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GynaecologyItalian Journal

of

The Official Journal of theSocietà Italiana di Ginecologia e Ostetricia

(SIGO)

Quarterly

& Obstetrics

Partner-Graf

Sept

embe

r 201

5 - V

ol. 2

7 - N

. 3 -

Qua

rter

ly -

ISSN

238

5 - 0

868

Gynaecology

Italian Journalof

The Official Journal of theSocietà Italiana di Ginecologia e Ostetricia

(SIGO)

Quarterly

& Obstetrics

Partner-Graf

Editor in Chief

Paolo Scollo, Catania

Editors

Herbert Valensise, Roma Enrico Vizza, Roma

Editorial Board

Cervigni Mauro, RomaChiantera Vito, NapoliCosta Mauro, GenovaDe Stefano Cristofaro, AvellinoDe Vita Davide, SalernoLa Sala Giovanni Battista, Reggio EmiliaLocci Maria Vittoria, NapoliMarci Roberto, RomaMonni Giovanni, CagliariRagusa Antonio Franco, MilanoSirimarco Fabio, NapoliTrojano Vito, BariViora Elsa, Torino

Editorial Staff

Roberto Zerbinati Serena Zerbinati

Management, Administrative officePartner-Graf Srl - Via F. Ferrucci, 73 - 59100 PratoTel 0574 527949 - Fax 0574 636250E-mail: [email protected]

The Italian Journal of Gynaecology & Obstetrics is a digital magazine.You can download it freely fromwww.italianjournalofgynaecologyandobstetrics.com orwww.italianjog.com

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Table of contents

Editorial. Italian Journal of Obstestrics & Gynaecology on web: a one-year balancePaolo Scollo

Low pregestational Fat Mass and subsequent maternal cardiovascular maladaptation in early pregnancy. The missing link for preeclampsiaGiulia Gagliardi, Grazia Maria Tiralongo, Ilaria Pisani, Damiano Lo Presti, Roberta Licia Scala, Gianpaolo Novelli, Barbara Vasapollo, Angela Adreoli, Herbert Valensise

Case-control study of the role of perineal application of an AC collagen/hyaluronic acid medical device on the maternal perineum at birthSilvia D’Ippolito, Alessia Fiorelli, Barbara Burlon, Giuseppa Caliri, Giovanni Scambia, Nicoletta Di Simone

Breastfeeding in italy: the role of obstetrician-gynecologistsRomana Prosperi Porta, Elise M. Chapin, Maria Grazia Porpora, Giuseppe Canzone

Serum levels of calcium and magnesium in pre-eclamptic- eclamptic patients in a tertiary institution 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

The potential role of preoperative serum cancer antigen CA 15-3 in the prognosis of breast cancer Adela Stoenescu, Daniel Herr, Christoph Gerlinger, Erich Franz Solomayer, Christoph Scholz, Ingolf Juhasz-Böss, Julia Radosa

Dangers and expenses of a first-level Obstetrics facility: a serious Italian concern Ugo Indraccolo, Anna Maria Iannicco, Mirella Buccioni, Giuseppe Micucci

It. J. Gynaecol. Obstet.2015, 27: N.3

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Italian Journal Of Obstestrics & Gynaecology on web: a one-year balancePaolo 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

Editorial

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IN GINECOLOGIA

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FARMACEUTICA MEV - Strada Cassia Sud, 175 - 53100 Siena (SI)Tel. 0577 378091/ Fax 0577 379970 - www.farmaceutica-mev.it

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LA NATURA CHE AIUTA

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Low pregestational Fat Mass and subsequent maternal cardiovascular maladaptation in early pregnancy. The missing link for preeclampsiaGiulia Gagliardi2, Grazia Maria Tiralongo2, Ilaria Pisani2, Damiano Lo Presti2, Roberta Licia Scala1; Gianpaolo Novelli4, Barbara Vasapollo1, Angela Adreoli3, Herbert Valensise2

1 AFaR (Fatebenefratelli Association for Research), Fatebenefratelli Hospital Isola Tiberina, Rome Italy2 Department of Obstetrics and Gynecology, Tor Vergata University, Rome and Fatebenefratelli Hospital, Isola Tiberina, Rome Italy3 Department of Physiology, Tor Vergata University, Rome Italy4 Department of Cardiology, San Sebastiano Martire Hospital, Frascati (Rome, Italy)

ABSTRACTObjective: 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.

Keywords: Total vascular resistance; bioimpedance; early and late preeclampsia; fat mass; pregestational BMI

SOMMARIOObiettivo: 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

Correspondence to: [email protected] 2015, Partner-Graf srl, PratoDOI: 10.14660/2385-0868-20

INTRODUCTIONSeveral 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

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


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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).

OBJECTIVEAim 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 maternal-neonatal outcome and that will beneficiate of preconception counselling about the importance of a change of diet.

METHODSA 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 pregnancy3) Certain dates of pregnancy4) Absence of maternal disease Exclusion criteria according to the protocol

were: 1) Undetermined gestational age2) Tobacco use3) Multiple pregnancy4) Maternal heart and other pre-existing

chronic disease5) 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. Pre-pregnancy 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 measurementElectrical 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

DOI: 10.14660/2385-0868-20

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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 measurementHaemodynamic 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 velocity-time 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 ANALYSISClinical data were compared by means of

indipendent samples Student’s t-test. Differences were considered as significant with p <0,05.

RESULTSIn 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 1Maternal 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

Pre-pregnancyBMI (Kg/m²) 22.4±3.1 21.9±2 ns

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 2Pre-pregnancy haemodynamic values

GROUP A GROUP B pSBP 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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Table 3Pre-pregnancy bioimpedence parameters

GROUP A GROUP B p

TBW 32.6±2.2 31.9±2.2 nsICW 14.6±2.4 17.1±2.6 nsECW 17.9±3.4 14.8±2.7 nsFM 17.2±2.5 14.9±5 <0.05FFM 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.

Table 4First trimester haemodynamic parameters

GROUP A GROUP B pSBP 117.9±14.5 121.5±7.7 nsDBP 75±11.7 75.6±8.1 nsCO 7.1±0.8 5±1 <0.05

TVR 1020±88.9 1390.5±216.4 <0.05SV 88.4±10.6 70.8±13.9 <0.05HR 80.9±9.4 75.5±10.9 nsTFC 377.5±32.5 352.7±29.1 ns

DISCUSSIONMany 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

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

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.

Figure 1. Correlation Fat Mass/TVR

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REFERENCES1) 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: 578-58512) Segal KR, Burastero S, Chun H, Coronel P, Pierson RN Jr, Wang J. Estimation of extracellular and total body water by multiple-frequency bioelectrical-impedance measurement. Am J Clin Nutr 1991; 54: 26-913) 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.

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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

1 Department of Obstetrics and Gynecology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome

ABSTRACTA 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 seventy-two 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.

Keywords: perineum, lacerations, episiotomy, collagen, birth, perineal massage, hyaluronic acid.

SOMMARIOI 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.

INTRODUCTIONThe 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).

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


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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.

MATERIALS AND METHODSStudy design Case-control studySubjects 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

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 vulvo-vaginal massage (Figure 2).

Figure 1Pelvic 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.

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.

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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 vulvo-vaginal 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 analysisAll 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.

RESULTSA 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 3Perineal 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.

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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).

Figure 4Secondary 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.

Lower urinary tract• Urinary incontinence• Urgency and frequency• Slow or intermittent stream and straining• Feeling of incomplete emptryingBowel• Obstructed defecation• Functional constipation• Faecal incontinence• Rectal/anal prolapseVagina• Pelvic organ prolapse

Pain• Chronic pelvic pain• Pelvic pain syndrome

Sexual function• Dyspareunia (painful sexual intercourse)• Orgasmic dysfunction

Table 1Symptoms of pelvic floor dysfunction

Parameter Perilei

Gravidanza

Massage

(study group

n=47)

Control

(n=47)

p

Primigravid

(n)

31 31

Secondigravid

(n)

16 16

Age (years;

mean±SD)

31.42 ± 4.1 32.1 ± 3.8 ns

BMI (kg/m2)

median (range)

24 (20-24) 23 (19-24) ns

Gestational age

at delivery (wk)

(mean±SD)

39.2 ± 1.5 39.4±3 ns

Mean Birth

weight (gr,

mean±SD)

3250 ± 250 3330 ± 150 ns

Use of epidural

block (%; n° of

doses)

70%; 2±1 68%; 2±2 ns

Table 2Baseline characteristic of the study and control population

Outcomes Study group 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

Episiotomy 25 (53.1)* 33 (70.2)

Secondary outcomes

Intrapartum blood loss (cc; mean+SD) 245±30 223±40

Vacuum deliveries 0 4

Table 3Primary and secondary outcomes

*p<0.05



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DISCUSSIONThe 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 case-controlled 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 longer-lasting 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

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REFERENCES 1) Jelovsek JE, Maher C, Barber MD. Pelvic organ prolapse. Lancet 2007;369:1027-38. 2) Kearney R, Sawhney R, DeLancey JO. Levator ani muscle anatomy evaluated by origin-insertion pairs. Obstetrics and Gynaecology 2004;104:168–73.3) Messelink B, Benson T, Berghmans B, Bø K, Corcos J, Fowler C, et al. Standardization of terminology of pelvic floor muscle function and dysfunction: report from the pelvic floor clinical assessment group of the International Continence Society. Neurourology and Urodynamics 2005;24:374-80.4) Lal M, H Mann C, Callender R, Radley S. Does cesarean delivery prevent anal incontinence? Obstetrics and Gynecology 2003;101: 305-12.5) Law H, Fiadjoe P. Urogynaecological problems in pregnancy. J Obstetrics and Gynaecology 2012;32 :109-12. 6) Chan S, Cheung R, Yiu K, Lee L, Leung T, Chung T. Pelvic floor biometry during a first singleton pregnancy and the relationship with symptoms of pelvic floor disorders: a prospective observational study. British Journal of Obstetrics and Gynecology 2014;121:121-9. 7) DeLancey JO, Kearney R, Chou Q, Speights S, Binno S. The appearance of levator ani muscle abnormalities in magnetic resonance images after vaginal delivery. Obstetrics and Gynecology 2003;101:46–53.8) Snooks SJ, Swash M, Mathers SE, Henry MM. Effect of vaginal delivery on te pelvic floor: a 5-year follow-up. British Journal of Surgery 1990;77:1358-60.9) Weidner AC, Jamison MG, Branham V, South MM, Borawski KM, Romero AA. Neuropathic injury to the levator ani occurs in 1 in 4 primiparous women. American Journal of Obstetrics and Gynecol 2005;195:1851–6.10) Sultan AH, Kamm MA, Hudson CN. Pudendal

nerve damage during labour: prospective study before and after childbirth. British Journal of Obstetrics and Gynaecology 1994;101:22-8.11) Dietz HP, Lanzarone V. Levator trauma after vaginal delivery. Obstetrics and Gynecology 2005;106:707-12.12) Bagade P, Mackenzie S. Outcomes from medium term follow-up of patients with third and fourth degree perineal tears. Journal of Obstetrics and Gynaecology 2010;30:609-12.13) Albers LL. Reducing genital tract trauma at birth: launching a clinical trial in midwifery. Journal of Midwifery and Womens Health 2003;48:105-10.14) Ruckhäberle E, Jundt K, Bäuerle M, Brisch KH, Ulm K, Dannecker C, et al. Prospective randomised multicentre trial with the birth trainer EPI-NO for the prevention of perineal trauma. Australian and New Zealand Journal of Obstetrics 2009;49:478-83.15) Bodner-Adler B, Bodner K, Mayerhofer K. Perineal massage during pregnancy in primiparous women. International Journal of Gynaecology and Obstetrics 2002;78:51-3.16) Mei-dan E, Walfisch A, Raz I, Levy A, Hallak M. Perineal massage during pregnancy: a prospective controlled trial. The Israel Medical Association Journal 2008;10:499-502.17) Labrecque M, Eason E, Marcoux S, Lemieux F, Pinault JJ, Feldman P, et al. Randomized controlled trial of prevention of perineal trauma by perineal massage during pregnancy. American Jorunal of Obstetrics and Gynecology 1999;180:593-600.18) Beckmann MM, Stock OM. Antenatal perineal massage for reducing perineal trauma. Cochrane Database Systematic Reviews 2013;4: CD005123.19) Scarabotto LB, Riesco ML. Use of hyaluronidase to prevent perineal trauma during spontaneous delivery: a pilot study. The Journal of Midwifery and Womens

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.

DECLARATION OF INTERESTNone of the authors report declarations of

interest with the subject matter or materials discussed in the manuscript.



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Health 2008;53:353-61.20) Baessler K, Schuessler B. Childbirth-induced trauma to the urethral continence mechanism: review and recommendations. Urology 2003;62:39-44.21) Phillips C, Monga A. Childbirth and the pelvic floor: ‘‘the gynaecological consequences’’. Reviews in Gynaecological Practice 5: 15-22.22) Rizk DEE, Abadir MN, Thomas LB, Abu-Zidan F. Determinants of the length of episiotomy or spontaneous posterior perineal lacerations during vaginal birth. The International Urogynecological Journal of Pelvic Floor Dysfunctions 2005;16:395-400.

23) Fritel X, Schaal JP, Fauconnier A, Bertrand V, Levet C, Pigné A. Pelvic floor disorders 4 years after first delivery: a comparative study of restrictive versus systematic episiotomy. The British Journal of Obstetrics Gynecology 2008;115:247-52.24) Aki A, Api O, Bektas Y, Yilmaz AO, Yalti S, Unal O. Paracetamol vs dexketoprofen for perineal pain relief after episiotomy of perineal tear. Journal of Obstetrics and Gynaecology 2014;34:25-8. 25) Ismail SI, Emery SJ. Patient awareness and acceptability of antenatal perineal massage. The Journal of Obstetrics and Gynaecology 2013;33:839-43.

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Breastfeeding in Italy: the role of Obstetrician-GynecologistsRomana Prosperi Porta1, Elise M. Chapin2, Maria Grazia Porpora1, Giuseppe Canzone3

1 Department of Gynaecology, Obstetrics and Urology, “Sapienza” University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy.2 Baby Friendly Initiatives, Italian National Committee for UNICEF, via Palestro, 68, 00185 Roma3 Dept. of Maternal and Child Health - ASP Palermo,

ABSTRACTWe 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.

Keywords: breastfeeding, birthing practices, obstetricians’ role, baby friendly hospital initiative


SOMMARIOIn 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.

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

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 OBSTETRICIAN-G Y N E C O L O G I S T I N T H E PROMOTION AND SUPPORT OF BREASTFEEDING IN ITALY.

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 gynecological-obstetric 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

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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.

P R A C T I C A L I M P A C T O F BIRTH INTERVENTIONS ON BREASTFEEDING

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-to-skin 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.


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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 mother-child 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 non-pharmacological methods to relieve pain are essential. All mothers must be supported by competent people to initiate breastfeeding, but mothers who have

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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 pain-reducing 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 (beta-endorphins) 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 beta-endorphins 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.

CONCLUSIONSGiven 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 evidence-based management of breastfeeding. Midwives are an exception to model of separation who takes care of



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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.

The WHO/UNICEF Baby Friendly Initiative, with its multidisciplinary approach, is capable of overcoming the fragmented vision of the mother-baby, helping mothers make informed choices about infant and young child feeding. A well-informed woman will expect more, including the implementation of best practices according to international standard while an uninformed one will suffer mismanagement, blaming bad luck for not having enough milk. The OBGYN, like other healthcare workers, has a key role and a clear responsibility in preserving the entire reproductive process in a setting of social and emotional support, free from fear, from anxiety and danger. His/her “actions” during labor and childbirth, are not without consequences may indeed have repercussions on breastfeeding so the understanding of these issues, the ability to work in teams with other healthcare providers with the same breastfeeding training and respect the dyad mother-child can really help contribute to promoting breastfeeding.

REFERENCES1) World health organization, unicef. Global strategy for infant and young child feeding. Geneva: world health organization; 2002.2) Cleminson j, oddie s, renfrew mj, mcguire w. Being baby friendly: evidence-based breastfeeding support. Arch dis child fetal neonatal ed. 2014.39 Bettinelli me, chapin em, cattaneo a. Establishing the baby-friendly community initiative in italy: development, strategy, and implementation. J hum lact. 2012;28(3):297-303.4) Chapin em, cosentino r, speri l, bettinelli me. L’unicef italia e la promozione dell’allattamento materno lo sviluppo del programma “insieme per l’allattamento: ospedali & comunità amici dei bambini”. Quaderni acp. 2012;19(6):246-9.5) World health organization. Evidence for the ten steps to successful breastfeeding. Geneva: world health organization, division of child health and development, 1998 contract no.: who/chd/98.9.6) Schmied v, thomson g, byron a, burns e, sheehan a, dykes f. A meta-ethnographic study of health care staff perceptions of the who/unicef baby friendly health initiative. Women birth. 2014.7) Istat. Gravidanza, parto e allattamento al seno - anno 2013. Roma: istat, 2014 december 12. Report no.8) Grandolfo me, donati s, giusti a. Indagine conoscitiva sul percorso nascita, 2002: aspetti metodologici e risultati nazionali. No. Roma: istat, 2003.9) Nakar s, peretz o, hoffman r, grossman z, kaplan b, vinker s. Attitudes and knowledge on breastfeeding among paediatricians, family physicians, and gynaecologists in israel. Acta paediatr. 2007;96(6):848-51.10) Simard-émond l, sansregret a, dubé j, mayrand

m-h. [obstetricians/gynaecologists and breastfeeding: practice, attitudes, training and knowledge]. J obstet gynaecol can. 2011;33(2):145-52.11) Rautava s. Early microbial contact, the breast milk microbiome and child health. J dev orig health dis. 2015:1-10.12) Stuebe a. The risks of not breastfeeding for mothers and infants. Rev obstet gynecol. 2009;2(4):222-31.13) Ministero della salute, istituto superiore sanità, ceveas. Ceveas-sistema nazionale per le linee guida - gravidanza fisiologica--aggiornamento 2011. 2011.14) Cox k, giglia r, zhao y, binns cw. Factors associated with exclusive breastfeeding at hospital discharge in rural western australia. J hum lact. 2014.15) Dumas l, lepage m, bystrova k, matthiesen a-s, welles-nyström b, widström a-m. Influence of skin-to-skin contact and rooming-in on early mother-infant interaction: a randomized controlled trial. Clin nurs res. 2013;22(3):310-36.16) Tsai t-i, huang s-h, lee s-yd. Maternal and hospital factors associated with first-time mothers’ breastfeeding practice: a prospective study. Breastfeed med. 2015.17) National center for health statistics. Preliminary data [dec. 10, 2010]. Available from: http://www.cdc.gov/nchs.18) Ministero della salute. Relazione sullo stato sanitario del paese 2012-2013. Roma: ministero della salute; 2014 december 12.19) Graffy j, taylor j. What information, advice, and support do women want with breastfeeding? Birth-issues in perinatal care. 2005;32(3):179-86.20) Demirci jr, bogen dl, holland c, tarr ja, rubio d, li j, et al. Characteristics of breastfeeding discussions

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at the initial prenatal visit. Obstet gynecol. 2013;122(6):1263-70.21) Acog committee opinion no. 361: breastfeeding: maternal and infant aspects. Obstetrics and gynecology. 2007;109(2 pt 1):479-80.22) Academy of breastfeeding medicine protocol committee. Clinical protocol number #19: breastfeeding promotion in the prenatal setting. Breastfeed med. 2009;4(1):43-5.23) World health organization. International code of marketing of breast-milk substitutes. New york: who; 1981. 1-36 p.24) Appropriate technology for birth. Lancet. 1985;2(8452):436-7.25) World health organization, unicef, wellstart international. Baby-friendly hospital initiative : revised., updated and expanded for integrated care. Section 1, background and implementation geneva: world health organization and unicef; 2009. 26) Tew m. Do obstetric intranatal interventions make birth safer? Br j obstet gynaecol. 1986;93(7):659-74.27) Tew m. Safer childbirth?: a critical history of maternity care: springer us; 1995.28) Bergman nj, linley ll, fawcus sr. Randomized controlled trial of skin-to-skin contact from birth versus conventional incubator for physiological stabilization in. Acta paediatrica. 2004;93(6):779-85.29) Anderson g, chiu s, morrison b, ludington-hoe s. Skin to skin care for breastfeeding difficulties postbirth. In: field t, editor. Touch and massage in early child development. New brunswick, nj: johnson & johnson pediatric institute, l.l.c; 2004.30) Kennell j, mcgrath s. Starting the process of mother-infant bonding. Acta paediatr. 2005;94(6):775-7.31) Lagercrantz h, slotkin ta. The” stress” of being born. Scientific american. 1986.32) Matthiesen a-s, ransjo-arvidson a-b, nissen e, uvnas-moberg k. Postpartum maternal oxytocin release by newborns: effects of infant hand massage and sucking. Birth. 2001;28(1):13-9.33) Uvnäs-moberg k. Gastrointestinal hormones and pathophysiology of functional gastrointestinal disorders. Scand j gastroenterol suppl. 1987;128:138-46.34) Evans kc, evans rg, royal r, esterman aj, james sl. Effect of caesarean section on breast milk transfer to the normal term newborn over the first week of life. Arch dis child fetal neonatal ed. 2003;88(5):f380-2.

35) Zanardo v, nicolussi s, favaro f, faggian d, plebani m, marzari f, et al. Effect of postpartum anxiety on the colostral milk beta-endorphin concentrations of breastfeeding mothers. Journal of obstetrics and gynaecology. 2001;21(2):130-4.36) Procianoy rs, fernandes-filho ph, lazaro l, sartori nc. Factors affecting breastfeeding: the influence of caesarean section. Journal of tropical pediatrics. 1984;30(1):39-42.37) Samuels se, margen s, schoen ej. Incidence and duration of breast-feeding in a health maintenance organization population. American journal of clinical nutrition. 1985;42(3):504-10.38) Otamiri g, berg g, ledin t, leijon i, lagercrantz h. Delayed neurological adaptation in infants delivered by elective cesarean section and the relation to catecholamine levels. Early hum dev. 1991;26(1):51-60.39) Smith lj, kroeger miobpob. Impact of birthing practices on breastfeeding. Sudbury, mass.: jones and bartlett; 2010.40) Uvnäs-moberg k. The oxytocin factor : tapping the hormone of calm, love, and healing. Cambridge, ma: da capo press; 2003.41) Nissen e, uvnas-moberg k, svensson k, stock s, widstrom am, winberg j. Different patterns of oxytocin, prolactin but not cortisol release during breastfeeding in women delivered by caesarean section or by the vaginal route. Early human development. 1996;45(1-2):103-18.42) Rowe-murray hj, fisher jrw. Baby friendly hospital practices: cesarean section is a persistent barrier to early initiation of breastfeeding. Birth. 2002;29(2):124-31.43) World health organization. Managing complications in pregnancy and childbirth: a guide for midwives and doctors. Geneva, switzerland: world health organization; 2003.44) Kitzinger s, walters r. Some women’s experiences of episiotomy. London: national childbirth trust; 1981.45) Lederman rp, lederman e, work b, mccann ds. Anxiety and epinephrine in multiparous women in labor: relationship to duration of labor and fetal heart rate pattern. Am j obstet gynecol. 1985;153(8):870-7.46) Zanardo v, nicolussi s, giacomin c, faggian d, favaro f, plebani m. Labor pain effects on colostral milk beta-endorphin concentrations of lactating mothers. Biol neonate. 2001;79(2):87-90.47) Zanardo v, nicolussi s, carlo g, marzari f, faggian d, favaro f, et al. Beta endorphin concentrations in human milk. J pediatr gastroenterol nutr. 2001;33(2):160-4.


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Serum levels of calcium and magnesium in pre-eclamptic-eclamptic patients in a tertiary institutionAbiodun Olusanya1, Adekunle O Oguntayo1, Aliyu I Sambo2

1 Department of Obstetrics & Gynaecology, 2 Department of Chemical PathologyAhmadu Bello University Teaching Hospital, Shika Zaria, Kaduna State. Nigeria

Correspondence to: [email protected] Copyright 2015, Partner-Graf srl, PratoDOI: 10.14660/2385-0868-23

ABSTRACTWe 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 pre-eclampsia/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 pre-eclamptic 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 pre-eclampsia 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 pre-eclampsia-eclampsia.

Keywords: Serum, Calcium, Magnesium, Pre-eclampsia, Eclampsia, Pregnancy, Blood pressure.

SOMMARIOlo 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.

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

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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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). Pre-eclampsia 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). Pre-eclampsia 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 pre-eclampsia especially when the onset is below 32

weeks(14,19-21).Focus is currently on ways to prevent pre-

eclampsia 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).

MATERIALS AND METHODSThe 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.

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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 pre-eclampsia 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:

Magnesium was measured with Calmagite-EGTA-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;

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.

Calcium conc. (mmol/l) = X Concentration of standardAbsorption of sample

Absorption of standard

Magnesium conc. (mmol/l) = X Concentration of standardAbsorption of sample

Absorption of standard

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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 pre-eclamptics 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 be low h igh l ights the sociodemographic variables and the clinical parameters of the subjects studied. Mean age, mean gestational age, and parity between the pre-eclamptic/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.

Pre-eclampsia/EclampsiaN = 78

ControlN = 78 P Value

Demographic status

Age (years) 26.5 ± 6 27.4 ± 6 0.370*

G.A (weeks) 34.3 ± 3 34.0 ± 3 0.556*

Postpartum 6 (7.7%) 5 (6.4%)

Parity

Primigravidae 42 (54.8%) 43 (55.1%)

Multipara 26 (33.3%) 26 (33.3%) 0.968*

Grandmultipara 10 (12.8%) 9 (11.5%)

Booking status

booked 51 (65.4%) 76 (97.4%) 0.000**

unbooked 27 (34.6%) 2 (0.26%)

Socioeconomic status

Upper 15 (19.2%) 42 (53.8%)

Middle 22 (28.2%) 28 (35.9%) 0.000**

Lower 41 (52.6%) 8 (10.3%)

Clinical status

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/m2) 30.2 ± 0.05 28.2 ± 4.8 0.010**

Table1Sociodemographic variables and the clinical parameters of the subjects

**significant at p-value <0.05, *not significant at p-value >0.05

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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.

Laboratory Data Pre-Eclamptic

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**

Table 2Comparing the mean serum levels of calcium and magnesium of patients with pre-eclampsia, eclampsia, and control with ANOVA

Table 3Comparing 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 serum magnesium (mmol/l) 0.82±0.03 0.82±0.07 0.944**

At 95% CI, **significant at P-value <0.05

At 95% CI, *not significant at P-value >0.05

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Table 4Cross-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 p-value

test control test control test control

Subjects’ status

Test group 51 - 26 - 1 - 0.000**

Control group - 8 - 28 - 42

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 0.373*

30-34 9 1 4 8 0 7

35-39 6 2 2 1 0 5

≥40 1 1 1 1 1 0

Gestationalage(weeks)

≥28 4 0 1 4 0 2

29-33 16 2 9 8 0 10

34-38 20 3 12 11 1 21 0.636*

≥39 7 3 2 5 0 3

Postpartum 4 0 2 1 0 6

Parity

Primigravida 26 0 15 11 1 21

Multipara 20 2 6 14 0 17 0.477*

Grandmultipara 5 3 5 3 0 4

Booking status

Booked 30 7 20 27 1 42 0.000**

Unbooked 21 1 6 1 0 0

Social class

Upper 9 4 6 16 0 22

Middle 18 3 3 9 1 16 0.001**

Lower 24 1 17 3 0 4

**significant at P-value <0.05, *not significant at P-value >0.05

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Level of magnesium<0.66mmol/l 0.06-1.03mmol/l >1.03mmol/l p-value

test control test control test controlSubjects’ status

Test group 1 - 76 - 1 - 0.188*Control group - 0 - 74 - 4Age(years)

<20 0 0 11 9 0 020-24 0 0 18 16 1 025-29 0 0 25 24 0 3 0.000**30-34 0 0 13 15 0 135-39 0 0 8 8 0 0≥40 1 0 1 2 0 0

Gestationalage(weeks)

≥28 0 0 5 5 0 029-33 0 0 24 17 1 234-38 1 0 32 31 0 2 0.717*≥39 0 0 9 14 0 0

Postpartum 0 0 0 7 0 0Parity

Primigravida 0 0 42 32 0 4Multipara 1 0 24 33 1 0 0.477*Grandmultipara 0 0 10 9 0 0Booking status

Booked 1 0 50 72 0 4 0.889*Unbooked 0 0 26 2 1 0Social class

Upper 0 0 15 39 0 3Middle 0 0 22 27 0 1 0.493*Lower 1 0 39 8 1 0

Table 5Cross-tabulation of level of magnesium with status of subjects and their sociodemographic characters using Chi square

**significant at P-value <0.05, *not significant at P-value >0.05

Calcium Magnesium

Systolic blood pressure Pearson correlation -0.119 -0.075

Sig. (2.tailed) 0.300* 0.515*

N 78 78

Diastolic blood pressure Pearson correlation -0.103 -0.107

Sig. (2.tailed) 0.371* 0.351*

N 78 78

Table 6Correlation of serum calcium and magnesium with systolic and diastolic blood pressures in the test group

*correlation not significant at the 0.01 level (2-tailed) with P-value >0.05

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DISCUSSION 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 pre-eclamptic 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 pre-eclampsia 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 pre-eclampsia/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

Calcium MagnesiumSystolic blood pressure Pearson correlation -0.135 -0.113

Sig. (2.tailed) 0.239* 0.324*N 78 78

Diastolic blood pressure Pearson correlation -0.069 -0.208Sig. (2.tailed) 0.550* 0.068*N 78 78

Table 7Correlation of serum calcium and magnesium with systolic and diastolic blood pressures in the control group

*correlation not significant at the 0.01 level (2-tailed) with P-value >0.05

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REFERENCES1) Duley L, Henderson-Smart DJ, Walker GJA. Interventions for preventing pre-eclampsia and its consequences: generic protocol (Protocol). The Cochrane Library. 2009(2):1-142) 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.

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 life-threatening hypertensive conditions in developing countries. A report on Barriers and solutions to Treat Pre-eclampsia and Eclampsia. New York: Engender Health; 20077) 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; 105:402-109) Osungbade KO, Ige OK. Public Health Perspectives of Pre-eclampsia in Developing Countries: Implication for Health system strengthening. Journal of Pregnancy

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 pre-eclampsia/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

correlation was not significant, this finding may suggest a relationship between the deficiency of these trace elements and the risk of pre-eclampsia/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 pre-eclampsia/eclampsia and control groups.

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[Review]. 2011; 2011:1-610) 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):276-27312) Omole-Ohonsi A, Ashimi AO. Pre-eclampsia: a study of risk factors. Nigerian Medical Practitioner 2008; 53(6):99-10213) 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;115:112-11614) 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;33:130-13716) 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;2:249-25418) Williams PJ, Pipkin FB. The genetics of Pre-eclampsia and other hypertensive disorders of pregnancy. Best Practice and Research Clin Obstet Gynaecol 2011;25:405-41719) Chames MC, Livingston JC, Invester TS, Barton JR, Sibai BM. Late postpartum eclampsia: a preventable disease? Am J Obstet Gynecol 2002;186:1174-720) 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; 25:463-47622) Idogun ES, Imarengiaye CO, Momoh SM. Extracellular Calcium and Magnesium in Pre-eclampsia and Eclampsia. African Journal of Reproductive Health 2007;11(2):89-9423) Kumar A, Devi DG, Batra S, Singh C, Shukla DK. Calcium Supplementation for the prevention of pre-eclampsia. Int. J Gynecol Obstet 2009;104:32-36

24) Duckitt K, Harington D. Risk factors for Pre-eclampsia at antenatal booking: Systematic review of controlled studies. BMJ 2005; 330(7491):565.25) Resnick LM, Barbagallo M, Dominguez LT. Cellular-free 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):5196-520227) 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: relation to blood pressure and serum divalent Cations. Proc. Nat Acad Sci USA 1984; 81:6511-651529) American Heart Association Guidelines for cardiopulmonary resuscitation and Emergency cardiovascular care. American Heart Association Inc 2005; 112: iv-12-iv-12530) Abbort LG, Rude RK. Clinical manifestations of magnesium deficiency. Miner Electrolyte Metab 1993, 19:314-32231) Olusanya O, Okpere EE, Ezimokhai M. The importance of socioeconomic class in voluntary fertility in a developing country. W Afr J Med 1985;4:205-1232) Odigie IP, Anorlu RI, Adesiyun AE, Odum CU. Serum Ionized magnesium levels in Normal and Pre-eclamptic women in Lagos, Nigeria. Nig Qt J Hosp Med. 2004;14(2):178-18033) 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):231-23434) 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.com35) Akhtar S, Begum S, Ferdousi S. Calcium and Zinc Deficiency In Preeclamptic Women. J Bangladesh Sco. Phsiol. 2011, 6(2):94-9936) 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

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A very rare case of uterine PEComa HMB45 negative: primitive or relapse? Basilio Pecorino1, Giuseppe Scibilia1, Antonio Galia2, Paolo Scollo1.

1 Division of Gynecology and Obstetrics, Maternal and Child Department, Cannizzaro Hospital, Catania, Italy.2 Department of Pathology, Cannizzaro Hospital, Catania, Italy.

ABSTRACTPerivascular 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.

Keywords: immunohistochemistry; PEComa; primitive; rare tumors; relapse.

SOMMARIOI 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.


INTRODUCTIONPerivascular 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.

CASE PRESENTATIONOur case report concerns about a 54-year-

old romanian parous female, with negative clinical history for non-gynecologic disease or surgery. The patient was underwent in 1996 to subtotal hysterectomy and bilateral salpingo-oophorectomy 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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Figure 1. MRI T2-weighted imaging: pelvic oval mass, inhomogeneous density with hypodense center.

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 necrosis with high mitotic index (> 1x50 high power fields HPF). Immunohistochemical pattern was positive for desmin, S-100, actin 1A, epithelial membrane antigen (EMA), microphthalmia transcription factor (MITF), cytokeratin AE1/AE3 (CKAE1/AE3) and Melan-A, instead immunohistochemically negative for myogenin and HMB45. Figures 2 and 3 show particular

Figure 2.Tumour shows widespread and high reactivity for melan-A.

Figure 3. Epithelioid cells displaying large granular eosinophilic cytoplasm with rhabdoid morphology. Eccentric nucleus and prominent nucleoli.

DISCUSSIONIt is known that the prevalent sites of PEComa

are the gastrointestinal tract, genitourinary tract and retroperitoneum, but uterus is the 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 from a small part of uterine corpus left inside the pelvis.

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 pall iative 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.

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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 tongue-like 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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REFERENCES1) 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):526-5283) 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-45-positive epithelioid mesenchymal neoplasms with uncertain relationship to pure smooth muscle tumors. Am J Surg Pathol 2002;26:1–13.

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 patients with malignant PEComa. Ann Oncol. 2010 May;21(5):1135-7.

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.

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The potential role of preoperative serum cancer antigen CA 15-3 in the prognosis of breast cancerAdela Stoenescu2, Daniel Herr1, Christoph Gerlinger1, Erich Franz Solomayer1, Christoph Scholz2, Ingolf Juhasz-Böss1, Julia Radosa1

1 Department of Obstetrics and Gynaecology, University of Saarland, Homburg / Saar, Germany2 Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany

ABSTRACTBackground: 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.

SOMMARIOBackground: 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.


INTRODUCTIONBreast 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

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:


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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 METHODSIn 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

Characteristic Patients Percent Characteristic Patients Percent

Age< 50 years50-70 years> 70 years

122296168

20.82%50.52%28.66%

Menopausal statusPremenopausalPerimenopausalPostmenopausalMissing data

117354331

19.97 % 5.97 %73.89 %0.17 %

Histological diagnosisDuctal infiltrating carcinomaIn situ carcinomaMissing data

532495

91.57%8.43%0.85%

GradingG1G2G3Missing data

613391769

11.80%65.57%22.63%11.77%

Tumor sizeT1T2T3T4Missing data

297157272976

50.77%26.84%4.62%4.96%12.96%

Nodal involvementN0N1N2N3Missing data

400123201330

68.61%21.10%3.43%.26%5.11%

Metastatic siteM0M1Missing data

5382820

95.05 %4.95 %3.41 %

Her2-neu statusNegativePositiveMissing data

4368961

74.40 %15.19 %10.46 %

ER statusNegativePositive

109477

18.60 %81.40 %

PgR statusNegativePositiveMissing data

2133703

36.35 %63.14 %0.51 %

Local relapseNoYes

57115

97.44%2.56%

DeathNoYes

57412

97.95 %2.05 %

Table 1Main clinical-pathological tumor characteristic of 586 breast cancer patients

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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.

RESULTSRelationship 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

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.

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

A. Stoenescu et al.

Figure 1Relationship between CA 15-3 and tumor characteristics in non metastatic patients

Figure 2Relationship between CA 15-3 levels and tumor characteristics in metastatic patients

Chart a Chart b

Chart c Chart d

Chart e

Chart f Chart g

Chart h Chart i


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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).

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.

DISCUSSIONThe 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

Figure 3Relationship between CA 15-3 levels and receptor status in non metastatic and metastatic patients

Chart j Chart k

Chart l Chart m

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REFERENCES:1) Lamerz R, et al. Serum marker combinations in human breast cancer (review). In vivo. 1993;7:607-614.2) Stieber P, et al. Significance of bone alkaline phosphatase, CA 15-3 and CEA in the detection of bone metastases during the follow-up of patients suffering from brast carcinoma. Eur J Clin Chem Clin Biochem. 1992;30(12):809-14.3) Tondini C, et al. Comparison of CA 15-3 and carcinoembrionic antigen in monitoring the clinical course of patients with metastatic breast cancer. Cancer Res. 1988;48:4107-4112.4) Fateh-Moghadam A, et al. Sensible use of tumour markers. Marloffstein-Rathsberg: Hartmann Verlag; 1993, pp.11-31.5) Robertson JFR, et al. Objective measurement of therapeutic response in breast cancer using tumor markers. Br J Cancer 1991;64:757-763.6) Safi F, et al. The value of tumor marker CA 153 in diagnosis and monitoring breast cancer. A comparative study with carcinoembryonic antigen. Cancer 1991;68:574-582.7) Velaiutham S, et al. Does the pre-operative value of serum CA 15-3 correlate with survival in breast cancer? Asian Pacific J Cancer Prev, Vol 9. 2008:2254-448.8) Bast RC Jr, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology, J Clin Oncol, 19, 2001:1865-78.9) Duffy MJ, et al. High preoperative CA 15-3 concentrations predict adverse outcome in node-negative breast cancer: study of 600 patients with histologically confirmed breast cancer. Clin Chem, 50, 2004:559-63.

10) O’Hanlon, et al. An evaluation of preoperative CA 15-3 measurement in primary breast carcinoma. Br J Cancer 71, 1995: 1288-91.11) Daniele A, et al. Clinical usefulness of cancer antigen 15-3 in breast cancer patients before and after surgery. The open breast cancer journal, 5, 2013:1-6.12) Horobin JM, et al. Potential use of tumor marker CA 15-3 in the staging and prognosis of patients with breast cancer. J R Coll Edinb 1991;36:219-21.13) Berutti A, et al. Prognostic value in predicting 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:2082-4.14) Iaffaioli RV, et al. Impact of preoperative CA 15-3 levels in operable breast cancer. Comparison with tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA). Int J Biol Markers 1991;6:21-4.15) Cheung KL, et al. Tumour marker measurements in the diagnosis and monitoring of breast cancer. Cancer Treat Rev 2000, 26: 91–102.16) Duffy MJ. Biochemical markers in breast cancer: which ones are clinically useful. Clin Biochem 2001; 34: 347-52. 17) Cancer Research UK, (2012). UK Breast Cancer Incidence Statistics. Retrieved 11.9.2012, from http://info.cancerresearchuk.org/cancerstats/types/breast/incidence/18) Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.19) Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast Jr RC, American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007;25:5287-5312.

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

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 with these markers in the management of breast cancer.

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Dangers and expenses of a first-level Obstetrics facility: a serious Italian concernUgo 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.

ABSTRACTPurpose. 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.

Keywords: Cesarean section, expense, health policy.

SOMMARIOScopo. 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.

Correspondence to: [email protected] Copyright 2015, Partner-Graf srl, PratoDOI: 10.14660/2385-0868-26

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

expensive, and discussing the reasons of such expenses.

MATERIALS AND METHODSAdministrative 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


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which outpatient screening of complications was ineffective along with a wide proportion of low-risk 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 re-admission for puerperal complications (usually post-surgical complications) and, therefore, most increase in resources absorption (31.9%).

DOI: 10.14660/2385-0868-26

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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

Outcomes Indicators of expense

Cesarean section

odds ratio95% CI

p

Operative vaginal delivery

odds ratio95% CI

p

Hospitalizationswithout delivering

odds ratio95% CI

p

Puerperal complications

odds ratio95% CI

p

Days of hospital stay

Unstandardized coefficient

p

Expense score (days of hospital stay + outcomes)

Unstandardizedcoefficient

p

Overall estimation of the expense

(score coefficient x complication of pregnancy

rate)

Percentage of resources absorption

Hypertensive disordersof pregnancy2.5%

6.4982.732-15.454

p<0.001

2.4700.300-20.301

N.S.

4.1061.327-12.702

p=0.014

0.6310.083-4.796

N.S.

1.298p<0.001

2.018p<0.001

0.05

8.4%

Gestational diabetes8.7%

1.9161.152-3.189

p=0.012

1.5480.334-7.185

N.S.

1.5840.596-4.205

N.S.

0.3050.074-1.266

N.S.

0.194N.S.

0.458p=0.025

0.04

6.7%

Intraepathic cholestasis of pregnancy1%

2.2440.585-8.618

N.S.

/ / 1.9050.226-16.096

N.S.

0.284N.S.

1.180p=0.046

0.012

2%

IUGR1.7%

1.0390.315-3.425

N.S.

/ 1.2390.157-9.770

N.S.

/ 0.528N.S.

0.929p=0.038

0.016

2.7%

PROM16%

2.6261.776-3.882

p<0.001

0.3130.041-2.394

N.S.

0.1590.022-1.174

N.S.

1.1080.574-2.139

N.S.

0.309p=0.019

0.660<0.001

0.106

17.8%

Polyhydramnios/oligohydramnios5.1%

1.8840.977-3.636

N.S.

/ 1.3210.381-4.577

N.S.

1.6470.630-4.308

N.S.

0.492p=0.024

1.227p=0.038

0.063

10.6%

P r e v i o u s C e s a r e a n section12.1%

189.64979.716-437.022

p<0.001

/ 0.7480.256-2.182

N.S.

0.2100.051-0.865

p=0.031

0.210N.S.

1.568p<0.001

0.19

31.9%

Other complications8.1%

9.7396.079-15.603

p<0.001

0.7900.101-6.155

N.S.

3.5691.617-7.879

p=0.002

1.8430.881-3.854

N.S.

0.679p<0.001

1.459p<0.001

0.118

19.8%

U. Indraccolo et al.

Table 1Statistical calculation


124

REFERENCES1) www.senato.it/application/xmanager/projects/leg17/file/repository/relazioni/libreria/novita/XVI_Indagine_NascereSicuri/documenti%20appendice%20documento%20conclusivo/13.relazione%20sui%20punti%20nascita%20cominchiesta.pdf2) http://www.statoregioni . i t/Documenti/DOC_030072_137%20CU%20PRIMA%20PARTE.pdf3) http://www.snlg-iss.it/cms/files/LG_Gravidanza.pdf4) http://www.snlg-iss.it/cms/files/LG_Cesareo_finaleL.pdf5) 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.

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

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.

DOI: 10.14660/2385-0868-26

1. DENOMINAZIONE DEL MEDICINALE: MECLON® “20% + 4% crema vaginale” MECLON® “200 mg/10 ml + 1 g/130 ml soluzione vaginale”. 2. COMPOSIZIONE QUA-LITATIVA E QUANTITATIVA: Crema vaginale. 100 g contengono: Principi attivi: Metro-nidazolo 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 � ora batterica sensibile. MECLON® crema vaginale può essere impiegato anche nel partner a scopo pro� lattico. Soluzione vaginale. Coadiuvante nella terapia di cervico-vaginiti, vulvo-vaginiti causate da Trichomonas vaginalis anche se associato a Candida albicans, Gardnerella vaginalis ed altra � ora 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 pre-scrizione medica. Nelle trichomoniasi, maggior sicurezza di risultato terapeutico si veri� ca 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 steriliz-zazione 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 pro� lattico, 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, � no 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 � acone favorirà una più prolungata permanenza in vagina dei principi attivi e quindi una più ef� cace azione antimicrobica e detergente. Istruzioni per l’uso: Dopo aver versato il contenuto del � aconcino nel � acone, inserire la cannula vaginale sul collo del � acone stesso. Introdurre la cannula in vagina e somministrare l’intero contenuto. 4.3 Controindicazioni: Iper-sensibilità 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 im-piego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni, effetti collaterali ed avvertenze descritte per il prodotto summenzionato. Evitare il trat-tamento 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 impie-gato 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 de� nita 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 in-desiderati 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 ginecolo-gici/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 antipro-tozoaria 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 � ora acido� la 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 as-sociati nelle stesse proporzioni che sono presenti nel MECLON®. Anche l’attività anti-batterica 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 in� ussi negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE: 6.1 Elenco degli eccipienti: Crema vaginale. Eccipienti: Stearato di glicole e polietilenglicole; Pa-raf� na 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 incom-patibilità 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; � aconcini di polietilene; cannule vaginali di polietilene. 5 � aconi da 10 ml + 5 � aconi 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 � ac. 10 ml + 5 � ac. 130 ml + 5 cannule. Prezzo: € 13,80.

Medicinale non soggetto a prescrizione medica (SOP) . CLASSE C.

Riassunto delle Caratteristiche del Prodotto

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 ecci-pienti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA: Ovuli. 4. INFORMAZIONI CLINICHE: 4.1 Indicazioni terapeutiche: Cerviciti, cervico-vaginiti, vaginiti e vulvo-va-giniti da Trichomonas vaginalis anche se associato a Candida o con componente batteri-ca. 4.2 Posologia e modo di somministrazione: Lo schema terapeutico ottimale risul-ta 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 consi-gliato impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindi-cazioni, 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 impie-gato 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 scar-so 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 de� nita 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 aller-gica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati com-porta l’interruzione del trattamento. 4.9 Sovradosaggio: Non sono stati descritti sintomi di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE: 5.1 Proprietà farmacodinami-che: Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/effetti farmacodi-namici: 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 � ora acido� la 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 antimi-

cotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della comparsa dei feno-meni di resistenza. Studi microbiologici in vitro hanno dimostrato che l’attività trichomo-nicida 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 farmacoci-netiche: 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 risul-tata 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 tossi-cità 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 in� ussi negativi sullo stato gesta-zionale. 6. INFORMAZIONI FARMACEUTICHE: 6.1 Elenco degli eccipienti: Eccipienti: Miscela idro� la 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.

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