Vol. 27 - Italian Journal of Gynaecology and Obstetrics

Transcript

Italian Journal
of
Gynaecology
& Obstetrics
September 2015 - Vol. 27 - N. 3 - Quarterly - ISSN 2385 - 0868
The Official Journal of the
Società Italiana di Ginecologia e Ostetricia
(SIGO)
Quarterly
Partner-Graf
73
Italian Journal
of
Gynaecology
& Obstetrics
The Official Journal of the
Società Italiana di Ginecologia e Ostetricia
(SIGO)
Quarterly
Partner-Graf
Editor in Chief
Paolo Scollo, Catania
Editors
Herbert Valensise, Roma
Enrico Vizza, Roma
Editorial Board
Cervigni Mauro, Roma
Chiantera Vito, Napoli
Costa Mauro, Genova
De Stefano Cristofaro, Avellino
De Vita Davide, Salerno
La Sala Giovanni Battista, Reggio Emilia
Locci Maria Vittoria, Napoli
Marci Roberto, Roma
Monni Giovanni, Cagliari
Ragusa Antonio Franco, Milano
Sirimarco Fabio, Napoli
Trojano Vito, Bari
Viora Elsa, Torino
Editorial Staff
Roberto Zerbinati
Serena Zerbinati
Management, Administrative office
Partner-Graf Srl - Via F. Ferrucci, 73 - 59100 Prato
Tel 0574 527949 - Fax 0574 636250
E-mail: [email protected]
The Italian Journal of Gynaecology & Obstetrics is a digital magazine.
You can download it freely from
www.italianjournalofgynaecologyandobstetrics.com or
www.italianjog.com
It. J. Gynaecol. Obstet.
2015, 27: N.3
Table of contents
77
Editorial.
Italian Journal of Obstestrics & Gynaecology on web: a one-year balance
79
Low pregestational Fat Mass and subsequent maternal cardiovascular
maladaptation in early pregnancy. The missing link for preeclampsia
81
Case-control study of the role of perineal application of an AC collagen/
hyaluronic acid medical device on the maternal perineum at birth
86
Breastfeeding in italy: the role of obstetrician-gynecologists
93
Serum levels of calcium and magnesium in pre-eclamptic- eclamptic patients in
a tertiary institution
101
Paolo Scollo
Giulia Gagliardi, Grazia Maria Tiralongo, Ilaria Pisani, Damiano Lo Presti, Roberta Licia Scala,
Gianpaolo Novelli, Barbara Vasapollo, Angela Adreoli, Herbert Valensise
Silvia D’Ippolito, Alessia Fiorelli, Barbara Burlon, Giuseppa Caliri, Giovanni Scambia, Nicoletta Di
Simone
Romana Prosperi Porta, Elise M. Chapin, Maria Grazia Porpora, Giuseppe Canzone
Abiodun Olusanya, Adekunle O Oguntayo, Aliyu I Sambo
A very rare case of uterine PEComa HMB45 negative: primitive or relapse?
Basilio Pecorino, Giuseppe Scibilia, Antonio Galia, Paolo Scollo
111
The potential role of preoperative serum cancer antigen CA 15-3 in the prognosis
of breast cancer
115
Dangers and expenses of a first-level Obstetrics facility: a serious Italian
concern
121
Adela Stoenescu, Daniel Herr, Christoph Gerlinger, Erich Franz Solomayer, Christoph Scholz,
Ingolf Juhasz-Böss, Julia Radosa
Ugo Indraccolo, Anna Maria Iannicco, Mirella Buccioni, Giuseppe Micucci
77
Editorial
Italian Journal Of Obstestrics & Gynaecology on web: a one-year
balance
Paolo Scollo
One year has passed by when on 30th september 2014 the new version of the hystorical official SIGO
magazine on-web-format has been released.
At the beginning, the decision to change to a on-web-format preserving the characteristic format
with blue banner together with the SIGO Logo familiar to all of us that characterized for so many years
and leaving the printed version of the magazine was not easy for us. But we believed that in order to
improve its diffusion was crucial to make the Italian Journal easier to read and to consult not only to
Italian readers but also to International ones.
Since then, 5 issues has been published with 26 original articles from italian as well as international
researches and the Italian Journal of Obstetrics & Gynaecology website received 13000 visits from all
over the world. In the last year, the magazine has received the ISS registration, and soon will be indexed.
As you understand, such ambiciuos projects to make our prestigiuos and ancient Journal a modern
one will take a long time but the presente data demonstrates that we are working in the right direction.
But, as I wrote one year ago, all of that will be possible only with your contribution.
Prof. Paolo Scollo
S.I.G.O. President
79
V
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M
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O
FARM INECOL
IN G
LA NATURA CHE AIUTA
ClimaMEV
IncontinenzaMEV
VenaMEV
FARMACEUTICA MEV - Strada Cassia Sud, 175 - 53100 Siena (SI)
Tel. 0577 378091/ Fax 0577 379970 - www.farmaceutica-mev.it
Low pregestational Fat Mass and subsequent maternal cardiovascular
maladaptation in early pregnancy.
The missing link for preeclampsia
Giulia Gagliardi2, Grazia Maria Tiralongo2, Ilaria Pisani2, Damiano Lo Presti2, Roberta Licia
Scala1; Gianpaolo Novelli4, Barbara Vasapollo1, Angela Adreoli3, Herbert Valensise2
AFaR (Fatebenefratelli Association for Research), Fatebenefratelli Hospital Isola Tiberina, Rome Italy
Department of Obstetrics and Gynecology, Tor Vergata University, Rome and Fatebenefratelli Hospital,
Isola Tiberina, Rome Italy
3
Department of Physiology, Tor Vergata University, Rome Italy
4
Department of Cardiology, San Sebastiano Martire Hospital, Frascati (Rome, Italy)
1
2
ABSTRACT
Objective: Aim of the study is to identify patients at high risk
of hypertensive complication during pregnancy throughout
the assessment of pre-pregnancy maternal fat mass and TVR.
Methods: 38 healthy, normotensive women were subjected to
Bioimpedance during the antenatal visit and to haemodynamic
measurement throughout the USCOM method during the
antenatal visit and in the first trimester.
Results: Patients were divided into two groups during the first
trimester: Group A (n = 22) with TVR<1200 dynes.sec.cm-5,
Group B (n = 16) with TVR>1200 dynes.sec.cm-5. There were
no significant differences between the two groups in terms of
maternal age, parity, gestational age and BMI. Cardiac output,
stroke volume and TVR were statistically different between
the two groups during the preconceptional visit and during
the first trimester. Fat Mass (FM) was significantly greater in
the low TVR group (p <0.05) while no statistically significant
difference was found in the other bioimpendance parameters.
Discussion: Our data showed the poor accuracy of BMI in
expressing the maternal body composition compared with
bioimpendance. Moreover, in the group with low TVR is
possible to identify a subgroup with high fat mass that could
be at higher risk of late preeclampsia difficultly recognizable
throughout TVR and BMI. On the other side a too low fat mass
might negatively influence maternal adaptation to pregnancy.
Conclusion: Fat mass could be a better marker of body
composition and a target to monitor the effectiveness of dietary
changes improving maternal and neonatal outcome.
SOMMARIO
Obiettivo: Scopo dello studio è identificare pazienti ad alto
rischio di complicanze ipertensive in gravidanza attraverso la
valutazione della massa grassa pregestazionale e delle TVR.
Metodi: 38 donne sane, normotese sono state sottoposte a
bioimpedenziometria durante la visita preconcezionale e
a valutazione emodinamica attraverso il metodo USCOM
durante la visita prenatale e nel primo trimestre.
Risultati: Le pazienti sono state divise in due gruppi durante
il primo trimestre: gruppo A con TVR <1.200 dynes.sec.
cm-5, mentre il gruppo B con TVR> 1200 dynes.sec.cm- 5.
Non ci sono state differenze significative tra i due gruppi in
termini di età materna, parità, età gestazionale e BMI. Valori
significativamente differenti in termini di gittata cardiaca, gittata
sistolica e TVR sono stati riscontrati tra i due gruppi durante la
visita preconcezionale e durante il primo trimestre. La fat mass
(FM) è risultata significativamente maggiore nel gruppo A,
mentre nessuna differenza statisticamente significativa è stata
riscontrata negli altri parametri bioimpedenziometrici.
Discussione: Dai dati emerge la scarsa precisione del BMI
nell’esprimere la composizione corporea materna rispetto
alla bioimpedenziometria. Inoltre, nel gruppo con TVR basse
si identifica un sottogruppo con FM alta a maggior rischio
di preeclampsia tardiva. Dall’altro lato una FM troppo bassa
potrebbe influenzare negativamente l’adattamento materno
alla gravidanza.
Conclusione: La valutazione della FM e dei suoi cambiamenti
indotti dalla dieta potrebbero rappresentare un utile strumento
per migliorare l’outcome materno-fetale
Keywords: Total vascular resistance; bioimpedance; early and
late preeclampsia; fat mass; pregestational BMI
INTRODUCTION
Several studies have demonstrated the
correlation between maternal overweight and
obesity and pregnancy complications such as
pregnancy-induced hypertension (1). Moreover,
maternal weight changes between consecutive
pregnancies correlates linearly with risks of
these obesity related pregnancy complications,
suggesting a causal relationship(2).
Perlow and Morgan(3) observed hypertension
Correspondence to: [email protected]
Copyright 2015, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-20
in pregnancy to be very significantly frequent
in obese women. Many other findings have also
confirmed the link between hypertension and
excessive weight gain(4).
In the non-pregnant obese population, a 10%
reduction in body weight is recommended by the
National Institutes of Health as an initial weight
loss target to confer health benefits(5).
Currently, maternal body composition
evaluation in pregnancy is based on BMI
measurement. These index, although provides
distinction into normal, overweight and obese
81
2015, 27: N.3
DOI: 10.14660/2385-0868-20
patients is little accurate in describing body
composition in terms of fat mass, fat free mass
and water distribution. Bioimpendance, through
definition of free fat mass and fat mass percentage
provides the more accurate identification of those
patients who need a diet restriction, despite of a
normal BMI. With the improvement of prenatal
and peripartum care, pre-pregnancy BMI and
weight change in women during pregnancy are
gradually gaining attention.
In particular, many authors suggest that obese
women are at major risk to develop a late form of
preeclampsia(6). The concept of early and late PE is
more modern, and it is widely accepted that these
two entities have different etiologies and should
be regarded as different forms of the disease.
Early-onset PE (before 34 weeks) is commonly
associated with abnormal uterine artery Doppler,
foetal growth restriction (FGR), and adverse
maternal and neonatal outcomes. In contrast,
late-onset PE (after 34 weeks) is mostly associated
with normal or slight increased uterine resistance
index, a low rate of fetal involvement, and more
favorable perinatal outcomes(7, 8).
A novel method to evaluate an adequate
placentation is the assessment of Total Vascular
Resistance (TVR) which represents the steady
component of the afterload and includes the
uteroplacental circulation with a contribution
of 20% to 26% to the total reduction of systemic
vascular resistance in the second trimester (9).
These changes take place during early phases of
pregnancy: since the 5th week and most of TVR
fall (85 %) is seen at 16 weeks of gestation(10).
OBJECTIVE
Aim of the study is to assess the pre-pregnancy
maternal fat mass in women with high and low
TVR values assessed antenatally and during the
first trimester of pregnancy in order to identify a
group of patient at higher risk of poor maternalneonatal outcome and that will beneficiate of
preconception counselling about the importance
of a change of diet.
METHODS
82
A prospective observational study to test our
hypothesis was proposed to be conducted at the
San Giovanni Calibita Fatebenefratelli Hospital,
Department of Obstetrics and Gynaecology in
Rome over a continuous period from June 2013 to
May 2014. Approval of the local ethics committee
was obtained based on a submitted protocol and
informed consent was obtained from all patients
prior to enrolment. We included 38 healthy,
normotensive women during the first trimester of
pregnancy (from 5+0 to 11+6 weeks of gestation)
previously attending an antenatal “first visit” .
Inclusion criteria according to the protocol
were:
1) Normal BP at enrolment
2) Singleton pregnancy
3) Certain dates of pregnancy
4) Absence of maternal disease
Exclusion criteria according to the protocol
were:
1) Undetermined gestational age
2) Tobacco use
3) Multiple pregnancy
4) Maternal heart and other pre-existing
chronic disease
5) Chromosomal abnormalities and/or
foetal abnormalities suspected on
ultrasound
6) Use of medication other than iron
supplements
7) Conception by assisted reproductive
techniques
During the antenatal visit, patients were
subjected to Bioimpedance in order to evaluate
body water, fat mass and fat free mass distribution
and to haemodynamic measurement throughout
the USCOM method. For each patients were
calculated pre-pregnancy BMI index. Prepregnancy BMI was calculated as the ratio of
weight prior to pregnancy (kg) divided by
height (m2). During the first visit in pregnancy,
patients were subjected again to haemodynamic
measurement throughout the USCOM method.
Retrospectively, we divided our study
population in two groups according to the TVR
evaluated during the first trimester of pregnancy:
Group A (n =22) includes patients with TVR<1200
dynes.sec.cm-5, while Group B (n =16) includes
patients with values TVR> 1200 dynes.sec.cm-5.
BIA measurement
Electrical bioimpedance (BIA) readily measures
TBW, ECW and intracellular water (ICW)
without intervention. This method relies on the
conductance of an alternating electric current to
determine the total conductor volume of the body.
Because water and electrolytes are the main factors
affecting electrical conductance, TBW is assessed
by impedance sensors as changes in BIA and
converted to a display module. BIA measurements
were performed on each subject after a period
of rest to allow impedance equilibration. Body
G. Gagliardi et al.
mass index (BMI) was calculated according to
the formula weight/height2. BIA was measured
by determining resistance (R, Ω-Ohm) and
reactance (Xc, Ω-Ohm) using the Tefal scale
(Tefal, Rowenta). The device utilises a tetrapolar
impedance plethysmograph, with 4 aluminium
foil electrodes on the nonconductive surface of the
skin. The women, were examined fully clothed but
without shoes or socks, supine on a table made of
nonconductive materials. The BIA was measured
at 50 kHz (BIA50). The TBW was calculated using
the prediction formula of Lukaski(11), while ECW
was calculated using the prediction formula of
Segal(12), and ICW as the difference between the
two values (ICW=TBW-ECW).
Haemodynamic measurement
Haemodynamic measurements were acquired
with the USCOM 1A. The USCOM has been
validated against invasive gold standards and
flow probes and has proof of effectiveness in
pre-eclampsia(13). USCOM uses continuous-wave
Doppler to determine CO by a non-imaging
transducer placed at the suprasternal notch to
measure transaortic or transpulmonary blood
ﬂow. To calculate CO the transducer is placed in
the suprasternal notch or in parasternal interspace,
and the Doppler beam directed across the aortic
or pulmonary valve to acquire a spectral Doppler
flow profile displayed as a time-velocity plot.
Once the optimal flow profile is obtained, the
trace is frozen on the screen, and the flow profiles
automatically traced allowing the stroke volume
(SV) to be calculated as the product of the velocitytime integral and the cross-sectional area (CSA) of
the chosen valve. The CSA of the aortic valve is
determined from the proprietary height-indexed
regression equations. The CO is then calculated
from the product of the heart rate (HR) and SV.
Input of blood pressure provides for calculation
of TVR.
STATISTICAL ANALYSIS
Clinical data were compared by means of
indipendent samples Student’s t-test. Differences
were considered as significant with p <0,05.
RESULTS
In total 38 women were selected in our study.
The study population was divided into two
groups on the basis of the values of TVR: Group A
(n = 22) includes patients with TVR<1200 dynes.
sec.cm-5, while Group B (n = 16) includes patients
with values TVR>1200 dynes.sec.cm-5. Table 1
summarizes the main characteristics of the study
population. There were no significant differences
between the high and low TVR groups in terms of
maternal age, parity, or gestational age at the time
of assessment and BMI.
Table 1
Maternal characteristics
Group A
TVR<1200
(n=22)
Group B
TVR>1200
(n=16)
p
Age (years)
30.6±4.9
31.5±3.8
ns
Parity
1.02±0.6
1.01±0.8
ns
Gestational Age
(weeks)
8.0±1.4
7.69±1.4
ns
Gestational Age
(days)
1.9±1.5
1.2±1.8
ns
22.4±3.1
21.9±2
ns
Pre-pregnancy
BMI (Kg/m²)
Pre pregnancy haemodynamic and body
impedance variables are showed in Table 2 and
3 respectively, and displayed as mean ± standard
deviations.
There were no statistical differences between
SBP, DBP and HR in either high or low TVR group.
Mean Doppler determined haemodynamic
parameters of CO, SV and TVR were statistically
different between the two groups. Mean BIA
parameters demonstrated no statistically
significant difference in TBW, ICW, ECW and FFM
between the two groups.
Fat Mass (FM) was significantly greater in the
low TVR group (p <0.05).
Table 2
Pre-pregnancy haemodynamic values
GROUP A
GROUP B
p
SBP
119.9±10.5
123.5±5.7
ns
DBP
70±15.5
72.6±6.5
ns
CO
6.8±1
5.6±0.3
<0.05
TVR
1120±77.2
1350.8±124
<0.05
SV
87.4±10.6
72.8±18.7
<0.05
HR
80.9±9,4
75.5±10.9
ns
TFC
377.5±32.5
352.7±29.1
ns
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2015, 27: N.3
DOI: 10.14660/2385-0868-20
Table 3
Pre-pregnancy bioimpedence parameters
GROUP A
GROUP B
p
TBW
32.6±2.2
31.9±2.2
ns
ICW
14.6±2.4
17.1±2.6
ns
ECW
17.9±3.4
14.8±2.7
ns
FM
17.2±2.5
14.9±5
<0.05
FFM
44.4±4.4
4.6±3.1
ns
First trimester haemodynamic parameters
are showed in Table 4. Values of CO, SV and
TVR were statistically different between the two
groups.
a statistically significant difference in terms of fat
mass distribution.
This first result could be explained by the poor
accuracy of BMI in expressing the maternal body
composition compared to bioimpendace analysis.
We divided our patients on the basis of the TVR
in order to earlier identify a group of patients
at high risk to develop pregnancy complication
and we evaluated the body composition for both
groups. Unexpectedly, we found a low fat mass
in the group of patients at high risk (TVR>1200),
confirming the results of our previous study.
This finding is interesting because may suggest
that in the group with low TVR is possible to
identify a subgroup with high fat mass; this group
could be at higher risk of late preeclampsia that
Table 4
First trimester haemodynamic parameters
GROUP A
GROUP B
p
SBP
117.9±14.5
121.5±7.7
ns
DBP
75±11.7
75.6±8.1
ns
CO
7.1±0.8
5±1
<0.05
TVR
1020±88.9
1390.5±216.4
<0.05
SV
88.4±10.6
70.8±13.9
<0.05
HR
80.9±9.4
75.5±10.9
ns
TFC
377.5±32.5
352.7±29.1
ns
DISCUSSION
Many authors focused on the association
between a high risk of maternal and foetal
complication with maternal body mass index
(BMI) among overweight and obese women. These
data suggest that the use of maternal BMI is an
advantage because it is a valid proxy for adiposity
and that the correlation between maternal BMI
and total body fat is high, especially in early
pregnancy(14).
From the analysis of demographic
characteristics of our study population we found
no differences in antenatal maternal BMI, that are
similar between the two groups whereas from
the antenatal bioimpendance analysis we found
84
Figure 1. Correlation Fat Mass/TVR
could be difficultly recognizable throughout TVR
and BMI (Fig 1).
On the other side it is possible that a too low
fat mass might negatively influence the maternal
adaptation to pregnancy.
Several study focused on the importance of
improving antenatal maternal BMI in order to
reduce the pregnancy related complications. In
our study, we demonstrate that fat mass could be
a better marker of body composition and a target
to monitor the effectiveness of dietary changes.
In conclusions, an exhaustive prenatal
counselling based on the sensitization of patients
on dietary and lifestyle change could improve
pregnancy outcome.
G. Gagliardi et al.
REFERENCES
1) Lindsay CA, Huston L, Amini SB, Catalano PM.
Longitudinal changes in the relationship between
body mass index and percent body fat in pregnancy.
Obstet Gynecol 1997; 89:377-82. 39
2) Johansson S1, Villamor E2, Altman M3, Bonamy AK3,
Granath F3, Cnattingius S. Maternal overweight and
obesity in early pregnancy and risk of infant mortality:
a population based cohort study in Sweden. BMJ. 2014
Dec 2;349.
3) J. H. Perlow and M. A. Morgan, “Massive maternal
obesity and perioperative cesarean morbidity,” The
American Journal of Obstetrics and Gynecology, vol.
170, no. 2, pp. 560–565, 1994.
4) Thorsdottir, J. E. Torfadottir, B. E. Birgisdottir, and
R. T. Geirsson. “Weight gain in women of normal
weight before pregnancy: complications in pregnancy
or delivery and birth outcome” Obstetrics and
Gynecology, v. 99; 5,1,799–806, 2002.
5) Laura Schummers, SM, Jennifer A. Hutcheon, PhD,
Lisa M. Bodnar, RD, PhD, Ellice Lieberman, MD, DrPH,
and Katherine P. Himes, MD, MS Risk of Adverse
Pregnancy Outcomes by Prepregnancy Body Mass
Index. Obstet Gynecol 2015;125:133–43
6) Valensise H, Vasapollo B, Gagliardi G, Novelli GP.
Early and late preeclampsia. Two different maternal
hemodynamic states in the latent phase of the disease.
Hypertension. 2008 Nov;52(5):873-80.
7) Von Dadelszen P, Magee LA, Roberts JM.
Subclassification of pre-eclampsia. Hypertens
Pregnancy. 2003;22:143–148. 4.
8) Huppertz B. Placental origins of preeclampsia:
challenging the current hypothesis. Hypertension.
2008;51:970–975.
9) Valensise H, Novelli GP, Vasapollo B, Borzi
M, Arduini D, Galante A, Romanini C. Maternal
cardiac systolic and diastolic function: relationship
with uteroplacental resistance. A Doppler and
echicardiographic longitudinal study. Ultrasound
Obstet Gynecol. 2000; 15:487-497.
10) Clapp JF, Capeless E. Cardiovascular function
before, during, and after the first and subsequent
pregnancies. Am J Cardiol 1997; 80: 1469-1473.
11) Lukaski HC, Siders WA, Nielsen EJ, Hall CB.
Total body water in pregnancy: assessment by using
bioelectrical impedance. Am J Clin Nutr 1994; 59:
578-585
12) Segal KR, Burastero S, Chun H, Coronel P, Pierson
RN Jr, Wang J. Estimation of extracellular and total
body water by multiple-frequency bioelectricalimpedance measurement. Am J Clin Nutr 1991; 54: 26-9
13) Kager et al. Measurement of cardiac output in
normal pregnancy by a non-invasive two-dimensional
independent Doppler device. Australian and New
Zeland Journal of Obstetrics and Gynaecology
2009;49:142-144
14) Sewell MF, Huston-Presley L, Amini SB, Catalano
PM. Body mass index: a true indicator of body fat in
obese gravidas. J Reprod Med 2007;52:907-11.
85
Case-control study of the role of perineal application of an AC collagen/
hyaluronic acid medical device on the maternal perineum at birth
Silvia D’Ippolito1, Alessia Fiorelli1, Barbara Burlon1, Giuseppa Caliri1, Giovanni Scambia1,
Nicoletta Di Simone1
Department of Obstetrics and Gynecology, Policlinico A. Gemelli, Università Cattolica del Sacro
Cuore, Rome
1
ABSTRACT
A 43-year-old woman was referred to our Department Perineal
trauma (PT) following vaginal birth can be associated with short
and long term morbidity. Aim of our research was to study the
role of antenatal vulvo-vaginal and perineal application of a
creamy medical device containing AC collagen and hyaluronic
acid on the maternal perineum at birth. To this end seventytwo healthy pregnant women were approached and taught
how perform the massage and apply the device, starting from
the 28th gestational week up to delivery. Forty-seven of them
completed the study and compared with controls. A lower
incidence of PT and episiotomies and a shorter duration of 1st
and 2nd stage of labor was observed in the study group. No
significant differences when considering tears, intrapartum
blood loss, instrumental deliveries. As such, women should be
warned of the likely benefit of perineal massage and provided
with information on how to massage.
SOMMARIO
I traumi perineali (PT) dopo un parto vaginale possono essere
associati a morbilità a breve e lungo termine. Scopo della
nostra ricerca è stato quello di studiare l’effetto sul perineo
dell’applicazione vulvo-vaginale e perineale di una crema
contenente collagene AC e acido ialuronico. A tal fine 72 donne
con gravidanza fisiologica sono state arruolate durante la
28ma settimana di gestazione. Ad esse è stato insegnato come
eseguire il massaggio perineale per l’applicazione della crema
dalla 28ma settimana di gravidanza fino al parto. Quarantasette
donne hanno terminato lo studio e sono state confrontate con
delle pazienti di controllo. Nel gruppo di studio abbiamo
osservato una minore incidenza di PT e di episiotomie e una
durata più breve del 1 ° e 2 ° stadio del travaglio. Nessuna
differenza significativa se si considera le lacerazioni, la perdita
ematica intraparto, parti operativi. Le donne dovrebbero essere
informate dei benefici del massaggio perineale con una crema a
base collagene e dovrebbero essere istruite su come effettuare
il massaggio nel periodo antepartum.
Keywords: perineum, lacerations, episiotomy, collagen, birth,
perineal massage, hyaluronic acid.
INTRODUCTION
The female pelvic floor represents a region of
the body whose anatomic structures must prevent
incontinence and pelvic organ prolapse during
the elevations in abdominal pressure and motions
associated with daily physical activities; they must
also permit urination and defecation and allow
childbirth(1). The main components of the pelvic
floor include i) the levator ani muscle, whose
components are tonically contracted at rest and
act to close the genital hiatus and provide a stable
platform for the pelvic viscera; ii) the endopelvic
fascia, connective-tissue network that envelops
all organs of the pelvis and connects them to the
supportive musculature and bones of the pelvis.
This network holds vagina and uterus in their
normal anatomical location and stabilizes the
viscera to permit storage of urine and stool, coitus,
parturition, and defecation(1-2).
DOI: 10.14660/2385-0868-21
The physiological changes occurring during
pregnancy and the processes of childbirth have
a detrimental effect on the structure and function
of the muscles, nerves and fascial tissues, which
may result in a wide range of symptoms including
urinary or anal incontinence (Table 1) (3) . As
gestation progresses, the pregnant uterus produce
anatomical changes resulting in a wider opening
of the bladder neck, increased bladder motility
and and changes in the collagen and connective
tissues properties(4-6). Nevertheless, the processes
of vaginal delivery threaten the pelvic floor
functions. During the stage of the ‘crowning’
of the baby’s head, the widest part of the baby’s
head stretches the pelvic floor muscles, nerves and
endopelvic fascia. It is likely that such stretching
may contribute to PFD later in life (Figure 1).
Magnetic Resonance Imaging analysis performed
in primiparous and in nulliparous women showed
a higher frequency of defects in the levator ani
muscle in the first group (20% vs. 5%; 7). Pudendal
nerve injury can occur in 80% of women following
86
S. D’Ippolito et al.
Figure 1
Pelvic floor changes during pregnancy and delivery. (A) Intra-abdominal pressure changes in pregnancy due to the increased volume and
weight of the gravid uterus. The whole intra-abdominal pressure vector converge on the anterior area of pelvic floor (uro-genital hiatus) and
pregnancy related compensations in biomechanics and structure of the spine. The increased size of uterus and fetus causes the occurrence
of a backward compensation. The pelvis assumes a new angle to support the increased weight and volume. The center of gravity usually
shifts forward. With a greater angle of pelvic inclination, a greater curvature of the lumbar spine results. (B) Pelvic floor muscles distention
during vaginal delivery. Areas of midline and mediolateral episiotomies.
their first vaginal delivery(8-10). Finally Dietz et al.
by performing trans-perineal ultrasound scans
demonstrated that up to one-third of women
following vaginal delivery undergo avulsion/
tearing of the endopelvic fascia and that such
anatomical change is associated with postpartum
stress urinary incontinence three months following
delivery(11-12).
To date, different perineal techniques and
interventions are being used to slow down the
birth and allow the perineum to stretch slowly in
order to prevent perineal injury(13). Among these
the antenatal exercises with the mechanical trainer
EPI-NO ®, the intrapartum perineal massage
(hands-on tecnique) and the local application of
warm compresses are widely used by midwives
and birth attendants(13-14). Objective of our research
was to study the possible role of antenatal perineal
and vulvo-vaginal massage with a creamy medical
device containing AC collagen and hyaluronic acid
(Perilei Gravidanza®) on the maternal perineum at
birth.
gestation.
Inclusion criteria included healthy pregnant
women at 28 weeks gestation who were planned
for a vaginal delivery at our institution. Exclusion
criteria comprised a history of any vaginal
surgical procedure, any vaginal infection, multiple
gestation, use of a different perineal technique
during the current pregnancy and communication
difficulties (because of the difficulty to seek
informed consent).
Participants were provided with background
information regarding episiotomy and perineal
trauma during vaginal delivery. After consent,
the study coordinators instructed the women
as to how to perform the perineal massage by
providing them with written information about
the technique of conducting perineal and vulvovaginal massage (Figure 2).
MATERIALS AND METHODS
Study design
Case-control study
Subjects investigated
This study was performed between May 2013
and July 2014 at the Department of Obstetrics and
Gynecology, Policlinico A. Gemelli, Università
Cattolica del Sacro Cuore, Rome, Italy. It was
approved by the local institutional review board.
Healthy pregnant women eligible for the study
group were recruited mainly during antenatal
outpatient clinic during their 28th week of
Figure 2.
Vulvo-vaginal and perineal massage technique. A uniform
technique of conducting the perineal and vulvo-vaginal massage
was provided through written information. Women were taught
to apply a creamy medical device containing AC collagen and
hyaluronic acid with their thumbs inside the vulvo-vaginal region
and the posterior vagina (2–3 cm), and to gently press downwards
and slide to both sides at the same time up to the anterior vulvar
region. The stretching action was to be maintained until they felt
a slight sensation of burning or tingling, at which point they were
instructed to hold the pressure for 1 minute until the area turned
slightly numb.
87
2015, 27: N.3
DOI: 10.14660/2385-0868-21
88
Briefly, the women were taught to apply a
creamy medical device containing AC collagen
and hyaluronic acid (Perilei Gravidanza® cream,
©
Angelini Acraf S.p.A, Italy) with their thumbs
inside the vagina (2–3 cm), and to gently press
downwards and slide to both sides at the same
time. The stretching action was to be maintained
until they felt a slight sensation of burning or
tingling, at which point they were instructed
to hold the pressure for 1 minute until the area
turned slightly numb. The women were asked
to continue the massage back and forth over the
posterior distal half of the vagina for 10 minutes.
They were asked to begin this perineal and vulvovaginal massage starting from their 28th week of
gestation once a day for the first week and then
once a day on alternate days until delivery. In
order to improve and reinforce compliance and
for any questions that might arise, a weekly
telephone call to all participants was made by a
study coordinator throughout the study period.
All participants were instructed not to reveal
to the attending staff during labor whether they
performed perineal massage during gestation.
Attending midwives and physicians were asked
not to inquire about possible use of antenatal
perineal massage. No perineal massage during
the second stage of labor while the vertex was
in the crowning position was performed by
the midwifes. Midwifes were instructed not to
perform systematic episiotomy.
For each participant, upon arrival to the
delivery unit in active labor, data regarding
the following primary outcomes were added to
the medical file: perineal damage, episiotomy
performance. The duration of first and second
stage of labor, the method of delivery (i.e.,
instrumental vs. spontaneous), the intrapartum
blood loss were registered as seconday outcome.
For all participants the following additional
parameters were also evaluated: gestational age at
delivery labor, fetal birth weight, use of epidural
analgesia during delivery. The medical files
were filled out immediately postpartum by the
midwives assisting in the delivery.
Perineal outcomes were categorized into the
following: intact perineum; lacerations of the
perineum; first, second, third and fourth-degree
tears; performance of an episiotomy. Laceration
was defined as a perineal tear or bruise not
requiring suturing.
Women delivered by emergent cesarean
section were excluded from the study.
Statistical analysis
All analyses were performed with the use
of SPSS v.16.0 software. Continuous variables
were expressed as mean + SD or median and
interquantile range as appropriate. Wilcoxon
Mann-Whitney test was used for statistical
analysis. Statistical significance was accepted at
p<0.05.
RESULTS
A total of 72 patients (49 primigravid and 24
secondigravid) were approached for this study.
Forty-seven patients (31 primigravid and 16
secondigravid) completed the study. A total of
25 women were excluded because an urgent
cesarean section occurred during the course of
labor (16 women, 64%) or because of delivery at a
different hospital (2 women, 8%), preterm delivery
(mean gestational age of 29 weeks; 2 women,
8%), stillbirth (1 woman, 4%), poor adherence (3
patients, 12%), or loss at the follow-up (1 woman,
4%). The 47 patients in the study group were
compared with 47 controls matched for age, BMI,
parity, use of epidural analgesia during labor
(Figure 3).
Figure 3
Perineal massage trial profile.
Most (n=42) of the women in the control
group were recruited in the delivery room prior
to delivery and after verifying no prior use of
massage during the current pregnancy. Mean
maternal age was 31.42+4.1 years in the study
group and 32.1+3.8 in the control group. When
considering gestational age at delivery and fetal
birth weight, no significant differences were
observed in the groups (mean 39.2+1.5 and
mean 39.4+3 weeks, respectively). Other baseline
demographic characteristics were similar between
the two groups (Table 2). Our surveillance
telephone calls revealed that 81.3% of the women
performed the massage more than two-thirds of
the time, 14.48% between a third to two-thirds and
4.22% less than a third of the time.
We found a significant difference in the rate
of intact perineum in the massage group as
compared with the control group (14.1% vs. 2.1%,
P<0.05). While no significant differences in the
rate of tears/lacerations was observed (31.9%
vs 27.6%, p=0.390), the rates of episiotomy were
significantly lower in the study group (51.1%
νs. 70.2%, p<0.05; Table 3). No difference was
found between the groups when considering the
amount of intrapartum blood loss (p=0.497) and
the number of vacuum deliveries (p=0.13). On the
contrary a significantly reduction in the duration
of the first and second stage of labor was observed
(Figure 4).
Table 2
Baseline characteristic of the study and control population
Parameter
Perilei
Control
Gravidanza
(n=47)
p
Massage
(study group
n=47)
Primigravid
31
31
16
16
31.42 ± 4.1
32.1 ± 3.8
ns
24 (20-24)
23 (19-24)
ns
39.2 ± 1.5
39.4±3
ns
3250 ± 250
3330 ± 150
ns
70%; 2±1
68%; 2±2
ns
(n)
Secondigravid
(n)
Age (years;
mean±SD)
BMI (kg/m2)
median (range)
Gestational age
at delivery (wk)
(mean±SD)
Mean Birth
weight (gr,
mean±SD)
Figure 4
Secondary outcome. Duration of the first and second stage of labour.
CTR: control group. *p<0.05.
Almost 90% of the women in the massage
group stated that they would perform perineal
massage during their next pregnancy.
Use of epidural
block (%; n° of
doses)
Table 3
Primary and secondary outcomes
Outcomes
Table 1
Symptoms of pelvic floor dysfunction
Lower urinary tract
• Urinary incontinence
• Urgency and frequency
• Slow or intermittent stream and straining
• Feeling of incomplete emptrying
Pain
• Chronic pelvic pain
• Pelvic pain syndrome
Sexual function
• Dyspareunia (painful sexual intercourse)
• Orgasmic dysfunction
Control
Primary outcomes
n° (%)
n°
%
Intact perineum
7 (14.8)*
1 (2.1)
Tears (total)
15 (31.9)
13 (27.6)
First degree/
laceration
10
6
Second degree
5
5
Third-fourth degree
0
2
25 (53.1)*
33 (70.2)
Bowel
• Obstructed defecation
• Functional constipation
• Faecal incontinence
• Rectal/anal prolapse
Vagina
• Pelvic organ prolapse
Study group
Episiotomy
Secondary outcomes
Intrapartum blood loss
(cc; mean+SD)
Vacuum deliveries
*p<0.05
245±30
223±40
0
4
89
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DOI: 10.14660/2385-0868-21
DISCUSSION
90
The results of the present case-control study
showed a higher prevalence of deliveries with
intact perineum in patients performing antenatal
perineal and vulvo-vaginal massage with a
creamy medical device containing AC collagen
and hyaluronic acid (Perilei Gravidanza ®)
compared to patients no performing massage,
possibly suggesting a protective perineal effect of
the procedure. Even though we could not find a
statistically significant benefit regarding the rates
of all categories of perineal tears, the perineal
massage group showed a significant lower rate
of episiotomies, which explains the reason why
the antenatal perineal and vulvo-vaginal massage
with the medical device is in relation with
increased rate of deliveries with intact perineum.
A slight non-significant reduction in third-fourth
degree perineal tears and vacuum deliveries
was observed in the massage group. However
it is not possible to draw a clear-cut conclusion
based on these trends since a larger sample would
be needed. When considering the secondary
outcomes, no significant difference was observed
in the intrapartum blood loss. Surprisingly we
observed a significantly reduced duration of the
first and the second stage of labor.
Previous studies about the role of perineal
massage in preventing the perineal trauma did
not reach a definite consensus on this matter. By
studying a population of 531 primiparous women,
Bodner-Adler et al. could not find a significant
benefit of the perineal massage with respect to the
incidence of perineal trauma(15). A further casecontrolled trial by Elad Mei-dan et al. concluded
that the antepartum perineal massage, from
the 34th week of pregnancy up to delivery, had
neither a protective nor a detrimental significant
effect on overall spontaneous tears, episiotomy
rates and intact perineum rates(16). On the contrary
Labrecque et al. observed an absolute increase
of 9% in intact perineum in primigravid women
randomized to perform antenatal perineal
massage (4% vs 15%; P=0.001; 17). They also
reported a positive correlation with the duration
of treatment showing that women who practiced
perineal massage on less than one third, one third
to two thirds, and more than two thirds of the
assigned days had an intact perineum in 20%, 23%,
and 28% of cases, respectively. Finally, a recent
Cochrane, including four trials (2,497 women),
reported that antenatal digital perineal massage
is associated with an overall reduction in the
incidence of trauma requiring suturing (risk ratio,
RR, 0.91; 95% confidence interval, CI 0.86-0.96),
and of episiotomy (RR 0.84; 95% CI 0.74-0.95; 18).
In line with these results, our findings support
the role of perineal massage started from the 28th
gestational week in reducing the episiotomy rate
and increasing the number of deliveries with
intact perineum. In addition, in our study, we
recommended women to perform the massage in
the anterior vulvo-vaginal region and to locally
apply a specific medical device (perineal cream).
This device contains AC collagen and hyaluronic
acid which, through the massage, can penetrate
deeply the vulvo-vaginal and perineal mucosa. It
is possible that such a cream, through the positive
action of collagen and hyaluronic acid on perineal
skin and pelvic floor muscles tropism, improves
the elasticity of perineal tissues. One previous
trial demonstrated that hyaluronidase injections
in the perineum during labor are associated
with perineal relaxation and likelihood of an
intact perineum, thus suggesting a positive role
of hyaluronic acid during perineal distension(19).
However, hyaluronidase is not of common use
and, also, it requires to be locally delivered
through injections. On the contrary in our study
we used a cream locally applied through a less
invasive procedure, even though during a longerlasting period.
In our research, we observed a significantly
reduced rate of episiotomies in the study
group. According to the initial consideration of
episiotomy as a protective procedure against
perineal lacerations(20), it could be supposed a
higher frequency of spontaneous lacerations/
tears. On the contrary no statistically significant
differences were observed in the incidence of
any category of tears. In addition, no third-fourth
degree lacerations were observed in the study
group, although the limited number of patients
could not reach a significant result. Episiotomy
was initially considered a procedure used to
prevent lacerations and perineal tears. A recent
review reported that (i) there is no evidence of a
protective effect of routine midline/mediolateral
episiotomy on pelvic floor anatomy and function
and (ii) routine mediolateral episiotomy does
not reduce or prevent the rate of urinary or anal
incontinence and anal sphincter lacerations(20).
Furthermore, in the recent years, several reports
showed a reduction in pelvic floor strength and
increased perineal pain and dyspareunia as a
consequence of episiotomy (20-24). Based on the
observed lower episiotomy rate, our findings
are encouraging toward the consideration of
the perineal and vulvo-vaginal massage with
a medical device containing AC collagen and
hyaluronic acid as useful tool to prevent the
perineal trauma and the consequent reduction of
the strength of the pelvic floor. In our study we
did not investigate the degree of post-partum
perineal pain and the presence of dyspareunia,
nevertheless the reduction of episiotomies might
suggest a possible preventive effect.
Another unexpected finding of the study was
the significant reduction of the duration of the
first and second stage of labor. We are not able
to explain such observation: possibly the perineal
massage can increase a woman’s confidence in her
body’s ability to stretch and open for her baby by
relaxing more during labor.
It is important to note the some aspects may
have affected the results of our study: since
the women voluntarily chose to participate to
the study, our trial was not randomized. This
fact surely enhanced the compliance during
pregnancy in the study group, nevertheless the
perineal outcome was not favorably influenced.
Furthermore we included secondigravid women,
a fact that may have influenced the perineal
distension; in order to overcome this bias, women
were matched with secondigravid controls.
In conclusion antenatal digital perineal
massage with creamy medical device (AC
collagen and hyaluronic acid containing cream)
is linked to a reduced rate of perineal trauma
(mainly episiotomies) at birth, and is generally
well accepted by women(25). As such, women
should be warned of the likely benefit of perineal
massage and provided with information on how
to massage.
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DECLARATION OF INTEREST
None of the authors report declarations of
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Breastfeeding in Italy: the role of Obstetrician-Gynecologists
Romana Prosperi Porta1, Elise M. Chapin2, Maria Grazia Porpora1, Giuseppe Canzone3
1
2
3
Department of Gynaecology, Obstetrics and Urology, “Sapienza” University of Rome, Policlinico
Umberto I, Viale Regina Elena 324, 00161 Rome, Italy.
Baby Friendly Initiatives, Italian National Committee for UNICEF, via Palestro, 68, 00185 Roma
Dept. of Maternal and Child Health - ASP Palermo,
ABSTRACT
We report the exceptional case of an intrauterine fetal death
Data for 2013 from the italian national institute of statistics
(istat) show that the percentage of breastfeeding mothers in
italy is increasing, however these percentages are still far from
the standard recommended by the world health organization
(who). Not breastfeeding is rarely recognized as a possible
effect of the medicalization of birth but rather is perceived as
a mother’s choice, even though, according to a survey done
by the italian national institute of health in 2002, over 95% of
women in italy said they wanted to breastfeed. The authors
evaluate the role of the obstetrician-gynecologist who, together
with the other health professionals involved in pregnancy
and childbirth, all of whom have been trained and respect
the mother-baby dyad, can help promote breastfeeding in a
significant way.
SOMMARIO
In italia, sebbene la percentuale di madri che allattano stia
aumentando secondo i dati istat riferiti al 2013, ancora tali
percentuali sono lontane dallo standard richiesto dall’oms.
Il mancato allattamento raramente è riconosciuto come un
possibile effetto della medicalizzazione della nascita ma
piuttosto come una decisione materna sebbene nel 2002 il
95% delle donne ha dichiarato di voler allattare secondo una
indagine effettuata dall’iss. Gli autori valutano il ruolo del
ginecologo che, in team con gli altri operatori sanitari del
percorso nascita uniformemente formati e rispettosi della diade
madre-bambino, può realmente contribuire a promuovere
l’allattamento materno.
Keywords: breastfeeding, birthing practices, obstetricians’ role,
baby friendly hospital initiative
INTRODUCTION
The World Health Organization (WHO), UNICEF
and the International Societies of Pediatrics and of
Gynecology have all declared that breastfeeding is
crucial to maternal and child health, and consider it
a primary health prevention intervention. In 2002,
WHO and UNICEF developed a Global Strategy for
infant and young child feeding(1) which reaffirmed
the importance of exclusive breastfeeding in the first
6 months of life and of continuing breastfeeding
and complementary foods for 2 years, or as long
as desired by mother and child. In Italy, these
recommendations were published as part of a
legislative agreement between the Ministry of Health
and the regional governments in 2007 and, since then,
the Ministry has organized awareness campaigns to
promote breastfeeding, both for healthcare providers
and mothers. The goals of promoting breastfeeding,
and the Baby Friendly Initiatives in particular,
have been incorporated into various national and
regional Health Plans as well as Prevention Plans,
however meeting these goals necessitates a shift in
the paradigm of care given throughout pregnancy,
childbirth, and the first few years of a baby’s life.
One of the strategies proven to be effective in
DOI: 10.14660/2385-0868-22
protecting, promoting and sustaining breastfeeding
is the WHO/UNICEF “Baby Friendly Hospital
Initiative” (BFHI), which was launched in the early
‘90s, and quickly spread throughout the world(2).
In 2007 in Italy, the “Baby Friendly Community
Initiative” (BFCI) was added and included local
health centers and other available resources in the
community(3-5). Currently, there are 22 Baby Friendly
Hospitals (4.5% of births) and 6 Baby Friendly
Communities in Italy. The BFHI outlines the 10 steps
to follow in maternity wards so that a mother can
breastfeed her baby, while the BFCI has 7 steps that
were adapted from the BFHI for a local health clinic
setting. Although each of these steps is important and
depends on the others, some play a more central and
strategic role in the success of the project. The training
of healthcare personnel who work with pregnant
women and mothers has an extremely important role.
Part of the BFHI/BFCI process involves enhancing a
multidisciplinary approach and responsibility for
questions about infant feeding choices. Research has
shown that these changes are not immediate and
require much advance planning and buy-in from all
those involved in the pregnancy and birth process(6).
The first few days after birth are a particularly
sensitive period of time, and health workers’ skills,
knowledge and attitudes towards breastfeeding,
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as well as their ability to transfer these skills to new
mothers, can significantly influence a mother’s
breastfeeding experience. When seen from this
perspective, the support provided by health
professionals plays a decisive role, provided,
however, that all the professionals involved have been
trained according to international standards, and are
monitored periodically by evaluating the results.
According to the latest report from the National
Institute of Statistics (ISTAT) with data from 2013,
the percentage of mothers starting to breastfeed at
least once has increased compared to 2005 (85.5% vs.
81.1%). The average duration of “any breastfeeding”
has also continued to grow: from 6.2 months in 2000
to 7.3 months in 2005 to 8.3 in 2013. The average
number of months of exclusive breastfeeding is 4.1,
with the highest average duration (4.3 months) in
the province of Trent and the lowest in Sicily (3.5
months)(7) . These rates fall far below the targets of the
Global Strategy of 50% of exclusive breastfeeding at
six months. Not breastfeeding is rarely recognized as
a possible “side effect” of the medicalization of the
birth experience, but rather is perceived as a mother’s
choice, even though a study by the Italian National
Institute of Health in 2002 revealed that over 95% of
Italian women wanted to breastfeed(8).
The first few days of breastfeeding offer a special
window of opportunity, and there are many obstacles
and barriers that a mother encounters, even during a
brief hospital stay. Research(9, 10) has shown that one
of the first difficulties is the lack of specific training
for healthcare providers, and especially gynecologists
on breastfeeding management and, consequently,
the lack of information and support given by them
to mothers. Healthcare workers, in their different
roles, should inform and support women during
pregnancy, childbirth, and after discharge because
there are significant differences in health outcomes for
breastfeeding women and babies(2, 11, 12). Specifically,
mothers should be informed about the importance
of breastfeeding, the risks of artificial feeding and
the normal management of breastfeeding, including
practical help for getting the baby to the breast. In
almost half of the Italian maternity wards (46%)
mothers and newborns are routinely separated from
birth(13), when the importance of rooming-in during
the hospital stay is well documented(14-16).
ROLE OF THE OBSTETRICIANGYNECOLOGIST
IN
THE
PROMOTION AND SUPPORT OF
BREASTFEEDING IN ITALY.
94
In Italy, the obstetrician-gynecologist (ObGyn)
is the first healthcare professional that a pregnant
woman seeks out and the person she sees most
frequently during the 9 months of pregnancy: over
three quarters of women in Italy go to a private
ObGyn during pregnancy.
In the US, the National Center for Health Statistics
had estimated that there 25 million gynecologicalobstetric visits in 2006: 20 million consist of
routine prenatal testing, 2,379.024 of postpartum
examinations and 1.7 million medical tests(17). In Italy,
there is no precise figure as to the average number
of ObGyn visits that women have during pregnancy
and postpartum, but, over 84% of pregnant women
see an ObGyn more than 4 times when pregnant,
In 2013, 94.3% of women underwent the first visit
by the third month of pregnancy, and 37.6% had at
least 7 ultrasounds during pregnancy (as compared
to 23.8% in 2000 and 28.9% in 2005)(18). Each of these
visits therefore, becomes an opportunity for ObGyns
to inform their patients about the importance of
breastfeeding, to positively influence women and
to strengthen this choice after childbirth. Research
has shown that women are interested in discussing
breastfeeding during pregnancy: they want both
theoretical and practical information(19), although
they often do not receive it(20, 21). An evidence-based
protocol for promoting breastfeeding prenatally
underlines the importance of proactively addressing
and discussing issues related to preparing for
breastfeeding and knowing what to expect and what
to do if problems arise(22).
ObGyns may have the impression that this kind
of information is not within their scope of practice:
it perceived as something for the midwife and
pediatrician who assist at birth and prepare parents
for the return home. The only positive note is that this
perception means they are not targeted by formula
company sales representatives and, therefore, do not
risk violating the International Code on the marketing
of breast milk substitutes(23).
A possible obstacle to the promotion of
breastfeeding by ObGyns could be their lack of
training in medical school and residency about the
physiology of lactation and management, diagnosis
and treatment of the most frequent problems which
may occur during lactation, from blocked ducts
to mastitis. Nakar et al.(9) found that while many
physicians had positive opinions about breastfeeding,
most of them lacked the necessary information and
skills to effectively inform and support a mother.
While pregnancy and childbirth have become
more and more medicalized, in Italy as in other
Western countries, there has not been a similar
increase in actions on the part of health workers to
provide information, counseling and support on issues
R. Prosperi Porta et al.
that concern pregnancy and childbirth, especially
breastfeeding. A woman’s ObGyn has an impact on
the level of medicalization. A midwife is capable of
handling a normal pregnancy, labor and delivery,
while leaving conditions that are risky or pathological
to the obstetrician. The midwife, who is protective
of the mother and child in their individuality as well
as in their unity, is the professional most capable of
respecting the physiology and empowering women
during pregnancy, labor and delivery, and in the
postpartum period. The May 9, 1985, during the
Congress “Appropriate Technology for Birth”, held
in Forteleza, WHO produced 15 recommendations
that are based on the principle that every woman
has the fundamental right to receive proper prenatal
care, to play a central role in all aspects of this care,
including participation in the plan, in carrying out
and evaluating the assistance itself and that the social,
emotional and psychological are crucial to understand
and implement appropriate perinatal care(24). In fact, in
Italy, these recommendations were not implemented
for a long time and have only started in the last 15
years, mainly because of the WHO/UNICEF BFHI
project which has again focused attention on birth
practices. In 2012, the “Mother-Friendly Care” step
regarding procedures room in labor and delivery
that affect the outcome of breastfeeding were made
mandatory for the BFHI(25). The goal of this step is
to respect the physiology of birth, and includes the
points listed in Box 1.
PRACTICAL
IMPACT
BIRTH INTERVENTIONS
BREASTFEEDING
OF
ON
Solid international scientific evidence shows that
minimizing medical interventions and preserving
the normality of birth are associated with a more
physiological, easier and safer birth(26, 27). According to
ISTAT data, Italy is the country with the highest rate of
Caesarean sections (C-section) in the European Union:
36.3% in 2013, which is more than twice the WHO
recommendations and almost 10 percentage points
higher than the EU average (27%)(18). The negative
effects of a Cesarean section on breastfeeding are well
known to all, although they are mitigated when the
mother is supported by competent professionals. Step
4 of the BFHI is “Place babies in skin-to-skin contact
with their mothers immediately following birth for
at least an hour. Encourage mothers to recognize
when their babies are ready to breastfeed and offer
help if needed”. Immediate and prolonged skin-toskin contact is the most important strategy to help a
mother and baby start breastfeeding, while routine
separation of the mother-child is unjustified and
harmful(28). Immediate and prolonged skin-to-skin
supports all aspects of newborn adaptation, including
breastfeeding, which consequently improves
bonding/attachment, milk production and normal
baby’s sucking(29, 30). During this first hour, the levels
of catecholamines in the newborn are high, the pupils
Box 1: Mother-Friendly Care
Hospital policies indicate that they require mother-friendly labour and birthing practices and procedures including:
• Encouraging women to have companions of their choice to provide continuous
physical and/or emotional support during labour and birth, as desired. • Allowing women to drink and eat light foods during labour, as desired. • Encouraging women to consider the use of non-drug methods of pain relief
unless analgesic or anaesthetic drugs are necessary because of complications,
respecting the personal preferences of the women. • Encouraging women to walk and move about during labour, if desired, and
assume positions of their choice while giving birth, unless a restriction is
specifically required for a complication and the reason is explained to the
mother. • Care that does not involve invasive procedures such as rupture of the
membranes, episiotomies, acceleration or induction of labour, instrumental
deliveries, or caesarean sections unless specifically required for a complication
and the reason is explained to the mother. 95
2015, 27: N.3
DOI: 10.14660/2385-0868-22
96
are dilated, reflexes are sharp and the infant is in a
rather high state of alert(31). Infants in skin-to-skin
contact with their mother exhibit models of hand
coordination, sucking, massaging the breasts, moving
towards the breasts and starting sucking(32). This
contact between mother and child causes a hormonal
cascade, characterized mainly by the release of
oxytocin, which improves women’s self-confidence.
Tactile contact increases gastric secretion in the
mother and child, thereby promoting gastrointestinal
motility and digestion(14). Direct skin-to-skin contact
counteracts thermal instability in the newborn,
thereby preventing separation of the newborn from
the mother, and a worsening of hypoglycemia which
leads to inappropriate supplementation(33).
However, a national report revealed that only 69%
of Italian hospitals have immediate skin-to-skin after
birth, that the first breastfeed occurs within 2 hours of
birth only 57% of the time, and that an even smaller
number allow mothers who have had an elective
C-section to have skin-to-skin contact with their baby
at birth (18). Caesarean section exposes the mother to
possible complications that can interfere with motherchild attachment and compromise breastfeeding.
Learning to care for the baby in the postoperative
period can be very difficult, can undermine a
mother’s intention to breastfeed and increase the risk
of difficulties with latch and subsequent postpartum
depression. Breastfeeding promotes the normal
conclusion of the pregnancy and the transition to the
normal physiology of lactation. Infants who are born
by C-section have a higher risk of impaired sucking,
less transfer of milk from the breast the first 5 days
of life, which results in increased supplementation
with formula milk, which leads to breasts that are not
emptied, which causes the subsequent suppression of
lactation(34).
The choice of a C-section without labor reduces
fetal endorphins, and lower endorphins affect the
amount of colostrum and milk, as well as depriving
the baby of important components for alleviating pain
during a more difficult birth and compromising the
physiology of breastfeeding(35). Various authors report
exclusive breastfeeding rates that are lower in women
undergoing C-sections vs. those with vaginal births,
both at 2 weeks and 2 months of age(36, 37). Otamiri
noted that children born by TC were less excitable,
had a significantly lower neurological response
during the first 2 days of life and had lower levels of
catecholamines, all of which can be related to early
neurological responses in the infant(38, 39).
The ObGyn can underestimate the important role
of oxytocin during pregnancy, birth, breastfeeding
and skin-to-skin. Women who give birth vaginally
have higher levels of oxytocin than those who
undergo a C-section, and have a greater increase in
prolactin levels 20-30 minutes after the initiation
of a feed, and the number of peaks is related to the
duration of the exclusive breastfeeding(40, 41).
In 2001, Fisher and Rowe-Murray studied the
impact of childbirth on the operational implementation
of the “early initiation of breastfeeding within 30
minutes of birth” prospectively. Women who had
undergone a C-section showed a significant delay
in the beginning of breastfeeding: in Baby Friendly
Hospitals (BFH), 27% of mothers began breastfeeding
within 30 minutes of birth and 60% after 60 minutes,
while in the 3 non BFH, no mothers who had
undergone a C-section had been able to let her baby
latch at the breast(42).
In addition to C-sections, episiotomies also appear
to interfere with breastfeeding. Performed during a
vaginal birth to increase the opening of the birth canal
in order to facilitate the birth of the child, it sometimes
causes lacerations that extend to the rectum, fistulas
and dysfunction of sphincter muscles. Much research
has been published in support of a non-routine and
selective use of episiotomies.
Even the WHO recommends limited use of
this practice and numerous guidelines have been
published about this which reaffirm that there
is no scientific evidence of potential damage to
the perineum, future vaginal prolapse or urinary
incontinence in the case of no episiotomy(43).
Unfortunately, despite these authoritative
recommendations, routine episiotomies are still so
widespread worldwide and are almost always done
without the woman’s informed consent. Its impact on
the outcome of breastfeeding, however, has not been
well documented. As early as 1981, Kitzinger carried
out a study on the perception of women about their
pain from episiotomy and how much this distracted
from breastfeeding: 17% of the group with episiotomy
and 21% of episiotomies and lacerations reported
major disturbances during breastfeeding while only
3% of those without problems to the perineum did(44).
Skin-to-skin between mother and baby during the
suturing of the episiotomy promotes the production of
endogenous endorphins including oxytocin, causing
a physiological relief from pain and facilitating early
lactation.
Because prevention is better than treating,
preventing possible damage at birth continues to
be the best strategy. Safeguarding the physiology
labor, a mother’s choice, the freedom to move and
assume positions of choice, light eating and drinking,
avoiding invasive procedures and routine use of nonpharmacological methods to relieve pain are essential.
All mothers must be supported by competent people
to initiate breastfeeding, but mothers who have
children with problems must be so even more, even if
these newborns will be under the neonatologist’s care.
Oxytocin plays a key role during labor,
childbirth, lactation, mother-child bonding, sexuality,
development of self-confidence, digestion, calm and
healing. Adrenaline is the antagonist of oxytocin in
every situation or event that raises adrenaline levels
in labor, delivery, or postpartum mothers reduces,
inhibits or undermines the myriad of psychological
or physiological processes necessary for optimal
development of breastfeeding in the mother-child
dyad. The negative influence of fear and stress on the
progress of labor is well documented in the literature.
More than 30 years ago, Lederman et al. measured
levels of catecholamines in blood samples of healthy
first-time mothers in labor and found high levels of
adrenaline in the early stage of labor in women who
had a slower labor and abnormal heartbeat fatal(45).
Separating a healthy mother from her healthy
newborn immediately after birth has never been
proven as safe and effective, and has been shown
to cause negative effects(12). However, both healthy
newborns and even more so those with problems
should not be separated from their mothers and
should not be denied the comfort of being held their
mother’s arms, fed and cuddled using the of painreducing properties of colostrum and milk.
Research has confirmed that the type of labor
have an impact on the beginning of lactogenesis
II (start of copious milk secretion). A delay in the
production of copious milk puts the baby at risk of
insufficient caloric intake, exposure to artificial milk,
problems in sucking, as well as compromising the
start of breastfeeding and undermining the mother’s
confidence in her ability to breastfeed. “Not enough
milk” is the most frequent cause of supplementation
of breastfeeding and delaying the start of lactogenesis
II is the negative consequence on the difficulties of
labor.
During labor endogenous opioids (betaendorphins) are produced, and increase with
the intensity of the contractions, reaching a peak
with the approach of childbirth. These natural
neurotransmitters that increase during labor dull or
modulate the mother’s pain and pass through the
placenta to the fetus is so it is ready for life outside
the womb. These waves of hormones in the mother
and fetus increase the production of surfactant, which
clears the lungs of the newborn in preparation for
extrauterine breath; mobilize brown fat for warmth
and caloric support of body functions; provide a rich
supply of blood to the heart and brain of the infant
and trigger bonding between mother and child.
The beta-endorphins produced during labor
and present in colostrum and breast milk protect
the child from pain. Zanardo et al. found that betaendorphins in colostrum were significantly higher
in mothers who had given birth vaginally compared
with those who underwent an elective C-section with
epidural anesthesia and without labor(46). They also
collected samples of beta-endorphins in colostrum
and transitional milk at 4, 10 and 30 days after giving
birth in three groups of mothers: one group had
given birth vaginally at term, another had given birth
vaginally preterm (35.6 weeks +/- 0.3 days) and a
third group with an elective C-section at term(47).
The beta-endorphins were significantly higher in
the first 10 days postpartum in the colostrum of
mothers who had given birth vaginally, while the
highest concentrations were in mothers who had
given birth preterm. They hypothesized that the
high level of beta-endorphins in colostrum and
transitional milk could be related to the adaptation to
stress and other potential conditions. The discovery
of the highest levels in mothers of preterm infants,
who need to have greater adaptability, suggests a
protective role in preterm birth. The administration of
epidural anesthesia causes a sharp drop in levels of
beta-endorphins.
CONCLUSIONS
Given the impact of birth practices on
breastfeeding, the OBGYN should no longer
claim that breastfeeding is just for midwives and
pediatricians and does not concern him/her, since
the BFHI has amply demonstrated that breastfeeding
involves all maternity staff transversely. The greater
the collaboration with the mother-child dyad,
using a common language and a non-judgmental
communicative approach, the more effectively
they will be able to protect, promote, and support
breastfeeding. It is important that ObGyns have
appropriate knowledge about the practice of
breastfeeding. A sufficient amount of time should
be given to both the physiology and pathology
of lactation during residency in obstetrics and
gynecology. “Mothers and babies form an inseparable
biological and social unit; the health and nutrition
of one group cannot be divorced from the health
and nutrition of the other”(1). Unfortunately, the
moment of birth divides work responsibilities: birth
is the domain of the ObGyn, while infant care is the
responsibility of pediatricians. The responsibility
of breastfeeding does not belong to one single
profession: it requires the collaboration of all. The
program of study for residents in pediatrics and
gynecology still does not always include evidencebased management of breastfeeding. Midwives are
an exception to model of separation who takes care of
97
2015, 27: N.3
DOI: 10.14660/2385-0868-22
women during pregnancy, birth and postpartum. The
WHO has identified the midwife as a key healthcare
professional to follow pregnancy and normal birth
including recognizing risks and complications as well
as helping with breastfeeding. Although midwives are
very supportive of breastfeeding, unfortunately, they
do not normally have a specific training course (the
WHO/UNICEF 20-Hour Course, which is considered
the international standard training in breastfeeding)
in their program of study. Only recently in very few
midwifery programs in Italian universities has this
course has been included as part of their training.
In 2013 the Baby-Friendly University program was
launched in Italy, which includes a series of learning
outcomes about breastfeeding and counseling, in
addition to standard training, as well as an external
assessment by a team of UNICEF assessors at the end
of the Midwifery program. So far, only the University
of Milan-Bicocca was has completed the UNICEF
evaluation.
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99
Serum levels of calcium and magnesium in pre-eclamptic-eclamptic
patients in a tertiary institution
Abiodun Olusanya1, Adekunle O Oguntayo1, Aliyu I Sambo2
Department of Obstetrics & Gynaecology,
Department of Chemical Pathology
Ahmadu Bello University Teaching Hospital, Shika Zaria, Kaduna State. Nigeria
1
2
ABSTRACT
We report the exceptional case of an intrauterine fetal death
Objective: the aim of this study was to determine the serum
levels of calcium and magnesium in patients with preeclampsia/eclampsia and compare with those with normal
pregnancies. Materials and methods: venous blood samples
were collected from 48 patients with pre-eclampsia, 30
patients with eclampsia, and 78 normal pregnant women. All
the subjects were either in the third trimester or within the
puerperium. The blood samples were analysed for calcium
and magnesium using a colorimeter analyser. The data were
analysed using SPSS 17. Results: The serum calcium in the preeclamptic and eclamptic patients were significantly lower than
in normal pregnant women (2.05±0.4mmol/l, 1.9±0.2mmol/l
vs. 2.6±0.4mmol/l, p<0.000). Unlike serum calcium, serum
magnesium was lower in the patients with either preeclampsia or eclampsia compared with normal pregnant
women but the difference was not statistically significant.
Conclusion: this study revealed that serum calcium and
magnesium in preeclampsia/eclampsia are lower compared
to normal pregnancy. It was also revealed in this study that
serum calcium and magnesium are lower in patients with
eclampsia compared to patients with pre-eclampsia. These
findings support the hypothesis that hypocalcaemia and
hypomagnesaemia may play a role in the pathogenesis of preeclampsia-eclampsia.
Keywords: Serum, Calcium, Magnesium,
Eclampsia, Pregnancy, Blood pressure.
SOMMARIO
lo scopo di questo studio era di fattori che determinano i livelli
sierici di calcio e magnesio in pazienti con pre-eclampsia /
eclampsia e appare con Quelli con gravidanze normali. Materiali
e metodi: campioni di sangue venoso sono stati prelevati da
48 pazienti con preeclampsia, 30 pazienti con eclampsia, e 78
donne in gravidanza normale. Tutti i soggetti erano o nel terzo
trimestre o All’interno del puerperio. I campioni di sangue
sono stati analizzata per il calcio e magnesio utilizzando
un analizzatore colorimetro. I dati sono stati analizzata
utilizzando SPSS 17. Risultati: Il calcio sierico nei pazienti
pre-eclampsia e eclampsia erano significativamente più bassi
rispetto alle donne in gravidanza normale (2,5 ± 0.4mmol / l,
1,9 ± 0.2mmol / l vs 2.6 ± 0.4mmol / l, p <0.000). A differenza
di calcio sierico, del magnesio nel siero è stata inferiore nei
pazienti con o pre-eclampsia o eclampsia Rispetto alle donne
in gravidanza normali, ma la differenza non era statisticamente
significativa. Conclusioni: questo studio ha rivelato che il calcio
sierico e magnesio in preeclampsia / eclampsia sono Rispetto
inferiore alla gravidanza normale. E ‘stato rivelato in questo
also studio che il calcio sierico e magnesio sono più bassi nei
pazienti con eclampsia Rispetto ai pazienti con pre-eclampsia.
Questi risultati supportano l’ipotesi che l’ipocalcemia e
ipomagnesiemia possono giocare un ruolo nella patogenesi
della preeclampsia-eclampsia.
Pre-eclampsia,
INTRODUCTION
Hypertension is a common medical condition
during pregnancy and about 10% of women will
have their blood pressure recorded as above
normal at some point during the antenatal period
before delivery.1 It is estimated to complicate
about 5% of all pregnancies and 11% of first
pregnancies(2).
Pre-eclampsia is defined as hypertension
and significant proteinuria beginning during
the second half of gestation in a previously
normotensive and non-proteinuric pregnant
woman (2,3) . It complicates 4-8% of all
pregnancies(4,5). Eclampsia on the other hand, is
the new onset of grand mal seizures occurring
during or up to 6weeks after pregnancy that
do not have another identifiable cause (6,7). It
could also be defined as the development of
convulsions and/or unexplained coma during
DOI: 10.14660/2385-0868-23
pregnancy or postpartum in patients with signs
and symptoms of pre-eclampsia.8 Incidence of
eclampsia in developed countries ranges from
5-7 cases per 10,000 deliveries9, quite unlike in
developing countries where Nigeria belongs,
where the prevalence ranges from 2-16.7%(10-12).
Pre-eclampsia and eclampsia are not distinct
disorders but the manifestation of the spectrum
of clinical symptoms of the same condition.9
Once eclampsia occurs the risk to mother and
baby is substantial. WHO estimates that the
incidence of pre-eclampsia is seven times higher
in the low and middle–income countries than in
high-income countries, and the risk of a woman
in a low-income country dying of pre-eclampsia/
eclampsia is three hundred times that of a woman
in a high-income country(6,13)
Pre-eclampsia has remained a significant
public health threat in both developed and
developing countries(9). WHO had estimated
its incidence to be 7 times higher in developing
countries than in developed countries and a
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102
woman in a developing country is 300 times more
likely to die from pre-eclampsia and eclampsia(6,13).
Globally, pre-eclampsia and eclampsia account
for 10-15% of maternal deaths(14). Unlike in the
developed countries where pre-eclampsia and
eclampsia are associated with near-miss rather
than maternal death, death usually results from
eclampsia in the developing countries(15). The
high maternal morbidity and mortality in the
developing countries is due to barrage of factors
that include delays (Types I,II, and III), unbooked
status of patients, high parity, and multiple
convulsions before admission(9,16,17). It can also
lead to significant foetal morbidity and mortality,
including an increased incidence of placental
abruption, intrauterine growth restriction, and
preterm delivery(14)
To date, the aetiology of pre-eclampsia has
remained poorly understood but it has been
documented that pre-eclampsia is polygenetic
and is caused by a combination of maternal and
foetal genes with influence of environmental
factors.18 Pathogenesis of eclamptic convulsions
has also remained source of controversy(8).
The overall risk of seizure is approximately 1%
in developed countries8 and 2.3% in developing
countries6 and can occur at virtually any time
in pregnancy up to within the first 48 hours of
delivery, though it has been reported as late as
23 days postpartum(19). The reported frequency
of antepartum eclampsia ranged from 38-53%,
intrapartum eclampsia ranged from 18-30%,
while postpartum eclampsia had ranged from
11-44% respectively(6,8).
Pre-eclampsia and eclampsia are not distinct
disorders but the manifestation of the spectrum
of clinical symptoms of the same condition.9
Pre-eclampsia complicates about 4-8% of all
pregnancies(4,5) while the incidence of eclampsia
in Nigeria ranges from 2-16.7% unlike in
developed countries where its incidence ranges
from 5-7 cases per 10,000 deliveries (9). Preeclampsia could be mild or severe. It is mild
when the blood pressure is >140/90mmHg but
<160/110mmHg associated with proteinuria
of >0.3-3g/24hr without associated symptoms
but when there is a sustained blood pressure
that is ≥160/110mmHg measured twice, at least
6hours apart with evidence of other end organ
damage it is described as been severe (14). Preeclampsia could also be classified as being early
or late depending on whether it is occurring
prior to 34 weeks or not(14). There is significant
maternal-foetal morbidity associated with preeclampsia especially when the onset is below 32
weeks(14,19-21).
Focus is currently on ways to prevent preeclampsia based on the different theories
surrounding the aetiology of pre-eclampsia,
micronutrient supplements have been
investigated as potential preventive ways (22,23).
Hypocalcaemia has been reported in essential
hypertension in human and experimental
models of hypertension in animals, and has been
implicated in the pathogenesis of elevated blood
pressure(24). There is evidence that low serum
calcium may also be associated with increased
neuromuscular irritability and seizures (25) .
Interestingly, neuromuscular excitability,
vasoconstriction, elevated blood pressure,
and increased vascular sensitivity to pressor
agents are also characteristic of magnesium
depletion (27,28). The results from many clinical
studies show the relationship between the
aggravation of hypertensive complications
and change in concentration of various ions
especially calcium and magnesium in the serum
of pre-eclamptic and eclamptic mothers(5,22,26-28).
On the physiological basis, calcium plays
an important role in muscle contraction, a
decrease in extracellular calcium concentration
increases the excitability of nerve and muscle
cells and conversely an increase in extracellular
calcium concentration stabilizes the membrane
by decreasing excitability (5,29). The reduction
in serum calcium and increased intracellular
calcium can cause an elevation of blood pressure
in pre-eclampsia (6). Hypomagnesaemia also
increases hypertensive tendencies by increasing
angiotensin II action, decreasing levels of
vasodilatory prostaglandins (PGs), increasing
levels of vasoconstrictive PGs and growth factors,
increasing vascular smooth muscle cytosolic
calcium and impairing insulin release, thereby
producing insulin resistance and alteration of
lipid profile(30).
The Scientific and Ethical committee of the
Ahmadu Bello University Hospital, Zaria, Kaduna
State of Nigeria approved the study protocol, and
an informed written consent was obtained from
each participant before recruitment. The study
population consisted of 156 pregnant women in
the third trimester of pregnancy that presented
to the antenatal clinic, delivery suite, and the
postnatal ward of the hospital. Out of the 156
pregnant women 78 served as the control; while
48 had pre-eclampsia and 30 had eclampsia.
A. Olusanya et al.
The consecutive patients who met the inclusive
criteria were selected as they presented at the set
out locations in the hospital using the convenient
sampling method.
For the purpose of this study significant
hypertension and proteinuria were as defined
by the International Society for the Study of
Hypertension in Pregnancy (ISSHP), which are
blood pressure of ≥140/90mmHg and proteinuria
of ≥2+ respectively. Korotkoff phase V was
used to designate the diastolic blood pressure.
Pregnant women with either a diagnosis of preeclampsia or eclampsia in the third trimester or
postpartum that were not on calcium supplement
and had not been commenced on magnesium
sulphate therapy were included in the study
while those with chronic medical illness like
diabetes mellitus and renal disease, multiple
gestation were excluded.
At presentation at the clinics, ward, or
delivery suite the blood pressure of each subject
was taken in the supine position with a left
lateral tilt using an Accoson table-top mercury
sphygmomanometer that had the appropriate
size cuff with the arm at the level of the heart.
After taking the blood pressure the mid-stream
urine sample was obtained and tested with
combi-9 urinalysis strip for proteinuria.
Height was measured with each subject
standing barefooted on a standard Seca
Stadiometer. The height was read from under
the head piece on the calibrated metre of the
stadiometer to the nearest 0.1cm. Weight was
measured using a calibrated weighing scale
(Camry digital weighing scale) without shoes
and subjects wearing light clothes; weight was
read to the nearest 0.1kg. All these were done at
presentation for those who were conscious while
the measurements of those that presented in a
state of unconsciousness were taken after they
had regained consciousness.
The socio-economic status (SES) of each of
the subjects was assessed using the husband’s
occupation and the subject’s educational
attainment as proposed by Olusanya et al.(31).
10ml of venous blood specimen was collected
by venepuncture with sterile 10ml syringe with
21G disposable hypodermic needle from the
ante-cubital vein without a tourniquet from
each subject after the skin over the site had been
swabbed clean with methylated spirit-soaked
cotton wool and allowed to dry.
Laboratory procedure: Each of the blood
samples collected was transferred into a plain
specimen bottle containing no anticoagulant
and allowed to clot for 30 minutes. It was then
centrifuged with Hettich centrifuge machine at
4000 rpm for 10 minutes to separate the serum
from the cells. The serum aliquots were harvested
with a clean Pasteur pipette into a plain bottle and
immediately stored at -200C in Haier Thermocool
deep freezer until the time of analysis. The
frozen samples were allowed to thaw at room
temperature before analysis. Albumin was
analysed for in the sera of the subjects so as to
factor out the real level of calcium, however, it
was observed that all the subjects had normal
albumin level so there was no need to calculate
for any factor. Serum calcium was measured by
colorimetric method. This is based on the principle
that calcium reacts with o-cresolphthalein
complexone in an alkaline medium to give a blue
coloured complex. Magnesium which interferes
with the reaction is bound out of solution by
8-hydroxyquinoline. The absorbance of the
standard and that of the complex were read with
Spectro-V16 spectrophotometer at a wavelength
of 650nm specified by the manufacturer of the
kit used in this study. The calcium concentration
was calculated by the formula:
Calcium conc. (mmol/l) =
Absorption of sample
Absorption of standard
X Concentration of standard
Magnesium was measured with CalmagiteEGTA-Colorimetric. Magnesium forms a purple
coloured complex when it reacts with calmagite
in alkaline solution. The interference by calcium
is prevented by the use of EGTA (ethylene
glycol tetraacetic acid). The intensity of the
colour formed is proportional to the magnesium
concentration in the sample. Reagent sample
mixture was then incubated for 5minutes at room
temperature. The absorbance of the standard
and the sample was measured against reagent
blank at a specific wavelength of 520nm using
Spectro-V16 spectrophotometer. Magnesium
concentration was calculated as follows;
Magnesium conc. (mmol/l) =
Absorption of sample
Absorption of standard
X Concentration of standard
For the purpose of this study the normal
reference values of serum calcium (2.1-2.6mmol/l)
and magnesium (0.66-1.03mmol/l) for the
Chemical Pathology laboratory of ABUTH were
used.
103
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DOI: 10.14660/2385-0868-23
The data obtained were analyzed using SPSS
version 17 for windows. The mean values of
serum level of calcium and magnesium obtained
from patients with pre-eclampsia and eclampsia
who met the set out criteria were compared
with those of the controls using ANOVA. The
values of the mean of serum level of calcium
and magnesium of patients with pre-eclampsia
were compared with eclamptic patients using the
student t-test to see if there was any significant
statistical relationship. A multivariate analysis
between these results and the sociodemographic
variables of the subjects was done using Chi
square. Correlation analysis was also carried
out between the systolic and diastolic blood
pressures and levels of calcium and magnesium
of the subjects. A p-value of equal to or less than
0.05 was considered to be statistically significant.
RESULTS
The total number of Parturients that were
cared for during the period of this study was
1,074 out of which 156 subjects met the set out
inclusion criteria; out of these 156 subjects 78 of
them had pre-eclampsia/eclampsia (i.e. 48 preeclamptics and 30 eclamptics) and they served
as the test group while the remaining 78 subjects
that served as control were normal pregnant
women. These two groups were matched for age,
gestational age, and parity.
Table
1
below
highlights
the
sociodemographic variables and the clinical
parameters of the subjects studied. Mean age,
mean gestational age, and parity between the preeclamptic/eclamptic and control groups were
not statistically different. There was significant
statistical difference between the mean systolic
and diastolic blood pressure of the test group and
the mean systolic and diastolic blood pressure of
the control group as shown in the table 1 below.
The differences in the mean weight and height of
the patients with pre-eclampsia/eclampsia and
control were not statistically significant.
Table1
Sociodemographic variables and the clinical parameters of the subjects
Pre-eclampsia/Eclampsia
N = 78
Control
N = 78
P Value
Demographic status
Age (years)
26.5 ± 6
27.4 ± 6
0.370*
0.556*
G.A (weeks)
34.3 ± 3
34.0 ± 3
Postpartum
6 (7.7%)
5 (6.4%)
Primigravidae
42 (54.8%)
43 (55.1%)
Multipara
26 (33.3%)
26 (33.3%)
Grandmultipara
10 (12.8%)
9 (11.5%)
booked
51 (65.4%)
76 (97.4%)
unbooked
27 (34.6%)
2 (0.26%)
Upper
15 (19.2%)
42 (53.8%)
Middle
22 (28.2%)
28 (35.9%)
Lower
41 (52.6%)
8 (10.3%)
SBP(mmHg)
171 ± 26
111 ± 11
0.000**
DBP(mmHg)
110 ± 16
67 ± 9
0.000**
Height(m)
1.57 ±0.06
1.59 ± 0.05
0.076*
Weight(kg)
74.6 ± 15
71.4 ± 13
0.155*
BMI(kg/m )
30.2 ± 0.05
28.2 ± 4.8
0.010**
Parity
0.968*
Booking status
0.000**
Socioeconomic status
0.000**
Clinical status
2
104
**significant at p-value <0.05, *not significant at p-value >0.05
A. Olusanya et al.
Table 2 below compares the mean serum
calcium and magnesium of the patients with
eclampsia, pre-eclampsia, and control using
ANOVA. There is a significant statistical
difference in the p-values of the different trace
elements studied. Table 3 below shows the
difference in the mean serum calcium and
magnesium in the pre-eclamptic and eclamptic
patients. The mean values were lower in the
eclamptic patients, however, there was no
significant statistical difference when their means
were compared using the student T-test.
Table 4 shows the Chi-square values of the
cross-tabulation of the serum calcium against
the status of the subjects studied and their
sociodemographic characteristics. Statistical
significance was observed between serum
calcium level and the status of the subjects
studied; their booking status as well as their social
class. Table 5 also shows the Chi-square values
of the cross-tabulation of the serum magnesium
against the status of the subjects studied and
their sociodemographic characteristics. Statistical
significance was only observed between serum
magnesium level and the age group of the
subjects.
As shown in tables 6 and 7 below, calcium and
magnesium showed negative correlation with
systolic and diastolic blood pressure values in the
test and control groups, however, the correlation
was not statistically significant.
Table 2
Comparing the mean serum levels of calcium and magnesium of patients with pre-eclampsia, eclampsia, and control with ANOVA
Laboratory Data
PreEclamptic
Eclamptic
Control
N=48
N=30
N=78
p-value
Mean serum calcium
(mmol/l)
2.05±0.4
1.9±0.2
2.6±0.4
0.000**
Mean serum
magnesium (mmol/l)
0.82±0.03
0.82±0.07
0.86±0.07
0.004**
At 95% CI, **significant at P-value <0.05
Table 3
Comparing the mean serum levels of calcium and magnesium of pre-eclamptic patients with eclamptic patients using
the student’s t-test
Laboratory Data
Pre-Eclamptic
Eclamptic
N=48
N=30
p-value
Mean serum calcium( mmol/l)
2.05±0.4
1.9±0.2
0.076**
Mean 0.82±0.03
0.82±0.07
0.944**
serum magnesium (mmol/l)
At 95% CI, *not significant at P-value >0.05
105
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DOI: 10.14660/2385-0868-23
Table 4
Cross-tabulation of level of calcium with status of subjects and their sociodemographic characters using Chi square
Level of calcium
<2.1 mmol/l
2.1-2.6 mmol/l
>2.6 mmol/l
test
control
test
control
test
control
Test group
51
-
26
-
1
-
Control group
-
8
-
28
-
42
p-value
Subjects’ status
0.000**
Age(years)
<20
4
0
6
1
1
8
20-24
13
3
6
3
0
10
25-29
18
1
7
14
0
12
30-34
9
1
4
8
0
7
35-39
6
2
2
1
0
5
≥40
1
1
1
1
1
0
0.373*
Gestational
age(weeks)
≥28
4
0
1
4
0
2
29-33
16
2
9
8
0
10
34-38
20
3
12
11
1
21
≥39
7
3
2
5
0
3
Postpartum
4
0
2
1
0
6
Primigravida
26
0
15
11
1
21
Multipara
20
2
6
14
0
17
5
3
5
3
0
4
Booked
30
7
20
27
1
42
Unbooked
21
1
6
1
0
0
Upper
9
4
6
16
0
22
Middle
18
3
3
9
1
16
Lower
24
1
17
3
0
4
0.636*
Parity
Grandmultipara
0.477*
Booking status
0.000**
Social class
**significant at P-value <0.05, *not significant at P-value >0.05
106
0.001**
A. Olusanya et al.
Table 5
Cross-tabulation of level of magnesium with status of subjects and their sociodemographic characters using Chi square
Level of magnesium
<0.66mmol/l
0.06-1.03mmol/l
>1.03mmol/l
test
control
test
control
test
control
Test group
1
-
76
-
1
-
Control group
-
-
74
-
4
p-value
Subjects’ status
0
0.188*
Age(years)
<20
0
0
11
9
0
0
20-24
0
0
18
16
1
0
25-29
0
0
25
24
0
3
30-34
0
0
13
15
0
1
35-39
0
0
8
8
0
0
≥40
1
0
1
2
0
0
0.000**
Gestational
age(weeks)
≥28
0
0
5
5
0
0
29-33
0
0
24
17
1
2
34-38
1
0
32
31
0
2
≥39
0
0
9
14
0
0
Postpartum
0
0
0
7
0
0
Primigravida
0
0
42
32
0
4
Multipara
1
0
24
33
1
0
Grandmultipara
0
0
10
9
0
0
Booked
1
0
50
72
0
4
Unbooked
0
0
26
2
1
0
Upper
0
0
15
39
0
3
Middle
0
0
22
27
0
1
Lower
1
0
39
8
1
0
0.717*
Parity
0.477*
Booking status
0.889*
Social class
0.493*
**significant at P-value <0.05, *not significant at P-value >0.05
Table 6
Correlation of serum calcium and magnesium with systolic and diastolic blood pressures in the test group
Calcium
Systolic blood pressure
Pearson correlation
-0.119
-0.075
Sig. (2.tailed)
0.300*
0.515*
N
Diastolic blood pressure
Magnesium
78
78
Pearson correlation
-0.103
-0.107
Sig. (2.tailed)
0.371*
0.351*
78
78
N
*correlation not significant at the 0.01 level (2-tailed) with P-value >0.05
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Table 7
Correlation of serum calcium and magnesium with systolic and diastolic blood pressures in the control group
Calcium
Systolic blood pressure
Pearson correlation
-0.135
-0.113
Sig. (2.tailed)
0.239*
0.324*
78
78
Pearson correlation
-0.069
-0.208
Sig. (2.tailed)
0.550*
0.068*
78
78
N
Diastolic blood pressure
Magnesium
N
*correlation not significant at the 0.01 level (2-tailed) with P-value >0.05
DISCUSSION
108
This study observed a statistically significant
lower serum calcium and magnesium levels
in patients with pre-eclampsia—eclampsia
compared to normal pregnant women. These
findings may suggest a possible involvement
of hypocalcaemia and hypomagnesaemia in the
aetiopathogenesis of pre-eclampsia-eclampsia.
The findings in this study agree with the findings
reported by other investigators: Sukopan et al(5)
in Thailand, Idogun et al(19) in Benin, Nigeria, and
Akinloye et al(26) in Oshogbo, Nigeria. However,
in contrary to the findings in this study Odigie et
al(32) in Lagos, Nigeria and Golmohammad lou et
al(33) in Iran did not find any significant difference
in the serum calcium and magnesium of preeclamptic women when compared with normal
pregnant women.
This study also revealed that the serum levels
of calcium and magnesium were lower in the
patients with eclampsia compared with levels in
the pre-eclamptic patients though the differences
were not statistically significant. This difference
in the levels of these micronutrients may be due
to the disease progression from pre-eclampsia
to eclampsia since it is a known fact that preeclampsia is a progressive disease.
Again, this study also revealed that the serum
calcium in the pre-eclampsia/eclampsia group
was below the lower limit of normal reference
range for this centre; however, the mean serum
magnesium was within normal range. On the
other hand, the mean values of both these two
micronutrients in the control group were within
normal range. It was also found out in this study
that majority of the patients in the pre-eclampsia/
eclampsia group were in the low socioeconomic
class, and when the sociodemographic variables
of the subjects were compared with their disease
status; the booking status and the socioeconomic
class showed a significant relationship. These
findings are consistent with the findings by
Omole-Ohonsi et al (12) in Kano, Nigeria in
their study of risk factors for pre-eclampsia
in 2008. Kano is about 150km from Zaria with
similar geographical ethnic characteristics.
The implication of these findings could be that
their dietary intake of calcium-rich food had
been inadequate. Though the natural trend of
homeostatic mechanism tends to maintain calcium
level but still the presence of lower level of serum
calcium in pre-eclamptic/eclamptic women
may indicate the chronicity of micronutrients
deficiency which may be a causative factor for
the occurrence of pre-eclampsia/eclampsia in
these patients. Various possible explanations
have been proposed by different investigators to
explore the link between nutritional deficiency
and pre-eclampsia/eclampsia(34) though research
findings from literature have suggested that
there is a relationship between nutritional
status of calcium and the onset of progression
of pre-eclampsia(23,34,35). While the cause of preeclampsia/eclampsia remains elusive to scientific
knowledge, calcium and magnesium deficiencies
are thought to be implicated (7,36). Decreased
serum calcium levels lead to an increase in the
parathyroid hormone levels, thereby increasing
the intracellular calcium levels, which leads
to an increase in the vascular smooth muscle
contraction and thus an increase in the blood
pressure. Reduced serum magnesium also
increases hypertensive tendencies by increasing
the vasoconstrictor effect of angiotensin II
and nor-adrenaline (30) . Since calcium and
magnesium are two intracellular ions that play
very important roles in cellular metabolisms and
they compete with each other, high magnesium
concentrations inhibit the release of acetylcholine
(Ach) while high calcium concentrations enhance
the release of Ach from the pre-synaptic nerve
A. Olusanya et al.
terminal (37). During cellular injury, there is
influx of calcium ions into the cell leading to
increased intracellular ions and loss of calcium
homeostasis (37). In pre-eclampsia/eclampsia
there is widespread vasospasm, ischemia, and
cellular hypoxia leading to reversible endothelial
injury(37). Since magnesium antagonises the effect
of calcium, in order to counteract intracellular
calcium migration there is also an influx of
magnesium into the cells. This could explain why
both calcium and magnesium were reduced in
the patients studied. This also forms the basis for
the use of magnesium sulphate in the prevention
and control of convulsion in pre-eclampsia/
eclampsia.
When serum calcium level was compared
with the status of the subjects studied and their
sociodemographic characteristics it was observed
that a statistically significant relationship
existed with the booking status of the subjects
and their socioeconomic class with p-values
being 0.000 and 0.001respectively. Low literacy
level and lack of economic power could have
contributed to their attitude to non-booking at
antenatal period and thereby resulting in their
inability to have enlightenment on benefits that
could be derived from eating calcium-rich food,
purchasing same, and other benefits of antenatal
care. However findings in other studies with
respect to magnesium have been conflicting,
with some findings showing significantly
lower serum magnesium in patients with preeclampsia/eclampsia while others did not find
any difference at al(5,22,26,32,33).
In this study inverse correlation of serum
calcium and magnesium with SBP and DBP in the
test and control groups was observed though the
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1) Duley L, Henderson-Smart DJ, Walker GJA.
Interventions for preventing pre-eclampsia and
its consequences: generic protocol (Protocol). The
Cochrane Library. 2009(2):1-14
2) Hofmeyr GJ, Duley L, Atallah A. Dietary calcium
supplementation for prevention of pre-eclampsia and
related problems: a systemic review and commentary.
Br. J. Obstet Gynaecol 2007;114:933-943
3) Pregnancy Hypertension. In: Cunningham FG,
Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY
(Eds). Williams Obstetrics 23rd Edition, McGraw-Hills
companies 2010; 706-756.
4) Miller DI. Hypertension in pregnancy. In: Decherney
A.H, Nathan L, Goodwin T.M and Laufer N. (Eds)
Current Diagnosis and Treatment Obstetrics and
Gynaecology, 10th edition, McGraw-Hill Medical
Publishing Division 2007; 321.
correlation was not significant, this finding may
suggest a relationship between the deficiency
of these trace elements and the risk of preeclampsia/eclampsia. This finding is consistent
with the findings by Akinloye et al(26) and Akhtar
et al(35) but in contrary to the findings in the
aforementioned studies the correlation was not
significant this may probably due to differences
in geographical locations of the patients studied.
Limitations of this study included the fact
that the dietary analysis of the participants was
not done there their calcium and magnesium
baselines were not known before the study, and
the anthropometric parameters of those who
presented in a state of unconsciousness were only
measured after they had regained consciousness.
CONCLUSION
This study established that serum calcium
and magnesium are significantly lower in patients
with pre-eclampsia/eclampsia compared to
normal pregnant women. It was also established
in this study that the serum levels of calcium and
magnesium in patients with eclampsia were less
compared to the level in pre-eclamptic patients.
This finding supports the fact that pre-eclampsia
is a progressive disease. This study also
established that among all the sociodemographic
variables of the subjects studied, only their
booking status and socioeconomic class showed
a statistically significant relationship with the
serum calcium. There is a negative correlation
between systolic and diastolic blood pressures
and serum calcium and magnesium in both preeclampsia/eclampsia and control groups.
5) Sukonpan K, Phupong V. Serum calcium and serum
magnesium in normal and pre-eclamptic pregnancy.
Arch Gynaecol Obstet 2005; 273:12-16.
6) Engender Health. BALANCING THE SCALES.
Expanding treatment for pregnant women with lifethreatening hypertensive conditions in developing
countries. A report on Barriers and solutions to Treat
Pre-eclampsia and Eclampsia. New York: Engender
Health; 2007
7) Sibai MB, Villar MA, Bray E. Magnesium
supplementation during pregnancy: a double-blind
study. Br. J. Obstet Gynaecol. 1988; 950:120-5.
8) Sibai BM. Diagnosis, Prevention, and Management
of Eclampsia. Obstet Gynecol 2005; 105:402-10
9) Osungbade KO, Ige OK. Public Health Perspectives
of Pre-eclampsia in Developing Countries: Implication
for Health system strengthening. Journal of Pregnancy
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[Review]. 2011; 2011:1-6
10) Population Council Nigeria. “Administering
Magnesium Sulphate to Treat severe Pre-eclampsia
and Eclampsia, 2009.Available at http://.popcouncil.
org/script/tellafriend.asp.
11) Olopade FE, Lawoyin TO. Maternal Mortality
in a Nigerian Hospital. Afr J Biomed Research,
2008;11(3):276-273
12) Omole-Ohonsi A, Ashimi AO. Pre-eclampsia: a
study of risk factors. Nigerian Medical Practitioner
2008; 53(6):99-102
13) Gaym A, Barley P, Pearson L, Admasu K,
Gebrehiwot Y. Disease burden due to Pre-eclampsia/
eclampsia and Ethiopian health system’s response. Int
J Gynecol Obstet; 2011;115:112-116
14) Turner JA. Diagnosis and management of
pre-eclampsia: an update. Int J Women’s Health,
2010;2:327-337
15) Duley L. The global impact of Pre-eclampsia and
Eclampsia. Semin Perinatol, 2009;33:130-137
16) Agida ET, Adeka BI, Jibril KA. Pregnancy outcome
in Eclamptics at the University of Abuja Teaching
Hospital, Gwagwalada, Abuja: A 3year review.
Nigerian J of Clinical Practice 2010;13(4):394-398
17) Agan TU, Archibong EL, Ekabua JE, Ekanem EL,
Abeshi SE et al. Trends in maternal mortality at the
University of Calabar Teaching Hospital, Nigeria,
1999-2009. Int J Women Health 2010;2:249-254
18) Williams PJ, Pipkin FB. The genetics of Preeclampsia and other hypertensive disorders of
pregnancy. Best Practice and Research Clin Obstet
Gynaecol 2011;25:405-417
19) Chames MC, Livingston JC, Invester TS, Barton JR,
Sibai BM. Late postpartum eclampsia: a preventable
disease? Am J Obstet Gynecol 2002;186:1174-7
20) Ganzevoort W, Rep A, Bonsel GJ et al. Dynamics
and incidence patterns of maternal complications in
early onset hypertension of pregnancy. Br. J. Obstet
Gynaecol 2007;114:741-750
21) Ganzevoort W, Sibai BM. Temporizing versus
interventionist management (Preterm and at term).
Best Practice & Research Clinical Obstet Gynaecol 2011;
25:463-476
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Extracellular Calcium and Magnesium in Preeclampsia and Eclampsia. African Journal of
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Calcium Supplementation for the prevention of preeclampsia. Int. J Gynecol Obstet 2009;104:32-36
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24) Duckitt K, Harington D. Risk factors for Preeclampsia at antenatal booking: Systematic review of
controlled studies. BMJ 2005; 330(7491):565.
25) Resnick LM, Barbagallo M, Dominguez LT. Cellularfree Magnesium Depletion in Brain and Muscle of
Normal and Pre-eclamptic pregnancy. Journal of the
American Heart Association 2004; 44:322-326.
26) Akinloye O, Oyewole OJ, Oguntibeju OO.
Evaluation of trace elements in pregnant women with
pre-eclampsia. Afr J Biotech. 2010;9(32):5196-5202
27) Altura B, Altura B. Magnesium ions and contraction
of Vascular Smooth Muscles: relationship to some
vascular diseases. Fed. Pro.1981; 40:2672-2679.
28) Resnik L, Gupta RK, Laragh JH. Intracellular free
Magnesium erythrocytes of essential hypertension:
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Proc. Nat Acad Sci USA 1984; 81:6511-6515
29) American Heart Association Guidelines for
cardiopulmonary resuscitation and Emergency
cardiovascular care. American Heart Association Inc
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magnesium deficiency. Miner Electrolyte Metab 1993,
19:314-322
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importance of socioeconomic class in voluntary
fertility in a developing country. W Afr J Med
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32) Odigie IP, Anorlu RI, Adesiyun AE, Odum CU.
Serum Ionized magnesium levels in Normal and Preeclamptic women in Lagos, Nigeria. Nig Qt J Hosp
Med. 2004;14(2):178-180
33) Golmohammad lou S, Amrabi A, Yazdian
M, Pashapour N. Evaluation of serum Calcium,
Magnesium, Copper, and Zinc levels in Women
with Pre-eclampsia. Iran J Med Sci December 2008;
33(4):231-234
34) Hofmeyr GJ, Lawrie TA, Atallah ÀN, Duley L.
Calcium supplementation during pregnancy for
preventing hypertensive disorders and related
problems (Review). The Cochrane Library. 2011, Issue
2. Available at http://www.thecochranelibrary.com
35) Akhtar S, Begum S, Ferdousi S. Calcium and Zinc
Deficiency In Preeclamptic Women. J Bangladesh Sco.
Phsiol. 2011, 6(2):94-99
36) Sibai BM. Prevention of Pre-eclampsia: A big
disappointment. Am J Obstet Gynecol 1998;179:1275-8
37) Fawett WJ, Haxby EJ, Male DA. Magnesium:
physiology and pharmacology. Br J Anaesth
1999;83:302-20
A very rare case of uterine PEComa HMB45 negative: primitive or
relapse?
Basilio Pecorino1, Giuseppe Scibilia1, Antonio Galia2, Paolo Scollo1.
Division of Gynecology and Obstetrics, Maternal and Child Department, Cannizzaro Hospital, Catania,
Italy.
2
Department of Pathology, Cannizzaro Hospital, Catania, Italy.
1
ABSTRACT
Perivascular epithelioid cell tumors (PEComas) represent a
rare group of tumours with uncertain malignancy potential
exhibiting an immunophenotype characterized by actin and
Human Melanoma Black 45 (HMB45) immunoreactivity.
Our case concerns about a rare malignant uterine perivascular
epithelioid cell tumour diagnosed in a patient underwent
to subtotal hysterectomy with unclear diagnosis, 12 years
before. Histological diagnosis after colposcopic exam with
biopsy revealed a perivascular epithelioid cell tumor, with
immunohistochemical profile negative for HMB45. Negativity
for HMB45, already described in literature, could be due to
important cellular modifications of tumoral tissue.
In our case, tumour was unresectable, progression of disease
occurred during medical treatment and the patient died after 6
months. Lack of information about first surgery doesn’t allow
to surely categorized the tumor as primitive or relapse.
Further studies are necessary to understand some
immunohistochemical anomaly like negativity for HMB45.
SOMMARIO
I tumori a cellule epitelioidi perivascolari (PEComa)
rappresentano un gruppo raro di neoplasie che esibiscono
un immunofenotipo caratterizzato da actina ed Human
Melanoma Black 45 (HMB45). Il nostro caso clinico riguarda
un raro tumore a cellule epitelioidi perivascolari maligno
dell’utero diagnosticato in una paziente sottoposta a
isterectomia subtotale con esame istologico dubbio, 12 anni
prima. La diagnosi istologica dopo colposcopia con biopsia è
stata di tumore a cellule epitelioidi perivascolari, con profilo
immunoistochimico negativo per HMB45. La negatività per
HMB45, già descritta in letteratura, potrebbe essere dovuta
a importanti modificazioni cellulari del tessuto tumorale.
Nel nostro caso, la neoplasia era inoperabile, si è verificata
progressione di malattia durante il trattamento chemioterapico
e la paziente è deceduta dopo 6 mesi. La mancanza di
informazioni riguardo il primo intervento chirurgico non
consente di diagnosticare con certezza la neoplasia come
primitiva o come recidiva. Successivi studi sono necessari per
comprendere alcune anomalie immunoistochimiche come la
negatività per HMB45.
Keywords: immunohistochemistry; PEComa; primitive; rare
tumors; relapse.
INTRODUCTION
Perivascular epithelioid cell tumors
(PEComas) represent a rare group of tumours
with unpredictable malignancy potential. The
term “PEComa” was originally coined by
Zamboni et al. In 1992(1) and it is the current
nomenclature for tumors composed of pecs,
other than angiomyolipoma (AML), clear
cell myomelanocytic tumor of the falciform/
ligamentum teres (CCMT), clear cell sugar tumor
of the lung (CCST), lymphangioleiomyomatosis
(LAM) and clear cell tumors of the pancreas,
rectum, peritoneum, uterus, vagina, thigh
and heart (2). The recent literature has paid
respectable attention to tumors exhibiting an
immunophenotype consistent with a perivascular
epithelioid cell (PEC) differentiation characterized
by actin and Human Melanoma Black 45 (HMB45)
immunoreactivity(3). Our case is a very rare uterine
PEComa negative for HMB45.
DOI: 10.14660/2385-0868-24
CASE PRESENTATION
Our case report concerns about a 54-yearold romanian parous female, with negative
clinical history for non-gynecologic disease or
surgery. The patient was underwent in 1996 to
subtotal hysterectomy and bilateral salpingooophorectomy in Romania with histological
evidence of uterine corpus tumoral lesion,
without specific histological diagnosis. The
patient was admitted to our hospital in 2012
July for abdominal pain and genital bleeding.
Computed tomography (CT) findings highlighted
an oval mass measuring 90x65 mm with origin
from Douglas pouch between bladder and
rectum, inhomogeneous density with hypodense
center; positive left iliac and obturator nodes,
aortic carrefour and right inguinal nodes.
Magnetic resonance imaging (MRI) revealed a
necrotic hypodense solid mass of vaginal vault
measuring about 65x70 mm, with high cellularity
and highly vascularized tissue (MRI T2-weighted,
Figure 1). Positron emission tomography (PET)
scan revealed a considerable accumulation of
radiotracer in the pelvic region, especially in the
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DOI: 10.14660/2385-0868-24
Figure 1.
MRI T2-weighted imaging: pelvic oval mass, inhomogeneous
density with hypodense center.
112
histologic features of tumour.
In consideration of the above , pathologists
made diagnosis of malignant PEComa.
During hospital stay hepatitis B was
diagnosed and antiretroviral therapy was
started. In consideration of unresectable tumour,
multidisciplinary team including gynecologic
oncologist, medical oncologist, radiotherapist
and pathologist, proposed palliative
chemotherapy with gemcitabine 800 mg/m2
(total dose 1200 mg), every 21 days for 3 courses,
between october to december 2012. CT and MRI
imaging performed during treatment revealed
progression of disease, so the team proposed
home support therapy. The patient died after 6
months in Romania.
previous localization of uterus, with positive
left iliac lymph nodes. Pap smear highlighted
numerous squamous metaplastic and atypical
epithelioid cells. Colposcopy revealed a large,
hard and bleeding mass (8 cm) wich involved
the entire vaginal vault. A colposcopically
directed biopsy of the mass was performed and
histological examination revealed a malignant
mesenchymal neoplasm based on epithelioid cells
displaying large granular eosinophilic cytoplasm,
round vesicular nucleus and prominent nucleoli;
pleomorphic multi-nucleated cells, neoplastic
alveolar-like distribution pattern cells and tumor Figure 3.
necrosis with high mitotic index (> 1x50 high Epithelioid cells displaying large granular eosinophilic cytoplasm
power fields HPF). Immunohistochemical pattern with rhabdoid morphology. Eccentric nucleus and prominent
nucleoli.
was positive for desmin, S-100, actin 1A, epithelial
membrane antigen (EMA), microphthalmia DISCUSSION
transcription factor (MITF), cytokeratin AE1/
It is known that the prevalent sites of PEComa
AE3 (CKAE1/AE3) and Melan-A, instead are the gastrointestinal tract, genitourinary
immunohistochemically negative for myogenin tract and retroperitoneum, but uterus is the
and HMB45. Figures 2 and 3 show particular most commonly reported site of involvement of
PEComa (accounting for about 40% of reported
cases). In this report we described a case of
unusual epithelioid tumor of uterus, 12 years after
of unclear diagnosis of uterine neoplasm.
The issue about origin of tumour was
evaluated. In consideration of the particular site
of lesion, we considered differential diagnosis
between soft tissue and uterus PEComas. Also
if many informations about first surgery were
not available, we know that the patient was
underwent to a subtotal hysterectomy.
In fact, we think that colposcopic directed
biopsy was performed to a mass originated from
transformation of the cervix and probably also
Figure 2.
from a small part of uterine corpus left inside the
Tumour shows widespread and high reactivity for melan-A.
pelvis.
B. Pecorino et al.
It’s known that differential diagnosis of soft
tissue and gynecologic PEComas is predominantly
guided by the location of the tumor, as well as
by his morphology(4). In consideration of both
elements this tumour would be diagnosed as
uterine PEComa.
PEComa represents a very heterogeneous
group of neoplasm, whit many types of cellular
and immunohistochemical patterns. Vang
and Kempson (5) described eight examples of
PEComa distinguishing a morphologic variety
of neoplasms including tumors with a tonguelike growth pattern composed of sheets of
HMB45-positive clear epithelioid cells, which
they called group A, to circumscribed tumors
composed of hyalinized stroma and neoplastic
cells focally positive for HMB45 and extensively
immunoreactive for actin and desmin, which
they referred to as group B.
Epithelioid cells with eosinophilic to clear
cytoplasm and positive immunostaining for
both melanocytic and myoid differentiation are
distinctive features of PEComas(6). Histological
examination of our tumor revealed epithelioid
cells displaying with large granular eosinophilic
cytoplasm, round vesicular nucleus and prominent
nucleoli, and dual expression of melanocytic and
myoid markers.
Among rarer uterine tumours, leiomyosarcoma
is the most common subtype of uterine sarcoma.
Often, clinical features of PEComas are the same
of leiomyosarcoma, including abnormal vaginal
bleeding, palpable pelvic mass and pelvic pain.
Histological diagnosis of leiomyosarcoma
can be difficult since many smooth muscle
tumor of the uterus show hypercellularity,
severe nuclear atypia and high mitotic rate.
Sometimes differential diagnosis between
PEComas and leiomyosarcomas is simplified by
immunohistochemistry and molecular biology,
because the latter express only smooth muscle
markers such as desmin, caldesmon, actin and
histone deacetylase.
In our case, the uterine PEComa can’t be
exactly categorized by Vang and Kempson
classification, because, as described above,
immunohistochemical study revealed no
reactivity for HMB45, but histological diagnosis
was supported by presence of both melanocytic
and muscular elements. In fact, all PEComas
display dual expression of melanocytic (HMB-45,
Melan A, NKIC3, MITF, tyrosinase) and smooth
muscle (actin, desmin, caldesmon, calponin)
markers(6). However, high immunoreaction for
actin and desmin supports classification in the
group B by Vang and Kempson.
Folpe and colleagues(4) recently reviewed 61
cases of PEC-oma, which 100% were HMB-45
positive, 59% were smooth muscle actin positive,
41% were Melan-A positive, 33% were CD117
positive, 31% were desmin positive, 11% were
S-100 positive, and 0% was cytokeratin positive.
Immunohistochemical pattern represents a
very important tool for diagnosis of PEComa but
it’s not sufficient to determine the final diagnosis
because there are different patterns, models
are heterogeneous and results can be various.
Our case report requested specific analysis for
differential diagnosis of PEComa with other
muscolar neoplasms, because, as described
above, immunohistochemical evaluation didn’t
highlight the usual positivity for HMB45. The
case herein presented showed strong and
diffuse staining for both Melan-A and MITF,
two melanocytic markers, wich is not an usual
finding in other tumors like sarcomas. Moreover,
immunohistochemical reactivity for Melan-A and
actin was significant for diagnosis of PEComa
while negativity for HMB45, already described
in literature(7), could be due to important cellular
modifications of tumoral tissue. About this, a
very interesting theory is that PEComa originates
from transfomation of a smooth muscular cells
tumour. In fact Silva et al. (8) described a case
of leiomyosarcoma in wich primitive tumour
was negative for HMB45 while after 7 years
metastatic tumour was reactive for HMB45
and pathologists diagnosed it as perivascular
epithelioid cells malignant tumour. In our case,
in consideration of the lack of information about
first diagnosis, presumable theory could be that
previous tumor was a misdiagnosed PEC-oma
but we cannot be totally definitive about this.
The optimal treatment for this group of
tumour is not well established but surgery
seems to be the gold standard for primitive
PEComas and metastatic ones, with purpose to
obtain adequate resection margins(9). Treatment
for locally advanced and metastatic tumour are
different, including surgery, chemotherapy and
radiotherapy. Recent literature(10) has highlighted
the efficacy of mammalian target of rapamycin
(mtor) inhibitors in the patients affected from
malignant PEComas but there is not sure evidence
yet about the gold standard chemotherapy of
PEComas and further studies are necessary to
demonstrate the optimal treatment. We used
gemcitabine for palliative treatment accounting
the unavailability of recent described target
therapies.
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DOI: 10.14660/2385-0868-24
In our case, analysis and study of the patient
was difficult for absence of clinical information
about first diagnosis and surgical treatment
performed in Romania. In fact, we speculate
about difficult and inadequate first surgical
treatment, but description of surgery and specific
histological diagnosis are not available. The
patient was admitted to our hospital with a
big mass invading pelvic organs as bowel and
bladder, low performance status, resulting in
unresectable tumour. In consideration of entire
clinical history, we can surely categorize the
neoplasm as a malignant tumor, but it’s known
that there are specific features to analytically
determine the malignancy potential.
Biological behavior of PEComas is difficult to
define(2). Folpe and colleagues(4) proposed that the
disease could be classified into three subgroups,
including the benign, uncertain malignant
potential, and malignant. These criteria for
malignancy are: size of >8.0 cm, mitotic count
of >1 per 50 HPF and necrosis, with benign,
uncertain malignant potential and malignant
categories based on the presence of none, 1 or ≥2
of these three criteria, respectively. The benign
tumor has no alarming features (e.g. Diameter
of the tumor≤5 cm, non-infiltrative, non-high
nuclear grade and cellularity, mitotic rate≤1x50
HPF), while uncertain malignant potential tumor
shows pleomorphous or multinucleated giant
cells only, or sized over 5 cm in diameter only. In
this regard size of tumour (over 5 cm in diameter)
and high mitotic rate are two important indicator
of relapse. In our case, lack of information about
surgery doesn’t allow to surely categorized
our tumor as primitive PEComa or relapse of
this. If presented tumor is a primitive PEComa,
size and mitotic rate index establish that our
uterine PEC-oma is a malignant tumour by
classification described, with high percentage of
relapse. Again, it’s known that relapse is itself
an important indicator of malignancy. So, in
consideration of both theories, we classified the
tumour as a malignant PEComa.
In conclusion, PEComas are rare uncertain
malignancy tumors. Diagnosis is based on
microscopic histology and immunohistochemical
pattern while prognosis is influenced by
biological behavior and stage of disease at the
time of diagnosis. Further studies are necessary to
understand some immunohistochemical anomaly
like negativity for HMB45, also if it’s a rare event.
REFERENCES
1) Zamboni G, Pea M, Martignoni G, et al. Clear cell
“sugar’’ tumor of the pancreas: a novel member of
the familyof lesions characterized by the presence of
perivascular epithelioid cells. Am J Surg Pathol 1996;
20(6):722-30.
2) GAN Mei-fu, YU Chun-kai, JIN Mei, LU Hong-sheng
and LI Hiu-ming. Perivascular epithelioid cell tumor
of the uterus: report of three cases. Chin Med J 2007;120
(6):526-528
3) Bonetti F, Pea M, Martignoni G, et al. The perivascular
epithelioid cell and related lesions. Adv Anat Pathol.
1997;4:343–358.
4) Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL,
Weiss SW. Perivascular epithelioid cell neoplasms of
soft tissue and gynecologic origin: a clinicopathologic
study of 26 cases and review of the literature. Am J
Surg Pathol. 2005 Dec;29(12):1558-75.
5) Vang R, Kempson RL. Perivascular epithelioid cell
tumor (‘PEComa’) of the uterus: a subset of HMB-45positive epithelioid mesenchymal neoplasms with
uncertain relationship to pure smooth muscle tumors.
Am J Surg Pathol 2002;26:1–13.
114
6) Teresa Pusiol, Doriana Morichetti, Maria Grazia
Zorzi, Surace Dario HMB-45 Negative Clear Cell
Perivascular Epithelioid Cell Tumor of the Skin Acta
Dermatovenerol Croat 2012;20(1):27-29.
7) Yamagata Y1, Kawauchi S, Tamura H, Murakami
A, Sasaki K, Sugino N. A case of HMB45-negative
perivascular epithelioid cell tumor (PEComa) of the
uterine corpus: a possible diagnostic application of
molecular-cytogenetic analysis. Eur J Gynaecol Oncol.
2009;30(2):216-9.
8) Elvio G. Silva Diane C. Bodurka Maria A. Scouros
Alberto Ayala A uterine leiomyosarcoma that became
positive for HMB45 in the metastasis. Annals of
Diagnostic Pathology 9 (2005) 43–45.
9) Henry B Armah and Anil V Parwani Malignant
perivascular epithelioid cell tumor (PEComa) of the
uterus with late renal and pulmonary metastases: a
case report with review of the literature. Diagnostic
pathology 2007 Dec 3;2:45.
10) Italiano A, Delcambre C, Hostein I, et al.
Treatment with the mTOR inhibitor temsirolimus in
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May;21(5):1135-7.
The potential role of preoperative serum cancer antigen CA 15-3 in the
prognosis of breast cancer
Adela Stoenescu2, Daniel Herr1, Christoph Gerlinger1, Erich Franz Solomayer1, Christoph
Scholz2, Ingolf Juhasz-Böss1, Julia Radosa1
1
2
Department of Obstetrics and Gynaecology, University of Saarland, Homburg / Saar, Germany
Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany
ABSTRACT
Background: Serum CA 15-3 has been the most frequently
investigated tumor marker in breast cancer. The most
important application for CA 15-3 is in monitoring therapy
in patients with advanced breast cancer. CA 15-3 levels have
also been demonstrated to predict outcome in breast cancer.
However, the potential role of CA 15-3 as a prognostic marker
for breast cancer was investigated only in a few studies.
Methods: In a retrospective study, we investigated the
association of the serum levels of CA 15-3 with tumor
characteristics as prognostic factors of the disease. 586 female
breast cancer patients confirmed by histopathological reports
were included in the study. Information concerning age,
menopausal status, diagnosis, and clinical pathology were
collected for each patient. CA 15-3 serum levels were evaluated
at time of the primary diagnosis.
Results: Our results suggest that elevated pretreatment serum
marker values were correlated with poor prognosis and death
from the disease. By comparing CA 15-3 levels in metastatic
and non-metastatic disease, we found a statistically significant
difference between the two categories. This study demonstrates
a correlation between stage of breast cancer and CA 15-3
positivity rates. The higher the breast cancer stage, the more
likely the CA 15-3 level will be elevated. The CA 15-3 level was
similarly significantly related to death from disease. We found
no correlation between CA 15-3 levels and recurrences of the
disease.
Conclusion: Elevated preoperative serum level of CA 15-3 is
significantly correlated with the presence of distant metastatic
disease. Our data supports CA 15-3 as a useful parameter in
the management of breast cancer preoperatively as well as in
an adjuvant setting.
Keywords: Antigen CA 15-3, Breast cancer.
INTRODUCTION
Breast cancer is the most common cancer in
women worldwide(18). Nearly 1.1 million patients
are diagnosed with breast cancer yearly(17). The
number of cases worldwide has significantly
increased in the last years. New strategies for
managing breast cancer are needed.
CA 15-3 is a high-molecular-weight mucin
glycoprotein and is the most widely used
serum marker in breast cancer for follow-up
care and monitoring the treatment of patients
with advanced disease (5,6). For monitoring the
treatment of advanced breast cancer, CA 15-3
levels decrease in approximately 70 % of patients
DOI: 10.14660/2385-0868-25
SOMMARIO
Background: Il CA 15-3 sierico è il marcatore tumorale più
frequentemente studiato nel cancro al seno. L’applicazione
più importante per il CA 15-3 è nel monitoraggio in pazienti
con carcinoma mammario avanzato. E’ stato dimostrato che
Livelli di CA 15-3 sono in grado di predire l’esito del cancro al
seno. Tuttavia, il ruolo potenziale di CA 15-3 come marcatore
prognostico per il tumore al seno è stato valutato solo in pochi
studi.
Metodi: In uno studio retrospettivo, abbiamo valutato
l’associazione tra i livelli sierici di CA 15-3 e le caratteristiche
del tumore come fattori prognostici della malattia. 586
pazienti con carcinoma mammario confermato da rapporti
istopatologici sono state incluse nello studio. Informazioni
riguardanti età, stato menopausale, la diagnosi e patologia
clinica sono stati raccolti per ogni paziente. I livelli sierici di
CA 15-3 sono stati valutati al momento della prima diagnosi.
Risultati: I nostri risultati suggeriscono che i valori elevati
dei marker sierici pre-trattamento sono correlati con prognosi
infausta e la morte per malattia. Confrontando i livelli di CA
15-3 in casi di malattia metastatica e non metastatica, abbiamo
riscontrato una differenza statisticamente significativa tra le
due categorie. Questo studio dimostra una correlazione tra lo
stadio del cancro al seno e i livelli di CA 15-3.
Più avanzato è lo stadio del cancro al seno, più è probabile
che il livello di CA 15-3 sia elevato. Il livelli di CA 15-3 sono
stati correlati in maniera analoga e significativa alla morte per
malattia. Non abbiamo riscontrato alcuna correlazione tra i
livelli di CA 15-3 e le ricorrenze della malattia.
Conclusioni: Elevati livelli sierici pre-operatori di CA 15-3
sono significativamente correlati con la presenza di metastasi
a distanza. I nostri dati supportano il CA 15-3 come parametro
utile nella gestione preoperatoria del cancro al seno così come
nella scelta della terapia adiuvante.
with chemotherapy-induced breast cancer
regression and increase in 80 % of patients with
progressive disease[19].
Because of its low sensitivity (15-35 %),
the routine use of CA 15-3 as a screening or
diagnostic tool for primary breast cancer is not
recommended(1-4). Elevated levels of CA 15-3 are
found in only 3 % of patients with non-metastatic
breast cancer and in up to 70 % of patients with
metastatic disease(16). Increasing and decreasing
levels show correlation with breast cancer
progression and regression, respectively.
Nonmammary malignancies in which elevated
CA 15-3 levels have been reported include: lung,
colon, pancreas, primary liver, ovary, cervix, and
endometrium. Mild increased concentrations
were observed in benign conditions, such as:
115
2015, 27: N.3
DOI: 10.14660/2385-0868-25
hepatitis, liver cirrhosis, lung, kidney, ovarian,
breast (mastopatie, fibroadenom).
The potential role of CA 15-3 in prognosis of
breast cancer has been analyzed in a few studies,
which came to inconsistent results. It has been
reported that patients with elevated preoperative
CA 15-3 levels had a worse outcome than patients
with low levels(9). The ASCO guidelines found the
data insufficient to recommend the routine use of
CA 15-3 measurements for screening, monitoring
response to treatment, diagnosis, or staging. The
ASCO guidelines recognized that in the absence
of readily measurable breast cancer, an increasing
CA 15-3 might be used to suggest progression of
disease.
Our aim was to investigate the association of
CA 15-3 concentrations with clinicopathological
parameters and outcomes in patients with breast
cancer.
PATIENTS AND METHODS
In a retrospective study, we investigated the
association of the serum levels of CA 15-3 with
tumor characteristics as prognostic factors of the
disease.
The study population enrolled a total of
586 consecutive participants with a histologic
diagnosis of breast cancer or carcinoma in situ,
treated at the Department of Gynaecology of the
University of Saarland between January 2010
and December 2012. Information concerning
age, menopausal status, diagnosis, and clinical
pathology were collected for each patient and are
summarized in Table 1. The participants were
monitored for tumor recurrence or death during
a mean follow-up period of 17.5 months.
The breast cancer patients were staged
according to TNM-UICC classification. 532
patients were diagnosed histologically with
ductal infiltrating carcinoma, while 49 of
carcinoma in situ. Tumor size was classified as
T1 (less than or equal to 2 cm) in 297 (50.77%), T2
(tumor size between 2 and 5 cm) in 157 (26.84%),
T3 (tumor size more than 5 cm) in 27 (4.62 %) and
T4 (tumor extends to chest wall) in 29 (4.96 %) of
the cases. There were 400 patients with negative
lymph nodes and 162 patients with positive
lymph nodes. Main tumor characteristics are
shown in Table 1.
Pretreatment serum CA 15-3 measurements
were available for 510 participants. CA 15-3
serum levels were evaluated at time of the
Table 1
Main clinical-pathological tumor characteristic of 586 breast cancer patients
116
Characteristic
Patients
Percent
Characteristic
Patients
Percent
Age
< 50 years
50-70 years
> 70 years
122
296
168
20.82%
50.52%
28.66%
Menopausal status
Premenopausal
Perimenopausal
Postmenopausal
Missing data
117
35
433
1
19.97 %
5.97 %
73.89 %
0.17 %
Histological diagnosis
Ductal infiltrating carcinoma
In situ carcinoma
Missing data
532
49
5
91.57%
8.43%
0.85%
Grading
G1
G2
G3
Missing data
61
339
17
69
11.80%
65.57%
22.63%
11.77%
Tumor size
T1
T2
T3
T4
Missing data
297
157
27
29
76
50.77%
26.84%
4.62%
4.96%
12.96%
Nodal involvement
N0
N1
N2
N3
Missing data
400
123
20
13
30
68.61%
21.10%
3.43%
.26%
5.11%
Metastatic site
M0
M1
Missing data
538
28
20
95.05 %
4.95 %
3.41 %
Her2-neu status
Negative
Positive
Missing data
436
89
61
74.40 %
15.19 %
10.46 %
ER status
Negative
Positive
109
477
18.60 %
81.40 %
PgR status
Negative
Positive
Missing data
213
370
3
36.35 %
63.14 %
0.51 %
Local relapse
No
Yes
571
15
97.44%
2.56%
Death
No
Yes
574
12
97.95 %
2.05 %
A. Stoenescu et al.
primary diagnosis and were not used in our
study to monitor response to breast cancer
treatment. The cut-off level for serum CA 15-3
was established at 30 U/ml.
The statistical analyses were carried out using
Statistical Analysis System version 9.2 statistics
software. The Kruskal-Wallis test was used for
relating CA 15-3 levels to clinicopathological
parameters. A p-value of less than 0.05 was
considered to be significant.
RESULTS
Relationship between CA 15-3 and tumor
characteristics in adjuvant patients
Serum levels of CA 15-3 in patients with
carcinoma in situ did not differ significantly as
compared with patients with invasive breast
cancer (20.85 U/ml vs. 64.58 U/ml, p>>0.05).
There were significant correlations between
tumor size and CA 15-3 levels in our analysis.
CA 15-3 concentrations were higher in patients
with larger tumors; p= 0.0377. However, patients
with T4 breast cancer had lower CA 15-3 level
(mean 17.72 U/ml) than patients with T1, T2 and
T3 tumors.
The CA 15-3 concentrations were independent
of grading, nodal burden, local disease
Figure 1
Relationship between CA 15-3 and tumor characteristics in non
metastatic patients
Chart a
Chart c
Chart e
recurrence, ER, pgr and Her2 expression. A
detailed breakdown of distribution of CA 15-3
levels in relation to tumor characteristics is
shown in Figure 1.
Relationship between CA 15-3 and tumor
characteristics in patients with metastatic
disease
26 patients with available data had already
distant metastasis at time of their initial breast
cancer diagnosis as follows: 5 patients had lung
metastases, 8 bone metastases, 2 liver metastases
and the others had more than one location
of distant metastasis. Patients with primary
metastatic disease had a mean CA 15-3 level of
79.45 U/ml, significantly higher than patients
without metastasis; p< 0.0001.
The relationship between tumor marker level
and clinical and histopathologic characteristics of
the patients is shown in Figure 2. CA 15-3 level
seemed to be increased linearly with tumor size
in patients with metastatic disease.
Figure 2
Relationship between CA 15-3 levels and tumor characteristics in
metastatic patients
Chart f
Chart g
Chart h
Chart i
Chart b
Chart d
However, the observed differences of CA 15-3
levels between T1, T2, T3 and T4 tumors are not
significant. Although a tendency for increased
CA 15-3 levels in patients with axillary metastases
was observed, this difference again did not reach
statistical significance. Non-significant elevations
of CA 15-3 were observed in patients with G2 and
G3 tumors.
We evaluated correlation of CA 15-3 level
at the time of primary diagnosis with ER, pgr
and Her 2 expressions. A mean serum CA 15-3
concentration of 20.64 U/ml was observed
in patients with triple negative breast cancer
without metastasis, while patients with distant
117
2015, 27: N.3
DOI: 10.14660/2385-0868-25
metastasis had a mean level of 33.90 U/ml.
Patients with hormone receptor negative, Her2/
neu positive, and metastatic tumor had a mean
CA 15-3 level of 23.28 U/ml. CA 15-3 levels were
correlated with ER, pgr and Her2 positivity.
Patients with hormone and Her2/neu receptor
positive metastatic breast cancer had a mean CA
15-3 level of 54.78 U/ml. High concentrations of
CA 15-3 (mean level 114.5 U/ml) were observed
in patients with metastatic, hormone receptor
positive and Her2/neu negative disease,
significantly higher than in patients without
metastasis; p< 0.0001 (Figure 3).
Figure 3
Relationship between CA 15-3 levels and receptor status in non
metastatic and metastatic patients
Chart j
Chart l
Chart k
Chart m
During the follow-up period, 12 patients
(2.05%) died, 11 of which due to breast cancer.
For 8 patients with available data, significantly
higher CA 15-3 levels were found at time of
diagnosis (mean level 671.4 U/ml); p= 0.0006.
Out of these 8 patients, 2 patients had no distant
metastasis and slightly higher CA 15-3 values
(mean 27.3 U/ml) compared to survivors.
DISCUSSION
118
The classic prognostic markers in breast
cancer such as axillary lymph node status, tumor
size, histological grade, and receptor expression
require tissue sampling, are costly and cannot
by themselves predict the risk of development of
distant metastasis and outcome in patients with
breast cancer. Tumor markers that can accurately
predict overall survival, which can identify
the group of patients needing close follow up
and those who will benefit most from adjuvant
therapy, are needed. Serum CA 15-3 has been the
most frequently investigated tumor marker in
breast cancer.
The most important application for CA 15-3 is
in monitoring therapy in patients with advanced
breast cancer(15). CA 15-3 levels have also been
demonstrated to predict outcome in breast
cancer(9). However, the potential role of CA 15-3
as a prognostic marker for breast cancer was
investigated only in a few studies. Our results
suggest that elevated pretreatment serum marker
values were correlated with poor prognosis and
death from the disease.
By comparing CA 15-3 levels in metastatic and
non-metastatic disease, we found a statistically
significant difference between the two categories.
CA 15-3 can stratify patients into high and low
risk groups. Patients in the high risk group
have a poor prognosis, a higher risk of distant
metastasis, of death from the disease and need
close follow-up and most likely benefit from
adjuvant therapy.
This study demonstrates a correlation between
stage of breast cancer and CA 15-3 positivity rates.
The higher the breast cancer stage, the more likely
the CA 15-3 level will be elevated. Our results are
comparable to results from other analyses with
a similar study design(7,10). Surprisingly, the 5
patients from our study with T4 non-metastatic
tumors had a significantly lower CA 15-3 level
in our analysis. A normal result does not prove
absence of cancer(7,8).
The CA 15-3 level was also significantly
related to death from disease. The higher the
CA 15-3 levels, the poorer is the prognosis. In
line with our findings, Duffy et al. Evaluated the
relationship between CA 15-3 levels and patient
outcome and has shown that high preoperative
levels of CA 15-3 are associated with an adverse
patient outcome(9). Survival may be poorer in
patients with an elevated serum marker level
because of the statistically significant relationship
between CA 15-3 and metastasis. Other
authors have published similar observations.
For example, Daniele et al., Berutti et al. And
Horobin et al. Reported that high preoperative
levels of CA 15-3 can predict poor outcome in
patients with breast cancer(11-13). They confirmed
our findings that patients with abnormal CA
15-3 levels have a shorter disease-free interval
and overall survival rate compared to those with
normal levels.
We found no correlation between CA 15-3
levels and recurrences of the disease. Daniele
et al. And Iaffaioli et al., however, found that
patients with abnormal preoperative CA 15-3
A. Stoenescu et al.
levels are significantly associated with early
recurrence of the disease(11,14).
These results confirmed that elevated
preoperative serum levels of CA 15-3 are
significantly correlated with the presence of
distant metastatic disease. However, CA 15-3 has
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3) Tondini C, et al. Comparison of CA 15-3 and
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5) Robertson JFR, et al. Objective measurement of
therapeutic response in breast cancer using tumor
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9) Duffy MJ, et al. High preoperative CA 15-3
concentrations predict adverse outcome in nodenegative breast cancer: study of 600 patients with
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not been shown to be a more useful prognostic
tool than the routine traditional markers. Elevated
CA 15-3 level is a useful parameter for predicting
clinical outcomes and it may be used collectively
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10) O’Hanlon, et al. An evaluation of preoperative CA
15-3 measurement in primary breast carcinoma. Br J
Cancer 71, 1995: 1288-91.
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CA 15-3 in the staging and prognosis of patients with
breast cancer. J R Coll Edinb 1991;36:219-21.
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overall survival of two mucinous markers: CA 15-3
and CA 125 in breast cancer patients at first relapse of
disease. Eur J Cancer 1994;30A:2082-4.
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15-3 levels in operable breast cancer. Comparison
with tissue polypeptide antigen (TPA) and
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1991;6:21-4.
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P, Taube S, Somerfield MR, Hayes DF, Bast Jr RC,
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119
Dangers and expenses of a first-level Obstetrics facility: a serious Italian
concern
Ugo Indraccolo1, Anna Maria Iannicco1, Mirella Buccioni1, Giuseppe Micucci1
1
Complex Operative Unit of Obstetrics and Gynecology of Civitanova Marche, hospital of Civitanova
Marche, Area Vasta 3 – Marche.
ABSTRACT
Purpose. Estimate the expense of an Obstetrics facility with
more than 500 births/year and less than 1000 births/year.
Methods. Starting from 1262 hospitalizations, we assessed the
outcomes of each hospitalization (Cesarean section, operative
vaginal delivery, hospitalization in pregnancy without
delivering, hospitalization after delivering for puerperal
complications) and combine them with days of hospital
stay (with a scoring system) and with rates of pregnancy
complications. Therefore, we estimated the expense like
increase of resources absorption for pregnancy complication.
Multivariable logistic e multilinear regression analyses was
used for inference.
Results. Increase in resources absorption is: 8.4% for
hypertensive disorders of pregnancy, 6.7% for gestational
diabetes mellitus, 2% for intrahepatic cholestasis, 2.7% for
intrauterine growth restriction, 17.8% for premature rupture
of membranes, 10.6% for oligohydramnios/polyhydramnios,
31.9% for previous Cesarean, 19.8% for other complications.
Discussion. As Cesareans cause directly and indirectly the
rise in expense, it should be avoided. However, the rise in
Cesareans sections is justified by the unavailability of the
operating room to allow a Cesarean sections in emergency.
Despite gouvernative efforts, this is still a serious concern for
first-level Obstetrics units in Italy.
SOMMARIO
Scopo. Stimare la spesa sanitaria di una struttura di primo
livello ostetrico (fra 500 e 1000 parti l’anno). Metodi. A partire
da dati amministrativi di 1262 ospedalizzazioni, sono stati
valutati gli esiti di cisacun ricovero (Cesareo, parto operativo
vaginale, ricovero in gravidanza senza parto, ricovero in
puerperio dopo il parto) e sono stati combinati con i giorni di
degenza (con un sistema a punteggio) a con le frequenze delle
complicazioni della gravidanza. Pertanto, è stato possibile
stimare la spesa sanitaria come incremento nell’assorbimento
di risorse. Sono state usate la regressione logistica multivariata
e la regressione multilineare per inferenza.
Risultati. L’incremento nell’assorbimento di risorse avviene:
per l’8.4% per disturbi iperensivi della gravidanza, per il 6.7%
per il diabete gestazionale, per il 2% per la colestasi intraepatica
della gravidanza, per il 2.7% per lo IUGR, per il 17.8% per le
rotture premature di membrane, per il 10.6% per le diagnosi di
oligoamnios o poliamnios, per il 31.9% per i cesarei pregressi,
per il 19.8% per atre complicazioni.
Discussione. Siccome sono i Cesarei a a causare direttamente
ed indirettamente l’aumento della spesa sanitaria,
bisognerebbe evitarli. L’aumento dei tagli Cesarei è comunque
giustificato dalla indisponibilità della sala operatoria per
consentire un taglio cesareo in emergenza. Nonostante
l’impegno governativo, questo è ancora un grave problema per
le strutture ostetriche di primo livello in Italia.
Keywords: Cesarean section, expense, health policy.
INTRODUCTION.
Since 2008, the parliamentary commission of
inquiry on the errors in health field and on the
causes of regional income deficit has assessed
many items of obstetrical care, concluding
that hospitals with low numbers of birth/year
provide a worst care in labour and delivery in
Italy(1). This behaviour should have an immediate
impact on health expense. After this warning, a
gouvernative effort has provided a reorganization
of hospitals with low number of birth, aiming to
improve obstetrical care thereby reducing health
expense(2). We judge that this efforts have been
vain.
The aim of this report is to estimate the
expense of an Obstetrics facility with more
than 500 births/year and less than 1000 births/
year (after reorganization, the facility is labeled
as a first level Obstetrics unit), highlighting
which kind of obstetrical complication is most
DOI: 10.14660/2385-0868-26
expensive, and discussing the reasons of such
expenses.
Administrative data from the 2013 to June
2014 were extracted from the whole hospitalized
patients of the Complex Operative Unit of
Obstetrics and Gynecology of Civitanova Marche,
Area Vasta 3. This is a first level Obstetrics unit,
with number of deliveries between 500 and 1000/
years. Data were limited to the hospitalizations
of the second and third trimester of pregnancy
(1262 hospitalizations). In the second and
third trimester of pregnancy, the obstetrical
complications of a low-risk Obstetrics setting
were screened and managed according with the
resources of the Obstetrics unit (by referring the
preterm pregnancies below 34 weeks to a second
level unit, without initiating an hospitalization
if possible). Therefore, we are able to assess a
very small sample of hospitalized patients in
121
2015, 27: N.3
DOI: 10.14660/2385-0868-26
122
which outpatient screening of complications was
ineffective along with a wide proportion of lowrisk pregnant admitted to the Obstetrics unit.
We check the diagnosis-related groups
(DRGs) for pregnancy complications and for
obstetrical interventions for assessing the
primary outcomes of pregnancy complications
in this sample. Moreover, administrative data
were able to provide days of hospital stay and
duplicate hospitalizations during pregnancy or in
the puerperal period.
To estimate the expense, we combine the
outcomes of each hospitalization (Cesarean
section, operative vaginal delivery, hospitalization
in pregnancy without delivering, hospitalization
after delivering for puerperal complications)
with days of hospital stay. A scoring system was
adopted as following. The “expense score” was
built by summing the outcomes Cesarean section
(score 2, if present), operative vaginal birth (score
1, if present), hospitalization without delivering
(score 1, if present), puerperal complications
(score 1, if present), along with days of hospital
stay. This score estimates the increase of
resources absorption in case of Cesarean (most
physicians and nurses efforts, more drugs
use, occupation of delivery room, etc.), in case
of operative delivery (more drugs use, more
efforts of midwives and Obstetricians), in case
of duplicate hospitalizations for complications
during pregnancy and after delivery (duplicate
efforts of nurses, physicians, midwives, drug
use, etc.). The increase of resources absorption is
directly related with health expenses, who cannot
be exactly quantized.
Logistic regression analyses and multilinear
regression analyses were built for assessing
which complication of pregnancy independently
associates with outcomes (Cesarean section,
operative vaginal delivery, hospitalization
without delivering, puerperal complications),
with days of hospital stay and with the “expense
score”. We do not insert in statistical analyses the
complications of pregnancy occurred in labour
(fetal distress or intrapartum cardiotocographic
abnormalities and dystocia during labour),
because those complications in a low-risk
population are considered as causing normal
resources absorption in routine obstetrical care.
The regression coefficients calculated for
the “expense score” was corrected for the rate
of pregnancy complications (unstandardized
coefficient of regression * rate of pregnancy
complication, as coded by DRGs), and converted
in a percentage scale of increasing in resources
absorption. SPSS 16.0 was used for calculations.
p<0.05 was set for significance.
RESULTS.
Table 1 provides rates of principal
complications of pregnancy and portrays the
odds of a given outcome (Cesarean section,
operative vaginal birth, hospitalization in
pregnancy without delivering, hospitalization
after delivering for puerperal complication).
The Table 1 provides also the unstandardized
coefficients for days of hospital stay and for the
expense score along with the percentage scale
of increase in resources absorption for each
pregnancy complication. Both results of logistic
regression analyses and of multilinear regression
analyses are provided as multivariate results
(odds ratios with 95% CI and unstandardized
regression coefficients).
The hypertensive disorders of pregnancy
have a rate of 2.5% among DRGs. They associate
more often with Cesarean sections, with
hospitalizations without delivering and with a
long lasting time of hospitalizations. They are
the most expensive complication for a low-risk
Obstetrics unit, but, in light of they low rate,
they do not absorb an high amount of resources
(estimated increase of resource absorption: 8.4%).
Gestational diabetes mellitus, as diagnosed
by using the new restrictive criteria(3), slightly
increases the odds to undergo Cesarean
section, thereby absorbing 6.7% of increasing in
resources. Intrahepatic cholestasis of pregnancy
is uncommon and seems to need more hospital
stay without causing any significant change
in other outcomes (increasing in resources
absorption: 2%). Same behavior seems to have
the intra-uterine growth restriction (IUGR)
diagnosis (increasing in resources absorption:
2.7%). Premature rupture of membranes (PROM)
diagnosis is common (16% of DRGs) and leads
to more Cesarean sections and hospital stay
(increasing in resources absorption: 17.8%).
Oligohydramnios and polyhydramnios are less
common diagnosis (5.1% of DRGs) but cause more
hospitalization time with a 10.6% of increasing in
resources absorption. Previous Cesarean section
is the commonest complication of pregnancy
(12.1% of DRGs) and is always managed with
a repeated Cesarean in the Obstetrics unit of
Civitanova Marche, thereby causing more readmission for puerperal complications (usually
post-surgical complications) and, therefore,
most increase in resources absorption (31.9%).
U. Indraccolo et al.
Finally, other complications (rate 8.1% of DRGs)
cause an increase in resources absorption of
19.8%, needing more often a Cesarean section,
more hospitalizations without delivering,
more hospital stay. Those complications are
mainy: breech presentation (24.3%), other
malpresentations or mechanic dystocia not
occurring in labour (11.7%), tween pregnancies
(6.8%), placenta abruption (5.8%), intrauterine
fetal deaths (3.9%), placenta praevia (2.9%) and
miscellaneous complications (38.8%). Among
the latter group, there are some gynecologic
pathologies (leyomiomas, ovarian cysts,
adhesions, endometriosis), unspecified bleeding,
infectious diseases, cord disorders, venous
disorders.
DISCUSSION.
In this first level Obstetrics unit, the most
expensive complication of pregnancy is the
group of hypertensive disorders of pregnancy,
but the most important absorption of resources
is the diagnosis of previous Cesarean. Such
behaviour could be generalized to the majority of
low-risk Obstetrics unit in Italy. Italian practice
guidelines suggests to offer a trial of labour after
Cesarean if the Obstetrics unit is able to provide
an immediate access to the operating room(4).
However, many first-level Obstetrics unit in Italy
are not able to allow an emergent Cesarean in case
of suspected uterine rupture. This problem is due
to the structural criticality of many hospitals who
have not the operating room close to the delivery
room. Additionally, the operating room could be
not immediately available for a Cesarean even
if it is close to the delivery room. Therefore, for
preventing an harmful loss of time, Obstetrics
and Gynecologists are forced to plan a repeated
Cesarean. The repeated Cesarean realizes the
31.4% of Cesareans in Italy(5). This rate could be
significantly reduced, because 60% of women
with a previous Cesarean delivers vaginally(6).
Preventing unnecessary repeated Cesareans in
Table 1
Statistical calculation
Outcomes
Indicators of expense
Cesarean section
Operative
vaginal delivery
Hospitalizations
without delivering
Puerperal
complications
Days of
hospital stay
Expense score
(days of hospital
stay + outcomes)
odds ratio
95% CI
p
odds ratio
95% CI
p
odds ratio
95% CI
p
odds ratio
95% CI
p
Unstandardized
coefficient
p
Unstandardized
coefficient
p
Hypertensive disorders
of pregnancy
2.5%
6.498
2.732-15.454
p<0.001
2.470
0.300-20.301
N.S.
4.106
1.327-12.702
p=0.014
0.631
0.083-4.796
N.S.
1.298
p<0.001
2.018
p<0.001
Gestational diabetes
8.7%
1.916
1.152-3.189
p=0.012
1.548
0.334-7.185
N.S.
1.584
0.596-4.205
N.S.
0.305
0.074-1.266
N.S.
0.194
N.S.
0.458
p=0.025
Intraepathic cholestasis
of pregnancy
1%
2.244
0.585-8.618
N.S.
/
/
1.905
0.226-16.096
N.S.
0.284
N.S.
1.180
p=0.046
0.012
IUGR
1.7%
1.039
0.315-3.425
N.S.
/
1.239
0.157-9.770
N.S.
/
0.528
N.S.
0.929
p=0.038
0.016
PROM
16%
2.626
1.776-3.882
p<0.001
0.313
0.041-2.394
N.S.
0.159
0.022-1.174
N.S.
1.108
0.574-2.139
N.S.
0.309
p=0.019
0.660
<0.001
Polyhydramnios/
oligohydramnios
5.1%
1.884
0.977-3.636
N.S.
/
1.321
0.381-4.577
N.S.
1.647
0.630-4.308
N.S.
0.492
p=0.024
1.227
p=0.038
189.649
79.716-437.022
p<0.001
/
0.748
0.256-2.182
N.S.
0.210
0.051-0.865
p=0.031
0.210
N.S.
1.568
p<0.001
9.739
6.079-15.603
p<0.001
0.790
0.101-6.155
N.S.
3.569
1.617-7.879
p=0.002
1.843
0.881-3.854
N.S.
0.679
p<0.001
1.459
p<0.001
Previous
section
12.1%
Cesarean
Other complications
8.1%
Overall estimation
of the expense
(score coefficient x
complication of pregnancy
rate)
Percentage of resources
absorption
0.05
8.4%
0.04
6.7%
2%
2.7%
0.106
17.8%
0.063
10.6%
0.19
31.9%
0.118
19.8%
123
2015, 27: N.3
DOI: 10.14660/2385-0868-26
low-risk Obstetrics unit is cost-effectiveness but
would lead to a gouvernative policy of building
new hospitals for allowing the trial of labour after
Cesarean with the operating room immediately
available. Such an organization is also safe,
and prevents injuries from other complications
of pregnancy needing an emergency use of
operating room. However, currently, building
new hospitals would dissipate a lot of economic
resources in Italy and it does not seem feasible.
To slightly reduce the expense of a low-risk
Obstetrics facility, it could be improved the
diagnosis and management of oligohydramnios
and of polyhydramnos (rate 5.1% of DRGs) and
the management of malpresentation and twin
pregnancies (group of other complications of
pregnancy, rate 8.1% of DRGs). The sonographyc
evaluation of amniotic fluid volume should be
improved avoiding unnecessary interventions(7).
External cephalic version for breech
presentation (8) and fetal head digital rotation
for persistent posterior position (9,10,11), or other
REFERENCES
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leg17/file/repository/relazioni/libreria/novita/XVI_
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documento%20conclusivo/13.relazione%20sui%20
punti%20nascita%20cominchiesta.pdf
2)
http://www.statoregioni.it/Documenti/
DOC_030072_137%20CU%20PRIMA%20PARTE.pdf
3) http://www.snlg-iss.it/cms/files/LG_Gravidanza.
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4) http://www.snlg-iss.it/cms/files/LG_Cesareo_
finaleL.pdf
5) Lauria L, Lamberti A, Buoncristiano M, Bonciani
M, Andreozzi S. (Ed.). Percorso nascita: promozione
e valutazione della qualità di modelli operativi. Le
indagini del 2008-2009 e del 2010-2011. Roma: Istituto
Superiore di Sanità; 2012. (Rapporti ISTISAN 12/39).
6) Knight HE, Gurol-Urganci I, van der Meulen JH,
Mahmood TA, Richmond DH, Dougall A, Cromwell
DA. Vaginal birth after caesarean section: a cohort
study investigating factors associated with its uptake
and success. BJOG. 2014;121:183-92.
124
obstetric maneuvres could be able to reduce the
number of Cesareans as well, thereby reducing
the cumulative increase in previous Cesareans by
years. However, if an Obstetrics and Gynecologist
chooses to perform an external cephalic version
or another obstetrical maneuvre attempting
to avoid a Cesarean, he should be aware that
sometimes he needs to perform an emergent
Cesarean section for complications occurring at
the time of that maneuvre. Again, in a first-level
Obstetrics unit, those complications are difficult
to manage without the immediate availability of
the operating room.
In conclusion, the unavailability of an
operating room in the first level Obstetrics
units is dangerous and causes an extraordinary
rise in expense for the Italian health system,
because Obstetrics and Gynecologists are forced
to perform planned Cesareans for the best of
prudence. This is still the most serious concern
for the first level Obstetrics facilities in Italy.
7) Nabhan AF, Abdelmoula YA. Amniotic fluid index
versus single deepest vertical pocket as a screening test
for preventing adverse pregnancy outcome. Cochrane
Database Syst Rev. 2008;3:CD006593.pub2.
8) Hofmeyr GJ, Kulier R. External cephalic version for
breech presentation at term. Cochrane Database Syst
Rev. 2012;10:CD000083.
9) Graham K, Phipps H, Hyett JA, Ludlow JP,
Mackie A, Marren A, De Vries B. Persistent occiput
posterior: OUTcomes following digital rotation: a
pilot randomized controlled trial. Aust N Z J Obstet
Gynaecol. 2014;54:268-74.
10) Sen K, Sakamoto H, Nakabayashi Y, Takeda Y,
Nakayama S, Adachi T, Nakabayashi M. Management
of the occiput posterior presentation: a single institute
experience. J Obstet Gynaecol Res. 2013;39:160-5.
11) Reichman O, Gdansky E, Latinsky B, Labi S,
Samueloff A. Digital rotation from occipito-posterior
to occipito-anterior decreases the need for cesarean
section. Eur J Obstet Gynecol Reprod Biol. 2008;136:25-8.
125
Riassunto delle Caratteristiche del Prodotto
1. DENOMINAZIONE DEL MEDICINALE: MECLON ® “20% + 4% crema vaginale”
MECLON® “200 mg/10 ml + 1 g/130 ml soluzione vaginale”. 2. COMPOSIZIONE QUALITATIVA E QUANTITATIVA: Crema vaginale. 100 g contengono: Principi attivi: Metronidazolo 20 g; Clotrimazolo 4 g. Eccipienti: contiene sodio metil p-idrossibenzoato e sodio
propil p-idrossibenzoato. Per l’elenco completo degli eccipienti, vedere paragrafo 6.1.
Soluzione vaginale. Flacone da 10 ml. 10 ml contengono: Principio attivo: Clotrimazolo
200 mg. Flacone da 130 ml. 130 ml contengono: Principio attivo: Metronidazolo 1 g.
Eccipienti: contiene sodio metil p-idrossibenzoato e sodio propil p-idrossibenzoato. Per
l’elenco completo degli eccipienti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA:
Crema vaginale. Soluzione vaginale. 4. INFORMAZIONI CLINICHE: 4.1 Indicazioni
terapeutiche: Crema vaginale. Cervico-vaginiti e vulvo-vaginiti causate da Trichomonas
vaginalis anche se associato a Candida albicans, Gardnerella vaginalis ed altra flora
batterica sensibile. MECLON® crema vaginale può essere impiegato anche nel partner
a scopo profilattico. Soluzione vaginale. Coadiuvante nella terapia di cervico-vaginiti,
vulvo-vaginiti causate da Trichomonas vaginalis anche se associato a Candida albicans,
Gardnerella vaginalis ed altra flora batterica sensibile. MECLON® soluzione vaginale può
essere impiegato anche dopo altra terapia topica od orale, allo scopo di ridurre il rischio di
recidive. 4.2 Posologia e modo di somministrazione: Crema vaginale. Somministrare
profondamente in vagina il contenuto di un applicatore una volta al giorno per almeno
sei giorni consecutivi, preferibilmente alla sera prima di coricarsi, oppure secondo prescrizione medica. Nelle trichomoniasi, maggior sicurezza di risultato terapeutico si verifica
con il contemporaneo uso di Metronidazolo per via orale sia nella donna non gestante
che nel partner maschile. Per un’ottimale somministrazione si consiglia una posizione
supina, con le gambe leggermente piegate ad angolo. Per ottenere una migliore sterilizzazione è preferibile spalmare un po’ di MECLON® crema vaginale anche esternamente,
a livello perivulvare e perianale. Se il medico prescrive il trattamento del partner a scopo
profilattico, la crema deve essere applicata sul glande e sul prepuzio per almeno sei
giorni. Istruzioni per l’uso: Dopo aver riempito di crema un applicatore, somministrare la
crema in vagina mediante pressione sul pistone, fino a completo svuotamento. Soluzione
vaginale. Somministrare la soluzione vaginale pronta una volta al giorno, preferibilmente al
mattino, oppure secondo prescrizione medica. Nella fase di attacco l’uso della soluzione
vaginale deve essere associato ad adeguata terapia topica e/o orale. L’irrigazione va
eseguita preferibilmente in posizione supina. Un lento svuotamento del flacone favorirà
una più prolungata permanenza in vagina dei principi attivi e quindi una più efficace
azione antimicrobica e detergente. Istruzioni per l’uso: Dopo aver versato il contenuto
del flaconcino nel flacone, inserire la cannula vaginale sul collo del flacone stesso. Introdurre
la cannula in vagina e somministrare l’intero contenuto. 4.3 Controindicazioni: Ipersensibilità verso i principi attivi od uno qualsiasi degli eccipienti. 4.4 Avvertenze speciali e
opportune precauzioni d’impiego: Evitare il contatto con gli occhi. Il consigliato impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni,
effetti collaterali ed avvertenze descritte per il prodotto summenzionato. Evitare il trattamento durante il periodo mestruale. Tenere il medicinale fuori dalla portata e dalla
vista dei bambini. 4.5 Interazioni con altri medicinali e altre forme di interazione:
Nessuna. 4.6 Gravidanza e allattamento: In gravidanza il prodotto deve essere impiegato solo in caso di effettiva necessità e sotto il diretto controllo del medico.
4.7 Effetti sulla capacità di guidare veicoli e sull’uso di macchinari: MECLON ®
non altera la capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati:
Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e
Clotrimazolo, le reazioni avverse riscontrate con le formulazioni topiche sono limitate a:
Disturbi del sistema immunitario: Non nota (la frequenza non può essere definita sulla
base dei dati disponibili): reazioni di ipersensibilità. Patologie della cute e del tessuto
sottocutaneo: Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale prurito,
dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio: Non sono stati
descritti sintomi di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE: 5.1 Proprietà
farmacodinamiche: Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/
effetti farmacodinamici: Il MECLON ® è una associazione tra Metronidazolo (M) e
Clotrimazolo (C). Il (M) è un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica. Ha effetto trichomonicida diretto ed è attivo su cocchi
Gram-positivi anaerobi, bacilli sporigeni, anaerobi Gram-negativi. Presenta attività spiccata
sulla Gardnerella vaginalis. Non è attivo sulla flora acidofila vaginale. Il (C) è un imidazolico
con spettro antifungino molto ampio (Candida, etc.). È attivo anche su Trichomonas
vaginalis, cocchi Gram-positivi, Toxoplasmi, etc. È stato documentato che l’associazione
Clotrimazolo-Metronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado
di conseguire tre vantaggi terapeutici principali: 1) Ampliamento dello spettro d’azione
antimicrobica, per sommazione degli effetti dei due principi attivi; 2) Potenziamento
dell’attività antimicotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della
comparsa dei fenomeni di resistenza. Studi microbiologici in vitro hanno dimostrato che
l’attività trichomonicida e antimicotica risulta potenziata quando il (M) e il (C) sono associati nelle stesse proporzioni che sono presenti nel MECLON®. Anche l’attività antibatterica esaminata su diversi ceppi di microorganismi è risultata elevata ed è emerso
un potenziamento di essa quando i due principi attivi del MECLON® vengono associati.
5.2 Proprietà farmacocinetiche: Dalle indagini farmacocinetiche sui conigli, cani e ratti
risulta che dopo ripetute applicazioni topiche di MECLON® non si rilevano concentrazioni
apprezzabili di Clotrimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella
donna il (M) e il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20%
circa. 5.3 Dati preclinici di sicurezza: La tossicità acuta del MECLON® nel topo e nel
ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a
dosi molto elevate (600 mg/Kg di (C) e 3000 mg/Kg di (M), sia da soli che associati).
Nelle prove di tossicità subacuta (30 giorni) il MECLON®, somministrato per via locale
(genitale) nel cane e nel coniglio, non ha determinato alcun tipo di lesione nè locale nè
sistemica anche per dosi molte volte superiori a quelle comunemente impiegate in terapia
umana (3-10 Dtd nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per
l’uomo = ca. 3,33 mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON® somministrato
durante il periodo di gravidanza per via topica vaginale nel coniglio e nel ratto non ha
fatto evidenziare alcun segno di sofferenza fetale per dosi die di 100 Dtd, nè influssi
negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE: 6.1 Elenco
degli eccipienti: Crema vaginale. Eccipienti: Stearato di glicole e polietilenglicole; Paraffina liquida; Sodio metile p-idrossibenzoato; Sodio propile p-idrossibenzoato; Acqua
depurata. Soluzione vaginale. Flacone da 10 ml. Eccipienti: Alcool ricinoleilico; Etanolo;
Acqua depurata. Flacone da 130 ml. Eccipienti: Sodio metile p-idrossibenzoato; Sodio
propile p-idrossibenzoato; Acqua depurata. 6.2 Incompatibilità: Non sono note incompatibilità con altri farmaci. 6.3 Periodo di validità: Crema vaginale: 3 anni. Soluzione
vaginale: 3 anni. 6.4 Precauzioni particolari per la conservazione: Questo medicinale
non richiede alcuna particolare condizione per la conservazione. 6.5 Natura e contenuto
del contenitore: MECLON® crema vaginale. Tubo in alluminio verniciato internamente
con resine epossidiche e fenoliche. Gli applicatori monouso sono di polietilene. Tubo da
30 g + 6 applicatori monouso. MECLON® soluzione vaginale. Flaconi di polietilene a
bassa densità; flaconcini di polietilene; cannule vaginali di polietilene. 5 flaconi da 10 ml
+ 5 flaconi da 130 ml + 5 cannule vaginali monouso. 6.6 Precauzioni particolari
per lo smaltimento e la manipolazione: Nessuna istruzione particolare. 7. TITOLARE
DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO: ALFA WASSERMANN
S.p.A. - Sede legale: Via E. Fermi, n. 1 - Alanno (PE). Sede amministrativa: Via Ragazzi
del ‘99, n. 5 - Bologna. 8. NUMERI DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN
COMMERCIO: MECLON® crema vaginale: A.I.C. n. 023703046. MECLON® soluzione
vaginale: A.I.C. n. 023703059. 9. DATA DELLA PRIMA AUTORIZZAZIONE/RINNOVO
DELL’AUTORIZZAZIONE: 11.05.1991 (GU 07.10.1991) / 01.06.2010. 10. DATA DI
REVISIONE DEL TESTO: Determinazione AIFA del 27 Ottobre 2010.
20% + 4% crema vaginale, tubo da 30 g + 6 applicatori.
Prezzo: € 12,50.
200 mg/10 ml + 1 g/130 ml soluzione vaginale,
5 flac. 10 ml + 5 flac. 130 ml + 5 cannule. Prezzo: € 13,80.
Medicinale non soggetto a prescrizione medica (SOP). CLASSE C.
1. DENOMINAZIONE DEL MEDICINALE: MECLON® “100 mg + 500 mg ovuli”. 2.
COMPOSIZIONE QUALITATIVA E QUANTITATIVA: Un ovulo da 2,4 g contiene: Principi
attivi: Metronidazolo 500 mg; Clotrimazolo 100 mg. Per l’elenco completo degli eccipienti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA: Ovuli. 4. INFORMAZIONI
CLINICHE: 4.1 Indicazioni terapeutiche: Cerviciti, cervico-vaginiti, vaginiti e vulvo-vaginiti da Trichomonas vaginalis anche se associato a Candida o con componente batterica. 4.2 Posologia e modo di somministrazione: Lo schema terapeutico ottimale risulta il seguente: 1 ovulo di MECLON® in vagina, 1 volta al dì. 4.3 Controindicazioni:
Ipersensibilità verso i principi attivi od uno qualsiasi degli eccipienti. 4.4 Avvertenze
speciali e opportune precauzioni d’impiego: Evitare il contatto con gli occhi. Il consigliato impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni, effetti collaterali ed avvertenze descritte per il prodotto summenzionato.
MECLON® ovuli va impiegato nella prima infanzia sotto il diretto controllo del medico e
solo nei casi di effettiva necessità. Tenere il medicinale fuori dalla portata e dalla vista
dei bambini. 4.5 Interazioni con altri medicinali e altre forme di interazione:
Nessuna. 4.6 Gravidanza e allattamento: In gravidanza il prodotto deve essere impiegato solo in caso di effettiva necessità e sotto il diretto controllo del medico. 4.7 Effetti
sulla capacità di guidare veicoli e sull’uso di macchinari: MECLON® non altera la
capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati: Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e Clotrimazolo,
le reazioni avverse riscontrate con le formulazioni topiche sono limitate a: Disturbi del
sistema immunitario: Non nota (la frequenza non può essere definita sulla base dei dati
disponibili): reazioni di ipersensibilità. Patologie della cute e del tessuto sottocutaneo:
Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale prurito, dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio: Non sono stati descritti sintomi
di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE: 5.1 Proprietà farmacodinamiche: Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni
di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/effetti farmacodinamici: Il MECLON® è una associazione tra metronidazolo (M) e clotrimazolo (C). Il (M) è
un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica.
Ha effetto trichomonicida diretto ed è attivo su cocchi Gram-positivi anaerobi, bacilli
sporigeni, anaerobi Gram-negativi. Presenta attività spiccata sulla Gardnerella vaginalis.
Non è attivo sulla flora acidofila vaginale. Il (C) è un imidazolico con spettro antifungino
molto ampio (Candida, etc.). È attivo anche su Trichomonas vaginalis, cocchi Grampositivi, Toxoplasmi, etc. È stato documentato che l’associazione ClotrimazoloMetronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado di conseguire
tre vantaggi terapeutici principali: 1) Ampliamento dello spettro d’azione antimicrobica,
per sommazione degli effetti dei due principi attivi; 2) Potenziamento dell’attività antimi-
cotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della comparsa dei fenomeni di resistenza. Studi microbiologici in vitro hanno dimostrato che l’attività trichomonicida e antimicotica risulta potenziata quando il (M) e il (C) sono associati nelle stesse
proporzioni che sono presenti nel MECLON®. Anche l’attività antibatterica esaminata su
diversi ceppi di microorganismi è risultata elevata ed è emerso un potenziamento di essa
quando i due principi attivi del MECLON® vengono associati. 5.2 Proprietà farmacocinetiche: Dalle indagini farmacocinetiche sui conigli, cani e ratti risulta che dopo ripetute
applicazioni topiche di MECLON® non si rilevano concentrazioni apprezzabili di
Clotrimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella donna il (M) e
il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20% circa. 5.3 Dati
preclinici di sicurezza: La tossicità acuta del MECLON® nel topo e nel ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a dosi molto elevate
(600 mg/Kg di (C) e 3000 mg/Kg di (M), sia da soli che associati). Nelle prove di tossicità subacuta (30 giorni) il MECLON®, somministrato per via locale (genitale) nel cane e
nel coniglio, non ha determinato alcun tipo di lesione nè locale nè sistemica anche per
dosi molte volte superiori a quelle comunemente impiegate in terapia umana (3-10 Dtd
nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per l’uomo = ca. 3,33
mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON® somministrato durante il periodo di
gravidanza per via topica vaginale nel coniglio e nel ratto non ha fatto evidenziare alcun
segno di sofferenza fetale per dosi die di 100 Dtd, nè influssi negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE: 6.1 Elenco degli eccipienti: Eccipienti:
Miscela idrofila di mono, di, tri-gliceridi di acidi grassi saturi. 6.2 Incompatibilità: Non
sono note incompatibilità con altri farmaci. 6.3 Periodo di validità: 3 anni. 6.4
Precauzioni particolari per la conservazione: Questo medicinale non richiede alcuna
particolare condizione per la conservazione. 6.5 Natura e contenuto del contenitore:
10 ovuli in valve in PVC, racchiusi in scatola di cartone. 6.6 Precauzioni particolari per
lo smaltimento e la manipolazione: Nessuna istruzione particolare. 7. TITOLARE
DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO: ALFA WASSERMANN
S.p.A. - Sede legale: Via E. Fermi, n. 1 - Alanno (PE). Sede amministrativa: Via Ragazzi
del ‘99, n. 5 - Bologna. 8. NUMERO DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN
COMMERCIO: A.I.C. n. 023703010. 9. DATA DELLA PRIMA AUTORIZZAZIONE/
RINNOVO DELL’AUTORIZZAZIONE: 27.11.1978 (GU 16.01.1979) / 01.06.2010.
10. DATA DI REVISIONE DEL TESTO: Determinazione AIFA del 27 Ottobre 2010.
100 mg + 500 mg ovuli, 10 ovuli. Prezzo: € 12,50.
Medicinale non soggetto a prescrizione medica (SOP). CLASSE C.

Vol. 27 - Italian Journal of Gynaecology and Obstetrics

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