Vol. 28 - Italian Journal of Gynaecology and Obstetrics

Transcript

Italian Journal
of
Gynaecology
& Obstetrics
September 2016 - Vol. 28 - N. 4 - Quarterly - ISSN 2385 - 0868
The Official Journal of the
Società Italiana di Ginecologia e Ostetricia
(SIGO)
Quarterly
Partner-Graf
1
Italian Journal
of
Gynaecology
& Obstetrics
The Official Journal of the
Società Italiana di Ginecologia e Ostetricia
(SIGO)
Quarterly
Partner-Graf
Editor in Chief
Paolo Scollo, Catania
Editors
Herbert Valensise, Roma
Enrico Vizza, Roma
Editorial Board
Cervigni Mauro, Roma
Chiantera Vito, Napoli
Costa Mauro, Genova
De Stefano Cristofaro, Avellino
De Vita Davide, Salerno
La Sala Giovanni Battista, Reggio Emilia
Locci Maria Vittoria, Napoli
Marci Roberto, Roma
Monni Giovanni, Cagliari
Ragusa Antonio Franco, Milano
Sirimarco Fabio, Napoli
Trojano Vito, Bari
Viora Elsa, Torino
Editorial Staff
Roberto Zerbinati
Serena Zerbinati
Management, Administrative office
Partner-Graf Srl - Via F. Ferrucci, 73 - 59100 Prato
Tel 0574 527949 - Fax 0574 636250
E-mail: [email protected]
The Italian Journal of Gynaecology & Obstetrics is a digital magazine.
You can download it freely from
www.italianjournalofgynaecologyandobstetrics.com or
www.italianjog.com
It. J. Gynaecol. Obstet.
2016, 28: N.2
Table of contents
5
Editorial
6
Benign Peritoneal Melanosis associated with atypical leiomyom
7
Madhuri Alwani, Ishan Shrivastava, Amit Varma, Ratna Thakur
Intrauterine transfusion versus Corticosteroids for treatment of immune fetal
hydrops secondary to Rh incompatibility with 6 months postnatal follow-up:
Case series with review of literature
11
Improving prescription of physical exercise in prophylaxis/therapy of
gestational diabetes: a survey from evidence to current recommendation
15
Aggressive late Sezary syndrome with pregnancy: A case presented with
generalized erythroderma and dyspnea
23
One Case of Severe Preeclampsia Who Died from Postpartum Complications Ten
Days after Caesarian Delivery
31
Polyglandular Autoimmune Syndrome in pregnancy: case report.
35
Centiles of weight of spontaneous and medically induced preterm births
in Lombardy
41
Tamer Mamdouh Abdeldayem, ElSayed El Badawy Mohamed, Ahmed El Habashy, Sherif Gaafar,
Ashraf Han, Aly Alaa Youssef
Cristina Bianchi, Michele Aragona, Alessandra Bertolotto, Pietro Bottone, Maria Calabrese, Ilaria
Cuccuru, Alessandra De Bellis, Anna Leopardi, Cristina Lencioni, Roberto Miccoli, Mary Liana
Mori, Serena Ottanelli, Matilde Romano, Gigliola Sabbatini, Maria Giovanna Salerno, Giuseppe
Trojano, Stefano Del Prato, Lorella Battini
Ahmed Samy El-Agwany
Myrvete Pacarada, Astrit M. Gashi, Albiona Beha, Bujar Obertinca
Basilio Pecorino, Maria Cristina Teodoro, Paolo Scollo
Fabio Parazzini, Sonia Cipriani, Stefania Noli, Ilaria Baini, Paola Agnesi Mauri, Mauro Busacca,
Michele Vignali, Giuseppe Trojano
5
2016, 28: N. 4
Editorial
Dear Friends,
Dear SIGO members,
in the last two year, since september 2014 to september 2016, Italian Journal of Obstertrics &
Gynaecology has been renewed and became an on-line magazine. Since then, 53 original articles were
published, reviews and case reports has been published. Two issues on 2014, four on 2015 and five on
2016. The site of the Italian Journal of Obstertrics & Gynaecology counted 16200 users, 18.550 sessions,
24.000 views. 72% of the users were italian, 10% from Europe and Asia, 7% from USA.
The present data clearly shows the growth of Italian Journal during the last years and how much is
changed trasforming from a national magazine to an international one.
Therefore, I would like to thank all the Italian Journal staff member and the editorial board for the
results achieved.
During the next National SIGO Congress that will be helded in Rome, a new council board of SIGO
will be elected and I ma sure that new projects will be done in order to improve our Journal.
Prof. Paolo Scollo
S.I.G.O. President
6
Italian Journal of
Gynaecology & Obstetrics
Benign Peritoneal Melanosis associated with atypical leiomyoma
Madhuri Alwani1, Ishan Shrivastava1, Amit Varma2, Ratna Thakur1
Department of Obstetrics and Gynaecology, Sri Aurobindo Medical College and PG Institute, Indore Ujjain Highway, Indore, Madhya Pradesh, India
2
Department of Pathology, Sri Aurobindo Medical College and PG Institute, Indore Ujjain Highway, Indore, Madhya Pradesh, India
1
ABSTRACT
Benign Peritoneal Melanosis is an extremely rare
condition with only a handful cases in the literature. It
is characterized by melanin pigment deposition in the
peritoneum. The pathogenesis of Peritoneal Melanosis
in particular, the origin of the pigment producing cells,
is unclear. We describe a case of Benign Peritoneal
Melanosis associated with atypical leiomyomya of the
uterus in a 40 year old woman. She presented with
increased blood loss during menses and recurrent
pain in abdomen since last 3 years. On USG Pelvis,
she was diagnosed as a case of fibroid uterus and was
posted for hysterectomy. During surgical procedure,
India ink colored (Black) pigmentation was seen in the
peritoneum and the complete lining peritoneum of the
pelvis was seen black. Only the body of the uterus, the
fallopian tubes and ovaries were spared. Biopsies of the
peritoneum showed pigment in the stroma and pigment
laden histiocytic aggregation and ultra structural study
found melanosomes in the cytoplasm of histiocytes.
Keywords: Benign Peritoneal Melanosis, Hysterectomy,
Melanosomes
INTRODUCTION
Benign Peritoneal Melanosis, a diffuse black
pigmentation of peritoneum, is a condition
characterized by melanin pigment deposition
in the peritoneum, mesentry, appendix surface,
pelvic peritoneum and surface of ovary [Kim et al
2002, Jaworski 2003]. It is of unknown origin and
it is an extremely rare condition with only handful
of cases in the literature.
Correspondence to: [email protected]
Copyright 2015, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-47
SOMMARIO
La Melanosi Peritoneale Benigna è una condizione
estremamente rara con pochi casi riportati in letteratura.
È caratterizzata da deposizione di melanina nel
peritoneo. La patogenesi della melanosi peritoneale
ed in particolare, l’origine della produzione delle
cellule pigmentate, è non-chiara. In questo articolo
descriviamo un caso di melanosi peritoneale benigna
associata a leiomyomya uterino atipico in una donna
di 40 anni La paziente ha presentato un aumento
della perdita di sangue durante le mestruazioni e
dolore ricorrente addominale negli ultimi 3 anni. Con
USG della Pelvi, è stata diagnosticata come un caso
di fibroma dell’utero ed è stata eseguita l’isterectomia.
Durante la procedura chirurgica, con la colorazione di
inchiostro di china (nero) il peritoneo e il rivestimento
del bacino è diventato nero. Solo il corpo dell’utero, le
tube di Falloppio e le ovaie sono stati risparmiati. Le
biopsie del peritoneo hanno mostrato pigmentazione
dello stroma e aggregazione istiocitaria pigmentata e
lo studio ultra-strutturale ha trovato melanosomi nel
citoplasma degli istiociti.
CASE REPORT
A 40 yr old female para 4 living 4, all full term
normal vaginal deliveries came to the OPD with
chief complaints of increased blood loss during
menses since last 1 year and pain in lower abdomen
and backache since 1 year. Her LMP was 20 days
back and during her present cycles she had a
heavy flow of menstrual blood for 6 to 7 days with
an interval of every 30 days. This was since last one
year. Previous cycles were regular with average
blood loss. She was married for 19 years and was
using barrier method of contraception. Her last
child birth was 15 years. There was no history of
any surgery in the past and no relevant medical
history. On general examination, all parameters
were within normal limits. Per abdomen nothing
abnormal was found. Cervix and vagina appeared
7
2016, 28: N. 4
healthy; Pap smear was taken which was reported
as inflammatory. On p/v examination cervix was
downwards backwards, uterus anteverted, 6-8
weeks in size and firm in consistency. Both fornices
were free. USG pelvis showed a submucosal to
intramural fibroid in anterior wall of the body of
uterus measuring 5.2 X 6.0 cms. Pap smear was
inflammatory. OT profile was done and decision
of hysterectomy was taken in view of symptomatic
fibroid uterus.
On opening the abdomen, when we reached
the peritoneum, we could see dark picture
through the peritoneum as if there was collection
of clotted blood. That gave us the suspicion of
ruptured chronic ectopic pregnancy or ruptured
hemorrhagic ovarian cyst that we might have
missed. After opening the parietal peritoneum
we could see complete dark black peritoneum
covering the inner lining of pelvis. Body of the
uterus, ovaries, fallopian tubes were spared uptil
uterovesical fold anteriorly and posteriorly till
rectovaginal fold of peritoneum. Biopsy was taken
from peritoneum and subtotal hysterectomy with
bilateral salpingo ophrectomy was done. Decision
of subtotal hysterectomy was taken as there was
dark pigmentation below the utero vesical fold of
peritoneum (shown in Figure 1). Bilateral salpingo
ophrectomy was also considered keeping in view
of again any pathology developing in ovaries in
future for which laparotomy may be required,
as this operative finding was a very rare and
unknown entity. Laparotomy was performed over
laparoscopy because patient was not affording
for laparoscopy and she wanted abdominal
hysterectomy. A sample of peritoneum was taken
and the specimen was sent for HPR. Patient stood
the procedure well and the post op was uneventful.
MACROSCOPIC FINDINGS OF THE
SPECIMEN
8
There was a flap like structure black in color
measuring 2.2X1.3X0.8 cms. Another specimen
was of uterus with both adnexa. H & E pictures
of peritoneum and underlying connective tissue
showed deposition of fine granular black material
in the submesothelial fibrous tissue (Figure 1C
&D). This material stains black with Masson
Fontana stain (A Stain for Melanin). On the basis of
surgical and histopathological findings, diagnosis
of Benign Peritoneal Melanosis was made.
Histopathological findings of uterus showed as
Atypical Leiomyoma of uterus.
Figure 1.
Surgical Picture of abdomen showing black colored
peritoneum(A&B),Hematoxylin and Eosins(10X) showing fibro
adipose tissue with brown black colored melanin pigment(C)
Hematoxylin and Eosins(40X) stained section of peritoneal biopsy
revealed fibrous connective tissue with deposition of brown black
colored pigment in the peritoneum. The pigment stained positive
with Masson Fontana stain and negative with Perls stain proving
the pigment to be Melanin (D).
DISCUSSION
Peritoneal melanosis, a diffuse black
pigmentation of peritoneum is a very rare
condition characterized by melanin pigment
deposition in the peritoneum, mesentery, appendix
surface, pelvic peritoneum and surface of ovary. It
is an extremely rare condition with only handful
of cases in the literature. Benign peritoneal
melanosis is of unknown origin. Confirmation of
the condition is done with peritoneal biopsies.
There are handful case reports showing
presentation of Peritoneal Melanosis.
Angelopoulos et al in 2013 reported a case of
Benign Peritoneal Melanosis in 35 year old
women with symptoms of abdominal and pelvic
pain. Diagnosis was done by laparoscopy and
confirmed by extensive peritoneal biopsies. Kim et
al in 2010 reported a case of peritoneal melanosis
associated with mucinous cystadenoma of ovary
and adenocarcinoma of colon. In that patient
India-ink-colored pigmentation was seen in the
peritoneum, in the omentum, and on the surface
of the ovary during the surgery. Pigment in the
stroma and pigment-laden histiocytic aggregation
were seen in biopsies of omentum and peritonium.
Likewise, another case of peritoneal melanosis
combined with serous cystdenoma of ovary was
reported by Kim et al 2002. Follow up of these
cases were not reported.
M. Alwani et al.
It has been described along with cystic
abnormalities of the ovary (serous, mucinous),
cystic teratomas of the ovary (Dermoid cysts),
colonic tumors, malignant melanomas and rarely
with genetic disorders (eg enteric duplication,
gastric triplication) [De la Torre 1997, Nada et
al 2000, Kim et al 2002, Hefaiedh et al 2009]. Our
patient had no GIT Symptoms. She did not report
any ovarian cyst or cyst “accident”.
There is no protocol yet mentioned for the
follow up of this clinical entity so we decided to
give the patient first follow up in 1 month, 2nd
follow up in 3 months and then every 6 months.
Prognosis of this condition is quite uncertain.
History and pattern of disease is unclear due to
scarcity of cases. Given associations with ovarian
pathology and gastrointestinal malignancies
we suggest confirmation of the condition with
REFERENCES
1) Angelopoulos G, Smith J H F, Farag K. Benign
Peritoneal Melanosis; a rare case report. BJOG.
2013;120(S1):406
2) De la Torre Mondragón L, Daza DC, Bustamante
AP, Fascinetto GV. Gastric triplication and peritoneal
melanosis. J Pediatr Surg. 1997; 32(12):1773-5.
3) Hefaiedh R, Fekih M, Kacem IH, Matri S, Boubaker
J, Filali A. [Peritoneal melanosis: a rare localization
of the melanoma: a case report]. Tunis Med.
2009;87(10):719-20[French]
4) Jaworski RC. Peritoneal “Melanosis”. Int J
GynecolPathol. 2003; 22(1):104.
peritoneal biopsies and further investigation
to exclude sinister pathology. This case was
chosen for publication because of its rarity, scary
presentation and it could be of research interest
ACKOWLEDGEMENTT
Authors would like to thank chairman, Sri
Aurobindo Medical College and PG Institute,
Indore for providing Infrastructure facilities to
carry out this research
DECLARATION OF
ACKOWLEDGEMENT
INTEREST
None
5) Kim NR, Suh YL, Song SY, Ahn G. Peritoneal
melanosis combined with serous cystadenoma of the
ovary: a case report and literature review. Pathol Int.
2002; 52(11):724-9.
6) Kim SS, Nam JH, Kim SM, Choi YD, Lee JH.
Peritoneal melanosis associated with mucinous
cystadenoma of the ovary and adenocarcinoma of the
colon. Int J Gynecol Pathol. 2010;29(2):113-6.
7) Nada R, Vaiphei K, Rao KL. Enteric duplication
cyst associated with melanosisperitonei. Indian J
Gastroenterol. 2000;19(3):140-1.
9
SIGO 2016
91° congresso
nazionale SIGO
56° congresso
nazionale AOGOI
23° congresso
nazionale AGUI
ROMA
Ergife Palace Hotel
16/19 Ottobre 2016
Segreteria organizzativa:
presidenti
Giovanni Scambia
Enrico Vizza
LA SALUTE AL FEMMINILE
TRA SOSTENIBILITA’
E SOCIETA’ MULTIETNICA
Associazione Ginecologi
Universitari Italiani
Italian Journal of
Intrauterine transfusion versus Corticosteroids for treatment of immune
fetal hydrops secondary to Rh incompatibility with 6 months postnatal
follow-up: Case series with review of literature
Tamer Mamdouh Abdeldayem1, ElSayed El Badawy Mohamed1, Ahmed El Habashy1, Sherif
Gaafar1, Ashraf Han1, Aly Alaa Youssef2
1
2
Department of Obstetrics and Gynecology, Faculty of Medicine, Alexandria University, Egypt.
Department of Obstetrics and Gynecology, Sant’Orsola Malpighi University Hospital, University of Bologna, Italy
ABSTRACT
Introduction: Immune hydrops fetalis is still a
challenging condition in fetal medicine. Corticosteroids
are established for immune suppression in auto-immune
disorders. Their use in cases of Rh isoimmunization is not
fully studied so the aim of our study was to evaluate its
role in fetal hydrops.
Methods: This study included six patients recruited from
January 2015 to December 2015 at fetal medicine centerAlexandria, Egypt. Patients were multiparous women
with Rh negative blood group and history of successful full
term delivery once before. They had clinical history of fetal
hydrops and subsequent intrauterine fetal death at 26-28
weeks of gestation in the subsequent pregnancies. Patients
were referred to the center at gestational age 22-32weeks
gestation. Three cases were treated by Cordocentesis and
transfusion of irradiated O negative red blood cells, Three
cases were treated by administration of prednisolone 20
mg tab twice a day for suppression of maternal anti-Rh
antibodies production. Ultrasonographic examination was
repeated every week. For cases whose fetuses survived
till 34 weeks gestation, 4 doses of Dexamethasone 6 mg
were given intramuscularly and cases were delivered by
elective caesarian section.
Results: Three progressed into sudden intrauterine fetal
death; two of them treated with transfusion and one with
corticosteroids. One, treated by transfusion, improved
and was delivered at 33 weeks gestation after full course
of dexamethasone administration to the mother. For the
other two cases treated by corticosteroids, both were
delivered at 34 weeks gestation, none developed hydrops
fetalis. Follow-up of the three surviving neonates was
done till 6 months after birth showed normal growth and
neurological development.
Conclusions: Corticosteroids could be of benefit in
treating fetal hydrops but this needs to be evaluated more
in a large studies.
Keywords: Steroids, Hydrops, Ultrasound, Anemia,
Pregnancy
DOI: 10.14660/2385-0868-48
SOMMARIO
L’idrope fetale immunomediata in medicina fetale
è ancora una condizione clinica indaginosa. I
corticosteroidi sono somministrati nei disordini
immuno mediati come terapia immuno soppressiva.
Il loro uso in caso di isomimmunizzazione Rh non
è ancora stato studiato a fondo, quindi lo scopo del
nostro studio è quello di valutarne il possibile ruolo nel
trattametno dell’idrope fetale.
Questo studio include sei pazienti che sono state
reclutate da gennaio 2015 a dicembre 2015 nel centro
di medicina fetale di Alessandria, in Egitto. Le pazienti
erano pluripare con gruppo sanguigno Rh negativo ed
in anamnesi una gravidanza portata fino al termine
con successo. Le pazienti incluse hanno avuto una
gravidanza con feto affetto da idrope fetale e successiva
morte intrauterina tra 26-28 settimane e sono giunte al
nostro centro tra le 22 e le 32 settimane di gestazione. Tre
dei casi inclusi nello studio sono stati trattati mediante
cordocentesi e trasfusione di globuli rossi irradiati O
negativo. Tre sono stati trattati con somministrazione
orale di prednisolone 20 mg per due volte al giorno
ai fini della soppressione della produzione materna di
anticorpi anti Rh. Gli esami ecografici sono stati ripetuti
ogni settimana. Le pazienti i cui feti sono sopravvissuti
oltre le 34 settimane di gestazione sono state trattate
mediante 4 dosi da 6 mg di desametasone per via
intramuscolo ed in questi casi è stato eseguito un taglio
cesareo elettivo.
Tre pazienti hanno avuto morte intrauterina fetale;
due di queste erano state trattate con trasfusione e una
con corticosteroidi. Una paziente trattata mediante
trasfusione è andata incontro a miglioramento e ha
partorito a 33 settimane dopo aver concluso la terapia
con desametasone. Per i due casi che sono stati trattati
con corticosteroidi, entrambi hanno partorito a 34
settimane senza sviluppare idrope fetale. I neonati
sopravvissuti sono stati sottoposti a follow up fino ai
6 mesi di vita e hanno mostrato un normale sviluppo
fisico e neurologico.
I corticosteroidi potrebbero essere di beneficio nel
trattare l’idrope fetale ma sono necessari studi con una
più ampia coorte di pazienti.
11
2016, 28: N. 4
INTRODUCTION
Immune hydrops fetalis is still a challenging
condition in fetal medicine. Incidence has
decreased dramatically in last decades after
introduction of the use of anti D immunoglobulins
after delivery, at 28-30 weeks gestation and
after any bleeding incidence during gestation(1).
Screening for Rh isoimmunization is through
anti-Rh antibodies, using indirect Coomb’s
test. Screening for fetal anemia is feasible using
values of peak systolic velocity in middle
cerebral artery(2). Established treatment is serial
intrauterine transfusion of irradiated O negative
red blood cells, whether into the umbilical vein
or intraperitoneal. These routes carry the risk of
intrauterine infection, preterm birth, intrauterine
fetal death and others(3-5).
Corticosteroids are established for immune
suppression in auto-immune disorders. Their use
in cases of Rh isoimmunization is not fully studied
so the aim of our study was to evaluate its role in
fetal hydrops.
METHODS
12
This study included six patients recruited
from January 2015 to December 2015 at fetal
medicine center-Alexandria, Egypt. Patients were
multiparous women with Rh negative blood group
and history of successful full term delivery once
before. They had clinical history of fetal hydrops
and subsequent intrauterine fetal death at 26-28
weeks of gestation in the subsequent pregnancies.
Patients were referred to the center at gestational
age 22-32 weeks gestation.
At recruitment, they were subjected to:
Assessment of ABO and Rh blood grouping,
Measurement of hemoglobin, postprandial
blood sugar and anti-Rh antibody titer and
Ultra-sonographic examination including:
Fetal biometry, anomaly scan including fetal
echocardiography and Peak systolic velocity in
middle cerebral artery.
Three cases were treated by Cordocentesis and
transfusion o irradiated O negative red blood cells, Three cases were treated by administration of
prednisolone 20 mg tab twice a day for suppression
of maternal anti-Rh antibodies production.
Ultrasonographic examination was repeated
every week. For cases whose fetuses survived till
34 weeks gestation, 4 doses of Dexamethasone 6
mg were given intramuscularly and cases were
delivered by elective caesarian section.
Use of corticosteroids for treatment of immune hydrops fetalis
RESULTS
All cases were Rh negative, with indirect
Coomb’s test showing anti-Rh antibodies titer
above 1/32.Gestational ages were 22-26 weeks
in the recruited cases. Middle cerebral artery
peak systolic velocity was above 1.5 MoM for
the gestational age in all three recruited cases.
Four cases showed fetal ascites at the time of
recruitment. Three of them were treated with
serial cordocentesis and O negative red blood cell
transfusion, guided by Peak systolic velocities in
middle cerebral artery. Of these four cases, three
progressed into sudden intrauterine fetal death;
two of them treated with transfusion and one
with corticosteroids. One, treated by transfusion,
improved and was delivered at 33 weeks gestation
after full course of dexamethasone administration
to the mother. Fetal weight was 1800 gms, severe
neonatal jaundice developed and was promptly
treated by exchange transfusion and phototherapy.
Neonate was discharged after 16 days. For the
other two cases treated by corticosteroids, both
were delivered at 34 weeks gestation, none
developed hydrops fetalis. Birth weights were 1900
and 1950 grams. Newborns developed hemolytic
anemia and jaundice at day one, necessitating
exchange transfusion, which was repeated three
times together with phototherapy. Fetuses were
discharged 12 and 14 days after delivery. Followup of the three surviving neonates was done till
6 months after birth showed normal growth and
neurological development.
DISCUSSION
Alloanti-D that is acquired during pregnancy
or by transfusion is a major cause of severe and
sometimes fatal haemolytic disease of newborns
and haemolytic transfusion reactions, respectively.
Isoimmunized mothers are destined to have
immune hydrops in all future pregnancies with
Rh positive fetuses. Treatment of these fetuses
is currently through repeated intrauterine
transfusion, Other modes of treatment include
plasmapheresis to dilute the anti-Rh antibodies
in maternal blood, with large volumes of plasma
needed for this procedure. Pharmaceutical
treatment is currently of limited use. In our case
series we proposed the use of relatively high
doses of corticosteroids for immune suppression
versus the established transfusion therapy. The
underlying principle is suppression of maternal
Anti-Rh antibodies which cross the placenta and
cause fetal hemolysis(3-6).
T. M. Abdeldayem et al.
Use of corticosteroids for treatment of immune hydrops fetalis
Early use of this mode of treatment was
successful to suppress antibodies, allowing the
bone marrow and reticuloendothelial system of
two fetuses to maintain adequate cardiovascular
function and tissue oxygenation. Liver affection
was not documented and no evidence of ascites,
pleural effusion nor subcutaneous oedema was
found in the two cases surviving on prednisolone
therapy. Second case showed hepatomegaly
at 33 weeks, 4 days, prompting the decision of
caeserian delivery after 4 doses of corticosteroids.
Conservative treatment till this age allowed
shorter period of admission at neonatal intensive
care unit and helped improve the outcome for
fetuses of both cases. Treatment with 40 mg
oral prednisolone helped save two fetuses of
isoimmunized mothers. It could be used alone or
in conjunction with other modes of treatment(3-6).
On the other hand, cases already presenting
with evidence of fetal ascites mostly agreed to
the transfusion therapy, with only one having
successful outcome. This method is more effective
in replacing hemolysis fetal red blood cells,
without slowing down the rate of hemolysis(6).
Isojima et al(7) reported the successful use
of plasmapheresis and high doses of gamma
globulins for dilution and neutralization of antiRh antibodies in one case.
Houston et al(8) reported another cases case
managed with the same combination, none of
them added corticosteroids.
In conclusion, we propose the addition of
40 mg oral prednisolone therapy to preganant
females, in addition to other modes of therapy,
whether transfusion or plasmapheresis and
REFERENCES
1) McBain RD, Crowther CA, Middleton P. Anti-D
administration in pregnancy for preventing Rhesus
alloimmunisation. Cochrane Database Syst Rev. 2015
Sep 3;9.
2) Mari G, Norton ME, Stone J. Society for MaternalFetal Medicine (SMFM) Clinical Guideline #8: the
fetus at risk for anemia--diagnosis and management.
Am J Obstet Gynecol. 2015 Jun;212(6):697-710
3) Bigelow CA, Cinelli CM, Little SE. Percutaneous
umbilical blood sampling: current trends and
outcomes. Eur J Obstet Gynecol Reprod Biol. 2016
May;200:98-101.
4) Aitken SL, Tichy EM. Rh(O)D immune globulin
products for prevention of alloimmunization
during pregnancy. Am J Health Syst Pharm. 2015 Feb
15;72(4):267-76.
immunoglobulin therapy. Prednisolone therapy is
cheap, it proved helpful on its own for obtaining
good outcome, and in combination with other
therapies prognosis could be more favorable.
CONCLUSIONS
Corticosteroids could be of benefit in treating
fetal hydrops but this needs to be evaluated more
in a large studies.
AUTHORS CONTRIBUTION:
All the authors contributed to protocol
development, data collection and management,
Data analysis and Manuscript writing/editing.
Ethical disclosure
Protection of human and animal subjects. The
authors declare that the procedures followed were
in accordance with the regulations of the relevant
clinical research ethics committee and with
those of the Code of Ethics of the World Medical
Association (Declaration of Helsinki).
Confidentiality of data. The authors declare
that they have followed the protocols of their work
center on the publication of patient data.
Right to privacy and informed consent. The
authors have obtained the written informed
consent of the patients or subjects mentioned in the
article. The corresponding author is in possession
of this document.
Conflict of interest. The authors declare no
conflict of interest.
5) Moise KJ Jr. Management of rhesus alloimmunization
in pregnancy. Obstet Gynecol. 2008 Jul;112(1):164-76.
6) Aitken SL, Tichy EM. Rh(O)D immune globulin
products for prevention of alloimmunization
during pregnancy. Am J Health Syst Pharm. 2015 Feb
15;72(4):267-76.
7) Isojima S, Hisano M, Suzuki T. Early plasmapheresis
followed by high-dose γ-globulin treatment saved a
severely Rho-incompatible pregnancy. J Clin Apher.
2011;26(4):216-8
8) Houston BL, Govia R, Abou-Setta AM. Severe
Rh alloimmunization and hemolytic disease of the
fetus managed with plasmapheresis, intravenous
immunoglobulin and intrauterine transfusion: A case
report. Transfus Apher Sci. 2015 Dec;53(3):399-402.
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Italian Journal of
Improving prescription of physical exercise in prophylaxis/therapy of
gestational diabetes: a survey from evidence to current recommendations
Cristina Bianchi1, Michele Aragona1, Alessandra Bertolotto1, Pietro Bottone11, Maria
Calabrese4, Ilaria Cuccuru5, Alessandra De Bellis6, Anna Leopardi8, Cristina Lencioni2,
Roberto Miccoli10, Mary Liana Mori7, Serena Ottanelli3, Matilde Romano11, Gigliola Sabbatini9,
Maria Giovanna Salerno11, Giuseppe Trojano11, Stefano Del Prato10, Lorella Battini11 on behalf
of Tuscany working group on “Diabetes, Pregnancy and Exercise”*
U.O. Malattie Metaboliche e Diabetologia, Azienda Ospedaliero-Universitaria Pisana, Pisa
U.O.C. Diabetologia e Malattie Metaboliche, Ospedale di Livorno
3
U.O. Ostetricia e Ginecologia, Ospedale di Arezzo
4
U.O. Diabetologia, Ospedale di Prato
5
U.O.S. Diabetologia, Ospedale di Lucca
6
U.O.C. Diabetologia, Ospedale di Pistoia
7
U.O.S. Diabetologia, Ospedale di Carrara
8
U.O.C Diabetologia e Malattie Metaboliche, Ospedale San Giovanni di Dio - Firenze
9
U.O. Diabetologia, Ospedale di Grosseto
10
Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa
11
U.O. Ginecologia ed Ostetricia, Azienda Ospedaliero-Universitaria Pisana, Pisa
1
2
ABSTRACT
Exercise has been proved to be safe during pregnancy
and to offer benefits for both mother and fetus;
moreover, physical activity may represent a useful
tool for gestational diabetes prevention and treatment.
Therefore, all women in uncomplicated pregnancy
should be encouraged to engage in physical activity
as part of a healthy lifestyle. However, exercise in
pregnancy needs a careful medical evaluation to exclude
medical or obstetric contraindications to exercise, and
an appropriate prescription considering frequency,
intensity, type and duration of exercise, to carefully
balance between potential benefits and potential
harmful effects. Moreover, some precautions related to
anatomical and functional adaptations observed during
pregnancy should be taken into consideration. This
survey summarized the suggested recommendations
for physical activity among pregnant women with focus
on gestational diabetes.
Keywords: Guidelines, Physical Activity, Gestational
Diabetes, Pregnancy.
SOMMARIO
Numerose evidenze suggeriscono che l’attività fisica è
sicura in gravidanza e offre benefici sia per la madre che
per il feto; inoltre, l’esercizio fisico può rappresentare
un utile strumento per la prevenzione e il trattamento
del diabete gestazionale. Pertanto, tutte le donne
in gravidanza non complicata dovrebbero essere
incoraggiate ad impegnarsi in attività fisica come parte
integrante di uno stile di vita sano. Tuttavia, l’esercizio
fisico in gravidanza necessita di una attenta valutazione
medica per escludere controindicazioni mediche od
ostetriche, e una prescrizione appropriata che tenga
conto della frequenza, dell’intensità, del tipo e della
durata dell’esercizio, per bilanciare con attenzione i
benefici e gli effetti indesiderati potenziali. Inoltre,
dovrebbero essere prese in considerazione alcune
precauzioni relative ai fisiologici adattamenti anatomici
e funzionali che si osservano durante la gravidanza.
Questa survey riassume le raccomandazioni attualmente
suggerite per l’attività fisica nelle donne in gravidanza
con particolare attenzione al diabete gestazionale.
INTRODUCTION
Gestational Diabetes Mellitus (GDM) is the most
common metabolic complication of pregnancy. Its
DOI: 10.14660/2385-0868-49
prevalence is increasing worldwide accordingly
with increasing of obesity and the number of
obese pregnant women(1). Significant evidences
suggest that physical activity may represent a
simple, inexpensive and useful tool for GDM
prevention and treatment(2). However, exercise
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2016, 28: N. 4
Gestational diabetes and exercis
in pregnancy needs a careful evaluation and
appropriate prescription. To implement a proper
prescription of exercise during pregnancy, we
examined the published international guidelines
for exercise in pregnancy(3-9) complicated or not
by diabetes and summarize in this survey the
suggested recommendations for physical activity
among pregnant women with focus on GDM.
includes: maternal education, diet modifications,
exercise, drug treatment and fetal surveillance
(Figure 1).
The initial management of GDM involves diet
modifications and implementation of regular
physical activity. If adequate glycemic control is not
been achieved, drug treatment is prescribed with
the aim to reach the target maternal blood glucose
levels and hence indirectly for the fetus (17-19).
GESTATIONAL
DIABETES:
SCREENING, DIAGNOSIS AND
MANAGEMENT
Briefly, GDM is defined as a carbohydrate
intolerance of varying degree of severity with
first diagnosis during pregnancy and a natural
dispelling of the hyperglycemic condition
after child birth(4). GDM, when undiagnosed
or inadequately treated, has many detrimental
consequences for the woman, the fetus and the
child(10-15).
Since 2011, the Italian National Health System
guidelines recommend a selective screening for
GDM based on risk factors. According to national
guidelines, high risk women are those with
previous GDM, obesity (pre-gestational BMI≥30
kg/m2), fasting plasma glucose between 100 and
125 mg/dl, in the first trimester of pregnancy;
while at medium risk are women aged 35 years
or older, overweight (pre-gestational BMI 25-29.9
kg/m2), with family history of type 2 diabetes,
previous fetal macrosomia, ethnic group at GDM
high risk. Based on this stratification, in high
risk women an early screening between 16th18th gestational week was recommended, to be
repeated later (24th-28th gestational week) in case
of normal glucose tolerance, while in medium
risk women the screening was scheduled between
24th-28th gestational week. Diagnosis of GDM is
based on IADPSG/WHO 2013 criteria. (Table 1).
Table 1. Diagnostic criteria for GDM (IADPSG/WHO 2013) 16.
2 hours -75 g OGTT
Glucose
concentration threshold*
Fasting plasma glucose
1-h plasma glucose
2-h plasma glucose
≥ 5.1 mmol/l (92 mg/dl)
≥ 10.0 mmol/l (180 mg/dl)
≥ 8.5 mmol/l (153 mg/dl)
*One or more of these values from a 75-g OGTT must be equaled or
exceeded for the diagnosis of GDM 16.
16
The primary aim of GDM treatment is blood
glucose control in order to reduce the elevated
risk for short and long term complications for both
mother and offspring. The approach for GDM
Figure 1. Key elements in the management of gestational diabetes.
A PHYSICAL ACTIVITY DURING
PREGNANCY: BENEFITS AND RISKS
Exercise has been proved to be a beneficial
therapeutic tool during pregnancy (Table 2).
Recent studies showed that exercise was safe and
advantageous for glucose control for women with
GDM, improved cardiovascular functions (fitness,
blood pressure, peripheral edema), preeclampsia
prophylaxis, varicose veins and deep vein
thrombosis, decreased lower back pain and had
benefits on mood and psychological wellbeing;
decreased risk of preterm delivery, length of labor
and delivery complications; furthermore exercise
has an important role in limitation of weight gain
and fat retention after delivery, also improving self
image(20-21). Maternal exercise has also been shown
to provide significant benefits to the fetus health:
increased amniotic fluid, increased in placenta
viability and volume, increased vascular function,
faster placenta growth and greater villous tissue,
more adequate birth weight and lower risk of
preterm birth, improved neurodevelopment and
lower fetal body fat percentage(22-25). Therefore,
considering the benefits of exercise during
pregnancy, it’s necessary that it becomes an
integral part of treatment strategies in women
during pregnancy and particularly in case of
pregnancy complicated by GDM.
Exercise prescription requires knowledge
of the potential risks and assessment of the
L. Battini et al.
Gestational diabetes and exercise
Table 2. Benefits of maternal exercise
Benefits to the mother
•
•
•
•
•
•
•
•
•
•
•
Improved glucose control
Decreased lower back pain
Improve cardiovascular functions
Decreased preeclampsia
Improved muscle tone
Reduced lenght of labour
On mood and psychological wellbeing
Improved self image
Control in weight gain
Facilitating post partum weight loss
Reduced costipation and bloating,
fatigue and insomnia
Benefits to the foetus
•
•
•
•
•
•
•
•
•
Lower heart rate response to acute
maternal exercise
Increased amniotic fluids
Increase in placenta viability and volume
Increase in vascular function
Faster placental growth and greater
villous tissue
Higher tolerance to labour
Lower birth weights
Lower risk of preterm birth
Improved neurodevelopment and lower
body fat percentage
physical ability to engage in various activities.
As with any clinical population, there are some
contraindications to exercise also in pregnancy.
Moreover, some anatomical and physiological
change occurring during pregnancy should
be taken into account in prescribing exercise.
Therefore, clinical evaluation of each pregnant
woman should be conducted before physical
activity is recommended and exercise programs
should be tailored by appropriately trained and
qualified practitioners.
Pregnant women with GDM don’t need
suggestions or special precautions for physical
activity other than those recommended in women
with normal glucose tolerance but, considering
the presence of hyperglycemia, they need to
take into account the recommendations for the
physical activity outlined for the pre-gestational
diabetes too, especially when GDM requires
a pharmacological treatment that could cause
hypoglycemia. Considering the lack of large cohort
studies implementing exercise as treatment of
GDM, the suggested recommendations have been
derived from exercise guidelines in pregnancy
and exercise in type 2 diabetes guidelines(26-31).
Although currently there is only a GDM specific
exercise prescription guideline published(32), we
suggest to develop italian recommendations to
allow proper application of physical activity
practice as an effective tool in glucose control to
prevent, delay or treat GDM.
I N D I C A T I O N
A N D
CONTRAINDICATIONS TO
PHYSICAL ACTIVITY DURING
PREGNANCY
All women in uncomplicated pregnancy
should be encouraged to engage in physical
activity as part of a healthy lifestyle. [Level of
evidence II, Recommendation B]
Benefits to the child
• Infants have higher behaviour regulatory
ability and orientation
• At the age of five children have less body
fat, higher general language intelligence
and oral language
Women with complicated pregnancy have
been discouraged from the practice of physical
activity to avoid a worsening of the underlying
disease or negative impacting both maternal and
fetal outcomes. The absolute contraindications
represent conditions where exercise is not
recommended, while relative contraindications
are conditions where the risks may outweigh
the benefits of regular physical activity and
should be individually evaluated (Table 3).
Therefore, clinical evaluation of each pregnant
woman should be performed before physical
activity is recommended. [Level of evidence V,
Recommendation B]
STARTING A NEW EXERCISE
PROGRAM DURING PREGNANCY
Starting a new exercise program should be
considered already in the pre-conceptional period,
especially in women who are overweight-obese
and/or have other risk factors for GDM (previous
gestational diabetes, age > 35 years, family history
for diabetes, high-risk ethnic group) in order to
avoid excessive weight gain during pregnancy
and prevent GDM (33) [Level of evidence III,
Recommendation B].
Previously active women can continue the
regular practice of physical exercise, as long as
the pregnancy is uncomplicated, and the activity
practiced meets the safety criteria in terms of
type, intensity and frequency of exercise as
suggested below-Table 4 (34). [Level of evidence III,
Recommendation B].
In sedentary women, especially those in
which the gestational diabetes is diagnosed, an
exercise program could be initiated in the second
trimester, when the nausea, vomiting, and fatigue
(sometimes intense in the first trimester) have
passed and before the physical limitations of
the third trimester occur. [Level of evidence VI,
Recommendation C].
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2016, 28: N. 4
Table 3. Relative and absolute contraindications for the practice of physical activity during pregnancy.
Absolute
Obstetric complications
• Ruptured membranes
• Preeclampsia
• Pregnancy-induced hypertension
• Premature labour during current pregnancy
• Persistent bleeding (second or third trimester)
• Incomplete cervix or cerclage
• Placenta previa (placental implanting into lower uterus) after 26
wk of gestation
• High order multiple gestation (≥ triplets)
Medical complications
• Restrictive lung disease
• Hemodynamically significant heart disease
• Severe anaemia (Hb <10 g/dL)
• Extreme morbid obesity
• Extremely underweight (BMI < 12 kg/m2)
• Poorly controlled seizure disorder
• Poorly controlled hyperthyroidism
• Poorly controlled type 1 diabetes
EXERCISE PRESCRIPTION DURING
PREGNANCY
Consideration should be given to frequency
of exercise sessions, intensity of exercise, type
of exercise and its duration, to carefully balance
between potential benefits and potential
harmful effects. We identified in the FITT model
(Frequency, Intensity, Time/duration and Type Table 4) a valid tool to prescribe physical activity
during pregnancy in order to prevent and treat
GDM (35).
Table 4. FITT
(Frequency, Intensity, Time / duration and Type) model.
FFREQUENCY
Begin at 3 times per week and progress to 4
times per week
IINTENSITY
Exercise to not excessively increase the heart
rate. The proper intensity is one that lets you
continue the conversation while exercising
(Talk Test)
T
Start from a minimum of 15 minutes per
session, 3 times a week (according to an
appropriate target heart rate) to a maximum of
about 30 minutes per session, 4 times a week
(to the appropriate heart rate).
TIME
TTYPE
Preferably use large muscle groups (such
as those that are put in motion for walking,
stationary bike, swimming, aquatic exercise,
low impact aerobics). Avoid the exercises
with use of weights or resistance; those that
can cause falls; sports at high altitude and
underwater.
FREQUENCY AND DURATION
18
Aerobic exercise should go on for a minimum
of 15 minutes per session, 3 times a week
(according to an appropriate target heart rate), and
should be increased gradually during the second
trimester up to a maximum of approximately
30 minutes per session, 4 times to week (to the
Relative
Obstetric complications
• History of spontaneous abortion or premature labour in previous
pregnancies
• Twin pregnancy after 28th week
• Intrauterine growth restriction in current pregnancy
• Previous spontaneous abortion
• Anaemia (Hb >10 g/dL)
• Twin pregnancy after 28 wk
Behaviour habits and medical complications
• Heavy smoking
• History of extremely sedentary lifestyle
• Orthopaedic limitations
• Poorly controlled hypertension
• Chronic bronchitis
• Unevaluated maternal cardiac arrhythmia
• Malnutrition or eating disorder
• Obesity (BMI >40 kg/m2)
appropriate heart rate) (36). [Level of evidence IV,
Recommendation C]. To optimize the metabolic
benefits of physical activity, due to the transient
improvement of insulin action and passive glucose
uptake for up to 48 hours, exercise should be
conducted with no more than two consecutive
days between sessions.
Aerobic activity should be preceded by a
short (10-15 min.) warming up and followed by
a short (10-15 min.) cool-down phase that include
stretching and relaxation exercises. [Level of
evidence VI, Recommendation C].
Intensity
The best way to prescribe and monitor the
intensity of physical activity is evaluating the
heart rate based on age and the rating of perceived
exertion (RPE), simultaneously.
Heart rate: In pregnancy, at rest, there is a
physiological increase in heart rate from 10 to
15 beats/minute(37). The target heart rate during
exercise, depending on the age of the woman
(Table 5), representing about 60-80% of peak
aerobic capacity for a pregnant woman (38) [Level
of evidence VI, Recommendation C].
Table 5. Heart Rate Intervals useful for pregnant women.
Maternal age
(years)
Fitness level
Heart rate range
(beats/minute)
< 20
-
140-155
Low
Active
Fit
Low
Active
Fit
129-144
135-150
145-160
128-144
130-145
140-156
20-29
30-39
L. Battini et al.
Classification of perceived physical activity:
Choosing carefully the desirable heart rate, it is
useful to compare it with the scale that assesses the
individual’s perception of physical activity (Borg’s
scale, Table 6) (39). An interval between 12 and
14 is appropriate for most of pregnant women.
[Level of evidence VI, Recommendation C].
Precautions for exercise during pregnancy
Although it is useful to exercise all muscle
groups, precautions shall be taken, in part related
to anatomical and functional adaptations that are
observed during pregnancy (Figure 2).
Table 6. Borg’s scale of perceived physical activity
6
7
8
9
Very Somewhat
very light light
10
11
12
13
Light Somewhat
hard
14
15
Hard
16
17
Very
hard
18
19
20
Very
very hard
Talk Test: A simple, alternative or complement
system for assessing the adequacy of physical
exercise intensity is represented by the “talk test”:
if a woman is able to maintain a conversation
during exercise means that the intensity of
exercise is adequate; It should be reduced if the
conversation is not possible. [Level of evidence
VI, Recommendation C].
TYPE
Exercise for the development and the
maintenance of adequate physical fit in pregnant
women consists of activities that improve both the
cardio-respiratory (aerobic exercise, consisting of any
activity that uses large muscle groups rhythmically
and continuously) and musculoskeletal status
(strength and flexibility exercises) [Level of evidence
VI, Recommendation C].
However, some elements should be considered
when prescribing physical activity during
pregnancy.
A wide range of recreational activities appears
to be safe for pregnant women. The safety of
each sport is largely determined by the specific
movements required by the exercise. Activities
with a high risk of falling or abdominal trauma
should be discouraged. Activity with a high
potential for physical contact (such as ice hockey,
football, and basketball) or falls (horseback riding,
downhill skiing, ...) can cause severe trauma to
both mother and fetus and therefore should be
discouraged. Scuba diving should be avoided
during pregnancy, because the fetus is at risk
for decompression sickness. Caution should
be also in the practice of physical exercise at
high altitude (> 2500 m). [Level of evidence VI,
Recommendation C].
The most popular form of aerobic activity
during pregnancy is walking, however, also water
exercise may be an excellent choice of exercise
during pregnancy.
Figure 2. Anatomical and physiological adaptation during
pregnancy and related potential risks during exercise.
Musculo-skeletal adaptation: The increase in
weight can increase the pressure on all the joints,
especially hips and knees, causing discomfort
for normal joints and increase in damage in
previously unstable joints. Furthermore, due to the
increase of weight and abdomen, pregnant women
usually develop lumbar lordosis, which leads to
changes in posture, predisposing them to loss of
balance and increased risk of falls. Finally, during
pregnancy there is an increase of the laxity of the
ligaments, due to the higher levels of estrogen and
relaxin. This could predispose pregnant women to
a higher risk of tearing and distortions.
Cardiovascular adaptation: Pregnancy induces
an increase in blood volume, frequency and cardiac
output, and a reduction in systemic vascular
resistance (40). These hemodynamic changes seem
to establish a circulatory reserve, necessary to
provide nutrients and oxygen to the mother
and fetus at rest and during moderate physical
activity(41). After the first trimester, the supine
position results in relative obstruction of venous
return and therefore decreased cardiac output. For
this reason, the supine position should be avoided
as much as possible during both rest and exercise.
Furthermore, the maintenance of the motionless
standing should be avoided because it is associated
with a significant decrease in cardiac output.
Respiratory adaptation: Pregnancy is
associated with increase of about 50% of the
ventilation, increase in arterial oxygen tension,
especially in the first trimester, increased uptake of
oxygen and its baseline consumption(42). Because
19
2016, 28: N. 4
of the increased requirement of oxygen at rest
and increased work of breathing caused by the
pressure exerted on the diaphragm by increased
uterine volume, the availability of oxygen for the
execution of aerobic exercise during pregnancy
decreases.
Thermoregulation: During pregnancy, the
basal metabolic rate, and thus heat production, has
increased. The dissipation of excess heat generated
during exercise can be a potential problem, since
some studies suggest that hyperthermia (body
temperature > 39°C) during the first 45-60 days
of gestation can also be teratogenic in humans (43).
The increase in body temperature during exercise
is directly related to the intensity of exercise (44). If
the production of heat exceeds the heat dissipation
capacity, for example during exercise in hot, humid
conditions or during very high intensity exercise,
the temperature may further rise. The exercise
should, therefore, be preferably performed in a
thermo-neutral environment or under controlled
environmental conditions (conditioning). [Level
of evidence VI, Recommendation C]. Moreover,
since during prolonged exercise the loss of fluid
through sweat can impair the dissipation of heat,
it must be maintained a proper hydration.
In women with gestational diabetes, especially
REFERENCES
20
1) IDF Diabetes Atlas. Seventh edition, 2015.
2) Carolan-OIah MC. Educational and intervention
programs for gestational diabetes mellitus (GDM)
management: An integrative review. Collegian
2016;23(1):103-14.
3) U.S. Department of Health and Human Services. 2008
Physical Activity Guidelines for Americans. ODPHP
Publication No. U0036. Washington, D.C: 2008. at
http://www.health.gov/paguidelines
4) ACOG. Exercise during pregnancy and the
postpartum period. ACOG Committee Opinion No.
267. Obstet Gynecol. 2002; 99(1):171–173.
5) Davies G, Wolfe L, Mottola M, MacKinnon C. Joint
SOGC/CSEP clinical practice guideline: Exercise in
pregnancy and the postpartum period. Can J Appl
Physiol 2003; 28(3):330–341.
6) Wolfe L, Davies G. Canadian guidelines for exercise
in pregnancy. Clin Obstet Gynecol 2003; 46(2):488–495.
7) Royal College of Obstetricians and
Gynaecologists. Exercise in pregnancy. RCOG
Statement No. 4 - January 2006 at http://www.
rcog.org.uk/files/rcog-corp/uploaded-files/
RCOGStatement4ExercisePregnancy2006.pdf
insulin-treated, it is necessary to minimize the risk
of an episode, however rare, of hypoglycemia.
Therefore, glucose self-monitoring should be
recommended before and after physical exercise.
If exercise is particularly prolonged, glucose
monitoring should be performed also during
physical activity. Moreover, if glycemia before
exercise is ≤ 70 mg/dl, it is useful to posticipate
the exercise after the intake of glucose and the
restoration of an adequate blood glucose level.
Finally, it may be important to perform physical
activity after at least one hour of rapid acting
insulin administration, in order to further reduce
the risk of hypoglycemia.
Indication to the interruption of physical activity
Pregnant women should be asked to stop
physical activity in case of occurrence of:
•Excessive shortness of breath, feeling short of
breath or rapid heartbeat
•Chest pain
•Painful uterine contractions
(more than 6-8 per hour)
•Vaginal bleeding
•Any “gush” of fluid from the vagina
(suggesting premature rupture of membranes)
•Dizziness or weakness
8) Sports Medicine Australia. SMA statement: the
benefits and risks of exercise during pregnancy. J Sci
Med Sport 2002; 5(1):11–19.
9) Metzger BE, Coustan DR. Summary and
recommendations of the Fourth International
Workshop-Conference on Gestational Diabetes
Mellitus. The Organizing Committee. Diabetes Care
1998; 21 Suppl 2: B161-B167
10) Coustan DR, Imarah J. Prophylactic insulin
treatment of gestational diabetes reduces the incidence
of macrosomia, operative delivery,and birth trauma.
Am J Obstet Gynecol 1984; 150: 836-842
11) Hod M, Merlob P, Friedman S, Schoenfeld A, Ovadia
J. Gestational diabetes mellitus. A survey of perinatal
complications in the 1980s.Diabetes 1991; 40 Suppl 2:
74-78
12) Crowther CA, Hiller JE, Moss JR, et al. Australian
Carbohydrate Intolerance Study in Pregnant Women
(ACHOIS) Trial Group. Effect of treatment of
gestational diabetes mellitus on pregnancy outcomes.
N Engl J Med 2005;352:2477-86
13) Landon MB, Spong CY, Thom E, et al. A multicenter,
randomized trial of treatment for mild gestational
Diabetes. N Engl J Med 2009;361:1339-48
14) Bellamy L, Casas JP, Hingorani AD, et al. Type
2 diabetes mellitus after gestational Diabetes:
a systematic review and meta-analysis. Lancet
2009;373:1773-1779
15) Pettit D, Bennett PH, Knowler WC, Baird HR, Aleck
KA. Gestational diabetes mellitus and impaired
glucose tolerance during pregnancy: long-term effects
on obesity and glucose intolerance in the offspring.
Diabetes Care 1985; 34: 119-122
16) Linea-guida Gravidanza fisiologica. Aggiornamento
2011. Diagnosi del diabete gestazionale, pag 169173. Accessibile al: www.salute.gov.it/imgs/C_17_
pubblicazioni_1436_allegato.pdf (visitato il 28/10/2013)
17) Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries
WS, Robinson JS. Effect of treatment of gestational
diabetes mellitus on pregnancy outcomes. N Engl J
Med 2005; 352: 2477-2486
18) Horvath K, Koch K, Jeitler K, et al. Effects of
treatment in women with gestational diabetes
mellitus: systematic review and meta-analysis. BMJ
2010;340,1395
19) Poolsup N, Suksomboon N, Amin M. Effect of
treatment of gestational diabetes mellitus: a systematic
review and meta-analysis. PLoS One 2014; 9: e92485
20) Prather H, Spitznagle T, Hunt D. Benefits of exercise
during pregnancy. PM R 2012; 4: 845-850
21) Rankin J. The effects of Antenatal Exercise on
Psychological Well-being, Pregnancy and Birth
Outcomes. Philadelphia: Whurr Publishers, 2002
22) Briend A. Maternal physical activity, birth weight
and perinatal mortality. Med Hypotheses 1980; 6:
1157-1170
23) Clapp JF, Capeless EL. Neonatal morphometrics
after endurance exercise during pregnancy. Am J
Obstet Gynecol 1990; 163:1805-1811
24) Clapp JF. Exercise during pregnancy. A clinical
update. Clin Sports Med 2000; 19: 273-286
25) Kalisiak B, Spitznagle T. What effect does an
exercise program for healthy pregnant women have
on the mother, fetus, and child? PM R 2009; 1: 261-266
26) Sigal RJ, Kenny GP, Wasserman DH, CastanedaSceppa C, White RD. Physical activity/exercise and type
2 diabetes: a consensus statement from the American
Diabetes Association. Diabetes Care 2006, 29(6):1433-8.
27) Balducci S, Zanuso S, Nicolucci A, et al.; for the
Italian Diabetes Exercise Study (IDES) Investigators.
Effect of an intensive exercise intervention strategy on
modifiable cardiovascular risk factors in subjects with
type 2 diabetes mellitus - A randomized controlled
trial: The Italian diabetes and Exercise Study (IDES).
Arch Intern Med 2010;170:1794-1803 .
28) Larose J, Sigal RJ, Khandwala F, Prud’homme
D, et al.; Diabetes Aerobic and Resistance Exercise
(DARE) trial investigators. Associations between
L. Battini et al.
physical fitness and HbA1(c) in type 2 diabetes mellitus.
Diabetologia 2011; 54:93-102.
29) Zanuso S, Jimenez A, Pugliese G, et al. Exercise for
the management of type 2 diabetes: a review of the
evidence. Acta Diabetol 2010; 47:15-22.
30) Sigal RJ, Kenny GP. New evidence for the value
of supervised exercise training in type 2 diabetes
mellitus. Arch Intern Med 2010; 170:1790-1791.
31) Madden KM. Evidence for the benefit of exercise
therapy in patients with type 2 diabetes. Diabetes,
Metab Syndr Obes 2013; 6: 233-239.
32) Padayachee C, Coombes JS. Exercise guidelines for
gestational diabetes mellitus. World J Diabetes 2015,
6(8): 1033-1044.
33) Institute of Medicine IOM(US) and National
Research Council (US) Committee to Reexamine IOM
Pregnancy Weight Guidelines. Weight gain during
pregnancy: reexamining the guidelines. National
Academy Press, Washington, 2009).
34) Hale RW, Milne L. The elite athlete and exercise in
pregnancy. Semin Perinatol 1996;20:277–84.
35) Evenson KR, Barakat R, Brown WJ, Dargent-Molina
P, Haruna M, Mikkelsen EM, Mottola MF, Owe KM,
Rousham EK, Yeo SA. Guidelines for Physical Activity
during Pregnancy: Comparisons From Around the
World. Am J Lifestyle Med 2014 ; 8(2): 102–121.
36) Wolfe LA, Hall P,Webb KA, Goodman L, Monga M,
McGrath MJ. Prescription of aerobic exercise during
pregnancy. Sports Med 1989;8:273–301.
37) Avery ND,Wolfe LA, Amara CE, Davies GAL,
McGrath MJ. Effects of human pregnancy on cardiac
autonomic function above and below the ventilatory
threshold. J Appl Physiol 2001;90:321–8.
38) Mottola MF, Davenport MH, Brun CR, Inglis SD,
Charlesworth S, Sopper MM. VO2peak prediction and
exercise prescription for pregnant women. Med Sci
Sports Exerc 2006 38(8):1389-95.
39) Borg GAV. Psychophysical bases of perceived
exertion. Med Sci Sports Exerc 1982;14:377–81.
40) Clark SL, Cotton DB, Lee W, et al. Central
hemodynamic assessment of normal term pregnancy.
Am J Obstet Gynecol 1989;161:1439–42.
41) Wolfe LA, Ohtake PJ, Mottola MF, et al.
Physiological interactions between pregnancy and
aerobic exercise. Exerc Sport Sci Rev 1989;17:295–351.
42) Prowse CM, Gaensler EA. Respiratory and acidbase changes during pregnancy. Anesthesiology 1965;
26:381–92.
43) Milunsky A, Ulcickas M, Rothman KJ, et al. Maternal
heat exposure and neural tube defects. JAMA 1992;
268:882–5.
44) Soultanakis HN, Artal R, Wiswell RA. Prolonged
exercise in pregnancy: glucose homeostasis,
ventilatory and cardiovascular responses. Semin
Perinatol 1996; 20:315–27.
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2016, 28: N. 4
* Tuscany working group on diabetes, pregnancy and
exercise:
Obstetricians-Gynecologists: Carmignani Arianna
(Pisa); Cattani Raffaella (Pisa); Fruzzetti Franca (Pisa);
Fulceri Marco Anselmo (Pisa); Manzan Laura (Prato);
Morini Paolo (Pisa); Nardi Elena (Prato); Trimarchi
Giuseppina Laura (Pisa).
Diabetologists: Bertoli Stefania (Viareggio);
Chatzianagnostou Kyriazoula (Pisa); Cosimi Sabrina
(Versilia); Crisci Isabella (Pisa); Di Filippi Marianna
(Pisa); Ghio Alessandra (Pisa); Magiar Alice Valeria
(Pescia); Ranchelli Anna (Arezzo); Salutini Elisabetta
(Pisa); Viti Secondina (Pescia).
Midwives: Arsa Paola (Pisa); Bronzini Vanna (Pisa);
Carli Eva (Lucca); Cerasa Cinzia (Pisa); Fiordelli Luisella
22
(Arezzo); Gulino Liliana (Pisa); La Placa Angela (Pisa);
Mazzetti Donatella (Arezzo); Moretti Enza (Pisa); Nelli
Letizia (Pisa); Sauro Giusi (Pisa); Tuccitto Concetta
Silvana (Pisa); Vignoni Stefania (Pisa).
Nurses: Augugliaro Angela (Pisa); Carnevale Marilena
(Pisa); Chiti Tiziana (Livorno); Del Freo Maria (Carrara);
Fanelli Stefania (Arezzo); Ferrari Stefania (Versilia);
Ginnetti Giulia (Livorno); Maltinti Maria Angela
(Livorno); Mattesini Mary (Arezzo); Nuvola Silvana
(Pisa); Zugno Andreina (Carrara).
Dietitians/Nutritionists: Breschi Alessia (Pistoia);
Calianno Alessandra (Pisa); Maffei Marzia (Viareggio);
Minutoli Terreni Tommaso (Pisa); Pistoia Laura (Pisa);
Simoncini Letizia (Lucca).
Italian Journal of
Aggressive late Sezary syndrome with pregnancy: A case presented with
generalized erythroderma and dyspnea
Ahmed Samy El-Agwany1
1
Department of Obstetrics and Gynecology, Faculty of Medicine, Alexandria University, Egypt
ABSTRACT
Introduction:
Non-Hodgkin lymphoma with pregnancy produces
management dilemma regarding obstetrical aspect.
Methods and results :
This case report delineates the management of a patient
diagnosed as Non-Hodgkin’s lymphoma 2 weeks after
delivery with ultimate demise of the patient from
progressive disease 3 months after delivery.
Conclusion:
The incidence of NHL is increasing and is associated
with an increased risk of maternal and neonatal
morbidity and mortality, and as such, women with
NHL may best be managed in specialized centers. Skin
lesions should be investigated appropriately to exclude
cutaneous lymphoma.
SOMMARIO
Introduzione:
Il Linfoma non-Hodgkin, durante la gravidanza, crea
un dilemma nella gestione dell’aspetto ostetrico.
Metodi e risultati:
Questo caso mostra la gestione di una paziente
diagnosticato con linfoma Non-Hodgkin, 2 settimane
di dopo il parto con decesso del paziente per la
progressione della malattia 3 mesi dopo il parto.
Conclusione:
L’incidenza di NHL è in aumento ed è associata con un
aumento del rischio di morbilità materna e neonatale e
di mortalità, e quindi, le donne con NHL possono essere
meglio gestite in centri specializzati. Le lesioni cutanee
dovrebbero essere studiate in modo appropriato per
escludere un linfoma cutaneo.
Keywords: Lymphoma, Pregnancy, Mortality, Skin
Lesion.
INTRODUCTION
The incidence of Non-Hodgkin lymphoma
during pregnancy is rare, with fewer than one
hundred cases reported(1). Most Non-Hodgkin
lymphomas that occur during pregnancy are
aggressive and delay of therapy until after
delivery appears to have poor outcomes according
to anecdotal case series. Consequently, some
investigators favor immediate therapy, even
during pregnancy. Termination of pregnancy
in the first trimester may be an option to allow
chemotherapy with or without radiation therapy
for women with aggressive NHL. During the
second and third trimester of pregnancy early
[email protected]
DOI: 10.14660/2385-0868-50
delivery when feasible may minimize or avoid
exposure of the fetus to chemotherapy or radiation
therapy. When possible, treatment should be
postponed until after an early delivery. Women
with indolent (slow-growing) Non-Hodgkin
lymphoma can usually delay treatment during
pregnancy with watchful waiting unless there
are clear indications for treatment, such as: local
symptoms due to progressive or bulky nodal
disease, compromise of normal organ function
presence of symptomatic extranodal disease,
such as effusions, cytopenias due to extensive
bone marrow infiltration, autoimmune hemolytic
anemia or thrombocytopenia, or hypersplenism(2).
Hodgkin disease is the most prevalent
lymphoma type seen in pregnancy due to age
distribution of patients(3). But it is very rare to see
NHL in pregnancy. Only 75 cases were reported
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2016, 28: N. 4
between 1937 and 1985(4). Prognosis is bad in a
high level NHL and average life period is 1.5
years; but in a low level one, prognosis is better
and average life period is 7.5 years(5). Lymphomas
during delivery are high level. Non-Hodgkin’s
lymphoma (NHL) is considered the fourth most
common cancer in pregnancy(6). In 1985, NHL in
pregnancy was estimated to occur in 0.8 cases
per 100 000 women, whereas more recent rates
suggest 1–5 per 100 000 pregnancies(7, 8). The low
incidence of pregnancy associated non-Hodgkin’s
lymphoma (PANHL) has precluded large clinical
trials, and data is restricted to retrospective series
and case reports(9). Increased maternal mortality
rates may also be due to the reported advancedstage disease at diagnosis in the majority of
patients with PANHL(10, 11).
Aggressive late Sezary syndrome with pregnancy
full blown picture of sezary syndrome inform
of lid ectropion,generalized erythroderma
with scaling,brittle nails and palmar, plantar
hyperkeratosis (Figure 2-4). Hb was 7.8 gm/dl,
WBC 1000/cmm,PLT 110000/cmm, SGOT 945,
SGPT 1026 IU/L, creatinine 3.45 mg%, INR was
3, albumin 1.4 g/% and high blood glucose level.
Mechanical ventilation was done but the patient
arrested and died about 2 weeks about 3 months
from delivery from cardiorespiratory failure due to
progressive disease.
CASE REPORT
24
A 32 year old woman, G2P1, previous I
cesarean section was presented to shatby maternity
university hospital on 1/1/2016 with red itchy
scaly plaques and papular skin lesions in a dark
skin colored patient at 39 weeks of gestation for
delivery for elective cesarean section. No medical
disease was detected. The lesions were not
properly investigated by the junior staff. They were
falsely diagnoed as pruritic papular and plaque
of pregnancy. Cesarean section was done and
patient was discharged home after 48 hrs. She was
readmitted one week after discharge with infected
gapped skin wound with the generalized scaly skin
lesions with darkening of skin color. Dermatology
consultation was done where skin biopsy and CT
were recommended revealed cutaneous T–cell
lymphoma as mycosis fungoides. CT revealed
bilateral enlarged intraparotid lymph nodes,
largest in the right about 2 cm, bilateral jugular
LN, largest was 1 cm, bilateral enlarged axillary
LN, largest was 3.5 cm, bilateral enlarged inguinal
LN, largest was 3.5 cm, enlarged submental LN,
largest was 1 cm and no mediastinal or paraortic
enlarged LN with diffuse subcutaneous oedema.
Single cycle chemotherapy was started but dyspnea
occurred with desaturation at room temperature,
pain in the right side of the chest. She was a nonsmoker and had no prior history of tuberculosis or
bronchial asthma. Chest Xray (Figure 1) revealed
right pleural effusion. Ultrasonography guided
Fine Needle Aspiration Cytology (FNAC) revealed
Non-Hodgkin Lymphoma. Bone marrow was
not done as the stage of NHL was advanced at
the time of presentation. Examination revealed
Figure 1. X-ray with right pleural effusion.
Figure 2. Intubated female for respiratory distress with skin lesions
and exfoliation over face, chest and upper limb..
DISCUSSION
The prognosis, survival and response of NHL
to therapy are related to the histological variant.
According to the most accepted classification
of Non–Hodgkin’s Lymphoma proposed by
Rappaport, the diffuse types have a poorer
prognosis than nodular ones (12). Aggressive
lymphomas also called intermediate-grade and
high-grade lymphomas grow and spread quickly
and are usually associated with severe symptoms.
A. S. El-Agwany et al.
Figure 3. Generalized erythroderma with oedema and scaling, palmar and plantar hyperkeratosis of all limbs.
Figure 4. Brittle nails characteristic of sezary syndrome
Aggressive lymphomas are seen more
frequently in patients who are HIV-positive, in
patients who are on immunosuppressant therapy
after organ transplantation or those who have
been treated previously for Hodgkin lymphoma or
in the presence of inherited immune disorders(14).
In our case no tests were done to find out the
possible cause of development of Non-Hodgkin’s
Lymphoma, but pregnancy itself is a state of
immunosuppression.
According to the Ann Arbor Classification
of Non-Hodgkin Lymphoma, NHL Stage IV
indicates extensive (diffuse) involvement in one
organ or site, with/without NHL in distant lymph
nodes as our case.
The treatment approach should be
individualized according to the period of gestation,
stage and localization of the disease, the presence
or absence of B symptoms (fever, night sweats,
and weight loss of more than 10% of the original
weight six months prior to first attendance) and
the progression of symptoms and signs(15). Almost
all NHL in pregnancy is high grade and most
rapid tumour growth is thought to occur in early
pregnancy and puerperium especially during
lactation as our case. Tumour masses of nonHodgkin’s lymphoma greater than 10 cm in size
or mediastinal mass occupying more than half
of the transverse thoracic diameter and raised
serum LDH represent poor prognostic signs.
Although both radiotherapy and chemotherapy
are potentially teratogenic, they can be used
safely in some circumstances during pregnancy. A
variety of protocols of combination chemotherapy
(CT) has been used for the treatment of NHL in
pregnancy in the reported cases with variant
outcomes. These are CHOP, (cyclophosphamide,
vincristin, adriamycin.prednisolone), VACOP-B,
CHOP with rituximab and last of all, autologus
stem cell transplantation with high–dose CT and
ESHAP protocol (Etoposide VP16, Cisplatin,
methylprednisolone and ephosphomide)(12-16).
Radiation with proper shielding can also
be given above the diaphragm during the first
trimester. Later on it can be used only in areas
away from the foetus(3). Chemotherapy alone
cures 30% to 40% of patients with advanced
disease of Stage III or Stage IV. Two strategies
for treating localized intermediate and high grade
Non-Hodgkin’s Lymphoma has emerged without
any convincing evidence in favor of either strategy
over the recent decades: Chemotherapy alone
with CHOP for 6-8 cycles, or a short course of
Chemotherapy (usually 3 cycles of CHOP) followed
by involved–field Radiotherapy. The presumed
advantages of chemotherapy alone are avoidance
25
2016, 28: N. 4
26
of long–term complications of radiotherapy and
the higher total doses of systemic therapy which
increases the potential for eliminating microscopic
sites of disease. The possible benefits of short
course Chemotherapy followed by Radiotherapy
are the reduction in the risk of cardiac toxicity due
to the lower total dose of Doxorubicin, the use of
two treatments and the advantage of radiation
directly to sites of detectable disease(20).
Cutaneous lymphomas are a distinct subset of
non-Hodgkin’s lymphoma (NHL), and that they
can be divided into cutaneous B-cell lymphomas
and cutaneous T-cell lymphomas. Unlike most
other types of lymphoma, which develop in
lymph nodes, people with cutaneous lymphoma
have a cancer of lymphocytes that develops
primarily in the skin. CTCL is the acronym for
cutaneous T-cell lymphoma, a general term for
several types of lymphomas of the skin that
derive from T-cells, including mycosis fungoides,
Sézary syndrome, primary cutaneous anaplastic
large cell lymphoma, lymphomatoid papulosis,
granulomatous slack skin disease, pagetoid
reticulosis, and subcutaneous panniculitis-like
T-cell lymphoma. Most CTCLs typically fall into
the category of indolent (i.e. chronic) lymphomas–
treatable, but not curable and usually not
lifethreatening. In CTCL, malignant T-cells travel
to the upper layers of the skin, causing a rash,
which leads to diagnosis. CTCL is sometimes
wrongly referred to as a skin cancer because it
affects the skin, but this is not a precise use of the
term “skin cancer”. Skin cancer is the designation
for cancers that develop from other, non-lymphoid
cells of the skin, including epidermal cells (which
lead to squamous cell carcinoma) and melanocytes
or pigment cells and (which lead to melanoma).
More common among men than women, CTCL
occurs more in patients older than 50 years of age
than in younger people.
It is important to know, too, that CTCL is not
contagious. It is not an infection and cannot be
passed from person to person. There is no known
cure for CTCL, though some patients enter long-term
remission with treatment and live symptom-free
for many, many years. The most recent research
indicates that patients diagnosed with the
early stages of the most common type of CTCL
– mycosis fungoides (which makes up about
70% of CTCL) – have a normal life expectancy.
The two most common types of CTCL are
mycosis fungoides (MF) and Sézary syndrome
(SS). Together, they make up about three quarters
of all CTCL. Mycosis fungoides is the most
common form of CTCL. Because of that, the terms
MF and CTCL are often used interchangeably, and
sometimes imprecisely. MF is an indolent type of
CTCL, follows a slow, chronic course and very
often does not spread beyond the skin. Over time,
in about 10% of cases, it can progress to lymph
nodes and internal organs.
Symptoms of MF can include flat, red, scaly
patches, thick raised lesions, and sometimes large
nodules called tumors. The disease can progress
over many years, often decades. MF patches and
plaques are often mistaken for eczema, psoriasis
or “non-specific” dermatitis until an exact
diagnosis is made. A common characteristic is
itching. MF is very difficult to diagnose in early
stages as symptoms and skin biopsy findings
are similar to other skin conditions, leading to
frequent misdiagnosis. Patients may go on for
years before a definitive diagnosis is established.
Both the clinical findings (based on both history
and examination) and the skin biopsy findings
are essential for diagnosis. Sézary syndrome is a
less common but more aggressive type of CTCL
that is related to MF but presents with very severe
itching, total body redness (erythroderma), intense
scaling of the skin and frequent hair loss. Lymph
nodes are usually enlarged, and the malignant
T-cells found in the skin are also seen circulating
in the bloodstream. SS is the only type of CTCL
that always affects the skin and the blood.
The skin may be red from head to toe. Tumor
cells are found in the blood, and lymph nodes
are larger than usual. The skin may be hot,
sore, extremely itchy, occasionally flaking and
burning. Oozing of clear fluid from the skin is
common. Because much heat is lost through the
skin, people often feel cold. Symptoms may be
accompanied by changes in nails, hair or eyelids.
Approximately 15% of patients with CTCL have
SS. This disease usually occurs in adults older
than 50 and is found more in men than women.
In general, B-cell non-Hodgkin’s lymphomas are
much more common than T-cell non-Hodgkin’s
lymphomas (85% versus 15%). However, in the
skin, the opposite is true: CTCL makes up about
75-80% of all cutaneous lymphomas, whereas
CBCL makes up about 20-25%. CBCLs are B-cell
non-Hodgkin’s lymphomas which originate in
skin-based B-cells. The fact that most skin-resident
lymphocytes are T-cells, rather than B-cells, may
explain the difference. Following are stages for
mycosis fungoides and Sézary syndrome: Stage
IA: Less than 10% of the skin is covered in red
patches or plaques. Stage IB: 10% or more of the
skin is covered in patches or plaques. Stage IIA:
Any amount of the skin surface is covered with
patches or plaques and lymph nodes are enlarged
and inflamed, but the cancer has not spread to the
nodes. Stage IIB: One or more tumors are found on
the skin, lymph nodes may be enlarged, but cancer
has not spread to the nodes. Stage III: Nearly all
of the skin is reddened and may have patches,
plaques or tumors; lymph nodes may be enlarged,
but cancer has not spread to them. Stage IVA:
Most of the skin is reddened and malignant cells
are found in the blood; cancer has spread to the
lymph nodes. Stage IVB: Most of the skin is red,
any amount of skin is covered in patches, plaques
or tumors, cancer has spread to other organs.
Tumors are raised “bumps” or “nodules” which
may or may not ulcerate. To be called a tumor,
generally a nodule has to be at least 1 cm in size,
or greater.
A common symptom is itching.
The most common form of cutaneous
lymphoma, mycosis fungoides, often presents
with an area of red, slightly scaly skin, usually
in sun-protected parts of the body, with variable
size and shape. Common locations for these
symptoms are the buttocks, trunk, upper thighs
– all areas that are typically shielded from sun
exposure. Patients with cutaneous lymphoma
find their outbreaks in sun-protected areas of
the skin because the natural UV component of
sunlight may have a protective effect against
mycosis fungoides. The exact reason, however, is
not known. Sézary syndrome (SS) is one type that
can present in generalized redness affecting 80%
or more of the skin’s surface. Patients with SS tend
to experience very intense itching, perhaps the
most intense and relentless itching that has ever
been described. They often lose large amounts
of skin during the night and may find their bed
sheets covered with skin flakes in the morning.
This variation presents more dramatically than
other types of the disease, making it easier
to diagnose because the presentation is more
unusual. Sézary syndrome patients will likely
also feel tired, have enlarged lymph nodes, may
run a fever and just generally feel sick. Common
Signs & Symptoms of Sézary Syndrome: Diffuse
scaling skin (erythroderma), Thickening of
palms and soles (hyperkeratosis), Hair thinning,
Eyelid margin thickening (ectropion), Itching and
Enlarged lymph nodes. The process for diagnosis
is similar for all types and may include a physical
exam and history; blood tests to identify antigens,
or markers, on the surface of cells in the blood;
and a skin biopsy (removal of a small piece of
tissue) for examination under the microscope by
a pathologist (a doctor who studies tissue and
cells to identify disease). Bone marrow biopsy
may occasionally be necessary to verify complete
staging of the disease. This is more likely to be
needed with cutaneous B-cell lymphomas than
cutaneous T-cell lymphomas.
To conduct an effective, informative biopsy,
patients need to be off topical steroids and
ultraviolet light treatment regimens for at least
a week or two. While these treatments may
provide temporary symptom relief, they can also
mask potential symptoms of skin lymphomas
and thus delay a patient’s definitive diagnosis.
Cutaneous T-cell lymphoma is a complex
disorder which often takes a significant amount
of time to diagnose. Various studies indicate
that the average time from first appearance
of symptoms to confirmed diagnosis of the
disease ranges from two to seven years. This
delay can lead to frustration for both the
patient and healthcare providers. The most
useful test is a skin biopsy because lesions that
appear very similar on the skin may look quite
different under the microscope. Many patients
require multiple biopsies before a satisfying
and complete diagnosis is made. The need for
multiple, sequential biopsies can be exasperating
and difficult for patients to understand. Mycosis
fungoides is difficult to diagnose in early stages
as the symptoms and skin biopsy findings are
similar to those of other conditions.
The best way to manage a disease like
cutaneous lymphoma is by assembling the right
team of physicians and support individuals to
guide your treatment course as dermatologist,
oncologist, radiation oncologist. Early stages
have typically been treated with skin-directed
therapy by dermatologists, with little oncology
input, and advanced stages have typically been
treated with systemic therapy by oncologists,
with little dermatology input. The only better
alternative to this scenario is the ideal situation
of a multidisciplinary clinic, where the entire
team of doctors is wholly focused and dedicated
to the care of patients with cutaneous lymphoma.
Multidisciplinary clinics, by definition, have an
oncologist and a dermatologist on site, both
in a leading role, in addition to a large number
of additional supporting staff. Such clinics,
unfortunately, are available only in a small
number of selected cancer centers. Treatment
choices for cutaneous lymphoma are directed
at either the skin (topical) or the entire body
(systemic). Medications you put on the skin
including topical corticosteroids, chemotherapies,
and retinoids (made from Vitamin A).
27
2016, 28: N. 4
• Light therapy (phototherapy) that exposes
affected areas of the skin to special ultraviolet
(UV) rays.
• Radiation therapy that uses high-dose X-rays
.Biologic therapies (or immunotherapies) use the
body’s own immune system to fight cutaneous
lymphoma.
• Retinoids are Vitamin-A related compounds
that are active in treating cutaneous lymphoma.
• Extracorporeal photopheresis (ECP) involves
taking blood from a vein and passing it through a
machine, where it is treated with a drug that makes
white blood cells (particularly T-lymphocytes)
more sensitive to UV light. The blood is then
exposed to UV light and returned to the body.
• Chemotherapy uses a single anticancer drug or
a combination of drugs.
Chemotherapy uses chemicals that interfere with
cell division, Bone marrow or stem cell transplantation
is considered in cases for patients with advanced
disease In general, early-stage patients (IA, IB, IIA)
should consider topically-applied medications or
ultraviolet light therapy over pills and IV medications
because they are usually very effective, have fewer
side effects, and the prognosis is usually very good.
Chemotherapy administered as single agent
or in combination may be used to treat the
manifestations of advanced cutaneous lymphoma.
Combination or multi-agent chemotherapy is
usually reserved for advanced stages of disease.
Methotrexate (Matrex ®) is an anti-metabolite
agent used for a host of immune-based diseases.
It interferes with folic acid metabolism in cancer
cells. In cutaneous lymphoma, this is administered
in oral form by pill weekly. Pralatrexate (Folotyn®)
is used in the treatment of transformed mycosis
fungoides and other aggressive non-Hodgkin’s
lymphomas such as peripheral T-cell lymphoma.
It is a folate metabolic inhibitor which targets the
same pathway as methotrexate. Patients receiving
pralatrexate therapy take a daily dose of folic
REFERENCES
28
1) Habib F.A. Pregnancy in a patient with nonHodgkin lymphomas: Qatar Medical journal 2002;
11(1).
2) Non-Hodgkin’s Lymphoma During Pregnancy,
General Information About Non-Hodgkin Lymphoma
During Pregnancy. http://cancer.gov
3) Macfarlane GJ, Evstifeeva T, Boyle P. International
patterns in the ocuurence of Hodgkin’s disease
in children and young adult males. Int J Cancer
acid and receive Vitamin B12 injections every 8
to 12 weeks. It is delivered intravenously every
3 weeks, followed by a rest week. Alemtuzumab
(Campath®) is a monoclonal antibody directed
against the CD52 antigen (surface marker) found on
both B-lymphocytes and T-lymphocytes. The use
of chemotherapy drug combinations in cutaneous
lymphoma should be discouraged because they
have never been proven to be more effective than
sequential single agents, and they are always
much more toxic. Combinations such as CHOP
(cyclophosphamide, doxorubicin, vincristine, and
prednisone), ESAHP (etoposide, solumedrol, highdose ara-C, and cisplatin), and GND (gemcitabine,
navelbine, and doxil) may be used when no other
therapy is available, or in rare circumstances as a
way to produce brief responses in preparation for a
bone marrow transplant.
CONCLUSION
Lymphoma is a rare disease in pregnancy. The
diagnosis of NHL in pregnancy may be delayed
because of reluctance to subject the patient to
investigation of skin lesions, X-rays and surgical
procedures for the non-specific symptoms
also may be mistaken for normal dermatoses
of pregnancy. Therefore this diagnostic delay
should be avoided by all means maintaining
a liaison between haematologist, oncologist
and obstetrician. Doctors should be a ware of
the normal skin lesions differentiating it form
abnormal ones.
Darkening of skin color especially hidden
areas from sun, generalized skin lesion, scaling,
redness and hyperkeratosis are not normal in
pregnancy. Cutaneous cell lymphoma should be
excluded in any skin lesion during pregnancy by
dermatological consultation.
1995;61:165-9.
4) Beksaç MS. Maternal Fetal T›p ve Perinatoloji.
Ankara: Nobel, 2001;733-4.
5) Haznedar R. Hematolojik Hastal›klar. Ankara:
Günefl Kitabevi, 1996;1:10:1298-1312.
6) Horowitz NA, Benyamini N, Wohlfart K, Brenner
B, Avivi I. Reproductive organ involvement in nonHodgkin lymphoma during pregnancy:A systematic
review. Lancet Oncol 2013; 14: 275–282.
7) 19. McLaren J, Taylor DJ, Bell SC. Increased incidence
of apoptosis in non-labour-affected cytotrophoblast
cells in term fetal membranes overlying the cervix.
Hum Reprod 1999; 14: 2895– 2900.
8) Jesus Ortega. Multiple agent chemotherapy
including bleomycin of non-hodgkin’s lymphoma
during pregnancy; Cancer cytopathology CA: A cancer
journal for clinician. 40(6): 2829-2835
9) Non-Hodgkin’s lymphoma during pregnancy:
Treatment - Health Professional Information:
10) National Cancer Institute via the Internet web site
at http://cancer.gov or call 1-800-4-CANCER
11) C.C. Lees, M. Tsirigotis, J.V.L. Carr and M.A.
Richards’ T cell non-Hodgkin’s lymphoma presenting
in the first trimester of pregnancy Postgrad Med J 1994;
70: 371-372.
12) Masuhiro Kazuo. Successful chemotherapy
during pregnancy complicated with non- Hodgkin’s
lymphoma. Advances In Obstetrics And Gynecology.
2001; 53(4): 323-328.
13) J.M. Rodriguez and M. Haggag. VACOP-B
chemotherapy for high grade non-Hodgkin’s
lymphoma in pregnancy; Clinical oncology 1995; 7(5):
319-320.
14) Michael Herold, Sabine Schnohr, Hans Bittrich.
Efficacy and Safety of a Combined Rituximab
Chemotherapy during Pregnancy Journal of Clinical
Oncology, 2001; 19(14): 34-39.
15) Pregnancies after high-dose chemotherapy
and autologous stem cell transplantation ASCT in
aggressive lymphomas. Blood, 2002; 100(2): 736-736.
16) Thomas P. Miller. Steve Dahlberg. Chemotherapy
alone compared with Chemotherapy plus Radiotherpy
for localized Intermediate and High grade NonHodgkin’s Lymphoma. The new England Journal of
Medicine 1998; 339(2): 21- 26.
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30
Italian Journal of
One Case of Severe Preeclampsia Who Died from Postpartum
Complications Ten Days after Caesarian Delivery
Myrvete Pacarada¹, Astrit M. Gashi ¹, Albiona Beha¹, Bujar Obertinca¹
1
Department of Obstetrics and Gynecology, University Clinical Centre of Kosovo, Pristine
ABSTRACT
Preeclampsia is clinically defined by hypertension and
proteinuria, with or without pathologic edema that
can happen after 20 week’s gestation, but can happen
well 4-6 weeks post partum. Worldwide, incidence of
preeclampsia is 5-14 percent of all pregnancies, while
severe preeclampsia can develop to about 25 percent
of all cases of preeclampsia. Severe preeclampsia is a
pathology that can often be complicated. This pathology
may lead to liver and renal failure, disseminated
intravascular coagulopathy (DIC), and central nervous
system (CNS) abnormalities. In world, preeclampsia
and eclampsia is responsible for about 14 percent of
maternal deaths per year. We present a case, from our
clinic, which has had serious complications after birth
and that ended with the death of the patient. Despite the
adequate management with the timely diagnosis and
therapy, patient died ten days after Caesarian delivery.
Keywords: Severe Preeclampsia; Eclampsia; Postpartum
Complications; Caesarian Delivery; Bad Outcomes
SOMMARIO
Preeclampsia è clinicamente definita da ipertensione
e proteinuria, con o senza edema patologica che può
accadere dopo la gestazione di 20 settimana, ma può
succedere ben 4-6 settimane dopo il parto.
In tutto il mondo, l’incidenza di preeclampsia è 5-14 per
cento di tutte le gravidanze, mentre preeclampsia grave
possono sviluppare a circa il 25 per cento di tutti i casi di
preeclampsia. preeclampsia severa è una patologia che
spesso può essere complicato.
Questa patologia può portare a fegato e insufficienza
renale, coagulopatia intravascolare disseminata (DIC), e
le anomalie del sistema nervoso centrale (SNC).
Nel mondo, preeclampsia e eclampsia è responsabile di
circa il 14 per cento delle morti materne ogni anno.
Presentiamo un caso, dalla nostra clinica, che ha avuto
gravi complicazioni dopo la nascita e che si concluse
con la morte del paziente. Nonostante una gestione
adeguata con la diagnosi tempestiva e la terapia, il
paziente è morto dieci giorni dopo il parto cesareo.
INTRODUCTION
MPre-eclampsia is clinically defined by
hypertension and proteinuria, with or without
pathological oedema that can happen after
20 week’sgestation, but can occur well 4-6
weeks post-partum (1) . Severe preeclampsia
defined as the presence of high blood pressure
(systolic blood pressure is 160 mm Hg or
higher and diastolic blood pressure 110 mm
Hg or higher). b). Impaired hepatic function
(doubling of the liver enzymes levels) c).
Epigastric pain or right upper quadrant pain
d). Renal insufficiency(doubling of the serum
creatinine levels). e). Pulmonary edema, f).Visual
Correspondence to: [email protected],
[email protected]
DOI: 10.14660/2385-0868-51
disturances g).Thrombocytopenia. Worldwide,
incidence of pre-eclampsia is 5-14 percent of all
pregnancies. In developing nations, incidence
of pre-eclampsia is 4-18 percent(2, 3). Severe preeclampsia can develop to approximately 25
percent of all cases of pre-eclampsia(4). Morbidity
and mortality in pre-eclampsia and eclampsia are
frequent. Severe pre-eclampsia may lead to liver
and renal failure, disseminated intravascular
coagulopathy (DIC), and central nervous system
(CNS) abnormalities. In world, preeclampsia
and eclampsia is responsible for approximately
14% of maternal deaths per year (50,000-75,000)
(5)
. A woman with severe preeclampsia ago, and
complicated in eclampsia or HELLP syndrome,
she has a 20% risk of developing preeclampsia in
her subsequent pregnancy(6-11).
31
2016, 28: N. 4
Severe Preeclampsia, Postpartum Complications and Bad Outcomes - A Case Report
CASE PRESENTATION
A 34-year-old woman who was 29 weeks
pregnant, was accepted in Department of
Obstetrics and Gynecology, University Clinical
Centre of Kosovo, in severe general condition,
with dyspnoea, expressed cyanosis, tachycardia,
epigastric pain. At the office of admission she
had a blood pressure of 90/60 mmHg, plus 105
beats per minute, saturation was 96. In physical
examination see a defect congenetal of curvature
of the spine (kyphoscoliosis). Skin and mucous
membranes were pale. Laboratory findings;
hemogram was normal, urine analysis (protein
1+). Biochemical laboratory tests: serum aspartate
aminotransaminase (AST), 67 IU/L; serum alanine
aminotransaminase (ALT), 120 IU/L; serum
lactate dehydrogenase (LDH), 839 IU/L; serum
urea 10.74 and creatine was normal; Triglyceride,
3.49 mmol/L; hemoglobin and platelet count
were normal. Coagulation profile was normal.
There were consultations with a cardiologist,
anesthesiologist and pulmonologist, was found
that the patient is in acute pulmonary edema.
With echocardiography is found pericardial
effusion, other parameters anatomical structure
of the heart to normal. Are done chest x-ray,
electrocardiogram and all necessary imaging
examinations. The patient was transferred to
intensive care unit, where intubated and connected
to the respiratory apparatus. After consultations
is completed diagnosis: 29 weeks pregnant,
Preeclampsia, Pericardial effusion, Pulmonary
edema, Respiratory insufficiency, Kyphoscoliosis,
Neurofibromatosis, Rh incompatibility. After
stabilization of vital parameters for several hours,
decided to terminate the pregnancy, obtained
a written consent of the patient. A Pfannenstiel
incision was made and a fetus the female was
delivered, who had birth weight 1340 grams
and apgar score 1 in the first minute and 3 in
the fifth minute. The patient was treated with
supplementary oxygen, crystalloid, antibiotics,
H2-blockers, LMWH, B-blockers, diuretic,
analgesic, enteral nutrition, vitamin preparations,
mucolytics, corticosteroids, anti hypertensive and
anti-emetic. After a week of treatment in intensive
care unit, the patient’s condition was improving,
REFERENCES
32
1) Lagana AS, Favilli A, Triolo O, Granese R, Gerli S.
Early serum markers of pre-eclampsia: are we stepping
forward? J Matern Fetal Neonatal Med. 2015 Nov 23. 1-5.
2) Villar J, Betran AP, Gulmezoglu M. Epidemiological
basis for the planning of maternal health services.
extubated and back again in Department of
Obstetrics and Gynaecology in monitoring by the
cardiologist, anaesthesiologist and pulmonologist.
After seven days reiterates the patient’s condition
deteriorates rapidly, the patient undergoes cardiac
arrest, despite the resuscitation measures, ends
with death (exitus letalis).
DISCUSSION
Pre-eclampsia is disseminated disease the
vascular endothelial malfunction and generalized
vasospasm. However, the pathophysiologic
mechanism for preeclampsia is very complex.
Severe preeclampsia can develop to approximately
25 percent of all cases of preeclampsia(12). In world,
preeclampsia and eclampsia is responsible for
approximately 14 percent of maternal deaths per
year(13). This disease may lead to liver and renal
failure, disseminated intravascular coagulopathy
(DIC), and central nervous system (CNS)
abnormalities and end with the death of patient.
Often clinicians could not predict the development
of life-threatening complications from
preeclampsia, development of rapid of this disease
may end very easily so fatal for the patient. The
correct management is very important for patients
with preeclampsia. The clinician must perform
a detailed assessment as history and physical
examination with careful. Laboratory values
including complete blood count, urine protein,
liver enzymes, and a coagulation profile should be
obtained. The patient in our case complained of
epigastric pain, breathing difficulties (dyspnoea),
in inspection she had expressed cyanosis, while in
auscultation tachycardia.
We present a case, from our clinic, which has
had serious complications after birth and that
ended with the death of the patient. Despite the
adequate management with the timely diagnosis
and therapy, patient died ten days after Caesarian
delivery.
Conflict of Interests
All the authors not have any conflict of interests
that of the monument to Victor Emmanuel II
WHO/RHR. 2001.
3) Khedun SM, Moodley J, Naicker T, et al. Drug
management of hypertensive disorders of pregnancy.
Pharmacol Ther. 1997. 74(2):221-58.
4) Sibai BM. Magnesium sulfate prophylaxis in
Severe Preeclampsia, Postpartum Complications and Bad Outcomes - A Case Report
preeclampsia: Lessons learned from recent trials. Am J
Obstet Gynecol. 2004 Jun. 190(6):1520-6.
5) WHO, 2004. Bethesda, MD. Global Burden of
Disease for the Year 2001 by World Bank Region,
for Use in Disease Control Priorities in Developing
Countries, National Institutes of Health: WHO. Make
every mother and child count. World Health Report,
2005, Geneva: World Health Orga... 2nd ed.
6) Sibai BM, Ramadan MK, Chari RS, et al. Pregnancies
complicated by HELLP syndrome (hemolysis, elevated
liver enzymes, and low platelets): subsequent
pregnancy outcome and long-term prognosis. Am J
Obstet Gynecol. 1995 Jan. 172(1 Pt 1): 125-9.
7) Chames MC, Haddad B, Barton JR, et al. Subsequent
pregnancy outcome in women with a history of HELLP
syndrome at < or = 28 weeks of gestation. Am J Obstet
Gynecol. 2003 Jun. 188(6):1504-7; discussion 1507-8.
8) Sibai BM, Sarinoglu C, Mercer BM. Eclampsia. VII.
Pregnancy outcome after eclampsia and long-term
prognosis. Am J Obstet Gynecol. 1992 Jun. 166(6 Pt
M. Paracada et al.
1):1757-61; discussion 1761-3.
9) Lopez-Llera M, Hernandez Horta JL. Pregnancy
after eclampsia. Am J Obstet Gynecol. 1974 May 15.
119(2):193-8.
10) Adelusi B, Ojengbede OA. Reproductive
performance after eclampsia. Int J Gynaecol Obstet.
1986 Jun. 24(3):183-9.
11) Sibai BM, Mercer B, Sarinoglu C. Severe
preeclampsia in the second trimester: recurrence risk
and long-term prognosis. Am J Obstet Gynecol. 1991
Nov. 165(5 Pt 1):1408-12.
12) Sibai BM. Magnesium sulfate prophylaxis in
preeclampsia: Lessons learned from recent trials. Am J
Obstet Gynecol. 2004 Jun. 190(6):1520-6.
13) WHO, 2004. Bethesda, MD. Global Burden of
Disease for the Year 2001 by World Bank Region,
for Use in Disease Control Priorities in Developing
Countries, National Institutes of Health: WHO. Make
every mother and child count. World Health Report,
2005, Geneva:World Health Orga... 2nd ed.
33
SIGO 2016
91° congresso
nazionale SIGO
56° congresso
nazionale AOGOI
23° congresso
nazionale AGUI
ROMA
Ergife Palace Hotel
16/19 Ottobre 2016
Segreteria organizzativa:
presidenti
Giovanni Scambia
Enrico Vizza
LA SALUTE AL FEMMINILE
TRA SOSTENIBILITA’
E SOCIETA’ MULTIETNICA
Associazione Ginecologi
Universitari Italiani
Italian Journal of
Polyglandular Autoimmune Syndrome in pregnancy: case report.
Basilio Pecorino1, Maria Cristina Teodoro1, Paolo Scollo1
1
Division of Gynecology and Obstetrics, Maternal and Child Department, Cannizzaro Hospital, Catania, Italy
ABSTRACT
Type III Polyglandular Autoimmune Syndrome is
a multiple endocrine disorders disease determined
by autoimmunity; it can be diagnosed if a patient
is affected by Type 1 Diabetes Mellitus and another
autoimmune disease, except Addison Disease, for
example Autoimmune Hashimoto Thyroiditis or Celiac
Disease.
R.D., 34-year-old woman (gravida 2 para 1), was
referred to the High Risk Pregnancy Outpatient
Clinic at Cannizzaro Hospital in Catania at 8 weeks’
gestation. She was affected from type III Polyglandular
Autoimmune Disease (Type 1 Diabetes Mellitus,
Autoimmune Hashimoto Thyroiditis and Celiac
Disease). Pre-conception glycated hemoglobin and
thyrotropin levels were normal. This pregnancy was
characterized by glycemic instability and the need to
increase the insulin units every month. The patient
was hospitalized at 32+6 weeks for monitoring fetus
and mother health because of inadequate glycemic
control and the high insulin dosage required. She was
delivered by caesarean section at 36+6 weeks because
of uterine contractions, the previous cesarean section,
glycemic instability and the gestational age. She
delivered a baby boy, birth-weight 3300 g, Apgar 8-9.
She was discharged in the fourth day after delivery
with good maternal and child prognosis. Literature
data and the experience derived by this case report
suggest some recommendations to improve obstetrics
and neonatologist outcome in the patients affected
from type III Polyglandular Autoimmune Syndrome:
pre-conception counseling, thyrotropin assay every 4-6
weeks, gluten-free diet, fasting and post-prandial blood
glucose level targets.
SOMMARIO
La Sindrome Polighiandolare Autoimmune di tipo
III è un disordine endocrino multi-organo su base
autoimmunitaria che può essere diagnosticato
in presenza di Diabete Mellito tipo 1 ed un’altra
endocrinopatia, ad eccezione della Malattia di Addison,
per esempio Tiroidite di Hashimoto o Morbo Celiaco.
RD, 34 anni, G2P1, è stata presa in carico dall’ambulatorio
di gravidanza a rischio dell’Ospedale Cannizzaro di
Catania nel corso della 8° settimana di amenorrea.
La paziente era affetta da Sindrome Polighiandolare
Autoimmune di tipo III (Diabete Mellito tipo 1, Tiroidite
di Hashimoto e Morbo Celiaco). I valori preconcezionali
di emoglobina glicata e tireotropina erano nella norma.
La gravidanza è stata caratterizzata da instabilità
glicemica con necessità di aumentare il dosaggio
insulinico ogni mese. La paziente è stata ricoverata a
32+6 settimane per monitoraggio materno-fetale, a causa
dello scarso controllo glicemico e l’elevato dosaggio
d’insulina richiesto. A 36+6 settimane è stato eseguito
taglio cesareo per l’insorgenza di attività contrattile
uterina in paziente già cesarizzata e con scarso controllo
glicemico; neonato maschio, peso alla nascita 3300,
Apgar 8-9. La paziente è stata dimessa in 4° giornata
post-operatoria con buona prognosi, sia materna
sia neonatale. I dati della letteratura e l’esperienza
derivante da questo caso clinico suggeriscono alcune
raccomandazioni per migliorare l’outcome ostetrico
e neonatologico nelle pazienti affette da Sindrome
Polighiandolare Autoimmune di tipo III: counseling
pre-concezionale, dosaggio della tireotropina ogni 4-6
settimane, dieta aglutinata, glicemia a digiuno e postprandiale entro i valori target.
Keywords: Pregnancy, Diabetes, Hashimoto, Celiac
Disease, Polyglandular Autoimmune Syndrome,
Management, Outcome, Counseling, Obstetrics,
Neonatologist.
DOI: 10.14660/2385-0868-52
35
2016, 28: N. 4
INTRODUCTION
36
Type III Polyglandular Autoimmune Syndrome
(PAS III) is a multiple endocrine disorders disease
determined by autoimmunity. PAS III can be
diagnosed if a patient is affected by Type 1 Diabetes
Mellitus (T1DM) and another autoimmune
disease, except Addison Disease, for example
Autoimmune Hashimoto Thyroiditis (AIT) or
Celiac Disease (CD). The prevalence of APS III is
1/20000(1). T1DM is an insulin-dependent diabetes
that occurs when activated T cells attack and
destroy most of the beta cells; often there are also
humoral autoimmunity events (auto-antibodies).
There is a genetic predisposition to T1DM, that is
caused by Human Leukocyte Antigen (HLA) gene
mutations but it’s also necessary the influence of
individual and environmental factors to determine
physiopathology of diabetes 2.
The HLA gene mutations determine high
individual predisposition to autoimmune disease
like T1DM, AIT and CD. In fact, it’s known that a
person affected from T1DM has higher risk of AIT
and CD, compared to healthy people(1,2).
AIT it is an autoimmune thyroiditis with
anti-TPO antibodies (thyroperoxidase), anti-TG
antibodies (thyroglobulin) and high serum TSH
concentrations in the chronic period of disease.
Treatment of AIT is based on levothyroxine
sodium to normalize TSH levels(1).
CD is defined as a pertinent intolerance
to dietary gluten. In 1888, Samuel Gee first
described the clinical features of coeliac sprue 1.
It is one of the most common genetic disorders.
Its incidence in the European population ranges
from 0.03 – 0.04% and the highest incidence rates
are found in the countries of northern Europe:
Sweden – 2.4/1,000 births, UK – 1.49/1,000. This
inflammatory state leads to changes in the small
bowel mucosa architecture including increased
infiltration of lymphocytes into the epithelial
cells, villous atrophy and crypt distortion. These
intestinal changes can lead to malabsorption
of macro - and micro - nutrients, resulting in
symptoms of malabsorption such as weight loss
and diarrhea(4). The only treatment available is the
elimination of gluten from the diet, which can lead
to mucosal lesions recovery.
In patients with diabetes type 1, celiac disease
has been significantly more frequently diagnosed
than in the general population(3). In patients
affected by diabetes type 1, celiac disease is
usually oligosymptomatic or asymptomatic and
the frequency of coexistence of both disorders
increases with patient’s age and duration
of diabetes(3). A reverse phenomenon is also
Polyglandular Autoimmune Syndrome in pregnancy
characteristic, i.e. higher prevalence of diabetes
type 1 in celiac disease patients and greater
frequency of diabetes-specific antibodies in this
group of patients(3).
Women have higher incidence of autoimmune
disease than men, with a 3:1 female/male ratio.
Furthermore, the most at-risk age is between 30
and 50 years, that is a potentially fertile period
of the woman’s life. Hence autoimmune diseases
have an important role to influence fertility and
to determine the outcome of pregnancy. In fact,
T1DM and autoimmune diseases increase the
risk of abortion, intra-uterine growth restriction
(IUGR), placental insufficiency, premature rupture
of membranes, cesarean section, pre-eclampsia/
eclampsia and preterm birth (4,5). Fortunately,
pregnancy often determines remission of
autoimmunity, and the management of these
patients is easier. In other cases, especially when
pre-conception counseling and planning are
inadequate, the management of pregnancy may
be difficult(6). In fact, diabetes decompensation can
determine reactivation of the other autoimmune
diseases in the patients affected from PAS.
We will show a case of a pregnant woman
affected from T1DM, AIT and CD (mixed type III
PAS) with the aim to advice a management of the
case with good both obstetrics and neonatologist
outcome.
CASE REPORT
R.D., 34-year-old woman (gravida 2 para 1) was
referred to the High Risk Pregnancy Outpatient
Clinic at Cannizzaro Hospital in Catania at 8
week’s gestation. Familial medical history was
positive for autoimmune disease and T1DM in her
brother. She was born by a vaginal delivery and
she was a macrosomic baby (birth-weight 4500 g).
She had a normal range BMI (22) on admission
and she suffered from Celiac disease, Hashimoto’s
thyroiditis medicated with levothyroxine 50 µg,
and type 1 diabetes. On admission she had HbA1c
within the normal range (5.9 %). She had menarche
at 12 years old, and she has always regular
menstrual cycle. Up to the first consultation, her
obstetric history was 2G 1P. The first pregnancy
was complicated by Gestational Diabetes in the
third trimester, and it resulted in cesarean section
for glycemic instability. She delivered a female
healthy preterm baby in Ancona Hospital (36+6
weeks, birth-weight 3310 g).
Similarly this pregnancy was characterized by
glycemic instability and the need to increase the
B. Pecorino et al.
insulin units every month. Also levothyroxine
raised to 75 µg because of a mild elevated TSH
level (TSH 3.58 µU/ml).
She suffered from iron deficiency anemia
(hemoglobin 10.8 g/dl; iron serum 39 mg/
dl) probably resulting from gastrointestinal
malabsorption.
Fetal monitoring is considered mandatory in
such pregnancies and all the diagnostic tests and
surveillance fetal health examination were regular
(first trimester screening; second and third
trimester ultrasounds; fetal echocardiography,
fetal biometry and umbilical artery Doppler
velocimetry).
The patient was hospitalized at 32+6 weeks
for monitoring fetus and mother health because
of inadequate glycemic control and the high
insulin dosage required (Humalog 26+25+24;
Lantus Solostar 36 units).
Blood pressure and routine blood examination
were normal: stable hemoglobin (10.8 g/dl),
low iron serum level (28 mg/dl); electrolytes
and function kidneys tests within normal limits
(serum sodium 137 mmol/L, potassium 3.7
mmol/L, clorum 108 mmol/L; creatinine 0.60
mg/dl and no proteinuria).
She followed a gluten-free 2000 calories diet,
she had daily diabetes visits and appropriate
insulin therapy modification. Strict glycemic
control continued throughout the entire
pregnancy and she self-monitored plasma
glucose 7 times daily: fasting glucose at 8 on
the morning; pre-meals and 1 H post-meals.
Furthermore, there were some episodes of severe
hypoglycemia in the evening and in the middle
of the night.
She was delivered by Caesarean section at
36+6 weeks because of uterine contractions, the
previous cesarean section, glycemic instability
and the gestational age. She delivered a baby boy,
birth-weight 3300 g, Apgar 8-9.
Post-operative course was regular and all
laboratory examinations were in the normal range
(hemoglobin 10.1 g/dl). After delivery, there was
a significant increase in insulin sensitivity; so, it
was necessary a reduction of the dose of insulin
to approximately 50 % of the pregnancy dose:
Humalog 8 UI+14 UI +10UI, Lantus 16 UI in the
night; and self-monitoring of plasma glucose
every two hours.
She was discharged in the fourth day after
delivery and she had a moderate glycemic control.
DISCUSSION
An autoimmune disease (AID) is characterized
by tissue damage, caused by self-reactivity of
different effectors mechanisms of the immune
system, namely antibodies and T-cells and/
or environmental predisposition. There is an
activation of the adaptive immune response with
tissue damage and inflammation in the absence of
any infection, exposure to toxins or tumor growth(1).
Type 1 diabetes is one of the most frequent
endocrine disorders. Although T1DM onset was
once thought to be restricted to children and
adolescents, it can occur at any age, with the
highest rate of incidence below the age of 30 years(3).
Approximately 50 T1DM susceptibility genes have
been identified to date. These genes also carry a
potential risk for various autoimmune diseases
occurring simultaneously or within a narrow time
interval and might explain to some extent why
additional endocrine autoimmune diseases are
comorbid in one third of all T1DM patients(8-12).
These associated autoimmune disorders are either
glandular diseases [e.g., Addison’s disease or
autoimmune thyroid disease (AITD)] that lead
to polyglandular autoimmune syndrome (PAS)
or non-glandular autoimmune diseases (e.g.,
rheumatoid arthritis or celiac disease)(7).
Several linkage studies showed the importance
of genetic predisposition and the association of
T1D with polymorphisms in the specific HLA loci
on chromosome 6p21.3 8. HLA class II loci are
assumed to be responsible for 40%-50% genetic
risk 8 and graded 1 as follows: the highest risk
was found in DR3/4 heterozygotes, followed by
DR4 homozygotes, DR3 homozygotes and DR4
heterozygotes combined with another DR allele (1).
Furthermore, many non-HLA polymorphisms
that appear to make a smaller contribution to the
manifestation of T1DM have been identified (1).
Nevertheless, a concordance rate lower than 50%
in monozygotic twins, a manifestation of T1DM in
10% of the carriers of high-risk genes and a 15-fold
difference in the disease incidence among European
Caucasians indicates that genetics alone cannot
explain disease onset (9). In contrast, an increase in
patients with low-risk or protective HLA genotypes
emphasizes the importance of environmental
factors such as viral infections, nutrition and
chemicals or epigenetics, respectively(1).
PAS, characterized by a combination of at
least two autoimmune endocrinopathies, can be
classified into a juvenile form (PAS type I) and an
adult form, which is then subdivided according to
the specific constellation of autoimmune glandular
diseases (PAS types II-III).
37
2016, 28: N. 4
38
1) Type I PAS (APECED-autoimmune
polyendocrinopathy–candidiasis–ectodermal
dystrophy): a monogenic autoimmune syndrome
caused by defects in the AIRE gene located on
chromosome 21. Its major components include
candidiasis of the skin and mucous membranes,
hypoparathyroidism, and Addison’s disease.
Its inheritance exhibits an autosomal recessive
pattern. PAS type 1 affects children around the age
of 10-12-10.
2) Type II PAS: defined as a combination
of autoimmune adrenal insufficiency with
autoimmune thyroid disease and/or type 1
diabetes mellitus. It is characterized by obligatory
occurrence of autoimmune Addison’s disease in
combination with thyroid autoimmune diseases
and/or type 1 diabetes mellitus. Women are three
times more likely to develop it than men(2, 3). The
prevalence of PAS II increases gradually in the
first decade of life and reaches the highest values
between 25-40 years of age 10.
3) Type III PAS: composed of autoimmune
thyroid diseases associated with endocrinopathy
other than adrenal insufficiency. It mainly affects
women in their 30s. Thyroiditis usually occurs
first. PAS III can be further classified into the
following three subcategories:
A – Autoimmune thyroiditis with immunemediated diabetes (T1DM) mellitus (also known
as polyglandular autoimmune syndrome type 3
variant);
B – Autoimmune thyroiditis with pernicious
anemia;
C – Autoimmune thyroiditis with vitiligo
and/or alopecia and/or other organspecific autoimmune disease (celiac disease,
hypogonadism, and myasthenia gravis), organnonspecific or systemic autoimmune diseases
(sarcoidosis, Sjögren syndrome, rheumatoid
arthritis)(11).
PAS type III is the most frequent subtype
of polyglandular autoimmune diseases 3.
The co-occurrence of autoimmune-induced
hypothyroidism (generally caused by chronic
lymphocytic Hashimoto’s thyroiditis) and T1DM
is often accompanied by hypoglycemia due to
increased insulin sensitivity. Hypothyroidism
leads to a reduction in glucose reabsorption in the
duodenum and glucose release from the liver.
Overt hyperthyroidism is accompanied in
50% of the cases by glucose intolerance and in
3% of the cases by overt diabetes. The impaired
glucose tolerance is due to decreased insulin
sensitivity and decreased hepatic storage of
glycogen, whereas both secretion of glucagon and
intestinal glucose absorption are enhanced leading
to hyperglycemia 3. Onset of T1DM in patients
autoimmune thyroid disease (Grave’s disease and
Hashimoto’s thyroiditis) occurred at a mean age of
34 years in 0.78% and 1.17% of cases, respectively 3.
PAS III syndromes exhibit polygenic
inheritance and are connected with the HLA
system. Several gene variations present in both
autoimmune thyroiditis and T1DM have been
identified. The most important susceptibility
genes are polymorphisms in protein tyrosine
phosphatase non-receptor type 22, cytotoxic
T lymphocyte antigen 4 (CTLA-4), MHC class
I polypeptide-related sequence A, and HLA.
Thus, the association of endocrine autoimmune
diseases is primarily due to a common genetic
predisposition. The HLA class II haplotypes
DRB1*03-DQA1*0501-DQB1*0201 and DRB1*04DQA1-0301-DQB1*0302 have been reported to
be associated with isolated T1DM as well as with
T1DM within the scope of adult PAS 3.
While a role for HLA class I-recognizing
CD8 T cells has been known to affect T1DM and
celiac disease, recent studies also showed a joint
susceptibility for these diseases in HLA class II 3.
HLA-DQ2 can be found in 90% of patients with
celiac disease and in 55% of patients with T1DM,
while HLA-DQ8 is present in approximately
10% and 70%, respectively (1). In patients with
HLA-DQ2-DQ8 heterozygosity, a transdimer
(DQ2α/8β) binds a gliadin peptide and T1Dspecific antigens, which implicates both gluten
and the gut microbiome as additional factors or
triggers for autoimmune (1).
We report this case of type 3 PAS since it
illustrates a number of interesting points.
• Firstly, the varied clinical disease meeting the
criteria for PAS IIIa and IIIc;
• Type 1 diabetes onset at adult age, after
two autoimmune diseases and after the first
pregnancy. So this one is the trigger point of
the pancreas autoimmunity;
• Thirdly, despite significant glycemic
instability with frequent episodes of
hypoglycemia, anemia due to iron deficiency;
there were no obstetric complications and no
adverse outcomes of the fetus.
There is very little published information
addressing the problem of polyglandular
autoimmune syndromes but there are data on the
single disorders. For example it is recognized that
AIT is associated with higher rates of infertility
due to anovulatory cycle, early miscarriages due
to the associated hormonal changes and to the
presence of anti-thyroid antibodies that may react
B. Pecorino et al.
against the structures of the placenta or fertilized
egg and cause problems in embryo implantation(7),
gestational hypertension, preterm birth, small for
gestational age(8).
Two main hypotheses can be made to explain the
higher risk of obstetric complications in women with
celiac disease. The malabsorption that characterizes
celiac disease may lead to nutrient deficiencies
(iron, vitamin B2), which can be associated with
adverse pregnancy outcomes, specifically, IUGR,
SGA, and LBW. Furthermore, women with celiac
disease often show increased levels of serum auto
anti-bodies, including anti-transglutaminase and
anti-thyroid antibodies that have been linked to
several pregnancy complications such as pre-term
birth and stillbirth(12).
It’s recommended a TSH assay every 4-6 weeks
during pregnancy in the patients affected from
AIT; goal TSH concentrations in pregnancy are
0,1-2,5 µU/ml in the first trimester, 0,2-3 µU/ml in
the second trimester and 0,3-3 µU/ml in the third
trimester(6).
Instead, management of T1DM in pregnancy
it’s already known. Particularly, it’s fundamental
the carbohydrate metabolism compensation in
the pre-conception phase to obtain glycosylated
hemoglobin (HbA1C) less than 7% or as close as
possible to 6%(6). Furthermore, diet and body mass
index (BMI) are important because reduction
of the weight body determines improvement of
carbohydrate compensation.
In our case report, the patient get pregnant
with adequate metabolic and endocrine balances
after pre-conception counseling: BMI=22,
HbA1C=5,9%, TSH=1,72 µU/ml and gluten-free
diet. In our opinion, according to literature data,
this pre-conception planning was very important
in order to obtain a good outcome for both mother
and child.
Hypoglycemia occurs in up to 50% of
pregnancies in women with T1DM; it may occur in
patient with bad insulin correction of an elevated
post-prandial glucose(6). Also hyperglycemia is
a serious complication of T1DM in pregnancy
because it may induce diabetic ketoacidosis
(DKA). Factors that may predispose to DKA
include infection, insulin omission or use of
medication such as glucocorticoids (to induce fetal
lung maturity)(6).
Management was difficult because of
instability glucose level without recommended
target (fasting 80-110 mg/dl, 1-hour post-meals
100-155 mg/dl 6) and consequent necessity to
repeatedly increase insulin dose. This issue could
be determined by T1DM and the other endocrine
disease with altered glucose absorption and
release; furthermore, insulin requirements change
according to gestational age, increasing in the
first 9 weeks, decreasing between 9 and 16 weeks,
increasing until the 37th week and decreasing in
the last weeks of pregnancy(6). In the reported case,
the patient was admitted to hospital stay during
the 33th week of pregnancy because of glucose
blood level instability despite the high insulin
doses, to prevent eventual hypoglycemia episodes
or to control them in hospital.
CONCLUSION
Type 1 diabetic patients exhibit an increased
risk of other autoimmune disorders such as
autoimmune thyroid and coeliac disease. So it
justifies an extensive serologic and functional
screening for additional autoimmune glandular
and gastrointestinal diseases, because early
detection of antibodies and latent organ-specific
dysfunction is advocated to take appropriate
action in order to prevent full-blown disease and
to identify both patients at risk for developing
PAS, as well as subclinical PAS that may already
be present.
In clinical practice regular screening of
autoantibodies is warranted because the test may
later become positive.
In families with clustering of T1DM patients
or in families of patients with PAS, the risk for
associated autoimmune diseases and endocrine
or autoimmune involvement of the first-degree
relatives is significantly high. Within a few
years, approximately one third of T1D patients
will develop thyroid autoantibodies and thyroid
dysfunction leading to PAS type III.
We should also examine gastrin, iron, and
vitamin B12 levels and perform a complete blood
count at yearly intervals.
This screening should also be done in patient
with recurrent obstetric complications (infertility,
miscarriages, preterm birth, low birth weight,
gestational hypertension, preeclampsia), because
an appropriate diet or therapy could prevent these
complications.
The combination of insulin treatment, diet and
self-monitoring of glucose levels is the cornerstone
of treatment optimization in TIDM pregnant.
Pregnant patients with T1DM and/or other
autoimmune disease are complex and require
a multi-specialist approach before and during
pregnancy which should include a diabetologist,
obstetrician (perinatal specialist), neonatologist
39
2016, 28: N. 4
and dietitian. This team approach can all improve
pregnancy outcomes for mothers and their infants.
Literature data and the experience derived by
this case report suggest some recommendations to
improve obstetrics and neonatologist outcome in
the patients affected from type III PAS:
- Pre-conception counseling, in order to
REFERENCES
1) A. Van den Driessche, V. Eenkhoorn, L. Van Gaal,
C. De Block* Type 1 diabetes and autoimmune
polyglandular syndrome: a clinical review. The
Netherlands Journal of Medicine. Vol. 67 No. 11 pag
377-387. December 2009
2) Martin P Hansen, Nina Matheis, George J Kahaly
Type 1 diabetes and polyglandular autoimmune
syndrome: A review. World J Diabetes 2015 February
15; 6(1): 67-79
3) Iwona Ben-Skowronek, Aneta Michalczyk, Robert
Piekarski, Beata Wysocka-Łukasik, Bożena Banecka.
Type III Polyglandular Autoimmune Syndromes
in children with type 1 diabetes mellitus. Annals of
Agricultural and Environmental Medicine 2013, Vol 20,
No 1, 140-146
4) Stephanie M. Moleski, Christina C. Lindenmeyer, J.
Jon Veloski, Robin S. Miller, Cynthia L. Miller, David
Kastenberg, Anthony J. DiMarino. Increased rates
of pregnancy complications in women with celiac
disease. Annals of Gastroenterology (2015) 28, 236-240
5) Gabriele Saccone, MD; Vincenzo Berghella, MD;
Laura Sarno, MD; Giuseppe M. Maruotti, MD, PhD;
Irene Cetin, MD; Luigi Greco, MD; Ali S. Khashan, PhD;
Fergus McCarthy, MD, PhD; Domenico Martinelli,
MD; Francesca Fortunato, MD; Pasquale Martinelli,
MD Celiac disease and obstetric complications: a
40
improve body weight and to obtain pre-conception
BMI, HbA1C and TSH target levels;
- TSH assay every 4-6 weeks and eventual
change of levothyroxine sodium dosage;
- Gluten-free diet;
- Fasting and post-prandial blood glucose
level targets.
systematic review and metaanalysis. American Journal
of Obstetrics & Gynecology. 225-234 February 2016
6) Anna Z. Feldman & Florence M. Brown. Management
of Type 1 Diabetes in Pregnancy. Curr Diab Rep (2016)
16:76
7) Ueda H, Howson JM, Esposito L, et al. Association of
the T-cell regulatory gene CTLA-4 with susceptibility
to autoimmune disease. Nature. 2003;423:506-11.
8) Van der Auwera BJ, Heimberg H, Schrevens AF, Van
Waeyenberge C, Flament J, Schuit FC. 5’ Insulin gene
polymorphism confers risk to IDDM independently
of HLA class II susceptibility. Diabetes. 1993;42:851-4.
9) Meier J, Bhushan A, Butler AE, Rizza RA, Butler
PC. Sustained β cell apoptosis in patients with longstanding type 1 diabetes: indirect evidence for islet
regeneration? Diabetologia. 2005;48:2221-8.
10) Eisenbarth GS, Gottlieb PA. Autoimmune
polyendocrine syndromes. N Engl J Med. 2004; 350(20):
2068-79.
11) Kahaly GJ. Polyglandular autoimmune
syndromdes. Eur J Endocrinol. 2009; 161(1): 11-20.
12) Stephanie M. Moleskia. David Kastenberga.,
Christina C. Lindenmeyerb., Anthony J. DiMarinoa.
J. Jon Veloskic. Increased rates of pregnancy
complications in women with celiac disease. Annals of
Gastroenterology (2015) 28, 236-240
Italian Journal of
Centiles of weight of spontaneous and medically induced preterm
births in Lombardy
Fabio Parazzini1,2, Sonia Cipriani2, Stefania Noli1, Ilaria Baini3, Paola Agnese Mauri1, Mauro
Busacca4, Michele Vignali4, Giuseppe Trojano4.
Dipartimento di Scienze Cliniche e di Comunità, Università di Milano, Milano, Italy
Fondazione IRCCS Cà Granda, Dipartimento Materno-Infantile, Ospedale Maggiore Policlinico,
Università degli Studi di Milano, Milano Italy
3
Department of Obstetrics Rotunda Hospita, Dublin, Ireland
4
Dipartimento Materno-Infantile, Ospedale Macedonio Melloni, Università degli Studi di Milano,
Milano Italy
1
2
ABSTRACT
Among preterm births, different clinical conditions are
included: mainly spontaneous and medical induced. In
fact, about 30% of preterm (particularly late preterm)
births are medically indicated and the birth weight of
these cases may differ from spontaneous preterm birth.
In this paper, we have analyzed separately the
percentiles of weight at birth in preterm births according
to spontaneous and induced births using data of all
deliveries in Lombardy, in the period of time between
1st January 2010 and 31th December 2013. The centiles
of weight were lower among medically induced births
in all the considered week of gestation and among
males and females.
This descriptive analysis of centiles of weight at
birth in Lombardy provides Italian obstetricians and
neonatologist with curves of fetal growth more closely
representing the population under cure, in particular
offer information at our knowledge not available before
on the distribution of centiles of weight at birth on
babies born preterm spontaneously or after induction
or elective cesarean section.
SOMMARIO
Tra le nascite pretermine, sono incluse diverse
condizioni cliniche: il parto spontaneo e quello indotto
per una indicazione clinica. In questo lavoro, abbiamo
analizzato separatamente i percentili di peso alla nascita
delle nascite pretermine in base alle nascite spontanee e
indotte utilizzando i dati di tutti i parti pretermine (2834° settimana di gestazione) in Lombardia, nel periodo
di tempo compre tra il 1 Gennaio 2010 e 31 dicembre
2013. I centili di peso erano più bassi tra i nati su
indicazione medica in tutte le settimane di gestazione
considerate e tra i nati di sesso maschile e i nati di sesso
femminile.
Questa analisi descrittiva dei centili di peso alla nascita
in Lombardia offre agli ostetrici ed ai neonatologi curve
di peso alla nascita che rappresentano più da vicino
la popolazione italiana, in particolare differenziando i
centili di peso alla nascita dei bambini nati pretermine
spontaneamente o dopo induzione medica o taglio
cesareo elettivo.
Keywords: Preterm Births, Induced Births, Centile of Weight
INTRODUCTION
Preterm birth rate is increasing worldwide(1);
this trend is mainly due to the rise in late preterm
(34-36 gestational week) births(2). A recent study
estimated that late preterm infants represent
almost a third of ventilated infants; about 30% of
late preterm infants required intensive care, and
15% presented with respiratory failure (3).
DOI: 10.14660/2385-0868-53
It has also been shown that elective cesarian
section (CS) are responsible of the increasing rate of
early term births(5).
Among preterm births, different clinical
conditions are included: mainly spontaneous and
medical induced. In fact, about 30% of preterm
(particularly late preterm) births are medically
indicated(6) and the birth weight of these cases may
differ from spontaneous preterm birth.
The available percentiles of weight at birth
by gestational age vary widely. Published data
41
2016, 28: N. 4
shown, for the same gestational week, differences
of hundreds of grams for the median values or for
the 5th and 95th percentiles(7-10). This is particularly
true for centiles of preterm births. Part of these
differences are due to the criteria used for the
definition of study births, further generally the
studies have considered together spontaneous
and medically induced preterm births. Thus it is
important to be available data from each countries
or regions and curves which consider separately
spontaneous and induced preterm births.
In Italy percentiles of weight at birth for
preterm births have been published(11, 12). None of
these analysis have, however, presented separately
the percentiles according to spontaneous and
induced births. In a companion analysis we have
published the centiles of weight at term birth(13),
in this paper we consider the centiles of preterm
births among births occurred in Italy during the
period 2010-2013.
METHODS
42
The general methodology of this study has
been described in a companion paper(13).
Briefly, this is a population based analysis
using data from two regional data base: CEDAP
and SDO database.
We analyzed data of all deliveries in a
Northern Italian Region (Lombardy) with a
population of about 10 millions inhabitants, in
period of time between 1st January 2010 and 31th
December 2013. Gestational age was considered as
completed week of gestation.
On the basis of these data we computed the
10th, 50th and 90th centile values of neonatal
birthweight from the 28th to 36th week of
gestation at delivery for the total population and
separately for spontaneous and medically induced
and deliveries by elective cesarean section.
In the computation of centiles we used the
methods reported in previous publications (14).
To evaluate the quality of birthweight data, we
compared the information reported in CedAP
data base and SDO data base. We applied the
Tukey’s methodology (14, 15) to identify outliers.
For each data base separately, we considered the
distribution of birthweight by sex and gestational
age. The cases with birthweight lower than the first
quartile minus twice the interquartile range (lower
Tukey limit) or higher than the third quartile plus
twice the interquartile range (upper Tukey limit)
were considered outliers. CedAP values were
considered in the analysis. In the cases where
Centiles of weight births in Lombardy
CedAP value was an outlier and SDO value were
not, CedAP data base value was corrected with
SDO data base value. Then we applied Tukey’s
methodology to CedAP data base distribution and
eliminated outlier cases.
For the purpose of the present analysis we
have defined medically induced birth group all
pharmacological induced deliveries and elective
cesarean sections.
RESULTS
We identified in the CedAP data base a total of
361.756 singleton babies, born in Lombardy region
(Northern Italy) during the period 1st January
2010 to 31st December 2013. This data base was
linked with SDO (discharge register) data base:
8.189 (2,3%) records were deleted.
After the exclusion of cases with missing values
on gestational age and sex of newborn (n=2850,
0,8%) and deletion of cases with outlier values of
birthweight (n=1250, 0,4%) we considered 349.467
newborns.
Among these, 18.780 (5,4%) births 28-36 weeks
of gestation were considered in present analysis.
Table 1 shows the distribution of maternal
characteristics of total population and separately
for spontaneous and medically induced births.
Medically induced birth were associated
with older maternal age, nulliparity and foreign
nationality.
The 10th, 50th and 90th centiles of weight at
birth for gestational age in the total population
and separately for spontaneous and medically
induced (induction and elective cesarean section)
births are shown in Table 2. The centiles of weight
were lower among medically induced births in
all the considered week of gestation and among
males and females.
DISCUSSION
The objective of the present analysis is to offer
information on centiles of weight at birth for
preterm births in Italy, considering women who
delivered in the period 2010-2013 in Lombardy.
As discussed in the companion paper,
information considered in the analysis are based
on routinely collected data base. However, the
quality and completeness of data considered was
generally satisfactory. For example there was no
missing values on birth weight and gestational
week of delivery was missing in less than 1% of
F. Parazzini et al.
Table 1. Characteristics of study subjects
Total Series
Native
Italian
Other country
Maternal age (yrs)
<20
20-29
30-39
40+
Parity
No
Yes
Assisted reproduction
Yes
No
All
N
Spontaneous Delivery
Pharmacological induced
Elective cesarean section
%*
N
%*
N
%*
N
%*
12833
5924
68,4
31,6
4633
2344
66,4
33,6
1426
604
70,2
29,8
3958
1615
71,0
29,0
320
5298
11285
1799
1,7
28,3
60,3
9,6
186
2289
3986
496
2,7
32,9
57,3
7,1
42
651
1176
157
2,1
32,1
58,0
7,7
44
1208
3589
715
0,8
21,7
64,6
12,9
10738
8042
57,2
42,8
3844
3146
55,0
45,0
1161
871
57,1
42,9
3268
2310
58,6
41,4
713
17991
18780
3,8
96,2
154
6810
6990
2,2
97,8
58
1968
2032
2,9
97,1
318
5233
5578
5,7
94,3
Table 2a. Birthweight centiles in total series and by type of delivery: male births
Total series
Spontaneous delivery
Pharmacologically induced Elective cesarean section
Gestational age
(weeks)
N10th 50th90th N10th 50th90th N10th 50th 90th N10th 50th90th
28
29
30
31
32
33
34
35
36
129 7801130138026 95012001470 1 114011401140 5274010151380
160 8651240150537109013101700 0 -- -- -- 6366011401460
230 9651445192055128016002660 3 139024202490 9385012501860
31511001640205093141017602160 3 165016501850 126105014001950
415 1290 1820 2250 123 1620 1950 2390 9 1490 20002350 1601130 16202115
68515102050267021318002180280027165020802880 244141018302490
124417302270 282040420002400 28901111900 23302800 426153020702740
220920202550 307086621602610 31102622090 25303030 578183024703070
477522302770 3280205523702820 32906462200 27403230 1088204027003270
Table 2b. Birthweight centiles in total series and by type of delivery: female births.
Total series
Spontaneous delivery
Pharmacologically induced Elective cesarean section
Gestational age
(weeks)
N10th 50th90th N10th 50th90th N10th 50th 90th N10th 50th90th
28
29
30
31
32
33
34
35
36
127 7101000133021 84010901450 1 122012201220 62670 9101270
135 8001220149034108013251520 0 -- -- -- 5675010001380
192 9701375235052122015802940 3 130023502800 7385012401700
26810501460190064137016601990 4 175019452210 13199013001770
366 1230 1745 2270 103 1640 1900 2570 6 1510 17353120 1771090 15302180
59514401970263017517202100289023176022403220 217130017702350
105916102170 263034419102255 27001231700 21702610 369148020002500
187518802440 294069620602500 30202411950 24302960 558167023002870
400121302640 3160162922802720 32005692120 26003060 1105200025703160
cases. We have no information on the quality of
definition of gestational age. This point could be
of major relevance considering early gestational
ages. However, in Italy, less than 4% of pregnant
women undergo the first examination after the
12 week of gestation (http://www.salute.gov.
it/imgs/C_17_pubblicazioni_2024_allegato.pdf
16). An interesting finding of this analysis is the
opportunity of analyzing separately centiles of
weight separately for spontaneous and induced
births: the centiles were lower among induced
births and births by elective cesarean section.
This finding should be considered in clinical
practices, in particular when we consider the
centiles of birth weight among spontaneous
preterm deliveries.
In conclusion this descriptive analysis of
centiles of weight at birth in Lombardy provides
Italian obstetricians and neonatologists with
curves of fetal growth more closely representing
the population under curve, in particular offer
information at our knowledge not available
before on the distribution of centiles of weight at
birth on babies born preterm spontaneously or
after induction or elective cesarean section.
Competing interestes: The authors declare
that they have no competing interests.
43
2016, 28: N. 4
REFERENCES
1) Anadkat, J.S., et al., Increased risk for respiratory
distress among white, male, late preterm and term
infants. J Perinatol, 2012. 32(10): p. 780-5.
2) Shapiro-Mendoza, C.K. and E.M. Lackritz,
Epidemiology of late and moderate preterm birth.
Semin Fetal Neonatal Med, 2012. 17(3): p. 120-5.
3) Mahoney, A.D. and L. Jain, Respiratory disorders
in moderately preterm, late preterm, and early term
infants. Clin Perinatol, 2013. 40(4): p. 665-78.
4) Barton, J.R., et al., Elective delivery at 34(0)(/)(7) to
36(6)(/)(7) week’s gestation and its impact on neonatal
outcomes in women with stable mild gestational
hypertension. Am J Obstet Gynecol, 2011. 204(1): p. 44 e 1-5.
5) Trojano G. et al The timing of elective caesarean
delivery at term in Lombardy: a comparison of 2010
and 2014 It. J. Gynaecol. Obstet. 2016, 28: N.2 p.48-51
6) Laughon, S.K., et al., Precursors for late preterm
birth in singleton gestations. Obstet Gynecol, 2010.
116(5): p. 1047-55.
7) Bonellie, S., et al., Centile charts for birthweight
for gestational age for Scottish singleton births. BMC
Pregnancy Childbirth, 2008. 8: p. 5.
8) Dobbins, T.A., et al., Australian national birthweight
percentiles by sex and gestational age, 1998-2007. Med
44
J Aust, 2012. 197(5): p. 291-4.
9) Goldenberg, R.L., et al., Intrauterine growth
retardation: standards for diagnosis. Am J Obstet
Gynecol, 1989. 161(2): p. 271-7.
10) Sankilampi, U., et al., New population-based
references for birth weight, length, and head
circumference in singletons and twins from 23 to 43
gestation weeks. Ann Med, 2013. 45(5-6): p. 446-54.
11) Gagliardi L, M.F., Pedrotti D et al. Standard
antropometrici neonatali prodotti dalla task-force
della Società Italiana di Neonatologia. Riv Ital Pediatr
1999;25:159-69.
12) Parazzini, F. et al., Weight at birth by gestational
age in Italy. Hum Reprod, 1995. 10(7): p. 1862-3.
13) Parazzini F. et al. Centiles of weight at term birth
according to maternal nationality in a Northern Italian
region. It. J. Gynaecol. Obstet. 2016, 28:N2 p.52-6.
14) Li Z., et al., Australian national birthweight
percentiles by sex and gestational age for twins, 20012010. BMC Pediatr, 2015. 15: p. 148.
15) Tukey JW. Exploratory data analysis, v.R., MA:
Addison-Wensley; 1977.
16)
http://www.salute.gov.it/imgs/C_17_
pubblicazioni_2024_allegato.pdf, C.d.A.a.P.C.A.d.e.n.
Riassunto delle Caratteristiche del Prodotto
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non altera la capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati:
Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e
Clotrimazolo, le reazioni avverse riscontrate con le formulazioni topiche sono limitate a:
Disturbi del sistema immunitario: Non nota (la frequenza non può essere definita sulla
base dei dati disponibili): reazioni di ipersensibilità. Patologie della cute e del tessuto
sottocutaneo: Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale prurito,
dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio: Non sono stati
descritti sintomi di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE: 5.1 Proprietà
farmacodinamiche: Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/
effetti farmacodinamici: Il MECLON ® è una associazione tra Metronidazolo (M) e
Clotrimazolo (C). Il (M) è un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica. Ha effetto trichomonicida diretto ed è attivo su cocchi
Gram-positivi anaerobi, bacilli sporigeni, anaerobi Gram-negativi. Presenta attività spiccata
sulla Gardnerella vaginalis. Non è attivo sulla flora acidofila vaginale. Il (C) è un imidazolico
con spettro antifungino molto ampio (Candida, etc.). È attivo anche su Trichomonas
vaginalis, cocchi Gram-positivi, Toxoplasmi, etc. È stato documentato che l’associazione
Clotrimazolo-Metronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado
di conseguire tre vantaggi terapeutici principali: 1) Ampliamento dello spettro d’azione
antimicrobica, per sommazione degli effetti dei due principi attivi; 2) Potenziamento
dell’attività antimicotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della
comparsa dei fenomeni di resistenza. Studi microbiologici in vitro hanno dimostrato che
l’attività trichomonicida e antimicotica risulta potenziata quando il (M) e il (C) sono associati nelle stesse proporzioni che sono presenti nel MECLON®. Anche l’attività antibatterica esaminata su diversi ceppi di microorganismi è risultata elevata ed è emerso
un potenziamento di essa quando i due principi attivi del MECLON® vengono associati.
5.2 Proprietà farmacocinetiche: Dalle indagini farmacocinetiche sui conigli, cani e ratti
risulta che dopo ripetute applicazioni topiche di MECLON® non si rilevano concentrazioni
apprezzabili di Clotrimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella
donna il (M) e il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20%
circa. 5.3 Dati preclinici di sicurezza: La tossicità acuta del MECLON® nel topo e nel
ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a
dosi molto elevate (600 mg/Kg di (C) e 3000 mg/Kg di (M), sia da soli che associati).
Nelle prove di tossicità subacuta (30 giorni) il MECLON®, somministrato per via locale
(genitale) nel cane e nel coniglio, non ha determinato alcun tipo di lesione nè locale nè
sistemica anche per dosi molte volte superiori a quelle comunemente impiegate in terapia
umana (3-10 Dtd nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per
l’uomo = ca. 3,33 mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON® somministrato
durante il periodo di gravidanza per via topica vaginale nel coniglio e nel ratto non ha
fatto evidenziare alcun segno di sofferenza fetale per dosi die di 100 Dtd, nè influssi
negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE: 6.1 Elenco
degli eccipienti: Crema vaginale. Eccipienti: Stearato di glicole e polietilenglicole; Paraffina liquida; Sodio metile p-idrossibenzoato; Sodio propile p-idrossibenzoato; Acqua
depurata. Soluzione vaginale. Flacone da 10 ml. Eccipienti: Alcool ricinoleilico; Etanolo;
Acqua depurata. Flacone da 130 ml. Eccipienti: Sodio metile p-idrossibenzoato; Sodio
propile p-idrossibenzoato; Acqua depurata. 6.2 Incompatibilità: Non sono note incompatibilità con altri farmaci. 6.3 Periodo di validità: Crema vaginale: 3 anni. Soluzione
vaginale: 3 anni. 6.4 Precauzioni particolari per la conservazione: Questo medicinale
non richiede alcuna particolare condizione per la conservazione. 6.5 Natura e contenuto
del contenitore: MECLON® crema vaginale. Tubo in alluminio verniciato internamente
con resine epossidiche e fenoliche. Gli applicatori monouso sono di polietilene. Tubo da
30 g + 6 applicatori monouso. MECLON® soluzione vaginale. Flaconi di polietilene a
bassa densità; flaconcini di polietilene; cannule vaginali di polietilene. 5 flaconi da 10 ml
+ 5 flaconi da 130 ml + 5 cannule vaginali monouso. 6.6 Precauzioni particolari
per lo smaltimento e la manipolazione: Nessuna istruzione particolare. 7. TITOLARE
DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO: ALFA WASSERMANN
S.p.A. - Sede legale: Via E. Fermi, n. 1 - Alanno (PE). Sede amministrativa: Via Ragazzi
del ‘99, n. 5 - Bologna. 8. NUMERI DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN
COMMERCIO: MECLON® crema vaginale: A.I.C. n. 023703046. MECLON® soluzione
vaginale: A.I.C. n. 023703059. 9. DATA DELLA PRIMA AUTORIZZAZIONE/RINNOVO
DELL’AUTORIZZAZIONE: 11.05.1991 (GU 07.10.1991) / 01.06.2010. 10. DATA DI
REVISIONE DEL TESTO: Determinazione AIFA del 27 Ottobre 2010.
20% + 4% crema vaginale, tubo da 30 g + 6 applicatori.
Prezzo: € 12,50.
200 mg/10 ml + 1 g/130 ml soluzione vaginale,
5 flac. 10 ml + 5 flac. 130 ml + 5 cannule. Prezzo: € 13,80.
Medicinale non soggetto a prescrizione medica (SOP). CLASSE C.
1. DENOMINAZIONE DEL MEDICINALE: MECLON® “100 mg + 500 mg ovuli”. 2.
COMPOSIZIONE QUALITATIVA E QUANTITATIVA: Un ovulo da 2,4 g contiene: Principi
attivi: Metronidazolo 500 mg; Clotrimazolo 100 mg. Per l’elenco completo degli eccipienti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA: Ovuli. 4. INFORMAZIONI
CLINICHE: 4.1 Indicazioni terapeutiche: Cerviciti, cervico-vaginiti, vaginiti e vulvo-vaginiti da Trichomonas vaginalis anche se associato a Candida o con componente batterica. 4.2 Posologia e modo di somministrazione: Lo schema terapeutico ottimale risulta il seguente: 1 ovulo di MECLON® in vagina, 1 volta al dì. 4.3 Controindicazioni:
Ipersensibilità verso i principi attivi od uno qualsiasi degli eccipienti. 4.4 Avvertenze
speciali e opportune precauzioni d’impiego: Evitare il contatto con gli occhi. Il consigliato impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni, effetti collaterali ed avvertenze descritte per il prodotto summenzionato.
MECLON® ovuli va impiegato nella prima infanzia sotto il diretto controllo del medico e
solo nei casi di effettiva necessità. Tenere il medicinale fuori dalla portata e dalla vista
dei bambini. 4.5 Interazioni con altri medicinali e altre forme di interazione:
Nessuna. 4.6 Gravidanza e allattamento: In gravidanza il prodotto deve essere impiegato solo in caso di effettiva necessità e sotto il diretto controllo del medico. 4.7 Effetti
sulla capacità di guidare veicoli e sull’uso di macchinari: MECLON® non altera la
capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati: Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e Clotrimazolo,
le reazioni avverse riscontrate con le formulazioni topiche sono limitate a: Disturbi del
sistema immunitario: Non nota (la frequenza non può essere definita sulla base dei dati
disponibili): reazioni di ipersensibilità. Patologie della cute e del tessuto sottocutaneo:
Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale prurito, dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio: Non sono stati descritti sintomi
di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE: 5.1 Proprietà farmacodinamiche: Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni
di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/effetti farmacodinamici: Il MECLON® è una associazione tra metronidazolo (M) e clotrimazolo (C). Il (M) è
un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica.
Ha effetto trichomonicida diretto ed è attivo su cocchi Gram-positivi anaerobi, bacilli
sporigeni, anaerobi Gram-negativi. Presenta attività spiccata sulla Gardnerella vaginalis.
Non è attivo sulla flora acidofila vaginale. Il (C) è un imidazolico con spettro antifungino
molto ampio (Candida, etc.). È attivo anche su Trichomonas vaginalis, cocchi Grampositivi, Toxoplasmi, etc. È stato documentato che l’associazione ClotrimazoloMetronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado di conseguire
tre vantaggi terapeutici principali: 1) Ampliamento dello spettro d’azione antimicrobica,
per sommazione degli effetti dei due principi attivi; 2) Potenziamento dell’attività antimi-
cotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della comparsa dei fenomeni di resistenza. Studi microbiologici in vitro hanno dimostrato che l’attività trichomonicida e antimicotica risulta potenziata quando il (M) e il (C) sono associati nelle stesse
proporzioni che sono presenti nel MECLON®. Anche l’attività antibatterica esaminata su
diversi ceppi di microorganismi è risultata elevata ed è emerso un potenziamento di essa
quando i due principi attivi del MECLON® vengono associati. 5.2 Proprietà farmacocinetiche: Dalle indagini farmacocinetiche sui conigli, cani e ratti risulta che dopo ripetute
applicazioni topiche di MECLON® non si rilevano concentrazioni apprezzabili di
Clotrimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella donna il (M) e
il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20% circa. 5.3 Dati
preclinici di sicurezza: La tossicità acuta del MECLON® nel topo e nel ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a dosi molto elevate
(600 mg/Kg di (C) e 3000 mg/Kg di (M), sia da soli che associati). Nelle prove di tossicità subacuta (30 giorni) il MECLON®, somministrato per via locale (genitale) nel cane e
nel coniglio, non ha determinato alcun tipo di lesione nè locale nè sistemica anche per
dosi molte volte superiori a quelle comunemente impiegate in terapia umana (3-10 Dtd
nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per l’uomo = ca. 3,33
mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON® somministrato durante il periodo di
gravidanza per via topica vaginale nel coniglio e nel ratto non ha fatto evidenziare alcun
segno di sofferenza fetale per dosi die di 100 Dtd, nè influssi negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE: 6.1 Elenco degli eccipienti: Eccipienti:
Miscela idrofila di mono, di, tri-gliceridi di acidi grassi saturi. 6.2 Incompatibilità: Non
sono note incompatibilità con altri farmaci. 6.3 Periodo di validità: 3 anni. 6.4
Precauzioni particolari per la conservazione: Questo medicinale non richiede alcuna
particolare condizione per la conservazione. 6.5 Natura e contenuto del contenitore:
10 ovuli in valve in PVC, racchiusi in scatola di cartone. 6.6 Precauzioni particolari per
lo smaltimento e la manipolazione: Nessuna istruzione particolare. 7. TITOLARE
DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO: ALFA WASSERMANN
S.p.A. - Sede legale: Via E. Fermi, n. 1 - Alanno (PE). Sede amministrativa: Via Ragazzi
del ‘99, n. 5 - Bologna. 8. NUMERO DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN
COMMERCIO: A.I.C. n. 023703010. 9. DATA DELLA PRIMA AUTORIZZAZIONE/
RINNOVO DELL’AUTORIZZAZIONE: 27.11.1978 (GU 16.01.1979) / 01.06.2010.
10. DATA DI REVISIONE DEL TESTO: Determinazione AIFA del 27 Ottobre 2010.
100 mg + 500 mg ovuli, 10 ovuli. Prezzo: € 12,50.
Medicinale non soggetto a prescrizione medica (SOP). CLASSE C.

Vol. 28 - Italian Journal of Gynaecology and Obstetrics

Transcript

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