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www.jpnim.com Open Access eISSN: 2281-0692
Journal of Pediatric and Neonatal Individualized Medicine 2015;4(2):e040228
doi: 10.7363/040228
Received: 2015 Aug 27; accepted: 2015 Sept 30; published online: 2015 Oct 26
How to reduce synthetic oxytocin
administration and stimulate
the production of endogenous
oxytocin in childbirth
Antonio Ragusa
Department of Obstetrics and Gynecology, Ospedale Apuane, Massa Carrara, Italy
Abstract
The purpose of this review is to examine synthetic and natural oxytocin
use in pregnancy and post-partum.
We distinguished synthetic oxytocin (Syntocinon®) use in labor as a uterine
contraction stimulant in two parts: the rst is for induction or augmentation of
labor; the second for prevention of post-partum hemorrhage (PPH).
Oxytocin, key hormone in the process of childbirth and lactation, is a
strong smooth muscle stimulant. For this reason it is widely used to induce/
augment labor and to prevent and cure PPH.
However, Syntocinon® can penetrate the placenta and reach fetal
circulation, thus causing various systemic effects on mother and fetus.
Oxytocin plays an important role as a neurotransmitter in the central nervous
system, affecting numerous neuro-behavioral functions and it is involved
in many types of parental behavior in humans and animals. It is, in fact,
involved in a wide variety of physiological and pathological functions such as
sexual activity, penile erection, ejaculation, pregnancy, uterus contractions,
milk ejection, maternal behavior, social bonding, and stress. Oxytocin has a
decisive role in the process of “bonding” between mother and child and in
that of social afliation.
We therefore explored the opportunity to reduce the use of Syntocinon®
in labor ward as a precautionary measure.
Finally, we place the emphasis on some techniques that will probably
increase the production of endogenous oxytocin.
Review
Proceedings of the 11th International Workshop on Neonatology and Satellite Meetings
Cagliari (Italy) · October 26th-31st, 2015
From the womb to the adult
Guest Editors: Vassilios Fanos (Cagliari, Italy), Michele Mussap (Genoa, Italy), Antonio Del Vecchio
(Bari, Italy), Bo Sun (Shanghai, China), Dorret I. Boomsma (Amsterdam, the Netherlands),
Gavino Faa (Cagliari, Italy), Antonio Giordano (Philadelphia, USA)
Proceedings
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Ragusa
Keywords
Oxytocin, pregnancy, augmentation, post-partum
hemorrhage, neuro-behavioral.
Corresponding author
Antonio Ragusa, Department of Obstetrics and Gynecology, Ospedale
Apuane, Massa Carrara, Italy; email: antonio.ragusa@gmail.com.
How to cite
Ragusa A. How to reduce synthetic oxytocin administration and
stimulate the production of endogenous oxytocin in childbirth.
J Pediatr Neonat Individual Med. 2015;4(2):e040228. doi:
10.7363/040228.
Oxytocin structure and function
Oxytocin is a pituitary neuropeptide hormone
composed of nine amino acids. It has a molecular
mass of 1,007 daltons. Oxitocyn is produced
by both mother and fetus and is produced as a
primary site from magnocellular neurons of the
paraventricular nucleus and the suprachiasmatic
nucleus of the hypothalamus, and it is also
synthesized peripherally in non-neural sources
such as ovary [1, 2] testis [3] adrenal gland [4],
thymus [5], and pancreas [6]. Some studies
found increased oxytocin levels at the onset of
labor and during labor compared to one or two
weeks before labor, reaching a peak when the
fetal head is delivered. However, there is a wide
variation of results reported in literature because
plasma oxytocin levels are difcult to measure,
because oxytocin has a half-life of a few minutes
and a plasma concentration lower than other
hormones, and because it is released in a pulsatile
pattern. Moreover, there are many differences
in experimental methods of study and in dosage
evaluation [7, 8]. Oxytocin is transported through
axons of the hypothalamic nuclei neurons
that end in the posterior lobe of the pituitary
gland (neurohypophysis) where it is processed
from pro-peptide into mature peptide. From
neurohypophysis, oxytocin is released into the
bloodstream by exocytosis, in response to a variety
of stimuli. This process takes place in the pituitary
gland during labor, lactation, uterine expansion,
stress, sexual stimulation and during different
kinds of social interactions. Oxytocin is involved
in the development and maintenance of attachment
between individuals, in bonding between mother
and child, in romantic love as well as in lial
love; in fact, maternal and romantic love share
the evolutionary purpose to maintain species, also
sharing a common nucleus of neural mechanism
[9]. All vertebrates have an oxytocin-like
nonapeptide hormone that supports reproductive
functions. Its genes are believed to result from
a gene duplication event; the ancestral gene is
estimated to be about 500 million years old and it
is also found in cyclostomata, modern members of
the Agnatha [10]. While the structure of oxytocin
is highly conserved in placental mammals, a
novel structure of oxytocin was recently reported
in marmosets, tamarins, and other new world
primates [11]. Much of the phenomena occurring
during labor and childbirth take place mainly
in the archaic structures of the brain, affected
by systems entirely involuntary, unconscious,
instinctive and genetically programmed, whose
action is intended to our survival. The network
more interested is the limbic system which is the
archaic brain interposed between rational brain
mechanisms and output of the nervous system.
The instinctive behaviors determined by it are
subjected to judgements culturally determined
and introduced by the neocortex, very developed
in our species, whose activity generates many
inhibitions, as well as during any sexual experience,
particularly inuenced by environmental stimuli.
As a result, the activation of oxytocin production
can be both cortical and subcortical as shown by
studies by Zeki et al. [12]. Oxytocin mRNA is
increased during labor in amnion, chorion, and
principally in the decidua [13]. Syntocinon® is
catabolized in the gastrointestinal tract, so it must
be administered by injection or as a nasal spray. Its
half-life is about three to ten minutes in the blood
when given intravenously. When administered via
nasal spray, Syntocinon® crosses the blood-brain
barrier and shows psychoactive effects in humans
[14]. Unlike intravenous administration, intranasal
Syntocinon® has a duration of at least 2.2 hours
and as long as 4 hours [15]. Syntocinon® probably
crosses the placenta in both directions by simple
diffusion. Concentrations are usually higher in
umbilical than in maternal blood. In addition,
umbilical artery oxytocin concentrations at term
(15-40 pg/ml) are higher than umbilical vein (4-12
pg/ml) and maternal (1-10 pg/ml) concentrations.
The umbilical A-V difference suggests that
oxytocin diffusion is mostly from fetal towards
maternal circulation [16]. When administered
during labor, Syntocinon® can quickly reach fetal
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circulation. The permeability is probably higher in
the maternal-to-fetal direction than in the reverse.
However, there are only a few studies on this topic,
sometimes with conicting results, therefore not
allowing to draw denitive conclusions. Moreover,
we are aware that Syntocinon® administration
induces the desensitization of oxytocin receptors
[17-20]. Syntocinon® is a strong smooth muscles
stimulant; it increases muscle cells sodium
permeability by depolarizing them, with a
consequent lowering of the excitability threshold.
In any case, we shouldn’t consider this single effect
of Syntocinon® in such a signicant moment as
childbirth; we should indeed take into account its
other systemic effects on mother and fetus in the
risk/benets ratio of Syntocinon® administration.
Part one: oxytocin for augmentation of labor
A reasonable approach based on Syntocinon®
pharmacokinetics for augmentation of labor
considers a starting dose of 2 mU/min, increased
by 2 mU/min every 40-45 minutes until regular
contractions are achieved, or for a maximum dose
of 20-30 mU/min. Syntocinon® administration
should consider its half-life (about 3-10 minutes)
and the time needed to reach a steady-state (about
4-5 plasma half-lives) [21]. Approximately 30-
40 minutes are required for any particular dose
of Syntocinon® to reach a steady-state and the
maximal uterine contractile response. Increasing
the Syntocinon® dose earlier than 30-40 minutes
can be dangerous since steady-state has not been
reached yet and the entire effect of the previous
administration has not been fully achieved.
All this seems reasonable, although waiting to
reach a steady state before considering the dose
inadequate is not proven by prospective trials
[22]. Note that each patient’s response to the same
Syntocinon® concentration is unique and both
uterine contractility and progress of labor should
be carefully monitored. That’s why epidemiologic
studies, evaluating just the mean and the median,
could draw approximate conclusions about
the optimal dosage for each single patient.
This is also the reason why the studies reach
conicting results, with some suggesting a low-
dose Syntocinon® infusion regimen, and some
others a high-dose one [23], whereas other papers
recommend an intermediate-dose Syntocinon®
regimen [24]. In conclusion, we can say that there
isn’t an ideal dose for each single woman, and,
therefore, the administration of Syntocinon® must
Synthetic oxytocin administration and endogenous oxytocin in childbirth
be personalized as per each single case. Uterine
activity evaluation is often inaccurate, therefore
any regimen based only on uterine contractile
pattern is not correct. Syntocinon® administration
is based also on the correct denition of uterine
contractions, such as:
1. the achievement of contractions of 200-220
Montevideo units (MVUs) of intensity;
2. one contraction every 2-3 minutes, lasting 80-
90 seconds, judged as strong on abdominal
palpation performed by an experienced midwife.
Once this kind of uterine activity is obtained,
there is no need to increase Syntocinon®
administration. If labor is not progressing, a more
accurate diagnosis or even a caesarean section
is indicated rather than a further increase in
the Syntocinon® dosage, that would determine
excessive and not physiological increase in uterine
contractions.
Quoting Steven Clark, “three unique
characteristics of oxytocin are of special note.
First, the onset of action of a given dose of dilute
oxytocin solution is relatively slow… Second, few
drugs in the entire medical armamentarium have
such an unpredictable therapeutic index… Finally,
with rare exception, the detrimental effects of
this drug are exclusively mediated through its
dose-related effects on uterine activity” [22].
Since the high variability in individual response
to Syntocinon® it would be extremely useful to
adopt a specic check list for its administration.
This could be a rather long and complex process
in an obstetric division and could take even more
than a year to be implemented, because introducing
a shared protocol requires different clinical
organizational steps [25]. If such a multifaceted
strategy is adopted, involving the entire obstetric
staff, Syntocinon® use could be improved,
according to clinical international guidelines. In the
Obstetric Division where I work, Syntocinon® use
is monitored by a specic check list: the midwife
in charge should ll out this written check list, put
on cardiotocography (CTG) every 30 minutes.
This checklist is composed of six items:
• at least one acceleration (15 beats per minute
x 15 seconds) in 30 minutes or an adequate
variability in the absence of accelerations;
• no more than one late deceleration in 30 minutes;
• no more than two variable decelerations in 30
minutes;
• no more than four contractions in 10 minutes;
• no contraction lasting more than 120 seconds on
abdominal palpation;
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• the uterus should be relaxed between
contractions.
If even a single item on the checklist can’t be
ticked by the midwife, the doctor will be consulted.
Audits regarding the correct use of this procedure
should be carried out at least once a year. In this rst
year of use of this new checklist, we had no reports
of any side effects imputable to Syntocinon® use in
1,700 deliveries. We shouldn’t forget that oxytocin
has been added to the list of 11 high-alert medications
designated by the Institute for Safe Medication
Practices (ISMP). Those drugs are dened as those
“bearing a heightened risk of harm when they are
used in error” and may require special safeguards
to reduce these risks of error [22]. Most allegations
in obstetric lawsuits relate in some manner to the
management of labor and delivery, and many of
those involve Syntocinon® misuse. A common
problem frequently reported in obstetric malpractice
claims is the inappropriate use of Syntocinon®,
with subsequent uterine hyper-stimulation, non-
reassuring fetal status, depressed newborns at birth,
long-term sequelae or even neonatal death [26].
Syntocinon® induced uterine hyper-stimulation
could have a strong impact on fetal oxygen status.
In fact, fetal oxygen saturation (FSpO2) decreases
during contractions reaching the lowest level about
92 seconds after the peak of the contraction, with
approximately 90 seconds required for FSpO2 to
return to previous levels. When contractions are
occurring every 2 minutes or even more frequently,
FSpO2 recovery to previous baseline levels is
incomplete [27]. The association between the
use of Syntocinon®, hyper-stimulation, and fetal
distress is well known and documented, and the
association between Syntocinon® and acidemia has
been quite thoroughly investigated. Syntocinon®
is an independent risk factor for acidemia at birth
even after correcting the confusing variables [28].
In this study of 472 cases of suspected malpractice,
177 babies (38%) were born with severe asphyxia,
due to non-recognition of signs of asphyxia in 98%
of cases and to an incautious use of Syntocinon®
in 71% of cases. In particular, Syntocinon® was
given without signs of uterine inertia to 49 women,
19 of whom were hyper-stimulated and 44 received
Syntocinon® despite severely pathological heart
tracings. Different studies reported an association
between acidemia at birth and Syntocinon®
administration [29].
Given the widespread and liberal use of
Syntocinon® during labor, this concept is of great
importance in the denition of obstetric care.
Studies in rats suggest that maternal
administration of Syntocinon® might adversely
affect central nervous system metabolic response
to hypoxia at birth [30]. In particular, intravenous
Syntocinon® injections to pregnant rats before
birth worsened the acute central nervous system
metabolic response to anoxia at birth, as assessed
by brain lactate and ATP levels in their neonatal
offspring. The results of this study appear to
run counter to in-vitro experiment results by
Tyzio et al. [31]. These authors demonstrated,
using brain slices, that maternal oxytocin exerts
a neuro-protective action on fetal neurons
during parturition. In conict with this in-vitro
experiment, the study of Patricia Boksa et al.
used a model of birth anoxia in-vivo, with the
advantage of involving a whole body response to
global anoxia, affecting multiple organ systems.
This systemic involvement, determined by
Syntocinon® administration, could be responsible
for the negative response to hypoxia documented
in this study. Probably, these different results are
due to the difference between endogenous oxytocin
and Syntocinon® administration.
The doctoral thesis of Maria Jonsson describes
four illuminating studies on the quality and amount
of Syntocinon® use in the delivery room [32]. We
will now focus on the rst three studies, leaving for
a moment the fourth study, which refers to the use
of oxytocin prophylaxis of excessive blood loss
during Caesarean sections, which will be the topic
of the second part of our paper. We can briey
draw some conclusions from these three studies.
First of all, convictions for negligence are,
with few exceptions, related to incorrect CTG
interpretation. In most cases, the inappropriate
management was correlated with a questionable
use of Syntocinon®. The lack of action, due
to the misreading of CTG and/or to misuse of
Syntocinon® or failure to suspend it are, in most
cases, the decisive causes of ominous outcomes.
There is a strong association between acidosis
at birth and uterine hyperkinesia in the two hours
before birth. Syntocinon® was administered in
most cases of uterine hyperkinesia. This, together
with the incorrect CTG interpretation, contributed
signicantly to determine acidosis at birth.
The duration of the second stage of labor is less
important and is not related to acidosis if operators
take into account the frequency of contractions.
Metabolic acidosis at birth is associated with sub-
optimal care during childbirth in half of the cases.
The high rate of suboptimal care, related to CTG
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interpretation and Syntocinon® use, proves a great
difference between guidelines and clinical practice.
Metabolic acidosis and subsequent neonatal
morbidity, could probably be avoided in 40-50%
of cases. For this reason, respect and adherence
to guidelines should be monitored continuously
[33-35]. We should abandon the concept that
increasing forces in labor is always the solution
to labor dystocia. After all, there is little evidence
regarding the general impact of Syntocinon® on
a slowly progressing labor, except that it shortens
labor, but we have known for a long time that
“shortening labor by force does not improve
clinical outcome” [36]. However, prolonged labor
is an important cause of maternal and perinatal
mortality and morbidity per se, irrespective of the
way we try to correct it. In the study of Laughon
et al., the composite maternal morbidity is higher
in nulliparous women who give birth in epidural
after a prolonged second stage of labor. Specic
morbidity is increased in this group of women
with a rate approximately three times higher of
chorioamnionitis, as well as an increased risk of
episiotomy, third- and fourth-degree perineal
tears and longer duration of hospitalization
(median one day longer). Multiparous women
who delivered after a prolonged second stage
regardless of epidural use had higher rates of
chorioamnionitis, higher odds of postpartum
hemorrhage and third- or fourth-degree perineal
tears after adjustment. However, the study didn’t
show signicantly increased risks for other serious
maternal complications, including need for blood
transfusions, cesarean hysterectomy, or intensive
care unit admission. The rate of neonatal morbidity
is increased by 11% for nulliparous and 9% for
multiparous, with a prolonged second stage, which
is about 2-3% higher than in delivery with a normal
second stage [37].
Thus, “failure of labor to progress” has
become one of the leading indications for primary
caesarean section all over the world, particularly
in rst-time mothers since a signicant proportion
of caesarean sections is performed for dystocia
[38]. Dystocia appears to be associated with a
signicantly increased maternal and neonatal
mortality and morbidity, and that is a major
problem both in terms of nances and public health
[38]. There is growing concern that caesarean
sections are performed too soon in many cases,
without exploring less invasive interventions that
could lead to vaginal birth. Adverse maternal and
neonatal outcomes seem to be related more to the
cause of dystocia or to augmentation of labor than
to prolonged labor per se. To identify the exact
cause of the slowness or non-progression of labor
in clinical practice can be difcult. However, the
evaluation of the progression of labor can not take
into account only cervical dilation, but should also
consider other factors, such as the descent and
rotation of the presenting part, the duration and
frequency of contractions, as well as hydration and
nutritional and psychological needs of the mother.
The uterine cervix that dilates slowly or the slow
descent of the fetal head are just warning signs, that
can properly be considered as screening tests. The
cause of this abnormality should then be searched
both in maternal and fetal conditions such as
stress, fasting, fetal trunk and head malpositions,
fetal distress, etc. [39]. If we use cervical dilation
curves as screening, and not as diagnostic tests,
we can try other therapeutic strategies and
not just augmentation with Syntocinon®. It is
demonstrated that encouraging women to walk in
the setting of a prolonged labor can be helpful [40].
This randomized clinical trial enrolled 57 women
(nulliparous and multiparous). In the ambulatory
group, only 50% of women received oxytocin,
conversely in the second group every woman had
oxytocin administered. Statistically signicant
differences between the two groups are: the average
duration of the second stage, which is lower in
the ambulatory group, stronger contractions in
the oxytocin group before the start of the active
phase of the second stage and a more positive
experience in the walking group. The test sample
was too small to estimate the effects on the health
of infants but women in the ambulatory group also
had lower use of analgesia in the rst stage, less
operative deliveries, more normo-reactive CTG
before the active phase of the second stage, and
fewer complications recorded in the post-natal
period. The practice to ambulate women with
consequent possible postponement of Syntocinon®
infusion, allows a better selection of those patients
needing Syntocinon® and therefore prevents the
administration of Syntocinon® to women who
would still have normal and effective contractions
later. Although the results of other studies are not
in complete agreement with the study of Hemminki
et al., certainly walking not impaired active labor
and is not harmful to the mothers or their infants
[39]. As evidenced by the study of Cluett et al.,
laboring in water under midwifery care may be
an option for slow progress in labor, reducing the
need for obstetric intervention, and offering an
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alternative pain management strategy [41, 42]. In
the case of occiput posterior position, asynclitism
or deected presentations, the woman should be
encouraged to change her posture in order to try
to correct fetal malposition [43]. If the change
of maternal posture cannot modify fetal position,
manual rotation of the fetal head is also possible
[44]. Another technique that can be used in case of
slow cervical dilation or slow descent of fetal head
is massage [45]. Indeed, massage has been proven
to increase oxytocin production and to decrease
ACTH blood concentration [46]. Moreover,
giving the patient the possibility of laboring in a
“pleasant” environment can probably also increase
the endogenous production of oxytocin [47]. In this
way, we can reduce Syntocinon® administration,
facilitating endogenous oxytocin production.
In our work group, we applied a protocol called
“Comprehensive Management”, using cervimetric
curves as a screening test. When cervical dilation
or presenting part progression were slow, we tried
to carry out a presumptive diagnosis of the cause of
dystocia (Fig. 1), followed by the above-mentioned
alternative correction techniques. Applying our
Comprehensive Management protocol, in the
rst six months of its implementation, the rate of
Figure 1. The Comprehensive Management of dystocia in labor.
The rst level shows the attempt to nd a cause of dystocia. The second level shows the possible areas of treatment. The third and
fourth levels show the standard treatment of dystocia, which is adopted only in the event of failure of the rst and second levels.
Level 1
Level 2
Level 3
Level 4
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oxytocin use for augmentation of labor decreased
signicantly from 28.1% (72/256 patients; 95%
CI: 22.7-34.1) to 14.2% after intervention (47/332
patients; 95% CI: 10.6-18.4) (Fisher’s exact test:
p < 0.0001) [48]. Later, in another Obstetric
Unit, improving further our Comprehensive
Management, we were able to reduce oxytocin
use in all deliveries from 19.8 % to 13.1% (p <
0.0008), also decreasing amniotomy from 19.8 %
to 11,19.2 % (p < 0.0001 ) [49].
After all what is the need of using Syntocinon®
so often in labor if there are no differences between
Syntocinon® administration versus no treatment
in terms of caesarean section rate, operative
vaginal deliveries and both maternal and neonatal
outcomes [50]?
Moreover, in rst-time mothers on epidural
there are no signicant differences between
patients augmented with Syntocinon® and non-
augmented patients in the primary outcomes of
cesarean section (RR 0.95 95% CI 0.42 to 2.12)
or instrumental delivery (RR 0.88, 95% CI 0.72
to 1.08). Similarly, there were no statistically
signicant differences between the two groups in
any of the secondary outcomes for which data were
available [51]. However, Syntocinon® is not free
from important biological effects also on the mother
[52]; the review of Al-Zirqi et al. [51] evaluates
uterine rupture trends over a period of 40 years in
Norway. The authors showed that incidence rates
per 10,000 deliveries in the rst, second, third,
and fourth decades were 1.2, 0.9, 1.7, and 6.1,
respectively. Signicant contributing factors to this
increase were higher rates of labor augmentation
with Syntocinon®, scarred uteri from previous
caesarean sections and labor induction with
prostaglandins or prostaglandins combined with
Syntocinon®. The authors concluded by arguing
that uterine rupture incidence was increased and
that obstetric interventions contributed to this
increase.
Moreover, is it proven that the amount of
intrapartum Syntocinon® administered in labor
predicts plasma oxytocin levels two months
postpartum; these levels are lower in patients treated
with Syntocinon®, suggesting a possible long-term
effect of this routine intervention, the consequences
of which are largely unknown [52, 53].
An interesting review was carried out to identify
the primary and secondary outcome measures
in randomized trials and systematic reviews that
measured the effectiveness of Syntocinon® to
treat the extension of the rst or second stage of
labor. The authors also identied any positive
health outcome in this eld. They included 33
publications, 28 RCTs in which at least one of
the two groups in the study received Syntocinon®
augmentation for delay in spontaneous labor (slow
progress) and ve systematic reviews. Almost
none of the studies included references to women-
centered outcomes (e.g. maternal experience of
pain, maternal perception of duration of labor) or
to positive health outcomes (for example intact
perineum or maternal self-esteem). Thus, the
literature demonstrates the urgent need for studies
on this topic [53].
Perinatal Syntocinon® administration was
associated with a 2.4 times increased odds of
bipolar disorders later in life. Syntocinon® was
also associated with decreased performances
on the Raven Matrices, but not on the Peabody
Picture Vocabulary Test. Childhood cognition
was not associated with later bipolar disorders.
The study has some limitations, for example
the childhood cognitive battery did not include
tests related to multiple domains of cognition
which have been associated with later bipolar
disorder and the sample size of children exposed
to Syntocinon® was quite modest. However,
the study provides evidence for a potentially
important perinatal risk factor for bipolar disorder
and cognitive impairment in childhood [54].
Additional preliminary data suggest caution in
Syntocinon® administration in labor [55]. Gregory
et al. performed an epidemiological analysis
using multi-variable logistic regression modeling
involving the North Carolina Detailed Birth Record
and Education Research databases [55]. The study
featured 625,042 live births linked with school
records, including more than 5,500 children with a
documented exceptionality designation for autism.
This work suggests that induction/augmentation
during childbirth is associated with increased odds
of autism diagnosis in childhood. However, great
caution is needed before changing completely
our clinical practice in the delivery room. It is
known that association doesn’t mean causality,
therefore SMFM (Society for Maternal-Fetal
Medicine) on Labor Induction or Augmentation
and Autism Spectrum Disorders (ASD) stated:
“SMFM has reviewed the evidence and feels that
the recent publication is far from denitive, uses
methodology that cannot prove causality and does
not indicate a causal relationship between labor
induction/augmentation and ASD. Therefore, this
single study should not be viewed as an incentive
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or provide justication for any change in practice
regarding labor induction and management” [56].
Studies from Europe and the United States
report that up to 50% of primiparas and 20% of
multiparas received Syntocinon® augmentation
during labor [57-60].
In mammals, the prevalence of dystocia
is generally not as high as we could expect
from a complex mechanism undergoing a huge
evolutionary selective pressure such as childbirth.
Childbirth is the nal event determining species
preservation. In horses, for example, dystocia
occurred in 10.1% of all births and the most
common causes of dystocia were abnormalities of
fetal position [61].
In dogs, dystocia is infrequently due to a lack
of force, conversely it is due to maternal causes in
37.9% of cases, to fetal reasons in 21.5% and in
34.7% of cases for a combination of both [62].
We should consider a slow cervical dilation
or a slow descent of fetal head as warning signs,
and we could properly include them in the
category of screening tests. We should apply to
human labor the paradigm that we always apply
when we try to carry out good medical practices:
diagnosis before therapy. The cause of dystocia
should then be searched both in maternal and fetal
conditions, such as stress, fasting, fetal trunk and
head malpositions, fetal distress, macrosomia,
fear of childbirth, growth restriction, dehydration.
Dystocia in labor is a syndrome not a disease
(Fig. 2). A syndrome is a set of medical signs
and symptoms that are correlated with each other
and, sometimes, with a specic disease and it can
be caused by various factors. Before increasing
forces using Syntocinon® we should consider rst
if the lack of force is the reason for dystocia. A
greater attention to the evidence and the analysis
of each clinical case lead to a reduction of the
intervention in labor [63]. The study by Chaillet
and colleagues [63] was performed to determine
whether a multifaceted 1.5-year intervention to
improve professional onsite training with audits
and feedback would reduce the rate of cesarean
delivery. Of 184,952 participants enrolled from
32 hospitals in Quebec, 53,086 gave birth in
the year preceding the intervention and 52,265
gave birth in the year after the intervention. The
Figure 2. Dystocia in labor as a syndrome.
In this gure dystocia is represented as a closed box that, when it’s opened, by identifying a presumptive etiology, allows to make the
diagnosis and consequently to act on the probable causes.
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intervention consisted of initial onsite training
by instructors from the Society of Obstetricians
and Gynecologists of Canada regarding evidence-
based management of labor and delivery, clinical
audits of indications for cesarean delivery,
feedback to clinicians, and implementation of
best practices. Women with low-risk pregnancies
had a signicant reduction in cesarean delivery
rate, whereas those with high-risk pregnancies
did not (adjusted risk difference, -1.7%; 95%
CI, -3.0% to -0.3%; p = .03 vs. p = .35; p = .03
for interaction). Also oxytocin use during labor
decreased in both groups, the decrease was greater
in the control hospitals (adjusted OR, 1.16; 95%
CI, 1.09 to 1.23; p < .001; adjusted risk difference,
3.2%; 95% CI, 1.9% to 4.6%). The lower rates of
cesarean delivery associated with this intervention
were not accompanied by adverse maternal or
neonatal effects, based on ndings of this cluster-
randomized controlled trial.
In conclusion, it is proven that mothers who
received Syntocinon® infusion during labor show
a signicant negative correlation between the
amount of Syntocinon® and their endogenous
oxytocin levels two days later (p = 0.019), so the
higher the dose of Syntocinon® administered
during labor, the lower their endogenous
oxytocin levels will be two days later [52, 64].
This could have huge epigenetic consequences
and probable effects on neuro-behavioral
development in some sensitive individuals. Blood
oxytocin concentrations are highly heritable
within families; its level is a strong predictor of
social functioning in autism spectrum disorder
children, in their unaffected siblings, and healthy
control children [65]; this study indicates that
dysregulated oxytocin biology is not uniquely
associated with ASD social phenotypes as widely
theorized, but instead variation in oxytocin
biology contributes to important individual
differences in human social functioning, including
the severe social impairments which characterize
ASD. In this study a change in oxytocin receptor
polymorphisms such as carriers of the “G” allele
of rs53576, showed impaired affect recognition
performance, while carriers of the “A” allele
of rs2254298 exhibited greater global social
impairments in all groups. Currently we are not
able to understand what fetuses may be adversely
affected by the administration of Syntocinon®
and which may not. Once we have discovered
this, we would get closer to having the so called
“tailored medicine” in the delivery room too.
Syntocinon® hasn’t been demonstrated to
be always an effective cure for dystocia during
labor, and must be used with caution, not only
in those patients we are reasonably sure that the
cause of dystocia has to be found in reduced or
ineffective uterine activity. In patients who have
not a disorder of uterine activity it is urgent to look
for other causes and hence other treatments for
dystocia. Syntocinon® remains a valuable strategy
in Obstetrics but, before we get to know more,
we should administer this drug cautiously and
in an attentive and adequate way. Furthermore,
we should learn to better select a population of
patients in which the increase in the strength of
uterine contractility is useful.
Part two: oxytocin for prevention of postpartum
hemorrhage
Postpartum hemorrhage (PPH) means a blood
loss of 500 ml or more after a vaginal delivery.
Hemorrhage is dened as severe if it is greater than
1,000 ml. A blood loss of 1,000 ml or more after a
cesarean section can be dened as abnormal [66].
Primary PPH is used to describe a loss of blood
within 24 hours from delivery while secondary
PPH occurs between 24 hours and 12 weeks
postpartum [67].
PPH is one of the most frequent causes of
mortality and morbidity in obstetric population
worldwide, causing about 25% of maternal deaths
each year [68]. In Italy PPH is the most important
cause of direct death during childbirth [69].
Most deaths take place 24-48 hours from
delivery [70]. 66% of deaths due to PPH are still
due to “substandard care” [71]. Moreover, PPH is
also cause of 73% of all serious morbidity during
pregnancy and is the most frequent obstetrical
cause of admission to intensive care units [72].
The possibility of an effective prevention for
this pathology must therefore be considered a
clinical priority.
However, important distinctions must be taken
into consideration with regards to where delivery
takes place, as well as between countries with low
income and limited health resources, and those
with high income and good healthcare resources.
Active treatment during third stage of labor
seems to be the chosen treatment to prevent PPH,
which reduces maternal blood loss and the risk of
PPH. A systematic review, including seven studies
concerning 8,247 women, showed that active
treatment during third stage of labor reduces the
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prevalence of PPH by about 60% [73]. The active
treatment of the third stage of labor is made up of
three elements:
1. early clamping of the umbilical cord;
2. controlled cord traction;
3. prophylactic oxytocic drug as the anterior
shoulder is delivered.
Out of these three elements, only the
administration of uterotonic prior to shoulder
delivery continues to have an unanimously
recognized effective role. In the past, early
clamping of the umbilical cord was considered
an important element of the active treatment of
the third stage, with clamping dened as early
if carried out 16 seconds after delivery, and late
if carried out one to two minutes after delivery.
Over time, no evidence has been found to show
that failure to carry out early clamping increases
the number of cases of PPH, both minor and
severe. On the other hand, late clamping, placing
the newborn on the mother’s abdomen, has many
advantages, as it improves haematological state,
reducing the risk of anemia, as well as promoting
cardiovascular and respiratory adaptation [74] and
bonding. Late clamping results in only a slight
increase in phototherapy treatment (+2%). The
other component of the treatment of the third stage
is the controlled cord traction, the validity of which
has been disproven by a randomized controlled
trial published by Gülmezoglu and colleagues
[75]. The authors demonstrated that out of 581
women managed without controlled cord traction,
only one had a blood loss of 1,000 ml or higher. If
carried out by untrained operators, controlled cord
traction increases the risk of uterine inversion by
from 1 to 7 times. In Gülmezoglu’s study, the main
factor that contained the overall rate of PPH at just
over 10%, in both groups, was the administration
of an injection of uterotonic at birth. The uterotonic
with the best cost/benets ratio is Syntocinon®; an
intramuscular dosage of 10 IU seems to be the best
treatment for the prevention of PPH. At present,
the only action deemed to be really important in the
reduction of PPH prevalence is the administration
of 10 IU of Syntocinon®. For women without risk
factors of PPH who deliver vaginally, intramuscular
administration of Syntocinon® (10 IU) is the chosen
treatment, while for women who have delivered
by cesarean section, slow intravenous infusion of
5 IU of Syntocinon® promotes uterine contraction
decreasing blood loss [76]. The administration of
Syntocinon® may, however, be inappropriate in
women with important cardiovascular disorders,
suggesting that for these patients we need to
consider a different kind of prevention without
cardiovascular effects. In these cases, tranexamic
acid (TA) could be an alternative medication
[77]. The results of a controlled double-blind vs.
placebo study demonstrated the effectiveness of
TA in reducing haemorrhages during and after
cesarean sections [78]. Another randomized
double-blind vs. placebo study carried out on 454
patients showed that intravenous administration
of 1 g of tranexamic acid 5 minutes after the
disengagement of the shoulder, in addition to the
active management of the third stage of labor,
reduces the amount of blood loss in vaginal
deliveries. In fact, in this study, the percentage of
PPH was lower in the experimental group (1.8%)
compared to control group (6.8%). This advantage
was not seen in cases of a blood loss greater than
1,000 ml. No thrombotic events were seen [79].
Moreover, as reported in part one, Syntocinon®
has numerous systemic effects since receptors
for oxytocin have been found in different tissues,
such as blood vessels, kidneys, ovaries, testicles,
the thymus gland, heart, pancreas and adipose
tissue [80]. Syntocinon® is responsible not only of
uterine contractions, but it is also involved in milk
ejection, in maternal behavior, in social bonding,
in the process of “bonding” between mother and
child, in stress and social afliation [9].
In the prevention or treatment of haemorrhage,
Syntocinon® reacts quickly, with a latency period
of less than one minute after an intravenous
injection, its half-life is 3 minutes and 2 to 4
minutes after an intramuscular injection. The
response of oxytocin lasts 30 to 60 minutes after
intramuscular/intravenous administration (less for
intravenous). Metabolic clearance speed is about
20 ml/kg per minute [81].
It is well known that Syntocinon® has serious
adverse maternal cardiovascular effects, including
hypotension, myocardial ischemia, arhythmia,
nausea, sickness, headache and hot ashes. Due
to structural similarities with vasopressin, it has a
moderate antidiuretic effect, and spill over effect
on the ADH receptor at high concentrations. An
excessive dosage of Syntocinon® can cause water
retention, hyponatremia, convulsions and coma,
specially if administered via intravenous with a
glucose solution [83, 84]. Moreover, Syntocinon®
can cause the release of Brain Natriuretic Peptide,
resulting in a clinical presentation of peripheral
vasodilatation, hypotension and increased cardiac
output, all mediated by an increase in the systolic
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range heart rate. Pulmonary artery pressure
increases considerably for at least 10 minutes
after a bolus of 10 IU of Syntocinon® during
general anesthesia. These effects can be poorly
tolerated in case of abnormal ventricular function,
aortic or mitral stenosis, and hypovolemia [82].
Syntocinon® must be administered with caution
to patients with susceptibility to myocardial
ischemia due to pre-existing cardiovascular
pathology, such as hypertrophic cardiomyopathy,
valvular and/or ischemic heart disease, including
coronary vasospasm, so it’s important to avoid
signicant changes in blood pressure and in
heart rate in these patients. Syntocinon® must
be administered with caution to patients with
“Long QT syndrome” and to patients taking
medication inuencing the length of the QTc
interval. In rare circumstances (incidence rate
< 0.0006), pharmacological induction of labor
with uterotonics, including Syntocinon®,
increases the risk of postpartum disseminated
intravascular coagulation (DIC) and the effect
is independent from the type of substance used.
This risk is increased particularly if the woman
has further risk factors for DIC, such as age over
35 and gestational age of more than 40 weeks.
Syntocinon® seems to have side effects on
bleeding, on coagulation and on brinogen level.
The frequency and mechanism with which these
interactions take place is relatively unknown [83].
The study of Golparvar et al. assessed the effects
on the forming of the clot and on circulation after
the administration of Syntocinon® according
to two different infusion regimens, 15 units/
hours and 30 units/hours respectively, in healthy
women who had given birth, by means of the
analysis of thromboelastography. The authors
concluded that Syntocinon® has a modest effect
of hypercoagulability on maternal blood, which
is increased as per the dosages administered [84].
Syntocinon® is considered an uncommon cause
of severe allergic reaction during delivery. It
was recently demonstrated that sensitization to
latex could be an important predisposing factor
to anaphylaxis after Syntocinon® infusion during
delivery [85]. With any method of administration,
Syntocinon® can cause the following side
effects: frequent effects (> 1/100) such as
headache, tachycardia, bradycardia, nausea,
sickness; uncommon effects (> 1/1,000) such as
arrhythmia [86]; rare effects (> 1/10,000) such as
anaphylactoid reaction associated with dyspnoea,
hypotension or shock, rash.
Many detailed guidelines can be found in
literature regarding the best use of uterotonic
substances and obstetrical interventions to carry
out in order to prevent PPH. However, changes
in the hemostatic mechanisms, considered
consequences to an uncontrolled bleeding, are
not taken into consideration as causes and,
consequently, as prevention of PPH. Interest
towards the coagulation pattern of a woman
giving birth was reassessed after the results of a
prospective study carried out in France from 2002
to 2004 were released. This study aimed to assess
if changes to the hemostasis markers are predictors
of the severity of PPH, and demonstrated a possible
relationship between the reduction of brinogen
levels and outcomes (PPH), with an increased risk
of severe haemorrhage of 2.63 (IC 95%) each 1
g/L of decrease in brinogen. However, the study
did not provide explanations regarding the cause of
brinogen reduction, and, therefore, at present, we
do not know if the reduction of brinogen levels
is a cause or a consequence of PPH [87]. Current
knowledge indicates that brinogen levels are
higher in pregnant women compared not pregnant
ones, and brinogen increase considerably in the
third trimester of pregnancy, in relation to the
levels of estrogens [88]. Conversely after delivery
a decrease in the levels of haematic estrogens
can be seen, with the consequent reduction of the
concentration of plasma brinogen, that continues
during the rst periods of postpartum [89]. This,
together with the intravascular deposition of brin
during postpartum, that leads to an increase in the
use of brinogen, enables to assign a rational to
the use of TA in the prevention of PPH. Studies of
placental biopsies, using an electronic microscope
show that after a normal delivery, a brin
extravascular network is formed immediately on
the endometrial surface [90]; the absence or lack of
formation of this network could be a cause of PPH
that has still not been studied. In fact, some studies
demonstrated the effectiveness of TA in reducing
haemorrhages during cesarean sections and vaginal
deliveries [78, 79]. Last but not least, as a recent
review suggests, TA remains stable for at least 12
weeks in a great variety of different conditions
and does not require refrigeration. Therefore,
considering the low rate of complications, the
possibility of oral administration, TA is an ideal
medication to reduce maternal mortality caused
by PPH specially in low income countries such as
Sub-Saharan Africa, where about 50% of deliveries
take place at home, and where the availability of
Synthetic oxytocin administration and endogenous oxytocin in childbirth
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Ragusa
this medication could reduce maternal mortality
caused by PPH by 30% (about 22,000 deaths per
year), thanking also to its low cost [91].
Syntocinon® showed great effectiveness in the
prevention of PPH so the other two components of
active management are not longer recommended.
Syntocinon® is the treatment of choice (grade A)
and can be used either after the shoulders expulsion
or rapidly after the placental delivery (grade
B). A dose of 5 or 10 IU must be administrated
intravenously over at least 1 minute or directly
by an intramuscular injection (professional
agreement) except in women with documented
cardiovascular disease in which the duration of
intravenous perfusion should be over at least 5
minutes (professional agreement). 5 or 10 IU can
be injected intravenously over 1 minute, and over
5 minutes in women with cardiovascular disease in
patients undergoing cesarean section (professional
agreement) [76]. However, this medication can
also have serious secondary effects, some of which
are still being studied, therefore it is important to
study the possibility of alternative medication such
as TA, which has lower systemic effects compared
with Syntocinon®, can be administered orally and
is affordable. Furthermore TA could be the best
prevention where the healthcare system is not
available or efcient.
However, we should consider that in countries
with high income, the situation differs greatly. In
these countries, with a good healthcare system,
healthy women with normal levels of hemoglobin
do not suffer any negative effects from a blood
loss of 500 ml, which is just a little higher than
the amount lost during a routine blood donation.
Looking in details at all maternal deaths in the
United Kingdom from 2006 to 2008, we can see
that out of 2.3 million women who gave birth, only
ve deaths were due to PPH:
• three of the ve women died due to insufcient
observation during the post-operative phase;
• one of the women had a level of hemoglobin of
7.5 before the cesarean section, had a blood loss
of 1-2 L during the operation, and died some
months later of pneumonia;
• the fth woman died alone at home after
unrecognized pregnancy and labor [92].
None of these women can be considered a
“healthy woman with normal levels of hemoglobin
and at low risk of haemorrhage”. It would be correct
to say that PPH is not one of the main causes of
maternal death in low-risk women, in a place with
expert doctors and midwives and in high income
countries. Therefore we could assist these patients
with an attitude that better respects physiology. If
a woman starts bleeding excessively after delivery,
it is obvious that an uterotonic treatment is needed
as soon as possible.
The attention of the personnel assisting patients
during childbirth and in the rst hours postpartum,
along with a prompt medical therapy in case
of PPH, could be the best and most affordable
prevention strategy for low-risk patients where the
healthcare system can guarantee a complete and
prompt assistance.
In conclusion we can decide to do PPH
prophylaxis or not but we should do our best to
guarantee the best strategy for every single patient
or group of patients, without going on with the
policy of “one size ts all”.
Declaration of interest
The Author declares that there is no conict of interest.
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