
cervical branch of the Vagus nerve specifically for the treatment of heart failure, an
application which so far appears to be successful (De Ferrari et al., 2011; Howland,
2014).
Perhaps VNS implantation in pregnant women has not been given much scientific
consideration because pregnant women, fetuses, and neonates (newborns) are given
special research protections in the United States Code of Federal Regulations
(OHRP, 2009), and because the FDA classifies implantable Vagus nerve
stimulators as Class III medical devices, which require a premarket approval
(PMA). Requirements of a PMA include non-clinical laboratory studies and clinical
studies (FDA, 2016). Given that VNS implantation is an invasive procedure and it
would be hard to justify the benefit of performing it for a single use in pregnant
women, it is understandable that it has not been an area of research that has been
actively pursued.
70
Recently, though, it has become known that there is a branch of the Vagus nerve
that extends into the external ear in humans, called the auricular branch of the
Vagus nerve (ABVN) (See Figure 24 and Figure 25) (Ellrich, 2011; Frangos et al.,
2015; Howland, 2014; Peuker & Filler, 2002). It has also been shown through
fMRI evidence that electrical stimulation of the outer ear results in a brain
activation pattern similar to that found in direct VNS (Frangos et al., 2015; Kraus et
al., 2013). Actually, transcutaneous Vagus nerve stimulation (tVNS), or electrical
stimulation of the Vagus nerve through the skin, has already been developed and
gammaCore® (electroCore LLC, Basking Ridge, NJ), a stimulator placed over the
left Vagal branch in the neck, has been shown to be effective in relieving cluster
headaches (Gaul et al., 2014). Similarly, NEMOS® (cerbomed, Erlangen,
Germany), a tVNS system that stimulates the ABVN, has been found to be
effective in treating epilepsy (Bauer et al., 2016).
71
Figure 24 – Diagram of Left Ear, Lateral View (Peuker & Filler, 2002)
72
Figure 25 – Diagrams of Lateral (left) and Medial (right) Surfaces of External
Ear and Associated Innervation and Vasculature: Abbreviations –
Auricular Branch of Vagus Nerve (ABVN), Auriculotemporal Nerve
(ATN), Great Auricular Nerve (GAN), Superficial Temporal Artery
(STA), Veins (V), Lesser Occipital Nerve (LON) (Peuker & Filler, 2002)
Curiously, there are not currently any tVNS systems that have received FDA
approval, although they would presumably be classified as a Class III device which
would require clinical trial data for each intended labeled use, and in fact there are
numerous clinical trials that are currently investigating potential applications for
73
tVNS (clinicaltrials.gov). Interestingly, there have been studies that have utilized a
type of CES unit to stimulate the ear in the region of the ABVN (Hein et al., 2013;
Howland, 2014). The FDA has classified CES units as Class III medical devices
labeled for use in treating anxiety, insomnia, and depression, but unlike the
implantable VNS devices they do not require a PMA prior to marketing. However,
changing the labeled use of a CES unit would probably require a PMA, so clinical
trials would be necessary regardless. There might be a better chance of tVNS being
accepted in clinical trials on women giving birth though, as it is noninvasive and
because several studies have noted that it is safe and well tolerated (Busch et al.,
2013; Lehtimäki et al., 2013; Stefan et al., 2012).
74
Chapter 11
Discussion
11.1 Motivation for This Research
In many ways, the field of obstetrics has been completely revolutionized in the last
hundred years. The twentieth century saw an unprecedented rise in the number of
births that took place in a hospital, increasing from less than five percent in 1900
(Wertz & Wertz, 1989) to fifty-six percent in 1940 and ninety-seven percent in
1962 (NCHS, 1962). Note that the statistics for 1940 and 1962 did not include the
nonwhite population, which consistently had lower rates of hospital deliveries
(NCHS, 1962). However, this number continued to rise for the whole population
and by the final years of the century ninety-nine percent of all births took place in
the hospital (Rooks, 1997). With childbirth increasingly taking place in a medical
setting, the 1900s also saw both the creation and widespread use of pharmacologic
agents to induce or speed up labor and block pain from being experienced during
labor and delivery.
In the mid-nineteenth century, the use of ether to control pain during childbirth was
first described (Channing, 1848; Heaton, 1946). Chloroform was also used, and
these anesthetics remained the only drugs used in obstetrics for a few decades
75
(Heaton, 1946). In the last quarter of the nineteenth century the drug nitrous oxide,
an inhaled anesthetic, was introduced to obstetrics (Heaton, 1946). At the start of
the twentieth century, a new form of pain control called twilight sleep, a
combination of scopolamine hydrobromide and morphine sulfate, was used to
produce amnesia and analgesia during the first stage of labor (Heaton, 1946;
Rooks, 1997). In 1944, caudal analgesia, a method for inserting a needle into the
epidural space of the sacrum for completely relieving pain during labor, was first
described (Galley & Peel, 1944). However, the caudal method only blocked the
nerves that convey pain during the second stage of labor, and in 1961 it was
suggested that lumbar epidural analgesia, where the epidural needle is inserted at
the lumbar rather than sacral level, is superior to caudal analgesia because it blocks
pain transmitted during both the first and second stages of labor (Bromage, 1961).
In the decades that have passed since then, lumbar epidural analgesia has become
the gold standard in labor analgesia (Posner et al., 2013). In fact, sixty-one percent
of women received an epidural during labor in 2008 (Osterman & Martin, 2011).
With such a large percent of the population now opting for epidural analgesia
during labor, there should be an equally significant amount of research being
conducted to determine exactly the effect, if any, that it has on labor. While a large
amount of this research has been conducted to determine the pharmacokinetics of
different analgesic drugs (D'angelo, Gerancher, Eisenach, & Raphael, 1998; Polley,
76
Columb, Naughton, Wagner, & van de Ven, 1999; Stienstra et al., 1995), there has
also been a considerable amount of research to determine how epidural analgesia
might affect the course of labor (Alexander et al., 1998; Bates et al., 1985;
Goodfellow et al., 1983; Leighton & Halpern, 2002a, 2002b).
Studies on the effects of epidural analgesia on labor have found that women who
have received an epidural have a decreased level of uterine activity even when
labor was induced by oxytocin (Alexander et al., 1998; Bates et al., 1985), a longer
second stage (Alexander et al., 1998; Cheng et al., 2014; Leighton & Halpern,
2002b) and possibly first stage of labor (Alexander et al., 1998), and an increased
risk of requiring oxytocin for labor dystocia (Alexander et al., 1998; Goodfellow et
al., 1983; Leighton & Halpern, 2002a, 2002b) compared to women who have not. It
is particularly interesting that uterine activity is decreased following an epidural
even if the labor was initiated with synthetic oxytocin. It is presumable that the
Ferguson reflex (Ferguson, 1941) could be blocked by epidural analgesia
(Goodfellow et al., 1983). The inhibition of uterine contractions following epidural
analgesia when labor is induced by oxytocin supports the role of the CNS in the
Ferguson reflex, as oxytocin does not cross the blood brain barrier (Altemus et al.,
2004; Landgraf & Neumann, 2004; Skalkidou et al., 2012) so it could be possible
that synthetic oxytocin acting on the uterus triggers the neural pathway to the PVN
resulting in the release of endogenous oxytocin to carry on the progression of labor.
77
However, it does not appear that research has yet been done to validate this
hypothesis, although it has been mentioned that the autonomic nervous system is
influenced by both endogenous and exogenous oxytocin (Porges, 2011).
Modern obstetrics textbooks do not make a direct association between epidural use
and increased oxytocin administration, but rather comment that epidural analgesia
is known to prolong the second stage of labor (Posner et al., 2013). It might not be
considered that important to obstetricians if oxytocin infusion is required to
stimulate the progression of a labor that has slowed after an epidural has been
administered, but unfortunately this perceived complacency has drawn criticism
about the overuse of oxytocin (Clark, Simpson, Knox, & Garite, 2009; Rooks,
2009). In fact, over half of all paid obstetric litigation cases involve the misuse of
oxytocin (Clark, Belfort, Dildy, & Meyers, 2008; Clark et al., 2009). It has been
noted that in no other field are potentially harmful drugs administered for the
convenience of the patient or practitioner (Clark et al., 2009). One thing that has
not been attempted in the initiative to reduce dependence on synthetic oxytocin
labor is to describe a method by which the mother’s own body can be used to
stimulate an increase in plasma oxytocin levels.
Research in a separate but related field has shown that women with complete SCI
above the level of spinal input of reproductive afferent nerves has shown that the
78
Vagus nerve provides an alternate sensory pathway in these women and even
accommodates their ability to experience an orgasm through cervical stimulation
(Komisaruk et al., 2006; Komisaruk et al., 2004). To eliminate the possibility that
any genital sensations were transmitted through the spinal cord, the researchers
only selected women for the study whose spinal cords had been completely severed
as a result of gunshot wounds (Komisaruk et al., 2004). What they found in fMRI
studies was that during cervical stimulation the NTS was activated in all women,
and in women that reached orgasm the PVN was activated, as well (Komisaruk et
al., 2004). This led the researchers to correlate this activation with the known
release of oxytocin that occurs during orgasm (Carmichael et al., 1987; Komisaruk
et al., 2004) However, this is not to say that for the Vagus nerve to stimulate the
release of oxytocin one must first have an orgasm.
Actually, research done on blood flow within the brain during VNS has shown that
the hypothalamus, where the PVN is located, exhibits a markedly increased blood
flow when the Vagus nerve is stimulated (Henry et al., 1998; Narayanan et al.,
2002). Electrical stimulation of the posterior pituitary gland has also been
associated with oxytocin release and was part of the series of experiments
conducted by Ferguson in his research (Ferguson, 1941). There is even evidence
that VNS stimulates the release of both oxytocin and vasopressin in the brain
(McEwen, 2004). With a seemingly apparent indication for the potential use of
79
VNS to stimulate oxytocin during parturition, it is something of a wonder that it has
not been previously addressed in the literature.
One of the likely reasons that VNS has not yet been explored for use in obstetrics is
the historically invasive nature of its use. The original VNS system consists of a
programmable stimulation device implanted in the chest with lead wires leading to
the cervical branch of the Vagus nerve located in the neck (Howland, 2014). This is
suitable for applications where VNS is used to treat a chronic disorder, but even
though a woman might experience childbirth more than once in her life it does not
justify implanting a permanent device with the sole goal of reducing the need for
synthetic oxytocin administration during childbirth. Also, in the one documented
case of a VNS study subject becoming pregnant and delivering while receiving
VNS a plan was developed to discontinue her VNS should any procedure utilizing
electrocautery, such as cesarean section, be required (Husain et al., 2005).
However, there has been a method of VNS developed more recently that
noninvasively stimulates the Vagus nerve from outside of the body and if
electrocautery were required the unit could be easily removed from the patient’s ear
without any risk to interference with the devices’ programming.
This method, tVNS, produces a brain activation pattern like that of direct VNS
when applied to the ABVN (Frangos et al., 2015; Hein et al., 2013). If further
80
research shows tVNS to have a physiologically identical response in the brain as
implanted VNS it could be of significant clinical importance in stimulating
endogenous oxytocin release during labor, especially in cases where women have
complete SCI or have received epidural analgesia. The noninvasive nature and
ready availability of stimulators that could be used for tVNS makes this both a
practical and potentially cost-effective area of research, as well. If found to be
effective, this technology could also save on delivery room and supply costs for
parents.
For example, in 1994 the Washington Post ran an article on a couple’s itemized
hospital bill which included a charge of almost $100 for synthetic oxytocin to
induce labor (Evans, 1994). The Consumer Price Index from the Bureau of Labor
Statistics was 143.6 in January 1994 (BLS, 1994) and 242.839 in January 2017
(BLS, 2017), indicating that oxytocin that cost $100 in 1994 would be almost $170
today. The CES units used one study on the effect of tVNS were the NET-2000 and
NET-1000 (See Figure 26) (Auri-Stim Medical, Inc., Denver, CO) (Hein et al.,
2013), and although the NET-2000 is no longer available the NET-1000 currently
sells for $650 from the manufacturer. However, part of the expense of the NET1000 is probably attributable to the fact that it also interfaces with smart devices as
part of its function as a music therapy device. A design like the NEMOS (See
Figure 27) would probably be much more cost effective than the NET-1000, as the
81
stimulator device is not integrated into the headset and therefore it would be
feasible to have a stimulator as part of the available delivery room equipment and
provide each patient that uses it with a new earpiece.
3
Figure 26 – The NET-1000 (left) and NET-2000 (right) CES units (From
http://net1device.com)
82
Figure 27 – The NEMOS Device for tVNS (from cerbomed.com)
11.2 Transcutaneous Vagus Nerve Stimulation
The foremost concern that needs to be addressed in any studies that lead to the
development of a tVNS device for use in obstetrics is safety for both the mother
and child. It is unclear why pregnant women have been excluded from studies
involving electrical stimulation, other than the fact that no research exists to show
that it is safe. This presents a matter of circular logic; the device is not used on
pregnant women because it is unknown if such devices are safe to use during
pregnancy so no studies are done on pregnant women, and as a result no data is
available to determine if the device is safe for pregnant women. However,
publications have also noted that there is no evidence that use of electrocautery is
83
suitable in pregnant women (Berghella, Baxter, & Chauhan, 2005; NCCWCH,
2004), yet it was used to perform cesarean sections several years earlier (Meyer,
Narain, Morgan, & Jaekle, 1997) and it appears as though it is now commonly used
in performing cesareans (Hofmeyr, Novikova, Mathai, & Shah, 2009).
Also, while CES and tVNS have not been evaluated for safety in pregnant women,
similar devices called transcutaneous electrical nerve stimulator (TENS) units have
been utilized during pregnancy (Keskin et al., 2012) and during labor
(Augustinsson et al., 1977; Bundsen, Peterson, & Selstam, 1981) with no negative
consequences. A later systematic review, however, concluded that TENS units had
no measurable for effect on relieving pain during labor (Carroll, Moore, Tramer, &
McQuay, 1997). Regardless, the fact that multiple studies conducted using TENS
units with electrodes placed much closer to the uterus than they would be with
tVNS is ample evidence that studies on the safety and efficacy of tVNS should not
pose an unnecessary risk to pregnant women.
While the single case study of a woman who went through pregnancy and
childbirth during participation in a VNS study indicates that tVNS would probably
not be harmful to the mother or child, this does not mean that studies should first be
conducted on pregnant women. It has been reported that VNS stimulates the release
of oxytocin in the brain (McEwen, 2004). First, research would need to be
84
conducted to determine if the release of oxytocin in the brain following VNS also
causes a significant increase in plasma oxytocin levels of test subjects. If it does,
then the temporal relationship between the VNS stimulation and plasma oxytocin
levels would need to be evaluated to determine if they fit into the timespan
necessary to be useful in labor.
After confirmation that VNS can significantly increase plasma oxytocin levels
within the timeframe of a normal labor, then further analysis should be performed
to determine the minimum, maximum, and optimal level of stimulation required to
be effective as well as the minimum treatment time to be effective and if there is a
maximum length of time were the effectiveness of the stimulation plateaus or
ceases. Full technical information for the NEMOS tVNS system is not readily
available, but is given for the NET-2000 stimulator in 510(k) documentation
submitted to the FDA showing substantial equivalence to the Alpha-Stim® 100
(See Figure 28 and Table 2) (Electromedical Products International, Inc., Mineral
Wells, TX).
85
Figure 28 - The Alpha-Stim 100 unit (left) and earclip electrodes (right) (from
https://alleviahealth.com/product/alpha-stim-100/ and
http://www.alpha-stim.com/product-category/alpha-stim-100/)
86
Table 2 – Comparison of Technical Details Between the NET-2000 and
Alpha-Stim Devices (from
http://www.accessdata.fda.gov/cdrh_docs/pdf6/K060158.pdf)
Both devices are classified as CES devices requiring a prescription, utilize a 9 volt
battery for power, have a maximum current of 600 μA, produce frequencies of 0.5,
87
1.5, and 100 Hz, generate bipolar asymmetric rectangular waves, and have silver
electrodes with self-adhesive pads and a conduction solution that are applied to the
ear lobes. The only major difference between the two devices is the treatment time,
which is 16.5 minutes for the NET-2000 and 10, 20, or 60 minutes for the AlphaStim 100. There is actually a wide degree of variability amongst the different
manufacturers of devices that electrically stimulate the outer ear.
For example, in a study that used the NEMOS to show that the ABVN creates a
similar brain activation pattern to that of direct VNS the participants were only
given seven minutes of stimulation while fMRI scans were performed (Frangos et
al., 2015). Interestingly, these scans showed that the NTS was activated during
tVNS, but not the hypothalamus (Frangos et al., 2015). However, in the study that
provided fMRI evidence of Vagus nerve involvement in conveying sensory
information during cervical stimulation in women with complete SCI it was shown
that the NTS was activated in all cases but the hypothalamus was only activated
when women achieved orgasm (Komisaruk et al., 2004). Thus, the duration of the
stimulation in the ABVN study may not have been long enough to elicit a response
by the hypothalamus, but it does not rule out the possible activation of the PVN by
tVNS.
88
Clearly, there is a large amount of research that needs to be conducted before any
tVNS studies should be performed on pregnant women. It first needs to be
established as a safe application in healthy humans and its efficacy in stimulating
endogenous oxytocin release must be thoroughly documented. Special controls
should also be used in developing any device to be used for tVNS studies to ensure
a minimal electrical shock risk to the mother and fetus. If these studies are
conducted and tVNS is found to have a viable application in obstetrics to increase
endogenous oxytocin release it could be of great clinical importance in reducing the
amount of synthetic oxytocin that is used in labor.
89
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