Since 2013 indexed in Societatea Română

de Obstetrică
Societatea Română
de Ultrasonografie
Societatea
Română
Societatea
de Uroginecologie
Societatea
de Endometrioză
și Ginecologie în Obstetrică și Ginecologie de HPV din România și Infertilitate Est-Europeană

IBI Factor 2014-15 is 3.43 JOURNAL FOR CONTINUING MEDICAL EDUCATION

Year VII • No. 26 (4) 2019 • DOI: 10.26416/Gine.26.4.2019

Since 2015 indexed in

EBSCO Academic Search Ultimate &
One Belt, One Road Reference Source

HIGH-RISK
PREGNANCY
OBSTETRICS
Ultrasound findings
of hypothyroidism during
pregnancy
page 15

GYNECOLOGY
Sacrocolpopexy –
advantages
and disadvantages
of abdominal and
laparoscopic approaches.
A systematic review
and meta-analysis
page 36

INTERDISCIPLINARY
Uropathogenic
Escherichia coli
and the related
virulence factors
page 44
PHOTO: SHUTTERSTOCK
 SEASONIQUE
Singurul contraceptiv oral combinat cu
regim extins de administrare

4
menstruaţii
levonorgestrel/etinilestradiol 150/30 µg, comprimate filmate
pe an
etinilestradiol 10 µg, comprimate filmate

Fără interval
liber hormonal
(HFI)*

Ameliorarea
simptomelor
asociate cu HFI
(cefalee, oboseală,
durere abdominală,
balonare etc)**

*Hormone free interval

**Edelman A et al. Hum Reprod 2006; 21(3); 573-578
Seasonique - Informații abreviate de prescripție
Seasonique 150/30 micrograme + 10 micrograme comprimate filmate. Compoziția calitativă şi cantitativă: Fiecare comprimat filmat roz conţine levonorgestrel 150 micrograme şi etinilestradiol 30
micrograme. Fiecare comprimat filmat alb conţine etinilestradiol 10 micrograme. Excipienţi: Comprimate roz: lactoză 63,02 mg per comprimat, E129 0,169 mg per comprimat şi E133 0,009 mg per comprimat.
Comprimate albe: lactoză 69,20 mg per comprimat. Forma farmaceutică: Comprimatele roz sunt rotunde, biconvexe, marcate cu “172” pe o faţă şi cu “T” pe cealaltă faţă. Comprimatele albe sunt rotunde,
biconvexe, marcate cu “173” pe o faţă şi cu “T” pe cealaltă faţă. Comprimatele albe sunt dispuse pe al cincilea (ultimul) rând al celui de-al treilea blister. Doar cel de-al treilea blister conţine cinci rânduri
de comprimate şi are formă rectangulară. Indicații terapeutice: Contracepţie orală. Doze şi mod de administrare: Seasonique este un contraceptiv oral cu regim extins în care comprimatele se administrează
continuu timp de 91 de zile. Fiecare cutie ulterioară de Seasonique se începe a doua zi după administrarea ultimului comprimat din cutia anterioară. Cutia de Seasonique este constituită din 84 comprimate
combinate de levonorgestrel 150 micrograme şi etinilestradiol 30 micrograme şi 7 comprimate de etinilestradiol 10 micrograme. Cum se utilizează Seasonique: Se administrează câte un comprimat zilnic,
timp de 91 de zile. Comprimatele se administrează pe cale orală, în fiecare zi la aproximativ aceeaşi oră, în ordinea indicată pe blister. Se administrează câte un comprimat roz care conţine levonorgestrel
şi etinilestradiol pe zi, timp de 84 de zile consecutive, urmat de un comprimat alb care conţine etinilestradiol, timp de 7 zile, perioadă în care, de obicei, apare sângerarea de întrerupere. Cum se începe
tratamentul cu Seasonique: Comprimatele trebuie administrate în fiecare zi, la aproximativ aceeaşi oră, dacă este necesar cu puţin lichid, în ordinea indicată pe blister. Se administrează câte un comprimat
zilnic, timp de 91 de zile consecutive. Se administrează câte un comprimat roz pe zi, timp de 84 de zile consecutive, urmat de un comprimat alb, timp de 7 zile. În timpul celor 7 zile de administrare a
comprimatelor albe poate să apară o sângerare de întrerupere. Fiecare ciclu ulterior de 91 de zile se începe, fără întrerupere, în aceeaşi zi a săptămânii în care pacienta a început prima cutie de Seasonique,
urmând aceeaşi schemă terapeutică. Abordare terapeutică în cazul omiterii comprimatelor: Eficacitatea contraceptivă poate fi redusă dacă femeia omite administrarea comprimatelor roz, mai ales în cazul
în care omite administrarea primelor comprimate din prima cutie. Dacă au trecut mai puţin de 12 ore de la ora la care a fost omisă administrarea comprimatului roz, comprimatul uitat trebuie administrat
imediat, iar tratamentul trebuie continuat în mod normal prin administrarea următoarelor comprimate la ora obişnuită. Dacă au trecut mai mult de 12 ore de la ora la care a fost omisă administrarea unuia
sau mai multor comprimate roz, protecţia contraceptivă poate fi redusă. Abordarea terapeutică în cazul comprimatelor omise se poate baza pe următoarele două reguli de bază: 1. administrarea comprimatelor
nu trebuie întreruptă niciodată pentru mai mult de 7 zile consecutive. 2. pentru a realiza supresia adecvată a axului hipotalamo-hipofizo-ovarian sunt necesare 7 zile de administrare neîntreruptă a
comprimatelor. Omiterea comprimatelor albe care conţin etinilestradiol (săptămâna 13): Comprimatele uitate nu mai trebuie administrate, iar administrarea comprimatelor următoare trebuie continuată la
ora obişnuită până la terminarea cutiei. Nu sunt necesare măsuri suplimentare de contracepţie. Dacă în săptămâna 13 (în timpul administrării comprimatelor albe) femeia nu prezintă sângerare de întrerupere,
trebuie exclusă posibilitatea unei sarcini înainte de începerea unui nou ciclu de 91 de zile. Recomandări în caz de tulburări gastro-intestinale: În cazul unor tulburări gastro-intestinale severe (de exemplu
vărsături sau diaree), absorbţia poate să nu fie completă şi sunt necesare măsuri contraceptive suplimentare. Dacă vărsăturile apar într-un interval de 3-4 ore după administrarea comprimatului, femeia
trebuie să respecte recomandările descrise pentru omiterea comprimatelor. Dacă femeia nu doreşte să-şi modifice schema normală de administrare a comprimatelor, poate să utilizeze un comprimat(e) roz
suplimentar(e) existent pe ultimul rând al cutiei (săptămâna 12). Copii şi adolescenți: Eficacitatea şi siguranţa Seasonique la femeile cu vârsta reproductivă sub 18 ani nu au fost încă stabilite. Contraindicații:
Contraceptivele orale combinate (COC) nu trebuie administrate în prezenţa nici uneia dintre condiţiile prezentate mai jos. În cazul în care oricare dintre aceste tulburări apare pentru prima dată în timpul
utilizării contraceptivelor orale combinate, medicamentul trebuie întrerupt imediat. Tromboză venoasă prezentă sau în antecedente (tromboză venoasă profundă, embolie pulmonară). Tromboză arterială
prezentă sau în antecedente (de exemplu infarct miocardic) sau tulburări prodromale (de exemplu angină pectorală sau atac ischemic tranzitor). Accident vascular cerebral prezent sau în antecedente. Prezenţa
unui (unor) factor(i) de risc pentru tromboza arterială, sever(i) sau multipli: diabet zaharat cu complicaţii vasculare, hipertensiune arterială severă, dislipoproteinemie severă. Predispoziţie ereditară sau
dobândită pentru tromboză venoasă sau arterială, cum sunt: rezistenţa la PCA, deficit de antitrombină III, deficit de proteină C, deficit de proteină S, hiperhomocisteinemie şi prezenţa de anticorpi
antifosfolipidici. Pancreatită sau antecedente de acest tip, dacă se asociază cu hipertrigliceridemie severă. Boală hepatică severă prezentă sau în antecedente, atât timp cât testele funcţiei hepatice nu au
revenit la valori normale. Tumori hepatice (benigne sau maligne) prezente sau în antecedente. Tumori maligne diagnosticate sau suspectate, dependente de hormoni sexuali. Sângerări vaginale de etiologie
necunoscută. Antecedente de migrenă cu simptome neurologice focale. În asociere cu preparate din plante care conţin sunătoare (Hypericum perforatum). Hipersensitivitate la substanţele active sau la oricare
dintre excipienţi. Control redus al ciclului menstrual: Similar tuturor contraceptivelor orale combinate, pot să apară sângerări neregulate (pete sau sângerări intermenstruale), în special în cursul primelor 3
luni de utilizare. Evaluarea medicală a oricăror sângerări menstruale neregulate trebuie efectuată în cazul în care sângerarea persistă. Comprimatele de Seasonique conţin lactoză. Pacientele cu afecţiuni
ereditare rare de intoleranţă la galactoză, deficit de lactază Lapp sau sindrom de malabsorbţie glucoza-galactoză nu trebuie să utilizeze acest medicament. Comprimatele roz de Seasonique conţin un colorant
roşu numit roşu allura AC (E129) şi un colorant albastru numit albastru briliant FCF (E133), care pot determina reacţii alergice. Fertilitatea, sarcina şi alăptarea: Seasonique nu este indicat în timpul sarcinii.
În general, utilizarea contraceptivelor orale combinate nu trebuie recomandată, până când mama care alăptează nu a ablactat complet copilul. În timpul utilizării contraceptivelor orale combinate, cantităţi
mici de steroizi contraceptivi şi/sau metaboliţii acestora pot fi excretaţi în laptele matern. Aceste cantităţi pot afecta copilul. Seasonique este indicat pentru prevenirea sarcinii. Reacții adverse: foarte frecvente
(≥1/10): metroragie; frecvente (≥1/100 şi <1/10): modificări ale dispoziţiei, scăderea libidoului, depresie, cefalee, migrenă, greaţă, durere abdominală, acnee, menoragie, sensibilitate la nivelul sânilor,
dismenoree, creştere în greutate. Perioada de valabilitate: 3 ani. Natura şi conținutul ambalajului: Fiecare cutie conţine 91 comprimate filmate (84 comprimate roz şi 7 comprimate albe) dispuse în 3
blistere: 2 X 28 comprimate filmate roz + 1 X (28 comprimate filmate roz + 7 comprimate filmate albe). Cele trei blistere din PVC-TE-PVDC/Al sunt prinse într-un buzunar pentru blistere ambalat în pungă
din folie şi cutie. Deținătorul autorizației de punere pe piață: Teva Pharmaceuticals S.R.L. data primei autorizări: Iunie 2015. Data revizuirii textului: Iunie 2015. Acest medicament se eliberează pe
bază de prescripție medicală (P6L). Înainte de prescriere vă rugăm consultați Rezumatul Caracteristicilor Produsului, disponibil la cerere. Acest material promoțional este destinat profesioniștilor din
domeniul sănătății.

▼ Acest medicament face obiectul unei monitorizări suplimentare. Acest lucru va permite identificarea rapidă de noi informaţii referitoare la siguranţă. Profesioniştii din domeniul sănătăţii sunt rugaţi să
raporteze orice reacţii adverse suspectate la adresa de email: PV-theramex-vigicare@pharmalex.com

Pentru informaţii suplimentare vă rugăm să contactaţi: IWH Rouge SRL, Admax Center, Office nr 2, 3-th floor, Pipera-Tunari Street no 1/I,Voluntari, Postal code: 077190, Romania
Tel: + 4 031 631 09 90; E-mail: safety.romania@teva-romania.ro, PV-theramex-vigicare@pharmalex.com, medinfo.ro@theramex.com

Administrare 91 de zile
84 comprimate filmate roz
RO/SEAS/19/0006

levonorgestrel/etinilestradiol 150/30 µg, comprimate filmate

etinilestradiol 10 µg, comprimate filmate 7 comprimate filmate albe
ABONARE
2019
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 Journal for continuing medical education

High-risk pregnancy –
diagnosis and treatment
Our journal last edition of this year
focuses on a series of papers regarding
high-risk pregnancies and their mana-
gement. The first article brings forward a
less discussed domain, the vitamin A de-
ficiency in pregnancy, which is the main
cause for child morbidity and mortality in
the developing world. As a conclusion, vi-
tamin A supplementation is necessary in
all pregnancies from endemic countries,
keeping in mind a maximum limit of
10,000 UI/day, because hypervitaminosis
can also cause congenital malformations.
The next paper addresses ultrasound
findings in hypothyroidism, which pro-
ves to be an efficient and cost-effective
method of diagnosis, with the sole pur-
pose of reducing the negative effects in
pregnancies.
A remarkable progress has been made
in the neonatal recovery of premature
babies born between 24 and 32 weeks of
pregnancy. Cardiotocography (CTG) is
an useful external tool for assessing the
well-being of babies, when interpreted
by an experienced observer. The article
presents a literature review on cardiovas-
cular and neurological development in
order to better understand and interpret
CTGs, leading, where possible, to the pro-
longation of pregnancies.
Moving on, preeclampsia – one of the
most frequent pathologies complicating
pregnancy – is observed from the point of
view of the new discoveries made in the
diagnosis and possible targets of treat-
ment: PIGF and sFlt-1 markers. The next
Reclamă GIN(26)2001
Furthermore, we present the rare
case of a 34-year-old woman with an
ova­r ­ian ectopic pregnancy, with emp-
hasis on the successful treatment using Prof. dr. Radu
minimally invasive surgery, leading to a Vlădăreanu
quick recovery. Editor-in-chief
The first articles of the gynecology
section present a systematic review and
meta-analysis of the advantages and
disadvantages of abdominal and lapa-
roscopic approaches for sacrocolpopexy,
finally stating that both methods resul-
ted in similar clinical outcomes, but with
less possible complications, and shorter
hospital stays and recovery for the lapa-
roscopic approach.
The field of malignant tumors is
addressed in a case report and litera-
ture review regarding sex cord-stromal
tumors of the ovary. Given the rarity of
this disease worldwide, it is important to
raise awareness amongst medical staff
and educate patients to seek medical at-
tention early.
As this year comes to an end, the
entire editorial team wishes all readers
and collaborators Merry Christmas and
a Happy New Year!

review of literature focuses on gestational

and preexisting diabetes treatment using
metformin, concluding that it is an effec-
tive and well-tolerated treatment, but
also that there is a need for more studies
on the long-term fetal effects.
content Year VII • No. 26 (4) December 2019

OBSTETRICS EDITOR-IN-CHIEF

9 Vitamin A in pregnancy
Professor Radu VLĂDĂREANU
DEPUTY EDITORS-IN-CHIEF
Mihaela Boţ, Mădălina Georgeta Sighencea, Andreea Borislavschi, Professor Daniel MUREȘAN
SL Mihai MITRAN
Mona Zvâncă, Răzvan Petca, Ana-Maria Plopan, Adriana Tecuci, Aida Petca EDITORIAL BOARD

15 Ultrasound findings of hypothyroidism during pregnancy Professor Victoria ARAMĂ; Dr. Diana BADIU;
Assoc. Professor Costin BERCEANU; Professor Camil BOHÎLŢEA;
Professor Elvira BRĂTILĂ; Professor Monica CÎRSTOIU;
Florina-Paula Păuleţ, Alexandru Baroș, Crenguţa Șerboiu, Monica Cîrstoiu Assoc. Professor Camelia DIACONU;

20 Antenatal electronic fetal heart monitoring for extremely Assoc. Professor Alexandru FILIPESCU;
Assis. Professor Sorin HOȘTIUC; Professor Crîngu-Antoniu IONESCU;
Professor Claudia MEHEDINŢU; Professor Marius MOGA;
and very preterm newborns Assoc. Professor Dan NĂVOLAN; Professor Liana PLEȘ;
Ali Saphia, A. Filipescu, Anca A. Simionescu Professor Cătălina POIANĂ; Lecturer Ana M.A. STĂNESCU;
Professor Simona VLĂDĂREANU; Professor Gabriela ZAHARIE

24 Current opinions on PlGF and sFlt-1 as reliable markers MIDWIVES AND NURSES SECTION COORDINATOR:
Licensed Midwife Daniela STAN
for preeclampsia (Vice-president of OAMGMAMR, Bucharest subsidiary)
SCIENTIFIC COMMITEE
Alexandra Bouariu, Mihaela Popescu, George Iancu, Radu Botezatu, Nurse responsible for general care Carmen MAZILU
Nicolae Gică, Gheorghe Peltecu, Anca Maria Panaitescu (President of OAMGMAMR, Bucharest subsidiary)
Nurse responsible for general care Anghelușa LUPU
28 Gestational diabetes and pre-existing diabetes – an approach (Vice-president of OAMGMAMR, Bucharest subsidiary)
Licensed assistant chief Anca MAREȘ
from the metformin perspective (Vice-president of OAMGMAMR, Bucharest subsidiary)
Nurse responsible for general care Corina GAGIU
Ana Maria Alexandra Stănescu, Ioana Veronica Grăjdeanu, (OAMGMAMR secretary, Bucharest subsidiary)
Camelia Cristina Diaconu INTERNATIONAL EDITORIAL COMMITEE
Professor Gianni MONNI (Cagliari, Italy)
32 Early diagnosis of ovarian pregnancy – a case report Professor Frank CHERVENAK (NY, USA)
Professor Valentin FRIPTU (Chișinău, Republic of Moldova)
Aida Petca, Cristina Oprescu, Florica Șandru, Răzvan-Cosmin Petca, Professor Liliana VOTO (Buenos Aires, Argentina)
Professor Ivica ZALUD (Honolulu, USA)
Mihai Cristian Dumitrașcu, Mihaela Boţ, Nicoleta Măru Professor Aris ANTSAKLIS (Athens, Greece)
Professor Eberhard MERZ (Frankfurt/Main, Germany)
DTP
GYNECOLOGY Ioana BACALU
PROOFREADING
36 Sacrocolpopexy – advantages and disadvantages of abdominal Florentin CRISTIAN
PHOTO PROCESSING
and laparoscopic approaches. A systematic review and meta-analysis Radu LEONTE
Mihai Cristian Dumitrașcu, Răzvan Fodoroiu, Cătălin George Nenciu, Florica
Şandru, Aida Petca, Răzvan Petca, Monica Mihaela Cîrstoiu
40 Sex cord-stromal tumors of the ovary: granulosa-stromal cell tumors.
Case report and literature review
Laura Mustaţă, Gheorghe Peltecu, Raluca Chirculescu, Anca Maria Panaitescu,
Nicolae Gică, Radu Botezatu, Ruxandra Gabriela Cigaran, Corina Gică, CEO
Simona MELNIC
George Iancu EDITORIAL MANAGER
Oana NEACȘU
MARKETING MANAGER
INTERDISCIPLINARY Luiza NICHIFOR
SALES MANAGER
44 Uropathogenic Escherichia coli and the related virulence factors George PAVEL
EVENTS MANAGER
Benyamin Salmani Pour Noghlbari, Mahsa Mozaffari Lavinia SIMION
ADMINISTRATIVE MANAGER
Dana STUPARIU
EVENTS SUBSCRIPTIONS MANAGER
Alina ROȘU

50 December 2019 – February 2020 Calendar abonamente@medichub.ro

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Copyright © 2019 MEDICHUB MEDIA, S.R.L.

Drepturile de autor pentru articolele și fotografiile
Reclamă GIN(26)2002

publicate aparţin exclusiv MEDICHUB MEDIA, S.R.L.

Reproducerea, totală sau parţială, și sub orice formă,
tipărită sau electronică, sau distribuţia materialelor
publicate se face numai cu acordul scris al Editurii.

ISSN 2344-2301
e-ISSN 2457-3566
ISSN-L 2344-2301
Responsabilitatea asupra conţinutului original al materialelor
aparţine în întregime autorilor. Persoanele intervievate
răspund de conţinutul declaraţiilor lor, iar utilizatorii
spaţiului publicitar, de informaţiile incluse în machete.
TER-RO-MEDA-09/2019/08
obstetrics
Vitamin A in pregnancy
Abstract
Vitamin A is a fat-soluble vitamin which does not only
perform a lot of systemic functions, but also plays an
important role in organogenesis. There are three active
forms of vitamin A: retinol, retinal and retinoic acid.
Vitamin A deficiency is the main preventable cause of
blindness worldwide and the primary cause of childhood
morbidity and mortality in the developing world. Maternal
vitamin A deficiency during pregnancy is associated with
high rates of maternal and infant mortality and with a
significant risk of premature birth, miscarriage or fetal
death. Both deficiency and hypervitaminosis A during
pregnancy are associated with congenital malformations,
but the teratogenic effect was described only for a daily
intake of more than 10,000 IU of preformed vitamin A
supplements. In conclusion, vitamin A supplementation is
recommended only for pregnant women from areas with
endemic avitaminosis A, in order to prevent nyctalopia.
Keywords: retinol, retinoic acid, congenital
malformations, vitamin A deficiency, teratogenesis,
hypervitaminosis
Submission date:
28.09.2019 Vitamina A în sarcină
Acceptance date: Suggested citation for this article: Boţ M, Sighencea MG, Borislavschi A, Zvâncă M, Petca R, Plopan AM, Tecuci A, Petca A. Vitamin A in pregnancy.
12.10.2019
Ginecologia.ro. 2019;26(4):9-12.
Introduction
Vitamin A is an essential nutrient and a fat-soluble
vitamin which performs a lot of systemic functions. Ad-
equate vitamin A is required for erythrocyte production,
tissue differentiation, normal development of bones and
teeth, immune competence, reproduction, proper gastro-
intestinal activity and vision. It also has an important
role during the embryonic development, being involved
in organogenesis(1-4).
There are two forms of vitamin A: preformed vitamin
A (retinol) and provitamin A (carotenoids), but the three
active forms are: retinol, retinal and retinoic acid(3). While
the retinoic acid is responsible for growth and develop-
ment, the retinol and retinal forms of vitamin A play an
essential role in maintaining the reproductive functions
and the normal vision(4).
Carotenoids may be converted to vitamin A in the
liver, where they will be ultimately stored(5). While
preformed vitamin A comes from animal sources from
the diet (liver, milk, eggs, cheese), the carotenoids
intake is based on plant sources, consisting of fruits
and vegetables (spinach, carrots, pumpkins, sweet
potatoes)(2,3,6,7). Taking into account that there is a
reduced absorption of vitamin A coming from plant
sources, it is quite useful the consumption of animal
food products, in order to maintain an adequate level
of vitamin A(5).
Year VII • No. 26 (4/2019)
ginecologia
Rezumat Mihaela Boţ1,2,
Mădălina
Vitamina A face parte din categoria vitaminelor liposolubile Georgeta
care, pe lângă funcțiile exercitate la nivel sistemic, joacă un
rol important în cadrul organogenezei. Vitamina A se prezintă Sighencea2,
sub trei forme active: retinol, retinal și acid retinoic. Deficitul Andreea
de vitamină A este nu numai principala cauză prevenibilă de Borislavschi2,
orbire la nivel mondial, dar și un factor etiopatogenic esențial Mona Zvâncă1,2,
în ceea ce privește morbiditatea și mortalitatea infantilă în Răzvan Petca1,3,
țările în curs de dezvoltare. Deficitul matern de vitamină A în
timpul sarcinii se asociază cu rate mari ale mortalității materne Ana-Maria
și infantile, dar și cu un risc semnificativ de naștere prematură, Plopan2,
avort sau moarte fetală. Atât deficitul, cât și hipervitaminoza Adriana Tecuci1,2,
A pe parcursul sarcinii sunt asociate cu apariția malformațiilor Aida Petca1,2
congenitale, însă efectul teratogen este descris doar în cazul 1. “Carol Davila” University
unui aport zilnic de peste 10.000 UI de vitamină A preformată of Medicine and Pharmacy,
provenind din suplimente. În concluzie, suplimentarea cu Bucharest, Romania
vitamină A este recomandată doar în cazul femeilor gravide 2. Obstetrics, Gynecology
din zone cu deficit endemic de vitamină A, cu scopul prevenției and Neonatology
Department,
nictalopiei. “Elias” University Emergency
Cuvinte-cheie: retinol, acid retinoic, malformații congenitale, Hospital,
Bucharest, Romania
deficit de vitamină A, teratogeneză, hipervitaminoză
3. “Prof. Dr. Theodor Burghele”
Clinical Hospital,
Bucharest, Romania
Corresponding author:
Mihaela Boț
E-mail: mihaelabot@yahoo.com
The need of vitamin A is increased during pregnancy
because of its essential role in supporting the maternal
metabolism and the fetal development. The recommended
daily dose in pregnant women is 770 μg/dL(5). Among popu-
lations with a low prevalence of vitamin A deficiency, it is
considered that the hepatic stores are sufficient to ensure
the daily requirement of this nutrient(5). On the other hand,
in case of an endemic vitamin A deficiency, it is recom-
mended daily or weekly supplementation, in order to pre-
vent nyctalopia(8).
Avitaminosis A is a severe public health problem in
many geographical regions, being considered the main
preventable cause of blindness(1). It is estimated that vi-
tamin A deficiency leads to blindness in 250-500 million
children worldwide, half of these children dying within
a year of vision loss(7). It is also a predisposing factor for
multiple comorbidities, such as: respiratory diseases,
meas­les, diarrhea, anemia, convulsive cough, thyroid
dysfunction, some dermatological lesions, and moder-
ate-severe forms of malnutrition in children(1,9,3). Thus,
vitamin A deficiency is the primary cause of childhood
morbidity and mortality in the developing world, espe-
cially in Africa and Southeast Asia(7).
Maternal vitamin A deficiency during pregnancy is as-
sociated with high rates of maternal and infant mortality
and with a significant risk of miscarriage, fetal death or
premature birth(9,10-12). In addition, both deficiency and
9
obstetrics
exposure to high doses of vitamin A during pregnancy
(over 10,000 IU/day) are related to many fetal congenital
malformations(3,10,12,15). Ensuring an adequate and balanced
diet in pregnancy has an essential role in the prevention
of avitaminosis A, since the toxicity of vitamin A is often
described in case of dietary supplements intake, especially
for those with preformed vitamin A(5).
Vitamin A deficiency in pregnancy
The vitamin A deficiency in pregnancy is an important
problem in public health system from developing countries,
affecting around 19 million pregnant women worldwide,
while other studies have shown an estimated 15% of preg-
nant women in low-income countries(1,11,14,15). Vitamin A
deficiency can result in malnutrition and inflammation,
affecting growth, development and functional outcomes.
It has an essential role for the maintenance of vertebral
identity, the prevention of malformations and for the de-
velopment of skeletal elements during embryogenesis(4).
It is associated with numerous factors, such as: low educa-
tional and socioeconomic status, unhealthy lifestyle during
pregnancy consisting in smoking and alcohol consump-
tion, as well as an advanced gestational age. Also, vita-
min A deficiency is still considered the main preventable
cause of night blindness, 8% of pregnant women having
vitamin A deficiency high enough to lead to this ocular
consequence(1,14).
The avitaminosis A is owing to an inadequate intake of
preformed vitamin A from animal food sources or carot-
enoids from fruits and vegetables(3). Subclinical vitamin A
deficiency is defined by serum retinol concentrations below
0.70 μmol/L (20 μg/dL), while severe defiency is character-
ized by plasma retinol concentrations below 0.35 μmol/L
(10 μg/dL)(3,4,9,14,16).
Some studies have shown that the serum level of retinol
can be used as a predictive factor for preeclampsia, being
reported low concentrations of plasma retinol in pregnant
women with preeclampsia and eclampsia. However, the role
of vitamin A in the etiopathology of pregnancy-induced
hypertension is not completely known(9). Although there
are some studies which have been found that vitamin A
and other antioxidants supplementation in pregnancy led
to a reduction in absolute risk for preeclampsia with 3%,
these results were statistically insignificant(17).
Maternal deficiency of vitamin A during pregnancy is
associated with high rates of maternal and infant mortal-
ity in the first year of life(11). Also, subclinical deficiency of
vitamin A in the third trimester of pregnancy increases the
risk of preterm birth and maternal anemia(9). Thus, there is
recommended the vitamin A supplementation in pregnant
women with a low socioeconomic status, avitaminosis A
being associated not only with an 1.8-fold increased risk
of maternal anemia(4,9,18), but also with a low level of serum
hemoglobin concentration in newborns(9). Some studies
have found that the supplementation with β-carotene or
any form of vitamin A during pregnancy reduces the risk
of anemia (Hb<11 g/dL) by 19%(19). The mechanisms of
anemia occurrence are related to some of the effects of
vitamin A, including: anti-infectious role, the modulation
10
of iron metabolism, and the increase of circulating level of
erythropoietin(9).
More than half of pregnant women with vitamin A defi-
ciency have nyctalopia, with a higher prevalence during the
third trimester of pregnancy, because of the acceleration of
fetal growth(3,20). Nyctalopia is one of the first clinical mani-
festations of vitamin A deficiency, along with conjunctival
xerosis and Bitot spots (keratin debris in the conjunctiva),
subsequently leading, in case of a severe and prolonged vi-
tamin A deficiency, to corneal scars, keratomalacia (drying
and clouding of the cornea with ulceration) and permanent
blindness. Another specific ocular manifestation owing
to avitaminosis A is xerophthalmia (dry eyes and failure
to produce tears)(2,3,21,22). Taking into account that half of
children with blindness due to vitamin A deficiency are
dying within one year from the occurrence of blindness,
promoting vitamin A supplementation in endemic deficit
areas is an important public health method which reduces
the infant mortality(13,23,24).
Vitamin A deficiency is a major cause of childhood mor-
bidity and mortality, being associated with severe immu-
nodepression, which predisposes to a high incidence of
respiratory infections and other infectious diseases, such
as diarrhea and measles(3,16). In children with avitaminosis
A, measles is a predisposing factor for conjunctival and cor-
neal affliction, this being associated with higher mortality
rate compared with cases of measles among children with
normal vitamin A status(3,25,26). Neonatal vitamin A sup-
plementation increases the resistance at infections, reduces
the incidence and severity of measles, with a significant
impact on cases of neonatal diarrhea, which are responsible
for about 30% of neonatal deaths(3,15).
Some studies showed that vitamin A deficiency in
mothers with HIV infection is associated with a 3-4-fold
increased rate of mother-to-child transmission(3,16,27). How-
ever, other studies including pregnant women and women
during breastfeeding have not shown significant benefits
of vitamin A supplementation on the rate of transmission
of HIV infection from mother to child(3,28).
A study which included 138 children with combined io-
dine and vitamin A deficiency has demonstrated increased
thyroid hormone and TSH concentrations, as well as an
increased risk of goiter, related to the severity of vitamin
A deficiency(3,29). Even without supplementation of iodine
deficiency, vitamin A administration led to reduced TSH
and thyreoglobulin concentrations, as well as a decrease in
thyroid gland volume(3,30).
It has been shown that vitamin A deficiency in preg-
nant women interacts with iron deficiency, which is an-
other major micronutrient. This can be explained not
only by the role of vitamin A in supporting the mobiliza-
tion and the transport of iron, but also by its importance
in hematopoiesis, a process requiring large amounts of
iron. In addition, it was found that simultaneous use
of vitamin A and iron supplements is more effective in
preventing the iron deficiency anemia than the use of
either of these nutrients alone(4).
Vitamin A deficiency is also associated with other condi-
tions, including follicular hyperkeratosis, characterized by
Year VII • No. 26 (4/2019)

excessive keratin synthesis in the hair follicles, with initial
localization at the extremities, but with the possibility of
generalization(3,31,32).
Another symptom of vitamin A deficiency is bron-
chopulmonary dysplasia, which is a form of chronic disease
with an unfavorable prognosis, occurring in approximately
one third of preterm infants less than 28 weeks of gesta-
tion. It has been shown that intramuscular administration
of 5000 IU of vitamin A three times per week during four
weeks in preterm infants has been associated with a signifi-
cant reduction in the risk of developing bronchopulmonary
dysplasia(3,32,33).
Animal studies have shown that severe vitamin A de-
ficiency in pregnancy induces abortion, fetal death and
fetal birth defects, mostly consisting in microphthalmia,
anophthalmia and abnormalities of the lung, cardiac and
urogenital systems. There have also been reported facial,
renal and diaphragmatic malformations, along with severe
enamel and dentin dysplasia. Other animal studies have
been found a relationship between the maternal vitamin
A deficiency and the occurrence of ocular defects, such as:
coloboma, penetration of the retina by mesodermal tissue,
retinal eversion, defects in the iris and low insertion of the
optic stalk(34). Subsequently, human studies have also dem-
onstrated a direct relationship between maternal vitamin
A deficiency during pregnancy and the development of
congenital ocular defects(4,10,12,16).
Hypervitaminosis A in pregnancy
and teratogenesis
Although vitamin A supplementation during pregnancy
can have many benefits, it has been shown that a daily
intake of more than 10,000 IU of preformed vitamin A
derived from supplements is associated with the occurrence
of congenital defects in 1 of 57 children. The teratogenic
risk is correlated with the intake of high doses of vitamin
A before the 17th week of gestation. In addition, the con-
genital defects were mainly observed in the tissues derived
from neural crest cells. There were described congenital
malformations such as transposition of the great vessels,
ventricular septal defect, multiple cardiac defects, hydro-
cephalus, craniosynostosis, and cleft lip(13,16).
For a daily intake of less than 10,000 IU of preformed
vitamin A supplements there was no risk of congenital mal-
formations, and β-carotene was also related with no risk
of teratogenic effects. However, isotretinoin – a synthetic
derivative of retinol – is contraindicated during pregnancy,
leading to a large number of major congenital defects(3,35,36).
It was found that 20% of fetuses who were exposed to
isotretinoin during pregnancy had craniofacial, cardiac,
thymic and central nervous system malformations. While
there were observed cranial malformations such as micro-
cephaly, hydrocephaly, micro- and macro-cerebellar dys-
genesis, the craniofacial anomalies included facial asym-
metry, cleft palate, micrognathism, stenosis or atrophy of
the external auditory canal and other malformations of
the external ear(36,37).
Another synthetic derivative of vitamin A is etreti-
nate, which can cause cardiac, thymic or limb congenital
Year VII • No. 26 (4/2019)
ginecologia
defects. In addition, it has a very long half-life of 120
days and accumulates in the body, through storage espe-
cially in the adipose tissue. This explains the persistence
of teratogenic risk in pregnant women over a long period
of time after cessation of exposure to this substance(37).
In addition to teratogenic risk, exposure to high doses
of vitamin A (25,000-33,000 IU/day) for long periods may
cause symptoms related to chronic toxicity, characterized
by headache, anorexia, weight loss, pruritus, bone and joint
pain, hepatomegaly and splenomegaly, hemorrhage or even
coma(3).
Recommendations regarding vitamin A
supplementation during pregnancy
Vitamin A supplementation during pregnancy is not
routinely recommended in order to prevent maternal
and infant morbidity and mortality(38). World Health
Organization recommends vitamin A supplementation
only for pregnant women from areas where avitaminosis
A is a severe public health problem, in order to prevent
nyctalopia(8). The reason is represented by the severe
outcomes of night blindness, which was associated with
a significantly increased risk of both postpartum and
pregnancy-related mortality, and also with a five-fold
increased risk in infection-related causes(39).
Vitamin A supplementation of deficient populations
is also important in the prevention of anemia, being
found that the use of supplements for a period longer
than two weeks raises the hemoglobin concentrations
by 0.2-1 g/dL(19).
In pregnant women with suspected low vitamin A
status, it can also be prescribed a well-balanced diet
rich in β-carotene-containing vegetables(16). Also, stud-
ies performed on Indonesian women have showed that
large-scale oil fortification with vitamin A improved
the vitamin A status of people living in poverty, being
a cost-effective way to reduce vitamin A deficiency and
its severe consequences(40).
Vitamin A deficiency is considered a severe public
health issue if at least 20% of pregnant women in the
population have serum retinol levels below 0.7 μmol/L,
or at least 5% of women have a history of nyctalopia
during a pregnancy which has occurred in the last 3-5
years(8).
The main forms of vitamin A found in dietary supple-
ments are retinyl acetate and retinyl palmitate, but reti-
noids (retinol, retinal and retinoic acid) or carotenoids
(most commonly β-carotene) can also be found(5). The
recommended vitamin A doses can be up to 10,000 IU/day
or up to a maximum dose of 25,000 IU/week(38,41).
The recommended daily dose in pregnant women is
770 μg/dL(5). The Teratology Society of United States
of America recommends that the daily total intake of
vitamin A should not exceed 8000 IU/day(16).
The administration of more than 25,000 IU of sin-
gle-dose vitamin A supplements between the 15th and
the 60th day post-conception has a teratogenic effect.
In addition, this kind of administration is considered
insecure, not being recommended(2,8,41).
11
obstetrics
The main goal during pregnancy is to ensure a healthy
and balanced diet for the pregnant woman, considering
that dietary supplementation, along with the weight
gain during pregnancy and the mother’s preconception
nutritional status are highly associated with the cranial
circumference, the weight and the length at birth(42). So,
the vitamin A supplementation is not a mandatory meas-
ure. Moreover, if the daily intake of vitamin A exceeds
8000 IU, it is no longer recommended the administration
of additional doses(2,8,41).
Conclusions
Vitamin A plays an essential role in embryonic develop-
ment, the maternal deficiency of this micronutrient during
pregnancy being associated with the occurrence of ocular
congenital malformations, abortion or fetal death.
The vitamin A deficiency has a higher prevalence
in the third trimester of pregnancy among pregnant
women with low educational and socioeconomic status
and an unhealthy lifestyle, this being considered one
of the most preventable causes of blindness worldwide.
Other comorbidities associated with avitaminosis A are:
1. Bastos Maia S, Costa Caminha MF, Lins da Silva S, Rolland Souza AS, Carvalho Dos
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12
anemia, respiratory disease, measles, diarrhea, thyroid
dysfunction and hyperkeratosis.
It has been shown that the daily intake of more than
10,000 IU of preformed vitamin A supplements before the
17th week of gestation has teratogenic effect, being associ-
ated with the occurrence of congenital malformations such
as: transposition of the great vessels, ventricular septal
defect, multiple cardiac defects, hydrocephalus, cranio-
synostosis and cleft lip. The teratogenic risk has not been
described for β-carotene or for doses of vitamin A lower
than 10,000 IU/day.
Considering this toxicity, vitamin A supplementation is
not routinely recommended, although it plays an important
role in reducing maternal and infant morbidity and mortal-
ity. World Health Organization recommends supplementa-
tion only for pregnant women from areas with endemic vita-
min A deficiency, in order to prevent nyctalopia. Therefore,
the healthy and balanced diet of the pregnant women is the
main method of preventing avitaminosis A in pregnancy. n
Conflicts of interests: The authors declare no con-
flict of interests.
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Year VII • No. 26 (4/2019)
 VACCIN
9-VALENT [Vaccin 9-valent
Papilomavirus Uman, Recombinant]

ÎMPOTRIVA HPV
RO-HPV-00001

Acest medicament se eliberează pe bază de prescripție medicală PRF

Pentru informații detaliate referitoare la produs, vă rugăm consultați Rezumatul caracteristicilor produsului Gardasil 9.
Acest medicament face obiectul unei monitorizări suplimentare. Acest lucru va permite identificarea rapidă de noi informații referitoare la siguranță. Profesioniștii din domeniul sănătății sunt rugați să raporteze orice reacții
adverse suspectate. DENUMIREA COMERCIALĂ A MEDICAMENTULUI Gardasil 9 suspensie injectabilă. Gardasil 9 suspensie injectabilă în seringă preumplută. Vaccin papilomavirus uman 9‑valent (Recombinant, adsorbit)
COMPOZIȚIA CALITATIVĂ ȘI CANTITATIVĂ 1 doză (0,5 ml) conține aproximativ: Papilomavirus uman1 tip 6, proteina L12,3 30 micrograme; Papilomavirus uman1 tip 11, proteina L12,3 40 micrograme; Papilomavirus uman1
tip 16, proteina L12,3 60 micrograme; Papilomavirus uman1 tip 18, proteina L12,3 40 micrograme; Papilomavirus uman1 tip 31, proteina L12,3 20 micrograme; Papilomavirus uman1 tip 33, proteina L12,3 20 micrograme;
Papilomavirus uman1 tip 45, proteina L12,3 20 micrograme; Papilomavirus uman1 tip 52, proteina L12,3 20 micrograme; Papilomavirus uman1 tip 58, proteina L12,3 20 micrograme [1Papilomavirus uman = HPV; 2proteina L1,
sub formă de particule asemănătoare virusului, produsă pe celule de drojdie (Saccharomyces cerevisiae CANADE 3C‑5 (tulpina 1895)) prin tehnologie ADN recombinant;3adsorbit pe sulfat hidroxifosfat amorf de aluminiu cu
rol de adjuvant (0,5 miligrame Al)]. Lista excipienților Clorură de sodiu. L‑histidină, Polisorbat 80, Borat de sodiu, Apă pentru preparate injectabile. FORMA FARMACEUTICĂ Suspensie injectabilă. Suspensie injectabilă
în seringă preumplută. Lichid limpede, cu un precipitat alb. Indicații terapeutice Gardasil 9 este indicat pentru imunizarea activă a persoanelor începând cu vârsta de 9 ani împotriva următoarelor afecțiuni cauzate de
HPV: leziuni premaligne și neoplasme care afectează cervixul, vulva, vaginul și anusul cauzate de tipurile HPV din compoziția vaccinului; veruci genitale (Condyloma acuminata) determinate de tipuri specifice de HPV.
Gardasil 9 trebuie utilizat în conformitate cu recomandările oficiale. Natura și conținutul ambalajului Gardasil 9 suspensie injectabilă: 0,5 ml suspensie într‑un flacon (sticlă) cu dop (halobutil) și un capac din plastic
detașabil (peste banda circulară din aluminiu) în ambalaj cu 1 doză. Gardasil 9 suspensie injectabilă în seringă preumplută: 0,5 ml suspensie în seringă preumplută (sticlă) cu piston (cauciuc bromobutilic cu înveliș din
FluroTec siliconat) și un capac (amestec sintetic izopren‑bromobutil), în mărimi de ambalaj de 1 sau 10 doze cu ace sau într‑o mărime de ambalaj de 10 doze fără ace. Este posibil ca nu toate mărimile de ambalaj să fie
comercializate. Doze și mod de administrare Persoane cu vârsta de 9 până la 14 ani inclusiv, la momentul primei injectări Gardasil 9 poate fi administrat conform unei scheme cu 2 doze (0, 6 – 12 luni). A doua doză trebuie
administrată într‑un interval de 5 până la 13 luni după prima doză. Dacă a doua doză de vaccin este administrată mai devreme de 5 luni după prima doză, trebuie administrată întotdeauna o a treia doză. Gardasil 9 poate
fi administrat conform unei scheme cu 3 doze (0, 2, 6 luni). A doua doză trebuie administrată la cel puțin o lună după prima doză și cea de‑a treia doză trebuie administrată la cel puțin 3 luni după cea de‑a doua doză. Toate
cele trei doze trebuie administrate în decursul unei perioade de 1 an. Persoane cu vârsta de 15 ani și peste, la momentul primei injectări Gardasil 9 trebuie administrat conform unei scheme cu 3 doze (0, 2, 6 luni). A doua doză
trebuie administrată la cel puțin o lună după prima doză și cea de‑a treia doză trebuie administrată la cel puțin 3 luni după cea de‑a doua doză. Toate cele trei doze trebuie administrate în decursul unei perioade de 1 an. Se
recomandă ca persoanele cărora li se administrează o primă doză de Gardasil 9 să completeze schema de vaccinare tot cu Gardasil 9. Nu s‑a stabilit necesitatea unei doze de rapel. Pentru Gardasil 9 nu s‑au efectuat studii
care să utilizeze o schemă mixtă (interșanjabilitate) de administrare a vaccinurilor HPV. Subiecților vaccinați anterior cu o schemă cu 3 doze de vaccin HPV tetravalent care include tipurile 6, 11, 16 și 18 (Gardasil), denumit
în continuare vaccinul HPV‑4, li se pot administra 3 doze de Gardasil 9. Vaccinul HPV‑4 a fost cunoscut, de asemenea, în unele țări, sub denumirea de Silgard. Copii și adolescenți (copii cu vârsta < 9 ani) Siguranța și
eficacitatea Gardasil 9 la copii cu vârsta sub 9 ani nu au fost stabilite. Nu sunt disponibile date. Femei cu vârsta ≥ 27 ani Siguranța și eficacitatea Gardasil 9 la femei cu vârsta de 27 ani și peste nu au fost. Mod de administrare
Vaccinul trebuie administrat prin injectare intramusculară. Locul de injectare preferat este în regiunea deltoidă a brațului sau în regiunea antero‑laterală superioară a coapsei. Gardasil 9 nu trebuie injectat intravascular,
subcutanat sau intradermic. Vaccinul nu trebuie amestecat în aceeași seringă cu niciun alt vaccin și soluție. Contraindicații Hipersensibilitate la substanțele active sau la oricare dintre excipienți. La persoanele care prezintă
hipersensibilitate după administrarea anterioară de Gardasil 9 sau Gardasil/Silgard nu trebuie să se administreze ulterior Gardasil 9. Atenționări și precauții speciale pentru utilizare Decizia de a vaccina o persoană
trebuie să ia în considerare riscul de expunere anterioară la HPV și potențialul de a avea beneficii ca urmare a vaccinării. Similar tuturor vaccinurilor injectabile, tratamentul și supravegherea medicală adecvate trebuie să fie
întotdeauna imediat disponibile, pentru eventualitatea apariției de reacții anafilactice rare după administrarea vaccinului. Sincopa (leșinul), uneori însoțită de cădere, poate să apară după sau chiar înaintea oricărei
vaccinări, în special la adolescenți, ca un răspuns psihogen la acul de seringă. Aceasta poate fi însoțită de mai multe semne neurologice cum sunt tulburări de vedere tranzitorii, parestezii și mișcări tonico‑clonice ale
membrelor în timpul recuperării. Prin urmare, persoanele vaccinate trebuie monitorizate pe o perioadă de aproximativ 15 minute după administrarea vaccinului. Este important să fie funcționale proceduri pentru a preveni
rănirea ca urmare a leșinului. Vaccinarea trebuie amânată la persoanele diagnosticate cu o boală febrilă acută severă. Cu toate acestea, prezența unei infecții minore, cum este o infecție ușoară a tractului respirator superior
sau febra cu valori mici, nu reprezintă o contraindicație pentru imunizare. Ca în cazul oricărui vaccin, este posibil ca vaccinarea cu Gardasil 9 să nu asigure protecția tuturor persoanelor vaccinate. Vaccinul asigură protecție
numai împotriva afecțiunilor determinate de tipurile HPV din componența vaccinului. De aceea, trebuie continuate măsurile de precauție adecvate împotriva bolilor cu transmitere sexuală. Vaccinul este destinat doar
pentru utilizare profilactică și nu prezintă niciun efect asupra infecțiilor cu HPV active sau bolii clinice instalate. Nu s‑a demonstrat că vaccinul are un efect terapeutic. De aceea, vaccinul nu este indicat pentru tratamentul
neoplasmului cervical, vulvar, vaginal și anal, al leziunilor displazice cervicale, vulvare, vaginale și anale de grad înalt sau al verucilor genitale. De asemenea, el nu este indicat pentru prevenirea progresiei altor leziuni deja
instalate determinate de HPV. Gardasil 9 nu previne leziunile determinate de unul dintre tipurile de HPV prezente în vaccin la persoanele infectate cu acel tip de HPV la momentul vaccinării. Vaccinarea nu este un substitut
pentru examenul medical cervical periodic, de rutină. Deoarece niciun vaccin nu este 100% eficace, iar Gardasil 9 nu asigură protecție împotriva tuturor tipurilor de HPV sau împotriva infecțiilor cu HPV existente la momentul
vaccinării, examenul medical cervical periodic de rutină este extrem de important și trebuie urmate recomandările locale. Nu există date disponibile privind utilizarea Gardasil 9 la persoanele cu răspuns imun insuficient.
Siguranța și imunogenitatea vaccinului HPV‑4 au fost evaluate la persoanele cu vârsta de 7 până la 12 ani, cunoscute a fi infectate cu Virusul Imunodeficienței Umane (HIV). Este posibil ca persoanele cu răspuns imun
insuficient să nu prezinte răspuns la vaccin, din cauza utilizării unei terapii imunosupresoare puternice, a unui defect genetic, a infecției cu Virusul Imunodeficienței Umane (HIV) sau din alte cauze. Acest vaccin trebuie
administrat cu precauție la persoanele cu trombocitopenie sau cu orice tip de tulburări de coagulare, deoarece la aceste persoane pot apărea sângerări după administrarea intramusculară. Studii de monitorizare pe termen
lung sunt în curs de desfășurare în prezent, pentru a determina durata perioadei de protecție. Nu sunt disponibile date de siguranță, imunogenitate sau eficacitate pentru a susține interșanjabilitatea Gardasil 9 cu vaccinuri
HPV bivalente sau tetravalente. Interacțiuni cu alte medicamente și alte forme de interacțiune Siguranța și imunogenitatea la persoane la care s‑a administrat imunoglobulină sau produse derivate de sânge în
decurs de 3 luni înainte de vaccinare nu au fost investigate în studii clinice. Utilizare concomitentă cu alte vaccinuri Gardasil 9 poate fi administrat concomitent cu o doză rapel de vaccin combinat difteric (d) și tetanic (T) cu
pertussis [componentă acelulară] (pa) și/sau poliomielitic [inactivat] (VPI) (vaccinuri dTpa, dT‑VPI, dTpa‑VPI), fără vreo interferență semnificativă cu răspunsul imun prin formare de anticorpi la oricare dintre componentele
vreunui vaccin. Această observație se bazează pe rezultatele dintr‑un studiu clinic în care un vaccin combinat dTpa‑VPI a fost administrat concomitent cu prima doză de Gardasil 9. Utilizare concomitentă cu contraceptive
hormonale În studiile clinice, 60,2% dintre adolescentele și femeile cu vârsta de 16 până la 26 ani cărora li s‑a administrat Gardasil 9 utilizau contraceptive hormonale în timpul perioadei de vaccinare. Utilizarea
contraceptivelor hormonale nu a părut să influențeze răspunsurile imune specifice în funcție de tip la Gardasil 9. Fertilitatea, sarcina și alăptarea Sarcina Conform unui număr mare de date privind femeile gravide (peste
1000 rezultate obținute din sarcini) nu s‑au evidențiat efecte malformative sau efecte toxice feto/neo‑natale ale Gardasil 9. Studiile la animale nu au evidențiat efecte toxice asupra funcției de reproducere. Cu toate acestea,
aceste date sunt considerate insuficiente pentru a recomanda utilizarea Gardasil 9 în timpul sarcinii. Vaccinarea trebuie amânată până la sfârșitul sarcinii. Alăptarea Gardasil 9 poate fi utilizat în timpul alăptării. În cadrul
studiilor, imunogenitatea vaccinului a fost comparabilă între femeile care alăptau și cele care nu alăptau. În plus, profilul reacțiilor adverse la femeile care alăptau a fost comparabil cu cel al femeilor din populația generală
de evaluare a siguranței. Nu s‑au raportat reacții adverse grave legate de vaccin la sugarii alăptați în timpul perioadei de vaccinare. Fertilitatea Nu sunt disponibile date la om privind efectul Gardasil 9 asupra fertilității.
Studiile la animale nu au evidențiat efecte nocive asupra fertilității. Efecte asupra capacității de a conduce vehicule și de a folosi utilaje Gardasil 9 nu are nicio influență sau are influență neglijabilă asupra capacității
de a conduce vehicule sau de a folosi utilaje. Cu toate acestea, unele dintre reacțiile menționate la „Reacții adverse” ar putea afecta temporar capacitatea de a conduce vehicule sau de a folosi utilaje. Reacții adverse Cele
mai fecvente reacții adverse observate la Gardasil 9 in studii clinice au fost reacții adverse la locul de injectare (84,8% dintre persoanele vaccinate, în decurs de 5 zile după oricare dintre administrări) și cefalee (13,2% dintre
persoanele vaccinate, în decurs de 15 zile după oricare dintre administrări). Următoarele reacții adverse au fost raportate spontan în timpul utilizării după punerea pe piață a vaccinului HPV‑4 și ar putea fi observate și în
timpul experienței după punerea pe piață a Gardasil 9. Experiența privind siguranța în timpul utilizării după punerea pe piață a vaccinului HPV‑4 este relevantă pentru Gardasil 9, deoarece vaccinurile conțin proteinele L1 HPV
pentru 4 dintre aceleași tipuri HPV. Deoarece aceste evenimente au fost raportate voluntar, datele provenind dintr‑o populație de dimensiuni necunoscute, nu este posibil să se estimeze în mod sigur frecvența acestora sau
să se stabilească, pentru toate evenimentele, o relație de cauzalitate cu expunerea la vaccin. Infecții și infestări: celulită la locul injectării; tulburări hematologice și limfatice: purpură trombocitopenică idiopatică,
limfadenopatie; tulburări ale sistemului imunitar: reacții de hipersensibilitate incluzând reacții anafilactice/anafilactoide, bronhospasm și urticarie; tulburări ale sistemului nervos: encefalomielită acută diseminată,
sindrom Guillain‑Barré, sincopă însoțită uneori de mișcări tonico‑clonice; tulburări gastro‑intestinale: vărsături; tulburări musculo‑scheletice și ale țesutului conjunctiv: artralgie, mialgie; tulburări generale și la nivelul
locului de administrare: astenie, frisoane, stare generală de rău. Supradozaj: Nu s‑au raportat cazuri de supradozaj. Incompatibilități În absența studiilor de compatibilitate, acest medicament nu trebuie amestecat cu
alte medicamente. Perioada de valabilitate 3 ani. Precauții speciale pentru păstrare Gardasil 9 suspensie injectabilă: A se păstra la frigider (2°C ‑ 8°C). A nu se congela. A se păstra flaconul în cutie pentru a fi protejat
de lumină. Gardasil 9 trebuie administrat cât mai repede posibil după ce a fost scos din frigider. Datele de stabilitate arată stabilitatea componentelor vaccinului timp de 72 ore în cazul păstrării la temperaturi între 8°C și
25°C sau între 0°C și 2°C. După acest interval, Gardasil 9 trebuie utilizat sau aruncat. Aceste date au scopul de a oferi recomandări profesioniștilor din domeniul sănătății numai în cazul variațiilor temporare de temperatură.
Gardasil 9 suspensie injectabilă în seringă preumplută: A se păstra la frigider (2°C ‑ 8°C). A nu se congela. A se păstra seringa preumplută în cutie pentru a fi protejată de lumină. Gardasil 9 trebuie administrat cât mai repede
posibil după ce a fost scos din frigider. Datele de stabilitate arată stabilitatea componentelor vaccinului timp de 72 ore în cazul păstrării la temperaturi între 8°C și 25°C sau între 0°C și 2°C. După acest interval, Gardasil 9
trebuie utilizat sau aruncat. Aceste date au scopul de a oferi recomandări profesioniștilor din domeniul sănătății numai în cazul variațiilor temporare de temperatură. Precauții speciale pentru eliminarea reziduurilor
și alte instrucțiuni de manipulare Gardasil 9 suspensie injectabilă: Înainte de a fi agitat, Gardasil 9 poate avea aspect de lichid limpede cu un precipitat de culoare albă. A se agita bine înainte de utilizare, pentru a forma
o suspensie. După ce este agitată energic, suspensia are aspectul unui lichid alb, tulbure. Înainte de administrare, suspensia trebuie inspectată vizual pentru evidențierea de particule și modificări de culoare. A se arunca
vaccinul dacă prezintă particule și/sau modificări de culoare. Se extrage doza de 0,5 ml de vaccin din flaconul unidoză, utilizând un ac și o seringă sterile. A se injecta imediat intramuscular (i.m.), de preferat în regiunea
deltoidiană a brațului sau în regiunea antero‑laterală superioară a coapsei. Vaccinul trebuie utilizat așa cum este furnizat. Se va utiliza toată doza de vaccin recomandată. Orice vaccin neutilizat sau material rezidual trebuie
eliminat în conformitate cu reglementările locale. Gardasil 9 suspensie injectabilă în seringă preumplută: Înainte de a fi agitat, Gardasil 9 poate avea aspect de lichid limpede cu un precipitat de culoare albă. A se agita bine
seringa preumplută înainte de utilizare, pentru a forma o suspensie. După ce este agitată energic, suspensia are aspectul unui lichid alb, tulbure. Înainte de administrare, suspensia trebuie inspectată vizual pentru
evidențierea de particule și modificări de culoare. A se arunca vaccinul dacă prezintă particule și/sau modificări de culoare. A se alege acul adecvat dimensiunii și greutății pacientului, pentru a asigura administrarea
intramusculară (i.m.). În ambalajele cu ace, sunt furnizate câte două ace cu lungimi diferite, pentru fiecare seringă. A se atașa acul rotindu‑l în direcția acelor de ceasornic, până când acesta se fixează ferm pe seringă. A se
administra întreaga doză conform protocolului standard. A se injecta imediat intramuscular (i.m.), de preferat în regiunea deltoidiană a brațului sau în regiunea antero‑laterală superioară a coapsei. Vaccinul trebuie utilizat
așa cum este furnizat. Se va utiliza toată doza de vaccin recomandată. Orice vaccin neutilizat sau material rezidual trebuie eliminat în conformitate cu reglementările locale.DEȚINĂTORUL AUTORIZAȚIEI DE PUNERE PE
PIAȚĂ MSD VACCINS 162 avenue Jean Jaurès 69007 Lyon Franța NUMĂRUL(ELE) AUTORIZAȚIEI DE PUNERE PE PIAȚĂ EU/1/15/1007/001; EU/1/15/1007/002; EU/1/15/1007/003; EU/1/15/1007/004 DATA PRIMEI
AUTORIZĂRI SAU A REÎNNOIRII AUTORIZAȚIEI Data primei autorizări: 10 iunie 2015 DATA REVIZUIRII TEXTULUI Aprilie 2019 Informații detaliate privind acest medicament sunt disponibile pe site‑ul Agenției Europene
pentru Medicamente http://www.ema.europa.eu. Raportarea reacțiilor adverse suspectate Este importantă raportarea reacțiilor adverse suspectate după autorizarea medicamentului. Acest lucru
permite monitorizarea continuă a raportului beneficiu/risc al medicamentului. Profesioniștii din domeniul sănătății sunt rugați să raporteze orice reacție adversă suspectată prin intermediul
Agenției Naționale a Medicamentului și a Dispozitivelor Medicale, Str. Aviator Sănătescu nr. 48, sector 1, București 011478‑ RO, Tel: +4 0757 117 259, Fax: +4 0213 163 497, e‑mail: adr@anm.ro.
 ginecologia

Ultrasound findings
of hypothyroidism during
pregnancy
Abstract Rezumat Florina-Paula
Păuleț1,
Hypothyroidism is the most common gestational en­do­­crine Hipotiroidismul este cea mai frecventă patologie endocrină Alexandru
disease. Globally, the most common cause for hy­po­thy­ care apare în timpul sarcinii. La nivel global, cel mai des
ro­idism is iodine deficiency. Other causes in­clude: genetic în­tâl­nită cauză pentru hipotiroidism este deficitul de iod. Baroș1,2,
va­riations that are responsible for TSH variations, prior Alte cauze in­clud: mutații genetice responsabile de variații Crenguța
thyroidectomy or ablative ra­dio­io­dine therapy, whereas ale TSH-ului, ti­ro­idec­tomie în antecedente sau radioterapia Șerboiu3,4,
secondary (pituitary) and tertiary (hypothalamic) causes ablativă, în timp ce hipotiroidismul secundar și cel terțiar sunt Monica Cîrstoiu1,2
are rare. Most inter­na­tio­nal guidelines suggest targeted rar întâlnite. Majoritatea ghidurilor internaționale sugerează 1. Department of Obstetrics
thyroid testing in pregnant women with risk factors for testarea ti­roidiană țintită a gravidelor care asociază factori de and Gynecology,
thyroid insuf­fi­ciency, such as living in iodine-replete areas. risc, precum cele care trăiesc în zone sărace în iod. Bucharest University
Emergency Hospital
Keywords: hypothyroidism, pregnancy, ultrasound, Cuvinte-cheie: hiotiroidism, sarcină, ecografie,
epidemiology epidemiologie 2. Department of Obstetrics
and Gynecology,
“Carol Davila” University
of Medicine and Pharmacy,
Submission date:
1.11.2019 Constatări ultrasonografice ale hipotiroidismului în timpul sarcinii Bucharest
Acceptance date: Suggested citation for this article: Păuleț FP, Baroș A, Șerboiu C, Cîrstoiu M. Ultrasound findings of hypothyroidism during pregnancy.
15.11.2019 3. Department of Cellular,
Ginecologia.ro. 2019;26(4):15-18. Molecular Biology
and Histology,
“Carol Davila” University
of Medicine and Pharmacy,
Bucharest

Introduction the similarities in the chemical structure of TSH and 4. Department of Radiology
and Medical Imaging,
In iodine-replete areas (Figure 1), the prevalence hCG glycoprotein, the high levels of hCG in maternal Bucharest University
of spontaneous hypothyroidism is between 1% and blood during early pregnancy stimulate furthermore Emergency Hospital

2% (about 10 times more common in women than
in men)(3). The epidemiological data suggest that the
children of women with low levels of free T4 may
have psychoneurological deficits(4) (Table 1). In clas-
sic areas of iodine deficiency, a similar range of defi-
cits in children has been described, where maternal
hypo­t hyroxinaemia rather than high serum TSH was
the main biochemical abnormality (10). Even in areas
previously thought to be iodine sufficient, there is
now evidence of substantial gestational iodine defi-
ciency, which may lead to low maternal circulating
T4 concentrations. In addition to the childhood neu-
ropsychological problems relating to low T4 values,
there is evidence that maternal TPOAb may result in
intellectual impairment even when there is normal
thyroid function(4).
Ultrasonography as a screening tool has a high sen-
sitivity and will result in findings that are common and
rarely have pathological significance(8).
The thyroid gland during pregnancy
During pregnancy, the production of T4 and T3 hor-
mones increases by 50%, which leads to an increase of
50% in the iodine requirement(11). Also, there is a rise
in the levels of TBG, resulting in lower levels of free T4
and a feedback stimulation of the thyroid gland. Due to
the thyroid gland(3). Disclosure: All authors have
participated equally
Fifty percent of pregnant women are estimated in developing this study.
to be positive for thyroid autoantibodies, indicating Corresponding author:
an underlying chronic autoimmune thyroiditis such Alexandru Baroş
E-mail: alexandrubaros@
as Hashimoto’s thyroiditis, TPOAb being the most yahoo.com
sensitive and specific autoantibodies. In these cases,
the immunosuppression of the pregnancy results in
a marked decrease in thyroid antibodies titer. In the
postpartum, however, there is a rapid return to the
pre-pregnancy thyroxine and triiodothyronine lev-
els, with an increase of thyroid antibodies – often
to a higher titer than the one present in the first
trimester (2).
Ultrasound aspects of hypothyroidism
The ultrasound examination of the thyroid gland
does not require prior patient’s preparation; it should
be preceded by a clinical consultation of the neck region,
following the symmetry, dimensions of the gland, as well
as the presence of cervical adenopathies.
The use of ultrasound examination of the thyroid
gland refers to the most accurate measurement of the
thyroid volume, hence providing the early diagnosis of
diffuse pathologies and the detection and characteriza-
tion of nodular lesions. Determining the volume of the
thyroid is one of the most common purposes for which

Year VII • No. 26 (4/2019)

15
obstetrics

Figure 1. Iodine-replete
areas. Adapted from
Gizak M, Gorstein
J, Andersson M.
Epidemiology of Iodine
Deficiency. In: Pearce EN
(ed). Iodine Deficiency
Disorders and Their
Elimination. Springer.
2017

it is resorted to thyroid ultrasound, the hypertrophy
of the thyroid gland being the most common thyroid
pathology in our geographical area.
Regarding the diagnosis of diffuse thyroid diseases,
thyroiditis is in the first place. In acute and subacute
thyroiditis, the clinical picture is suggestive of the diag-
nosis, the importance of ultrasound being in monitoring
the evolution of the disease under treatment.
In acute thyroiditis, the ultrasound of the gland high-
lights hypertrophy with multiple hypoechogenic areas,
imprecisely delimited, which may evolve under treat-
ment to remission or may evolve into abscess, needing
surgical drainage – spontaneous fistulation to mediasti-
num is to be avoided during pregnancy.
In subacute thyroiditis, the ultrasound aspect is ho-
mogeneous, hypoecogenic hypertrophy. Under treat-
ment (corticosteroid), it can evolve with healing – return
to the isoecogenic aspect, or persistence of hypoecogenic
areas that show the continuation of the inflammatory
process.
In chronic thyroiditis (Hashimoto’s lymphocytic thy-
roiditis), the contribution of the ultrasound is major,
especially due to the very poor clinical picture. The ul-
trasound aspect is suggestive: diffuse hypertrophy of the

Classification of hypothyroidism during pregnancy (adapted from Stagnaro-Green A, et al.).

Table 1
The universal screening for thyroid disease during pregnancy should be performed
(Best Practice & Research: Clinical Endocrinology & Metabolism; https://doi.org/10.1016/j.
beem.2019.101320)
Subtypes of thyroid disease Definition Adverse pregnancy outcomes
n preeclampsia
n gestational hypertension
n fetal death
elevated TSH in combination
1 Overt hypothyroidism n premature delivery
with a decreased fT4
n spontaneous abortions
n recurrent abortions
n cretinism
n preeclampsia
elevated TSH n impaired cognitive development of the
2 Subclinical hypothyroidism
with a normal range of fT4 offspring
n increased risk of perinatal mortality(5)
3 Isolated hypothyroxinemia decreased fT4 with a normal TSH n premature delivery(6)
n subfertility
the presence of one or both anti-thyroid n miscarriage
Thyroid antibody positivity
4 antibodies – TPOAb or TgAb, irrespective n recurrent miscarriage
in euthyroid women
of the thyroid function status n preterm birth
n maternal postpartum thyroiditis

16 Year VII • No. 26 (4/2019)

 ginecologia

Figure 2. Both lobes of the thyroid gland are of decreased size. Heterogeneous echogenicity with numerous minute hypoden­
si­ties within that represent tiny hypoechoic nodules. They are separated by fibrous echogenic septa. The gland parenchyma
shows increased vascularity on Doppler study. No detectable masses could be seen. Hashimoto’s thyroiditis with consequent
hypothyroidism (adapted from https://radiopaedia.org/cases/hashimoto-thyroiditis-with-consequent-hypothyroidism)

Figure 3. Increased vascularity on Doppler study in a 8-week pregnancy diagnosed with autoimmune thyroiditis
(dr. Crenguța Șerboiu – personal archive)

Figure 4. Pregnancy of 32-33 weeks with polyhydramnios and having a well-defined neck mass which was homo­
genously iso­echoic well defined and at anterior part of neck. The mass also shows extensive vascularity. Goiter is well
defined, solid ho­mo­ge­neous mass, present at the anterior part of the neck. An antenatal diagnosis of a fetal goiter was
made due to hypothyroidism. This was confirmed by postnatal clinical and lab examination of the baby (adapted from
https://radiopaedia.org/cases/fetal-goitre-due-to-hypothyroidism)

Year VII • No. 26 (4/2019)

17
obstetrics

120
Figure 5. The
100 distribution of pregnant
women diagnosed
80
with thyroid pathology
during 57 months
in the Department
60 of Obstetrics and
Gynecology of the
40 Bucharest Emergency
University Hospital
20

0
Hypothyroidism Hyperthyroidism Graves disease Autoimmune Hashimoto's
thyroidis thyroidis

Number of cases

gland, polycyclic contour, micronodular structure (nod- from society to society, country to country, year to year,
ules between 1 mm and 5 mm in diameter – “painted” and even within societies(2). In 2014, the European Thy-
appearance) and hypoecogenic. Also, there is evidence roid Association (ETA) published a guideline, recom-
of calcifications and increased vascularization, a pseu- mending universal screening for overt hypothyroidism.
dolobulated aspect through the development of fibrous However, this recommendation was not unanimous,
septa. The confirmation of the diagnosis is made by de- with two of the six authors dissenting(7). The obstetri-
termining TPOAb and thyroid hormones, Hashimoto’s cal societies recommend targeted instead of universal
thyroiditis being an autoimmune disease(7). screening. In 2015, the Practice Bulletin of The American
College of Obstetricians and Gynecologists (ACOG) rec-
Materials and method ommended for targeted screening and against universal
In a retrospective analysis of the cases admitted in screening in pregnant women(8).
the Department of Obstetrics and Gynecology of the
Bucharest Emergency University Hospital, from Janu- Conclusions
ary 2015 up to September 2019, we identified a number Thyroid ultrasound (TUS) is an optimal initial imaging
of 186 pregnancies marked by hypothyroidism and 11 tool used in the evaluation of hypothyroid disorders be-
cases with hyperthyroidism (Figure 5). cause it is noninvasive, available and doesn’t use any radia-
Fourteen cases of hypothyroidism also associated tion. It is widely used in the diagnostic workup of thyroid
hereditary thrombophilia, compared to 21 cases of dysfunction. In a hypothyroid patient, TUS may lead to
autoimmune thyroiditis and two cases of Hashimoto’s cost savings: if a typical autoimmune pattern is present on
lymphocytic thyroiditis. TUS, the measurement of antithyroid antibodies will not
be necessary for the diagnosis of Hashimoto’s thyroiditis.
Discussion TUS in these circumstances is especially valuable in case
The national societies of endocrinologists, obstetri- of women who wish to conceive or are pregnant. n
cians and gynecologists, as well as governmental agen-
cies have weighed in on the debate of universal screening Conflicts of interests: The authors declare no con-
for thyroid disease in pregnancy, with opinions varying flict of interests.

1. Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, et al. Keizer-Schrama SM, et al. Hypothyroxinemia and TPO antibody positivity are risk
References

Management of thyroid dysfunction during pregnancy and postpartum: an
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Suppl):S1-47.
2. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017
Guidelines of the American Thyroid Association for the diagnosis and management
factors for premature delivery: the generation R study. J Clin Endocrinol Metab. 2013;
98(11):4382-90.
7. Lazarus J, Brown RS, Daumerie, et al. 2014 European thyroid association guidelines
for the management of subclinical hypothyroidism in pregnancy and in children.
Eur Thyroid J. 2014; 3:76-94.
Reclamă GIN(26)0104

of thyroid disease during pregnancy and the postpartum. Thyroid. 2017; 27:315-89.
3. Walsh JP. Managing thyroid disease in general practice. Med J Aust. 2016; 205:179-84.
4. Flynn RV, MacDonald TM, Morris AD, et al. The thyroid epidemiology, audit and
research study; thyroid dysfunction in the general population. J Clin Endocrinol
Metab. 2004; 89:3879–84.
5. Van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn
M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity
before conception and in early pregnancy: a systematic review. Hum Reprod Update.
2011; 17(5):605-19.
6. Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, Visser WE, Visser W, de Muinck
8. ACOG. Practice Bulletin no. 148: Thyroid disease in pregnancy. Obstet Gynecol. 2015;
125:996-1005.
9. Surks MI, Ortiz E, Daniels GH et al. Subclinical thyroid disease: scientific review and
guidelines for diagnosis and management. JAMA. 2004; 291:228–38.
10. Knudsen N, Jørgensen T, Rasmussen S et al. The prevalence of thyroid dysfunction
in a population with borderline iodine deficiency. Clin Endocrinol (Oxf). 1999;
51:361–67.
11. Biondi B, Cooper DC. The clinical significance of subclinical thyroid dysfunction.
Endocr Rev. 2008; 29:76–131.

18 Year VII • No. 26 (4/2019)

 ,˘

KEDP/DACNZ9
 obstetrics

Antenatal electronic fetal heart

monitoring for extremely
and very preterm newborns
Ali Saphia1,
A. Filipescu1,
Anca A.
Simionescu2
1. “Carol Davila” University
of Medicine and Pharmacy,
Department of Obstetrics
and Gynecology,
“Elias” University Emergency
Hospital, Bucharest
2. “Carol Davila” University
of Medicine and Pharmacy,
Department of Obstetrics
and Gynecology,
Filantropia Clinical Hospital
of Obstetrics and Gynecology,
Bucharest
Corresponding authors:
Anca A. Simionescu
E-mail: asimion2002@yahoo.com
Abstract
Prematurity ranging from 24 to 32 weeks is an important
cause of neonatal mortality and morbidity. A remarkable
progress has been made over the last years into
maternal-fetal medicine and into resuscitating babies
at the borderline of viability, between 24 and 32 weeks
of gestation. Cardiotocographic recording (CTG) is an
important part of the fetal surveillance, a CTG within
normal limits theoretically allowing for the prolongation
of pregnancy. Nevertheless, the interpretation of CTG at
these gestational ages, outside labor, is difficult, as is the
definition of a suspicious/pathological CTG trace; there,
the interobserver variability must also be born in mind.
The clinical and laboratory test results must be taken into
account as well: maternal perception of fetal movements,
obstetrical associated pathologies (premature rupture
of membranes, high blood pressure, intrauterine growth
restriction etc.). The purpose of this article is to review the
usefulness of performing an antepartum CTG between
28 and 32 weeks of gestation and to define the proper
interpretation of the recorded parameters. A CTG trace with
persistent decelerations in case of premature rupture of
membranes or in a foetus with early onset of an intrauterine
growth restriction can contribute to an indication for
caesarean section. A reduction or absence of the baseline
variability of fetal heart rate or the isolated occurrence of
deceleration associated with a normal baseline variability
should be interpreted with caution for these cases.
Keywords: antepartum cardiotocography, extreme
prematurity, reactive trace, accelerations, decelerations
Rezumat
Prematuritatea între 24 și 32 de săptămâni reprezintă o cau­ză
importantă de mortalitate și morbiditate neonatală. S-au
înregistrat progrese în ultimii ani în domeniul medicinei ma­
terno-fetale și al reanimării feţilor la limita viabilităţii, în­tre
24 și 32 de săptămâni. Înregistarea cardiotocografică (CTG)
face parte din supravegherea fetală, un CTG în limite nor­
ma­le permițând teoretic prelungirea sarcinii. Interpretarea
CTG-ului la aceste vârste de gestație, în afara travaliului,
este însă dificilă, ca și definirea unui traseu suspect; există,
de asemenea, variabilitate interoperatorie. Interpretarea
CTG-ului trebuie să ţină cont și de contextul clinic și para­
clinic: perceperea mișcărilor active fetale, medicație, pa­to­logia
obstetricală asociată (ruptura prematură a mem­bra­nelor,
hipertensiunea arterială, restricția de creștere in­tra­­ute­rină
etc.). Obiectivul acestui articol este de a revedea uti­li­­ta­­tea
efectuării antepartum a CTG-ului între 28 și 32 de săp­tă­mâni
și interpretarea parametrilor înregistrați. Un tra­seu car­dio­
tocografic cu decelerații persistente în caz de mem­bra­ne rupte
prematur sau la un făt cu restricție de creștere in­tra­ute­rină
apărută precoce poate contribui la stabilirea indicației de
ope­raţie cezariană. Diminuarea sau lipsa variabilității ritmului
car­diac de bază trebuie interpretate cu precauție, ca și apariția
izo­la­tă a unei decelerații în cazul unei variabilități cardiace
sa­tis­fă­cătoare.
Cuvinte-cheie: cardiotocografie, prematuritate extremă,
variabilitate cardiotocografică, deceleraţii, acceleraţii

Submission date:
17.09.2019 Monitorizarea cardiotocografică în caz de prematuritate extremă
Acceptance date: Suggested citation for this article: Saphia A, Filipescu A, Simionescu AA. Antenatal electronic fetal heart monitoring for extremely and very preterm newborns.
3.10.2019 Ginecologia.ro. 2019;26(4):20-23.

Introduction of membranes between 24 and 32 weeks with conserv-

The progress of maternal-fetal medicine and of neo-
natal resuscitation units, starting from 24 weeks and
for a newborn weight of 600 grams, has resulted into
iatrogenic fetal extractions between 24 and 32 weeks
of gestation, many of which are based on the interpre-
tation of fetal cardiotocographic monitoring as being
pathological.
Prematurity ranging between 24 and 32 weeks is an
important cause of neonatal mortality and morbidity.
Iatrogenic prematurity involves a number of specific
problems related to the decision of fetal extraction. Such
an example are the pregnancies with premature rupture
ative treatment of prolongation, with risk of difficult
pulmonary adaptation (Stănculescu, 2015), pregnancy-
induced hypertension, restriction of intrauterine growth
with early onset or other obstetric pathologies that ap-
peared before 32 weeks, which require careful monitor-
ing and the decision of the premature birth.
Antepartum cardiocardiographic (CTG) recording is
part of fetal surveillance. In case of a high-risk pregnancy
(intrauterine growth restriction, premature rupture of
the membranes before 32 weeks etc.), the prolongation
of the pregnancy (which is desirable) also takes into ac-
count the interpretation of the CTG trace. The purpose

20 Year VII • No. 26 (4/2019)


of cardiotocographic monitoring is to identify a potential
fetal distress, intrapartum due to hypoxia/acidosis, so the
intervention is made at the right time to avoid intrauterine
fetal death or irreversible brain damage. Antepartum, CTG
monitoring analyzes the fetal heart rhythm, influenced by
the fetal nervous system, medication, catecholamines and
maternal and fetal pathologies (Gibb, 2008).
The elements tracked on the CTG pathway reflect the
function of the somatic and autonomic nervous system
in response to mechanical and hypoxic events. In 2019,
within the National Guidelines (www.sogr.ro/ghiduri-
clinice-2019-finale), The Romanian Society of Obstetrics
and Gynecology reviewed the issue of fetal monitoring in
pre-labor or labor, usually after 28 weeks, recommending
cautious interpretation of CTGs at these terms or even
continuous monitoring.
The physiological control over the fetal heart rate and
the results observed on the CTG pathway differ compared
to a term pregnacy, thus making the interpretation of the
trace difficult, with high interoperators variability. CTG
also remains an objective forensic evidence, its result being
associated with the status of these fetuses with increased
neonatal mortality and morbidity.
The objective of this article is to review the usefulness
of performing CTG between 28 and 32 weeks of gestation
and to define the recorded parameters and the pathological
CTG trace. We will present the CTG antepartum monitor-
ing of preterms between 28 and 32 weeks compared with
the CTG of the term babies, during labor.
CTG monitoring
CTG is an electronic method of recording fetal cardiac
activity along with uterine activity using two pressure
transducers externally attached to the maternal abdo-
men. Both components are recorded simultaneously on
paper. Monitors with ultrasound transducers and pa-
per running at a speed of 1 cm/minute are used in our
hospitals from Bucharest (Filantropia Hospital, “Elias”
Hospital). CTG monitoring is performed routinely after
39 weeks and during labor, but also for pregnancies over
26 weeks, requiring long-term hospital stay until birth
– for example, from premature rupture of membranes
until birth.
However, there are no clinical guidelines regarding
antepartum CTG monitoring of preterms. Based on
current scientific evidence, the use of CTG is not rec-
ommended as a routine in case of preterm pregnancies
(Ayres-de-Campos D et al., 2015; Housseine N et al.,
2019).
A Cochrane review of randomized trials found no evi-
dence to support the use of antepartum versus non-CTG
cardiotocographic monitoring to improve fetal progno-
sis. Nonetheless, these studies do not contain sufficient
accurate data to compare the two situations (Grivell RM
et al., 2015).
So, it is the obstetrician’s duty to interpret the CTG
in these situations and to guarantee the further devel-
opment and fetal viability without complications or to
indicate the birth.
Year VII • No. 26 (4/2019)
ginecologia
CTG interpretation in term pregnacies
Cardiotocographic recording reflects the control of
fetal cardiac activity. This is mediated by the central
nervous system, baroreceptors and chemoreceptors. In-
trauterine fetal activity is reflected in the increase in fetal
cardiac activity recorded in the form of accelerations on
the CTG pathway.
When a fetus is subjected to prolonged hypoxic episodes
associated with decreased pH level, the adrenal glands re-
lease catecholamines to increase heart rate. This compen-
satory mechanism shunts blood by targeting it to the vital
organs, causing peripheral vasoconstriction. This clinical
scenario that includes decelerations followed by the ab-
sence of accelerations, the increase of the baseline rhythm
and the gradual reduction of the variability is the typical
onset model of an evolving hypoxic event. The parasym-
pathetic nervous system is activated by the baroreceptors
located at the level of the carotid sinus or in the aortic arch,
secondary to the increase of fetal systemic blood pressure,
leading to the decrease of the vagal-mediated heart rate.
The CTG pathway recording of the fetal heart rate presents
itself as decelerations in case of umbilical cord or fetal skull
compression. The parasympathetic nervous system is ac-
tivated, leading to reflex variability or early decelerations,
with a rapid return to baseline (Chandraharan, 2010).
Chemoreceptors are located peripherally at the level of
the aortic and carotid bodies, and centrally, at the level
of the medulla oblongata. These receptors detect changes
in the blood biochemical composition and respond to de-
creased oxygen levels, increased levels of carbon dioxide
and increased levels of hydrogen ions. In the case of utero-
placental insufficiency (when carbon dioxide and hydrogen
ions accumulate, with decreasing oxygen concentration),
the chemoreceptors are activated and determine the activa-
tion of the parasympathetic nervous system, with the de-
crease of the heart rate which has a longer period of return
to baseline. These late decelerations are characteristic of
metabolic acidosis (Chandraharan, 2010).
During labor, contractions that increase in intensity and
frequency can cause compression of the umbilical cord and/
or fetal skull. Mechanical compression can cause early or
variable decelerations. If the hypoxic or mechanical event
persists for a long time, the fetus uses the adrenals as a
compensatory mechanism, thus resulting in a response
to stress, through the release of catecholamines. This is
the physiological mechanism of adaptation to a possi-
ble hypoxic or mechanical event during labor. Still, the
mechanism is not yet fully functional in the case of a
premature fetus, nor is it in cases marked by intrauterine
growth or fetal infections. However, the classic aspects of
a cardiotocographic trace of a fetus exposed to hypoxia
may not have the same characteristics or amplitude com-
pared to the case of prematurity (Gibb, 2008).
Figure 1 presents the cardiotocographic trace of a
28-week-and-5-day primiparous hospitalized for difficult-
to-control pregnancy-induced hypertension, treated with
Dopegyt® and Norvasc®.
The fetal heart rate is regulated by the autonomic nerv-
ous system, namely the sympathetic and parasympathetic
21
obstetrics
nervous system. The balance of these two systems deter-
mines the baseline heart rate and the baseline variability.
During fetal development, the sympathetic nervous sys-
tem responsible for survival – “fight or flight” – develops
earlier versus the parasympathetic nervous system that
develops during the third trimester. Thus, a premature
baby may have a higher baseline rhythm and an apparent
reduction in baseline variability due to the lack of sympa-
thetic nervous system opposability. Certain features of
fetal heart rate are gestational age dependent (Baschat AA,
2003). The interpretation of a CTG for a term pregnancy
and during labor (uterine contractions) tracks: the baseline
rhythm, variability, frequency, accelerations and decelera-
tions. The CTG pathway can be interpreted as: normal,
suspected anomaly and abnormal-pathological.
CTG interpretation between the 28th until
the 32nd week of gestation
The characteristics of the fetal heart rate differ in the
preterm babies, namely the baseline rhythm is higher,
varying around 155 bpm at gestational ages ranging
between 20 and 24 weeks, because the sympathetic and
parasympathetic systems develop differently depending
on the gestational age (Schneider U, 2018). Fundamen-
tal research has shown that, once the gestational age
advances, a gradual reduction of the baseline rhythm
can be noticed (Sorokin, 1982). These aspects reflect
immaturity, considering that the basic heart rate is the
result of the interaction between the involved physi-
ological mechanisms (Westgren, 1982).
As the fetus exceeds 30 weeks of gestational age, the
parasympathetic influence on the fetal heart rate de-
termines the gradual decrease of the baseline rhythm,
as well as changes in the pattern of accelerations. The
accelerations associated with fetal movements appear as
a consequence of somatic fetal activity and are initially
apparent in the second trimester. Before 30 weeks of
gestation, the frequency and amplitude of the accelera-
tions are reduced, having a peak of only 10 bpm for 10
seconds (Wheeler T, Murrills A, 1978).
Decelerations in the absence of contractions frequen­
tly occur in prematures with gestational ages ranging
Figure 1. Reassuring CTG for prematurity: fetal heart
rate baseline at 153 bpm, reduced baseline variability, a
variable deceleration ended in a normal fetal heart rate
22
between 20 and 30 weeks. Sorokin et al. describe a
lower depth and duration of these decelerations fre-
quently observed on CTG intrapartum routes (Sorokin
Y et al., 1982). Variable decelerations occur in 70-75%
of prematures compared with 30-35% in case of term
babies (Zanini et al, 1980).
Several theories have been proposed to explain the
fetal pattern, mentioning the decrease of the amniotic
fluid level, the reduction of Wharton gelatin, and the
incomplete development of the fetal myocardium which
results in reduced contraction force.
Baseline variability may be affected by incomplete
development of the autonomic nervous system. Variabil-
ity can be decreased secondary to fetal tachycardia with
decreased parasympathetic involvement and resulting
rhythmic baseline fluctuations. The reduction of vari-
ability is described in the preterm fetuses, but is has not
been quantified.
Cyclization of the fetal heart rate is considered an
indicator of fetal well-being (Chandrahan, 2010). This
appears in the form of segments with increased variabil-
ity – with or without accelerations – alternating with an
apparent reduction in variability. These are considered
to reflect fetal REM and non-REM fetal sleep stages,
extrapolating to adult sleep. This cyclization is stabi-
lized with the maturation of the central nervous system.
Cyclization may be absent due to the functional imma-
turity of the central nervous system and not to hypoxic
suffering in cases of extreme prematurity. Cyclization
starts at 23 weeks, and becomes evident between 26 and
32 weeks of pregnancy, when signs of fetal well-being
can be distinguished: the movements of the eyeballs,
the movements of the body, the synchronization of
the movements, which become evident after 32 weeks
(Hoyer et al., 2015).
Figure 2 shows the cardiotocographic route of a tri-
gravida admitted for cervical cerclage at 29 weeks of
gestation with intact membranes.
Figure 3 shows the carditocographic route of a 30-
week primiparous; fetus with intrauterine growth re-
striction, preeclampsia, gestational diabetes, digestive
stenosis, with a history of intrapartum fetal death.
Discussion and conclusions
There are significant differences of the CTG antepar-
tum monitoring in cases of extreme prematurity. Between
24 and 26 weeks, the baseline fetal heart rate is at the
upper limit of normal (150-160 bpm), due to the lack of
sympathetic nervous system opposability; a frequency
greater than 160 bpm is considered tachycardia. Persis-
tent tachycardia is most likely secondary to iatrogenic
cases (tocolysis), but attention should also be paid to a pos-
sible maternal infectious cause or the risk of chorioam-
nionitis in case of premature rupture of the membranes
outside labor. The baseline variability and cyclization can
be reduced secondary to the insufficient development
of the parasympathetic component. The administra-
tion of magnesium sulphate or even steroids may reduce
the baseline variability. Fetal heart rate variability is an
Year VII • No. 26 (4/2019)

Figure 2. Reassuring CTG: fetal heart rate baseline at
140-145 bpm, good baseline variability, accelerations,
no decelerations. There are few rare contractions
important clinical indicator of fetal acid-base balance, and
its absence is an indicator of cerebral asphyxia.
Accelerations at this gestational age may be absent or
significantly decreased, with reduced amplitude. Decel-
erations are common and may reflect the normal devel-
opment of cardioregulatory mechanisms. Thus, they are
not considered a sign of hypoxia, and intervention is not
recommended based on this parameter alone.
The frequency of variable decelerations is reduced after
27 weeks of gestational age. Variability should be within
normal parameters with the development of the autonomic
nervous system. The frequency of accelerations increases,
although the amplitude may remain at only 10 bpm.
A CTG study performed antepartum in fetuses with
intrauterine growth restriction indicates that the lack of
acceleration and decreased baseline variability could be
explained by chronic hypoxemia, associated with altera-
tion of the neurotransmitter system (Amorim-Costa C,
et al., 2017) .
Once gestational age advances, the fetal rhythm returns
to the normal range of 110-160 bpm. Baseline variability
greater than 5 bpm with signs of cyclization may occur in
weeks 30-32.
The predominance of variable decelerations will de-
crease and disappear after 30 weeks. These aspects reflect
myocardial development and increased glycogen reserves.
The persistence of late decelerations most likely reflects
uteroplacental insufficiency. In this situation, the blood
1. Stănculescu R, Târcomnicu I, Coroleucă C, Sărdescu G, Coman C. Review on the
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3(7):45-8.
2. Gibb D, Arulkumaran S. Fetal monitoring in practice. Churchill Livingstone, Elsevier,
2008.
3. Ghidurile SOGR 2019. Available at: www.sogr.ro/ghiduri-clinice-2019-finale
4. Ayres-de-Campos D, Spong CY, Chandraharan E. FIGO Intrapartum Fetal Monitoring
Expert Consensus Panel. FIGO consensus guidelines on intrapartum fetal
monitoring: Cardiotocography. Int J Gynaecol Obstet. 2015; 131(1):13-24.
5. Housseine N, Punt MC, Browne JL, et al. Delphi consensus statement on intrapartum
fetal monitoring in low-resource settings. Int J Gynaecol Obstet. 2019; 146(1):8-16.
6. Grivell RM, Alfirevic Z, Gyte GML, et al. Antenatal cardiotocography for fetal
assessment. Cochrane Database Syst Rev. 2015; (9):CD007863.
7. Chandraharan E. Rational approach to electronic fetal monitoring during labour in
“all” resource settings. Sri Lanka J Obstet Gynaecol. 2010; 32:77-84.
8. Baschat AA. Integrated fetal testing in growth restriction. Ultrasound Obstetr
Gynecol. 2003; 21:1-8
9. Schneider U, Bode F, Schmidt A, et al. Developmental milestones of the autonomic
nervous system revealed via longitudinal monitoring of fetal heart rate variability.
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ginecologia
Figure 3. Non-reassuring CTG: fetal heart rate baseline
at 150 bpm, reduced baseline variability, two variable
decelerations
circulation in the intervillous spaces is reduced, resulting
in the accumulation of carbon dioxide and hydrogen ions.
In the case of an uncompromised, nonacidemic fetus, in-
termittent hypoxia takes the form of decelerations with
transient fetal hypertension (Goupil et al., 1981).
The persistence of hypoxia causes acidosis, loss of the
compensatory mechanism, and may therefore cause per-
manent brain damage. In case of a normal developing fetus,
acidosis may take up to 90 minutes to install.
In conclusion, fetal electronic monitoring between 28
and 32 weeks may raise dilemmas related to clinical as-
pects, both antepartum and during labor. Although there
are recommendations and guidelines based on clinical
evidence for term births, the information is poor when
talking about a preterm fetus and associated pathologies.
Understanding the development of cardiovascular and the
neurological and physiology underlying fetal heart rate
variations is useful to figure out the aspects noticed on
the CTG pathway in order to be able to resolve a potential
hypoxia, given the fetus’ limited resources to combat it.
However, the decision must take into account the clini-
cal and paraclinical context of the obstetric case, as well as
the fetal ultrasound evaluation. In the future, additional
measures to establish the fetal well-being with certainty
could contribute to the prolongation of pregnancy. n
Conflicts of interests: The authors declare no con-
flict of interests.
PLoS One. 2018; 17;13(7):e0200799.
10. Sorokin Y, Dierker LJ, Pillay SK, et al. The association between fetal heart rate
patterns and fetal movements in pregnancies between 20 and 30 weeks’ gestation.
Am J Obstet Gynecol. 1982; 143(3):243-9.
11. Westgren M, Holmquist P, Svenningsen NW, et al. Intrapartum fetal monitoring in
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12. Wheeler T, Murrills A. Patterns of fetal heart rate during normal pregnancy. BJOG.
1978; 85(1):18-27.
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the preterm fetus. Am J Obstet Gynecol. 1980; 136(1):43-7.
14. Hoyer D, Schneider U, Kowalski EM, Schmidt A, Witte OW, Schleußner E, Hatzmann
W, Grönemeyer DHW, van Leeuwen P. Validation of functional fetal autonomic brain
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gestational ages? A study of 11687 fetuses from 25 to 40 weeks of pregnancy.
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Deceleration patterns. Eur J Obstet Gynecol Reprod Biol. 1981; 11(4):239-49.
23
 obstetrics

Current opinions on PlGF

and sFlt-1 as reliable markers
for preeclampsia
Alexandra Abstract Rezumat
Bouariu1,
Mihaela Preeclampsia is an increasingly frequent condition Preeclampsia este o condiție patologică ce afectează din ce
that affects pregnant women and, if undetected in a în ce mai frecvent femeia gravidă și, nedetectată în timp util,
Popescu2, timely fashion, can be a source of morbidity and mor­ poate fi o cauză de morbiditate și mortalitate, atât pentru
George Iancu1, ta­lity for both mother and child. Both PlGF and Flt-1 mamă, cât și pentru făt. Atât PlGF, cât și Flt-1 au fost implicate
Radu Botezatu1, have been involved in the mechanisms behind this în mecanismele care generează această patologie și sunt
Nicolae Gică1, patho­logy, and are currently being used both as diag­ actualmente utilizate ca markeri diagnostici, dar și ca posibile
Gheorghe nos­tic markers and possible therapeutic targets. ținte terapeutice.
Keywords: PlGF, sFlt-1, preeclampsia, PlGF/sFlt-1 ratio Cuvinte-cheie: PlGF, sFlt-1, preeclampsie, raportul PlGF/sFlt-1
Peltecu1,
Anca Maria
Panaitescu1
Submission date:
11.09.2019 Opinii actuale despre PlGF şi sFlt-1 ca martori fideli ai preeclampsiei
Acceptance date: Suggested citation for this article: Bouariu A, Popescu M, Iancu G, Botezatu R, Gică N, Peltecu G, Panaitescu AM. Current opinions on PlGF and sFlt-1 as reliable
1. Department of Obstetrics 28.09.2019
and Gynecology, markers for preeclampsia. Ginecologia.ro. 2019;26(4):24-27.
Filantropia Clinical Hospital
of Obstetrics and Gynecology,
Bucharest;
“Carol Davila” University
of Medicine and Pharmacy,
Bucharest Introduction located on these chromosomes’ regions has not yet
2. Department of Cardiology,
The reduction of both maternal and fetal mortality been proven(4). Chromosomal conditions associated
“Elias” University Emergency and morbidity is a long-standing objective in modern with changes in the structure or number of copies
Hospital, Bucharest;
“Carol Davila” University
medicine. Preeclampsia is an increasingly diagnosed pa- of chromosome 14q24 include not only a major sus-
of Medicine and Pharmacy, thology in pregnancy, with an incidence of up to 4.6%, ceptibility to a variety of cancers of blood-forming
Bucharest
thus explaining why the interest for its early detection cells (leukemias)(5), cancers of immune system cells
Corresponding author:
Gheorghe Peltecu
and timely treatment has peaked in recent years. (lymphomas)(5), asthma(6), epilepsy (7), but also con-
E-mail: gheorghe.peltecu@ Apart from the classical diagnostic criteria of preec- genital syndromes (FOXG1 syndrome)(8). In tumor
gmail.com
lampsia, the PlGF (placental growth factor), sFlt-1 (solu- cells (solid and hematological), PlGF expression cor-
ble fms-like tyrosine kinase receptor-1) and the PlGF/ relates positively with cancer severity and there is an
sFlt-1 ratio are gathering momentum as both diagnostic inverse relationship between PlGF and survival rate(9).
markers and possible options for therapy. It was observed that overexpression of PlGF can de-
crease angiogenesis, VEGF/PlGF heterodimers being
The structure and function of PlGF and Flt-1 less pro-angiogenic than VEGF homodimers(10), and
Dimeric glycoproteins, the placental growth factor, blocking PlGF can improve the quality of tumor vascu-
the vascular endothelial growth factor (VEGF) and the larization, as shown in another study (11). Data from a
Fos-induced growth factor (FlGF) are members of a fam- phase-1 study in patients with recurrent glioblastoma
ily of structurally related growth factors and share im- did not show improved survival after the treatment
portant biochemical and functional features(1). with an anti-PlGF monoclonal antibody in combina-
Abundantly expressed on the endothelial cells, the tion with anti-VEGF antibody bevacizumab(12).
vascular endothelial growth factor exerts its action The presence of PlGF was detected and researched
through the binding to VEGF receptor-1 (also denoted through immunohistochemistry studies in the vas-
Flt-1) and VEGF receptor-2 (also denoted Flk-1/KDR). culosyncytial membrane and in the media of large
Both the vascular endothelial growth factor and placen- vessels of the placenta villi(13). Another analysis, in situ
tal growth factor have the ability to stimulate the pro- hybridization, shows that PlGF is found in the villous
liferation of endothelial cells and angiogenesis in vivo(2). trophoblast, while VEGF is present in cells of mesen-
In fact, the placental growth factor is observed chymal origin within the chorionic plate(14). Northern
to be highly expressed in the feto-placental unit in blot analysis detected low levels of PlGF messenger ri-
all stages during human gestation, but also in inva- bonucleic acid in human heart, lung, thyroid, brain and
sive and non-invasive hydatiform moles (3). Human skeletal muscle(3). The same PlGF messenger ribonucleic
PlGF gene is encoded by chromosome 14q24 and has acid was observed in choriocarcinoma, umbilical vein
four isoforms, but the correlation among diseases endothelial cells and hepatoma(2). PlGF was detected

24 Year VII • No. 26 (4/2019)

 ginecologia

in the endometrial tissue during the secretory phase of endothelial cells, such as placental growth factor and
of the human menstrual cycle, but the role in embryo vascular endothelial growth factor(25). It was observed
implantation was not closely characterized(15). that once an individual threshold of angiogenic im-
It is known that placental growth factor expression balance is reached, the first clinical manifestations of
undergoes transcriptional and post-transcriptional reg- preeclampsia appear. The sFlt-1/PlGF imbalance can
ulation and the major stimuli of PlGF mRNA are the hy- become evident as early as one month before preec-
poxic conditions(2). Another research showed that PlGF lampsia develops clinically, especially in the most se-
stimulates the growth of certain types of endothelial vere and early-onset forms(26).
cells, which have derived from specific tissues, and the
main target for the angiogenic effects of PlGF is the en-
dothelium of post-capillary venules, which is more prone
to respond to mitogenic stimuli in comparison with the
umbilical cord vein endothelium(16).
The PlGF homodimer binds and induces autophos-
phorylation of VEGF receptor-1 (also known as Flt-1),
through the immunoglobulin-like domain 2 of the Flt-
1(16,17). PlGF 1 and 3 are diffusible isoforms and probably
affect targets in a paracrine manner, whereas PlGF 2
and 4 have heparin binding domains and act in an au-
tocrine manner. The activation of the VEGF receptor-1
intracellular signaling pathway leads to mitogenic and
chemotactic effects of PlGF on endothelial cells(2). Pla-
cental growth factor is pro-angiogenic, as it enhances the
activity of vascular endothelial cells, by competitively
binding to the VEGFR-1 receptor, allowing VEGF to bind
to VEGFR-2 which has stronger tyrosine kinase activ-
ity. PlGF amplifies VEGFR-2 response to VEGF bind-
ing through intermolecular transphosphorylation and
forms a heterodimer with VEGF, which may have either
pro-angiogenic, or anti-angiogenic effects(9).
Among the members of tyrosine kinases receptor-
type family, the vascular endothelial growth factor 1
(VEGFR-1) was first isolated from the human placenta
and mentioned as Flt-1 or Fms-like tyrosine kinase, due
to its structural similarity to members of the Fms fam-
ily(18). Flt-1 binds the VEGF-related growth factor PlGF
with high affinity and stimulates angiogenic activities.
PlGF is expressed in placental tissues, but the amino-
acid sequence of PlGF is 53% identical to that of VEGF(2).
The Ftl-1 gene is described on human chromosome
13q12-13(19) and has specific functions under conditions
of embryonal and pathological angiogenesis(20). In rela-
tion to chromosome 13, women carrying trisomy 13
fetuses have an increased risk of preeclampsia and high
circulating concentrations of sFlt-1 (soluble Flt-1)(21). Dur-
ing the early stages of the embryonal development,
Flt-1 is expressed in the primitive endothelial cells
outside the blood islands at 8.5 days and in the vas-
cular endothelial cells of the embryo(22). Flt-1 mRNA
is strongly expressed under hypoxic conditions in en-
dothelial cells(23). sFlt-1 is thought to be responsible for
the maternal dysfunctional hypoxic placenta (Figure
1), causing peripheral vasoconstriction in the attempt
to raise maternal blood pressure. The reason for this
mechanism is the tendency to increase the oxygenated
maternal blood flow through the intervillous space and
can lead to systemic vascular findings with preeclamp- Figure 1. Implication of sFlt-1 in the dysfunctional
sia(24). Flt-1 captures and inhibits pro-angiogenic factors placenta (sEng: soluble endoglin; sFlt-1: soluble fms-like
involved in the proliferation, survival and fenestration tyrosine kinase receptor-1)

Year VII • No. 26 (4/2019)

25
obstetrics
The importance of sFlt-1/PlGF ratio
The concentrations of PlGF depend on gestational
age, with a low level in the first trimester of normal
pregnancies, and they have the tendency to increase
from week 11 to week 12, with a peak value at week 30,
after which they decrease. This is in contrast with sFlt-1,
which increases towards the completion of pregnancy(27).
At the time of diagnosis with preeclampsia, as well
as in advance of syndrome onset, both urinary and se-
rum PlGF are low, due to a combination of decreased
expression and sFlt-1 binding(26). In early pregnancy, the
PlGF expression in the placenta is decreased in women
who develop preeclampsia, the level of serum PlGF be-
ing lower than in normal pregnancies, while the sFlt-1
level is unchanged. Later in pregnancy, there is a re-
ciprocal relationship between sFlt-1 and PlGF, with a
rising levels of total sFlt-1 and lower PlGF levels, which
is bound by sFlt-1(28). An important observation is that
both women with clinical suspicion of preeclampsia and
women without preeclampsia, who give birth to small-
for-gestational-age babies, have also low PlGF early in
pregnancy(29).
Based on the previously mentioned mechanisms and
useful for establishing the real risk of developing preec-
lampsia among pacients, the sFlt-1/PlGF ratio has been
studied enthusiastically. The PROGNOSIS study shows
that the sFlt-1/PlGF ratio and none of the markers taken
individually are predictive of the short-term absence
or presence of preeclampsia in women between 24 and
36+6 weeks of pregnancy (30). Another research, the
PELICAN study, showed that the PlGF test alone had a
Table 1 sFlt-1/PlGF ratio research data
Study Gestational age
PROGNOSIS study(30) 24-36+6 weeks of gestation
PELICAN study(31) 20-34 weeks of gestation
Verlohren et al., 2014(32) early-onset
preeclampsia
late-onset preeclampsia
*NPV: negative predictive value; PPV: positive predictive value; Sp: specificity; Sn: sensitivity
26
very high accuracy for predicting preeclampsia requir-
ing delivery within 14 days for women presented with
suspicion of preeclampsia between 20 and 34 weeks
of gestation(31) (Table 1). Verlohren et al., in 2014, ob-
served that the sFlt-1/PlGF ratio could be useful for
establishing an accurate diagnosis of preeclampsia at
different cutoffs, depending on the gestational age,
the early or late onset of preeclampsia(32) (Table 1).
The same research team raised the hypothesis that
the sFlt-1/PlGF ratio can also be useful to differentiate
the various hypertensive disorders of pregnancy, espe-
cially before 34 weeks(33). The studies aforementioned
have the disadvantage of being conducted on selected
population singleton pregnancies without congenital
anomalies, but insufficiently studied in situations such
as structural and chromosomal abnormalities or mul-
tiple pregnancies. On the other hand, a combination of
maternal characteristics, mean arterial pressure, uter-
ine artery pulsatility index, PAPP-A and PlGF, currently
widely used as a predictive algorithm at 11-13 weeks
gestation by the Fetal Medicine Foundation, detects
95% and 46% of women with early and late preeclamp-
sia, respectively with a false-positive rate of 10%(34).
Abnormal sFlt-1/PlGF ratio offers limited informa-
tion regarding similar antiangiogenic states, such as
HELLP (Hemolysis, Elevated Liver enzymes, Low Plate-
lets) syndrome, acute renal failure, refractory hyperten-
sion, pulmonary edema or fetal well-being impairment,
and therefore requires further research and other de-
tailed maternal and fetal evaluations to complete the
diagnosis and future outcome(35).
Results
sFlt-1/PlGf ratio≤38 sFlt-1/PlGf ratio>38
NPV 99.3% – first week PPV 36.7%
(95% CI; 97.9-99.9) (95% CI; 28.4-45.7)
NPV 97.9% – 2nd week Sp 83.1%
NPV 95.7% – 3rd week (95% CI; 54-77)
NPV 94.3% – 4th week Sn 66.2%
(95% CI; 79.4-86.3)
PlGF<100 pg/Ml
Sp 56% (95% CI; 89-99)
Sn 96% (95% CI; 49-63)
PPV 44% (95% CI; 36-52)
NPV 98% (95% CI; 93-100)
sFlt-1/PlGf ratio>85
Sp 99.5%
(95% CI; 97.7-100)
sFlt-1/PlGf ratio>100
Sp 95.5%
(95% CI; 92.9-100)
Year VII • No. 26 (4/2019)

Potential therapeutic targets
Despite its important predictive value, the sFlt-1/
PlGF ratio and both biomarkers alone were studied
as a potential target for therapies. In a pilot study,
Thadhani et al. confirmed that removing sFlt-1 with
dextran sulfate apheresis, from the excessive placen-
tal level secreted in the maternal circulation, was safe
to use during pregnancy and the gestational age of the
treated patients was prolonged(36,37).
Therefore, further randomized controlled trials
must confirm this hypothesis. Brownfoot et al. con-
ducted an experimental treatment for preeclampsia,
with pravastatin, which reduced sFlt-1 level in the
maternal circulation and decreased endothelial dys-
function in cell culture experiments(38).
The previous group published a pilot data suggest-
ing that pravastatin can positively interfere with clini-
cal and biochemical features of preterm preeclampsia,
but studies to confirm the importance of pravastatin
1. Bussolino F, Mantovani A, Persico G. Molecular mechanisms of blood vessel
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in randomized controlled trials are still under careful
observation(39).
Different PlGF treatment reports, on rodent mod-
els, evaluated the possibility of new means of treating
preeclampsia, using exogenous PlGF, by continuous
infusion via an intraperitoneal osmotic pump of re-
combinant human PlGF (rhPlGF)(40) or by transfection
of mice with adenovirus(41). The first method is shown
to reduce blood pressure, proteinuria and improve glo-
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of oxidative stress, while the second one reduced hyper-
tension but not proteinuria. Therefore, the treatment
of preeclampsia with PlGF needs to be further studied;
it seems promising, but many uncertainties remain. n
Conflicts of interests: The authors declare no con-
flict of interests.
Financial support statement: none declared.
Acknowledgement statement to Sorin Cojocaru for Figure 1.
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tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. J Am Soc Nephrol.
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(66):687-97.
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27
 obstetrics

Gestational diabetes
and pre-existing diabetes –
an approach from
the metformin perspective
Ana Maria Abstract Rezumat
Alexandra
Stănescu1, Metformin is one of the most used antidiabetic drugs, with În diabetologie, metforminul este utilizat frecvent, existând o
extensive experience, multiple benefits and low costs. The vastă experiență în utilizarea sa, cu multiple beneficii și costuri
Ioana Veronica issue of the benefits and risks of metformin administration reduse. Din ce în ce mai des, se ridică problema beneficiilor
Grăjdeanu1, during pregnancy is raised more and more frequently. și a riscurilor administrării metforminului în timpul sarcinii.
Camelia Cristina Although more research is needed, we wanted to review the Deși mai multe cercetări sunt necesare, am dorit să revizuim
Diaconu1,2 existing research data for both gestational diabetes and pre- cercetările existente atât din punctul de vedere al diabetului
1. “Carol Davila” University
existing diabetes. gestațional, cât și al diabetului preexistent sarcinii.
of Medicine and Pharmacy, Keywords: gestational diabetes, pre-existing diabetes, Cuvinte-cheie: diabet gestaţional, diabet preexistent,
Bucharest metformin metformin
2. Clinical Emergency
Hospital of Bucharest
Corresponding author:
Submission date:
15.10.2019 Diabetul gestațional și diabetul preexistent sarcinii – abordare
Ana Maria Alexandra Stănescu
E-mail: alexandrazotta@
Acceptance date:
2.11.2019 din perspectiva metforminului
yahoo.com Suggested citation for this article: Stănescu AMA, Grăjdeanu IV, Diaconu CC. Gestational diabetes and pre-existing diabetes – an approach from the metformin
perspective. Ginecologia.ro. 2019;26(4):28-31.

Introduction Subsequently, several studies have shown the efficacy

Metformin is one of the most used antidiabetic drugs,
with extensive experience, multiple benefits and low
costs. Both pre-existing diabetes and gestational dia-
betes are on the rise. Although initially metformin was
not used in pregnancy due to the lack of studies, issues
related to safety and the degree of passage of the pla-
centa, the actual perspective is different.
Hyperglycemia, even mild, during pregnancy is
associated with an increase in maternal, fetal and
neonatal adverse effects, with a change in lifestyle,
self-monitoring of blood glucose and pharmacological
intervention for glycemic control(1,2). Usually, insulin
is the therapeutic option in gestational diabetes, being
safe for the mother and the fetus. However, metformin
is an effective, easier to administer and less expensive
option, which is increasingly used by clinicians for ges-
tational diabetes.
One of the first mentions related to the administra-
tion of metformin in gestational diabetes was in 1975
at the Aberdeen International Symposium on Carbohy-
drate Metabolism in Pregnancy and Newborn(3). In 1980,
Coetzee et al. conducted observational studies regarding
the safety and efficacy of metformin administration in
pre-existing diabetes and gestational diabetes in women
from South Africa(4,5).
and lack of side effects when administering metformin
during pregnancy. These studies have shown that the
use of metformin does not increase the risk of miscar-
riage; metformin crosses the placenta, which can expose
the fetus. The long-term effects on fetal programming
and the offsprings of children exposed to intrauterine
metformin are not completely elucidated(6,7).
The action of metformin in the context
of pregnancy
Metformin improves insulin sensitivity, reduces he-
patic gluconeogenesis and increases peripheral glucose
uptake, with a minimal risk of hypoglycemia, and can
reduce the body weight by an average of 5.8%(8). In the
context of pregnancy, it is important to note that the
placenta expresses many isoforms of organic cationic
transporters (OTC) and therefore metformin readily
crosses the placenta(9). Fetal metformin concentrations
can reach at least 50% of the maternal concentration(10).
Placental transport to the developing fetus raises the
question of potential adverse effects on fetal develop-
ment. At present, it is not known whether the human
embryo expresses OTC; pre-implanted human embryos
have a low mitochondrial content and may therefore be
unresponsive to metformin(11). Metformin stimulates

28 Year VII • No. 26 (4/2019)


the 5’-adenosine monophosphate-activated protein ki-
nase (AMPK) activity in embryonic stem cell cultures
in mice in vitro, but the significance of this finding is
unclear, given the lack of effect on mouse embryos in
vivo(12,13).
The renal clearance of metformin is significantly in-
creased in the second half of pregnancy, consistent with
increased renal plasma flow and glomerular filtration
during pregnancy(14). For a proper glycemic control, pa-
tients with gestational diabetes may require high doses
of metformin (500-2500 mg/day). At doses above 2500
mg/day, maternal, fetal or newborn safety is unknown.
Type 2 diabetes pre-existing pregnancy
and metformin
The prevalence of type 2 diabetes is increasing, the
age of onset of type 2 diabetes is decreasing, and the age
of pregnant women is increasing, all of which lead to
an increasing prevalence of pregnant women with type
2 diabetes(15). These women have an increased risk of
obesity, pregnancy-induced hypertension, preeclampsia
and caesarean section(16).
Because metformin is a first-line therapy for type 2
diabetes, many future pregnant women with pre-exist-
ing diabetes are on metformin treatment, raising the
issue of metformin administration during pregnancy.
On the other hand, given the insulin resistance of preg-
nancy, it is likely that most women with type 2 diabe-
tes prior to pregnancy require insulin treatment during
pregnancy, to maintain glycemic control.
Even though insulin is needed, metformin may con-
tribute to improved maternal glycemic control, better
maternal weight control, and reduced insulin dose. In
women receiving metformin prior to pregnancy, the
discontinuation of it may lead to glycemic fluctuations
and increased insulin dose, especially in the second half
of pregnancy, when an additional physiological decrease
in insulin sensitivity occurs.
Hellmuth et al. conducted a retrospective study be-
tween 1966 and 1984, including 50 women (19 with
pre-existing type 2 diabetes), and have noted an increase
in preeclampsia and perinatal mortality with metformin
compared to sulphonylurea or insulin treatment(17).
Levitt et al. followed women with pre-existing type
2 diabetes under treatment with insulin or oral antidia-
betic agents before and during pregnancy. There was a
very high rate of perinatal mortality (125 to 1000 births)
in the group treated predominantly with metformin and
glibenclamide; women who switched to insulin from oral
medication had a perinatal mortality rate of 28 to 1000
births and in women who switched from diet to insulin
the rate was 33 to 1000 births(18).
Hughes and Rowan were unable to demonstrate any
difference in maternal and fetal adverse outcomes in
women taking metformin compared to those taking
insulin(19).
The National Institute for Health and Care Excel-
lence (NICE) recommends that women with pre-existing
type 2 diabetes receive metformin as an adjuvant or
Year VII • No. 26 (4/2019)
ginecologia
alternative to insulin during the preconception and dur-
ing pregnancy, when the likely benefits of improved glu-
cose control outweigh the potential for adverse effects(20).
Gestational diabetes and metformin
Gestational diabetes represents the diabetes that
occurs during pregnancy, its severity differing from
person to person. The prevalence of gestational diabe-
tes is increasing worldwide, as the age at which women
become pregnant increases and the prevalence of obesity
increases(21).
Rowan et al. managed to change the perspective on the
use of metformin in pregnant women; they studied 751
women with gestational diabetes, who were randomized
to either metformin or insulin. Most women with met-
formin required supplemental insulin (46%), but at con-
siderably lower doses than women receiving insulin alone.
Gastrointestinal adverse reactions resulted in the discon-
tinuation of metformin in 1.9% of women and in dose
reduction by 8.8%. Negative outcomes were recorded in
32% of the participants (regardless of whether metformin
or insulin was administered), being highlighted: neonatal
hypoglycemia (<2.6 mmol/L), respiratory distress, need
for phototherapy, Apgar score at 5 minutes <7 or preterm
birth. Severe hypoglycemia rates (<1.6 mmol/L) were re-
duced in the metformin group compared to the insulin
group. Maternal weight gain to term was significantly
lower in women taking metformin than in insulin-treated
group (0.4±2.9 kg in the metformin group and 2±3.3 kg
in the insulin group; p<0.001)(22).
Balani et al. compared 100 women with gestation-
al diabetes treated with metformin and 100 treated
with insulin. The incidence of gestational hyperten-
sion, preeclampsia and caesarean section was similar,
but the mean increase in maternal weight at term was
significantly lower in the metformin group. Pregnant
women on metformin treatment had a lower incidence
of prematurity, neonatal jaundice, with an overall im-
provement in neonatal morbidity compared to pregnant
women treated with insulin, but no differences in fetal
macrosomia were noted(23).
In another study, Balani et al. looked at women with
gestational diabetes and metformin treatment compared
to women with gestational diabetes who were on diet
alone. In the metformin-treated group, there was a ten-
dency to decrease fetal macrosomia and decrease the
gestational age, compared to the group that followed
only diet(24).
The National Institute for Health and Care Excellence
also recommends metformin for women with gestational
diabetes if blood glucose targets were not met through
changes in diet and exercise for 1-2 weeks, and also rec-
ommends insulin instead of metformin for women with
gestational diabetes, if metformin is contraindicated or
unacceptable(20).
When addressing the response to metformin treat-
ment, several factors that may predict a poor response to
metformin (Figure 1) should be considered, which may
result in combination insulin therapy(25,26).
29
obstetrics
Higher fasting glucose at diagnosis
Early detection of gestational diabetes
Past history of gestational diabetes
Older age at diagnosis
Elevated BMI
Higher baseline HbA1c or serum fructosamine concentration
Figure 1. Factors that can predict a poor response to metformin(27)
Other aspects
Women with polycystic ovarian syndrome may have
insulin resistance, and in combination with obesity, the
chances of conception and response to fertility treat-
ment decrease and the risk of miscarriage and gesta-
tional diabetes increases(28-30). Metformin is used in
polycystic ovarian syndrome to induce ovulation, re-
duce spontaneous abortion rates, prevent fetal growth
restrictions, and improve metabolic associations, such
as glucose intolerance(31,32).
Metformin is also considered an adjuvant therapy in
cancer treatment. The patients with type 2 diabetes on
metformin treatment have a lower risk of developing
cancer(33,34). However, due to inhibitions caused by met-
formin, the excessive use in mothers during pregnancy
may lead to an increased risk of their children developing
metabolic diseases later in life.
Following the risk of malformations in the embryo,
metformin administered in doses that stimulated the
AMPK activity in the maternal liver did not stimulate
the AMPK activity in the embryo, nor did it increase
congenital abnormalities. However, metformin stimu-
lated AMPK activity and inhibited the expression of
a gene associated with congenital malformations in
mouse embryonic stem cells that have been used as an
in vitro model to study diabetic embryopathy(12). Pre-
implanted human embryos are low in mitochondria and
are dependent on anaerobic metabolism, suggesting
30
that early human embryos may be unresponsive to
metformin(11).
In order for metformin to affect fetal or placental
physiology and development, the cells in these tissues
must be able to take over metformin. Because metfor­
min is positively charged at neutral pH, there must be
a strong potential of the mitochondrial membrane for
it to enter the mitochondrial matrix(35,36). Human pla-
centas express several OCT isoforms, and metformin
may indirectly affect the development of the fetus, for
example, by modified nutrient administration or pla-
cental growth. However, this requires further investiga-
tions(9,37). Eyal et al. estimated that the daily intake of
metformin transferred through breast milk to infants
was 0.13-1.28 mg(14). Metformin reaches into breast milk
in a clinically insignificant amount(38).
Conclusions
More and more practitioners consider metformin
therapy a good option during pregnancy, because it is
generally an effective and well-tolerated agent, with a
well-defined mechanism of action. However, there is a
need for more detailed studies to determine the degree
of fetal exposure and long-term safety following fetal
exposure. n
Conflicts of interests: The authors declare no con-
flict of interests.
Year VII • No. 26 (4/2019)

1. Farrar D, Simmonds M, Bryant M, et al. Hyperglycemia and risk of adverse
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31
 obstetrics
Early diagnosis of ovarian
pregnancy – a case report
Aida Petca1,2, Abstract
Cristina Oprescu2,
Florica Șandru1,2, Ectopic pregnancy is a serious health problem that leads to
ma­­ter­­nal mortality and morbidity. Ovarian pregnancy is a very
Răzvan-Cosmin rare variety of ectopic pregnancy and represents a medical
Petca2, chal­lenge in terms of its management. Although the incidence
Mihai Cristian of ovarian ectopic pregnancy is low, there is a high risk of severe
Dumitrașcu2,3, com­pli­ca­tions (hemorrhagic shock) if it’s not identified and
Mihaela Boț1,2, trea­ted in time. The symptoms of ovarian ectopic pregnancy
can be difficult to distinguish based on ultrasound imaging
Nicoleta Măru2 and clinical examination alone. Laparoscopic management
1. “Elias” University is required for definitive diagnosis and treatment. Identifying
Emergency Hospital,
Bucharest these emergent cases early is very important because of
the high risk of maternal death. We present the case of a
2. ”Carol Davila” University
of Medicine and Pharmacy, 34-year-old female who accused left lower abdominal pain,
Bucharest whilst she declared 5 weeks and 4 days of amenorrhea and a
3. Bucharest University po­si­tive pregnancy test. Transvaginal sonography identified
Emergency Hospital a gestational sac in the very proximity of the left ovary. La­pa­
Corresponding author: ro­scopy was performed and so we discovered a purple tu­mor,
Cristina Oprescu 3.5/3 cm, with intense vascular drawing, situated on the left
E-mail: cris221185@yahoo.com
ovary. Thus, primary ovarian ectopic pregnancy was diag­
nosed and confirmed by histopathology. The postoperative
evo­lu­tion was favorable, the patient being discharged the next
day postoperatively. Our purpose is to highlight the successful
treat­ment with a minimally invasive surgical technique of an
ova­rian pregnancy.
Keywords: ectopic pregnancy, ovarian pregnancy,
laparoscopy
Submission date:
24.09.2019 Diagnosticul precoce al sarcinii ovariene – prezentare de caz
Acceptance date: Suggested citation for this article: Petca A, Oprescu C, Șandru F, Petca RC, Dumitrașcu MC, Boț M, Măru N. Early diagnosis of ovarian pregnancy – a case report.
17.10.2019 Ginecologia.ro. 2019;26(4):32-34.
Introduction
Ovarian ectopic pregnancy is a rare type of ectopic preg-
nancy with an estimated prevalence between 1:7000 and
1:70,000, representing 3% of all ectopic cases(1).
The symptoms mimic those of ectopic tubal pregnancy
and can be difficult to differentiate only on the basis of
the ultrasound image and on the clinical and paraclinical
examination. The laparoscopic management is most often
required for the diagnosis and treatment of ovarian preg-
nancy. The early identification of these cases is imperative
because of the high risk of maternal death(2).
It usually ends in a gestational sac rupture in the first
trimester of pregnancy due to increased ovarian tissue vas-
cularization that will lead to internal bleeding and hypo­
volemic shock. The diagnosis is usually made by emergency
laparoscopy and histopathological evaluation(2). There are
two types of ovarian pregnancy: the primary ovarian preg-
nancy, when implantation occurs at the level of the ovary
32
Rezumat
Sarcina ovariană este o varietate foarte rară de sarcină ec­to­pică
și reprezintă o provocare medicală în ceea ce privește ma­nage­­
mentul acesteia. Deși incidența sarcinii ectopice ova­rie­­ne este
scăzută, există un risc ridicat de complicații se­ve­re (șoc he­mo­
ragic) dacă nu este identificată și tratată la timp. Simp­to­me­le
sarcinii ectopice ovariene pot fi dificil de diagnosticat doar pe
baza aspectului ecografic și a exa­me­nu­lui clinic. Abordul la­pa­
ro­scopic este necesar pentru un diag­nos­tic și tratament definitiv.
Iden­­ti­ficarea timpurie a aces­tor cazuri este foarte importantă,
din cauza riscului mare de deces matern. Prezentăm cazul unei
femei de 34 de ani care a acuzat dureri abdominale inferioare în
hipocondrul stâng, declarând 5 săptămâni și 4 zile de amenoree
și un test de sarcină pozitiv. Ecografia transvaginală a identificat
un sac gestațional în imediata apropiere a ovarului stâng. S-a
in­ter­ve­nit chirurgical pe cale laparoscopică și s-a constatat
pre­zen­ța unei formațiuni tumorale de culoare violacee, cu
di­men­siuni de 3,5/3 cm, cu desen vascular intens, situată pe
ova­rul stâng, diagnosticându-se o sarcină ectopică ovariană
primară, confirmată de examenul histopatologic. Evoluția
post­ope­ra­torie a fost favorabilă, pacienta fiind externată a doua
zi postoperatoriu. Scopul nostru este de a evidenția suc­ce­sul
tratamentului chirurgical minim invaziv în contextul unei sar­cini
ovariene.
Cuvinte-cheie: sarcină ectopică, sarcină ovariană, abord
laparoscopic
per prima, and the secondary ovarian pregnancy, when the
primary nesting occurs at the level of the fallopian tube
and subsequently the ovarian attachment results second
into tubal abortion(3).
Case presentation
We present the case of a 34-year-old female with a his-
tory of a full-term pregnancy, by caesarean section, in
2015, with previous regular menstrual cycle and with
declared intent to conceive again, also known with a total
thyroidectomy in 2017, in treatment with Euthyrox® 100
mcg, 1 cp/day, who was admitted into the surgical emer-
gency department of the “Elias” University Hospital, in
May 2019. She presented with left lower abdominal pain,
with 5 weeks and 4 days of amenorrhea and a positive result
on the pregnancy test. βHCG level was 7.749 mIU/mL. The
vaginal examination found a tender cystic mass palpable
in the left fornix. Transvaginal ultrasonography showed
Year VII • No. 26 (4/2019)

empty uterine cavity with 11 mm thickness. An ectopic
gestational sac and yolk sac seemed to be inside her left
ovary, and were identified close to the midline, which
correlated with her 6-week amenorrheea. The fetus and
fetal heart beat were not clearly seen. The vascular prolif-
eration called “ring of fire” – which is typical for ectopic
ovarian pregnancy – was detected around the gestational
sac. Her right ovary and tubal structures seemed to be
normal; no liquid in the Douglas sac. The diagnosis of left
ovarian ectopic pregnancy was established and the patient
was hospitalized for specialized treatment.
At the hospital, the patient was conscious, coopera-
tive, oriented temporally and spatially, with blood pres-
sure 100/50 mmHg, and heart rate 75/min. A physical
examination showed minimal tenderness in all sides of
her abdomen with an increase sensibility in the left lower
pelvic section. A speculum examination showed a small
amount of cervical bleeding. On the vaginal examina-
tion, the vagina and cervix were normal and the uterus
had a normal size; a tender chystic mass was palpable
in the left fornix.
Laboratory analyses showed a white blood cell count
(WBC) of 66.40/uL, hemoglobin (Hb) 12.9 g/dl, hematocrit
(Htc) 37.9%, thrombocytes 185,000 uL, beta human chori-
onic gonadotropin (β HCG) 7749, blood group 0I and Rh+,
and normal urine results. Laparoscopic surgery was decided
under general anesthesia with oro-tracheal intubation.
The laparoscopic surgery was performed, which re-
vealed: the uterus of normal macroscopic appearance,
Figure 1. Laparoscopic images of ovarian pregnancy
Year VII • No. 26 (4/2019)
ginecologia
the bilateral tubes and the right ovary were normal, at
the level of the left ovary there was a purple tumor (3.5/3
cm), with intense vascular drawing (Figure 1).
The incision of the tumor was practiced with the ex-
ternalization of an increased amount of blood and of
trophoblastic tissue; hemostasis was difficult to achieve,
the remaining ovary was sutured in order to ensure the
hemostasis. The abdominal cavity was washed, hemo-
stasis checked and drainage of the Douglas space was
placed.
The evolution of the patient was favorable, being dis-
charged 24 hours postoperatively.
The histopathological result revealed multiple frag-
ments representing blood clots and numerous chorionic
villi with non-specific modifications, trophoblast frag-
ments without circumferential arrangement; ovarian
stroma, no trophoblastic disease elements were identi-
fied; histopathological appearance of ovarian pregnancy
with non-specific changes.
Discussion
The diagnostic criteria for ovarian pregnancy are the
Springelberg criteria, described 100 years ago(4):
1. Gestation sac located in the ovary area.
2. The gestational sac is attached to the uterus by the
ovarian ligament.
3. Ovarian tissue present in the gestational sac identi-
fied histopathologically.
4. The uterine tube on the involved side is intact.
33
obstetrics
The risk factors for the onset of ovarian pregnancy are(5):
n Intrauterine devices.
n Pelvic inflammatory disease.
n Sexually transmitted diseases.
n Assisted reproduction techniques.
n Surgery in the pelvic aria in the past.
n Endometriosis.
n Ectopic pregnancy in the background.
n Salpingitis.
n Advanced maternal age.
n Multiparity.
The actual cause of the abnormal implantation is un-
clear. Some theories suggest that the abnormal implanta-
tion that occurs in the ovarian pregnancy is the result of
the following:
1. Migration of the embryo related to the presence of
certain conditions that cause epithelial lesions of the uter-
ine tube which alter the tubular motility(6).
2. Failure to release the egg from the broken follicle(7).
3. Inflammatory thickening of tuna albuginea(2).
The signs and symptoms that appear in the ovarian
pregnancy are: moderate or intense pelvic pain, vaginal
bleeding, amenorrhea, irregular menstrual cycle, nausea,
vomiting, constipation, hemorrhagic shock in case of a
rupture(5).
The ultrasound criteria in case of ovarian pregnancy
are: free endometrial cavity, gestational sac that is identi-
fied at the level of the ovarian parenchyma, yolk sac with
or without embryo image depending on the gestational
age, image “crown of fire” (vascular proliferation) visible
around the gestational sac, the presence of the ovarian
cortex including corpus luteum and follicles around and
with a much more pronounced echogenic ring than the
ovary(8). Most ovarian pregnancies rupture before the 40th
day of pregnancy, although there have been reports of a
number of pregnancies that reached the third trimester(9).
The differential diagnosis is made in this case with: cyst of
corpus luteum, hemorrhagic ovarian cyst, endometrioma,
tubal ectopic pregnancy, early intrauterine pregnancy or
stopped in evolution, and in case of negative pregnancy
test with appendicitis(10). The gold standard in the diag-
nosis and treatment of ovarian pregnancy is represented
by laparoscopy or laparotomy with histopathological con-
firmation. However, laparoscopy has many advantages
over laparotomy: shorter operative time, reduced blood
1. Marcus SM, Brinsden PR. Primary ovarian pregnancy after in vitro fertilization and
References
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7. Melcer Y, Maymon R, Vaknin Z, Pansky M, et al. Primary ovarian ectopic
pregnancy: still a medical challenge. J Reprod Med. 2016; 61(1-2):58-62.
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9. Choi HJ, Im KS, Jung HJ, Lim KT, Mok JE, Kwon YS. Clinical analysis of ovarian
pregnancy: a report of 49 cases. Eur J Obstet Gynecol Reprod Biol. 2011; 158(1):87-9.
10. Tehrani HG, Hamoush Z, Ghasemi M, Hashemi L. Ovarian ectopic pregnancy: a
34
loss, reduced hospitalization days and low postoperative
analgesia(10). When choosing the right treatment, the pa-
tient’s desire to obtain a pregnancy should be taken into
consideration. The conservative treatment with tropho-
blast resection or thinning or cystectomy with hemostatic
suture is preferable to ovarectomy because the patient
keeps her fertility(5).
The success of methotrexate in the management of ovar-
ian pregnancy is still undetermined and generally impracti-
cal, only a few case studies reporting its use(11-13). The single
dose of methotrexate and multidose were successfully used
to treat stable patients with ovarian pregnancy with hCG
levels up to 5200 mIU/mL. Most commonly, methotrexate
is used in the treatment of increased beta-hCG following
surgical treatment(14). Although it is less invasive than sur-
gical treatment, there have been many cases of failure and
even major ovarian bleeding(2,15).
In this case, we chose minimally invasive surgical treat-
ment to ensure a high success rate. The Taiwan Institute,
in a study of 110 patients with ovarian pregnancies over
21 years old, concluded that 70.9% of them were treated
by laparoscopy and 29.1% by laparotomy, and none of the
patients received drug treatment(16).
The treatment of ectopic pregnancies with the help of
laparoscopic surgery is best indicated because the pregnan-
cies are small in size, contain low consistency tissue which
allows the extraction of fragments through the laparo-
scopic incisions, using the endobag, and also the morcella-
tor allows the extraction of larger tissues(17). Due to a faster
postoperative recovery of the patient after a laparoscopic
intervention, the success rate in obtaining a normal intra­
uterine pregnancy is higher.
Conclusions
The diagnosis with the latest ultrasonography scanner
and the experience in laparoscopic surgery have proven
succes in treating ovarian pregnancy through minimally
invasive surgery. Laparotomy was avoided, hospitalization
days and costs were reduced, and the patient did not need
adjuvant treatments. This method is safe when performed
by an experienced operator and has the advantage of keep-
ing fertility for the future. n
Conflicts of interests: The authors declare no conflict
of interests.
rare case. Iran J Reprod Med. 2014; 12(4):281-4.
11. Shen L, Fu J, Huang W, Zhu H, Wang Q, Yang S, Wu T. Interventions for non-tubal
ectopic pregnancy. Cochrane Database of Systematic Reviews. 2014; 7:CD011174.
12. Chetty M, Elson J. Treating non-tubal ectopic pregnancy. Best Pract Res Clin Obstet
Gynaecol. 2009; 23(4):529–38.
13. Alalade A, Mayers K, Abdulrahman G, Oliver R, Odejinmi F. A twelve year analysis
of non-tubal ectopic pregnancies: do the clinical manifestations and risk factor
for these rare pregnancies differ from those of tubal pregnancies?. Gynecol Surg.
2015; 13(2):103-9.
Reclamă GIN(26)0105
14. Parker VL, Srinivas M. Non-tubal ectopic pregnancy. Arch Gynecol Obstet. 2016;
294(1):19-27.
15. Ghaneie A, Grajo JR, Derr C, Kumm TR. Unusual ectopic pregnancies:
sonographic findings and implications for management. J Ultrasound Med. 2015;
34(6):951–62.
16. Ko PC, Lo LM, Cheng PJ. Twenty-one years of experience with ovarian ectopic
pregnancy at one institution in Taiwan. Int J Gynaecol Obstet. 2012; 119(2):154–8.
17. Petca A, Veduta A, Mehedinţu C, Maru N, Petca R, Boţ M. Ectopic pregnancy
în rudimentary horn: early diagnosis and management. Ginecologia.ro. 2018;
20(2):20-2.
Year VII • No. 26 (4/2019)
 gynecology

Sacrocolpopexy –
advantages and disadvantages
of abdominal and laparoscopic
approaches. A systematic
review and meta-analysis
Mihai Cristian Abstract Rezumat
Dumitrașcu1,2,
Răzvan Pelvic organ prolapse has become a common problem Prolapsul genital a devenit o afecțiune frecventă în rândul
among women and, because of its increasing incidence, populației de sex feminin. În urma creșterii incidenței, au fost
Fodoroiu2, several surgical techniques have been developed. The current dezvoltate diferite tehnici chirurgicale pentru refacerea tul­­bu­­
Cătălin George gold standard surgical repair for pelvic or­gan prolapse is the rărilor de statică pelviană. Standardul de aur în ma­nage­­mentul
Nenciu1, abdominal sacrocolpopexy, be­cause of its high success rate acestei patologii a devenit sacrocolpopexia fo­lo­sind abordul
Florica Şandru1,3, and excellent anatomic out­come. La­pa­ros­copic sacrocol­ clasic abdominal, datorită rezultatului ana­tomic excelent și
Aida Petca1,3, popexy has become an alter­native for the ab­do­mi­nal eficienței metodei. Abordul laparoscopic în sacrocolpopexie a
approach. The aim of this systematic review is to compare the devenit o alternativă la abordul cla­sic. Sco­pul acestei sinteze
Răzvan Petca1, advantages and disadvantages between the laparoscopic este de a compara și prezenta avan­ta­jele și dezavantajele celor
Monica Mihaela sacrocolpopexy and the abdominal sacro­col­po­pexy. două modalități de abord al sa­cro­colpopexiei.
Cîrstoiu1,2 Keywords: laparoscopic sacrocolpopexy, abdominal Cuvinte-cheie: sacrocolpopexie laparoscopică,
1. “Carol Davila” University sacrocolpopexy, pelvic organ prolapse sacrocolpopexie abdominală, prolapsul organelor pelviene
of Medicine and Pharmacy,
Bucharest
2. Bucharest University
Submission date:
8.10.2019 Sacrocolpopexia – avantaje și dezavantaje între abordul abdominal
Emergency Hospital
3. “Elias” University
Acceptance date:
29.10.2019 și cel laparoscopic. Sinteză sistematică și metaanaliză
Suggested citation for this article: Dumitrașcu MC, Fodoroiu R, Nenciu CG, Şandru F, Petca A, Petca R, Cîrstoiu MM. Sacrocolpopexy – advantages
Emergency Hospital,
Bucharest and disadvantages of abdominal and laparoscopic approaches. A systematic review and meta-analysis. Ginecologia.ro. 2019;26(4):36-38.

Corresponding author:
Florica Sandru
E-mail: florysandru@yahoo.com

Introduction Materials and method

Pelvic organ prolapse (POP) is known to affect 30%
of women aged 50-89 years old, and it is predicted that
the morbidity of POP will increase by more than 40%
over the next 40 years(1). The procedure for POP repair
must be safe, effective, with a low recurrence rate, and
must improve sexual and urinary functions(2).
The current gold standard in the treatment of POP
is the abdominal sacrocolpopexy (ASC). In comparison
with the sacrospinous ligament fixation, ASC is asso-
ciated with longer recovery time and operative time,
but has a higher success rate, with less dyspareunia(3,4).
Over the past decades, the laparoscopic-assisted sac-
rocolpopexy (LSC) has become available, with similar
overall results as the abdominal approach. Although LSC
is less invasive, it requires greater surgical skills in order
to determine the proper plans for safe and effective dis-
section of the rectovaginal and vesicovaginal spaces(5).
The aim of this study was to compare the advantages
and disadvantages of different sacrocolpopexy techniques,
and to perform a systematic review of the outcomes.
A systematic review and meta-analysis was per-
formed. Abstracts and studies were selected using Med-
line search after applying exclusion and inclusion crite-
ria. A single investigator reviewed the studies and the
abstracts. The study selection process is demonstrated
in Figure 1. After meeting the inclusion criteria, stud-
ies were later excluded from the review based on the
exclusion criteria.
The inclusion criteria were: published original re-
search, comparison of the outcomes of ASC and LSC,
sample size in each group greater than 10, and the fol-
low-up duration more than three months. Studies were
excluded if the language was not English, and if the re-
sults of the studies did not include comparable results.
Results
Characteristics of the selected studies
A total of 53 papers were initially identified. Three
studies, including 996 patients, were retrieved(6-8). Over-
all, a number of 672 patients underwent ASC and 354

36 Year VII • No. 26 (4/2019)

 ginecologia

Records identified through database searching Figure 1. Flowchart

Identification

of study selection
(n=53) process

Records screened Records excluded (n=22)

Searching

(n=31) n no original data

n no comparison of ASC
versus LSC
n sampe size per group <10
n follow-up <3 months
Eligibility

Full text evaluated

(n=4)

Excluded (n=1)
n other language than English
Inclusion

Full text included

(n=3)

underwent LSC. The mean follow-up duration was 13.5
months after ASC and 9.1 months after LSC. Studies
included women undergoing concomitant vaginal repair
and anti-incontinence surgery. Paraiso et al. study also
included five women who underwent bowel resection due
to rectal prolapse associated with constipation symp-
toms(8). Table 1 summarizes the studies characteristics.
Table 2 summarizes the surgical outcomes comparison
between LSC and ASC.
Synthesis of results
Duration of surgery. The duration of surgery was
17.8% shorter in the ASC group in comparison with the
LSC group. This analysis was performed on all three
studies that involved 672 patients who underwent ASC
and 354 patients with LSC. The mean operation time
for ASC was 208 minutes, in comparison with 253 mean
operation time for LSC. The difference in the duration
of surgery was 45 hours(6-8).

Table 1 Characteristics of included studies

Participants
Reference Year Country Study design Study duration Follow-up Primary outcome
(LSC/ASC)

Compare demographic
Retrospective 6 years and 5.9 mo (LSC),
Hsiao et al. 2007 US 25/22 and perioperative
cohort 1 month 11 mo (ASC)
parameters

Compare perioperative
Retrospective 8 mo (LSC),
Nosti et al. 2014 US 11 years 273/589 and postoperative surgical
cohort 14 mo (ASC)
outcomes

Retrospective 6 years and 13.5 mo (LSC), Compare efficacy

Paraiso et al. 2005 US 56/61
cohort 3 months 15.7 mo (ASC) and safety

Year VII • No. 26 (4/2019)

37
gynecology
Table 2 LSC and ASC surgical outcomes comparison
Duration of surgery Intraoperative blood loss
Reference (minutes) (mL)
ASC LSC ASC
Hsiao et al. 185 220 195
Nosti et al. 222 272 150
Paraiso et al. 218 269 234
Mean value 208 253 193
Blood loss. Intraoperative mean blood loss in the ASC
group was 193 mL, being 63% higher than in the LSC
group, which had a significantly lower mean intraopera-
tive blood loss of 118 mL(6-8).
Hospital stay. ASC was associated with greater hos-
pital stay (mean hospital stay of 3.4 days) compared with
LSC (mean hospital stay of 1.33). This result estimated
that LSC had a 61% shorter hospital stay(6-8).
Postoperative ileus/small bowel obstruction
(SBO). It is well known that laparoscopical approach
offers a lower rate of complications. ASC is thus associ-
ated with increased risk of postoperative ileus and small
bowel obstruction. Nosti et al. reported 29 cases (out of
273 patients) of ileus and SBO in the ASC group. The
other two groups only reported seven cases in total. Out
of a total of 672 patients who underwent ASC, 5.35% had
ileus and SBO complications. As a comparison, the LSC
group reported only six cases, which represented 1.69%
of the patients enrolled in these studies(6-8).
Bladder and bowel injury. There was no significant
difference in rate of bowel and bladder injury between
the two groups(6-8).
Reoperation for prolapse surgery. There was no sig-
nificant difference in the rate of reoperation for prolapse
surgery between ASC and LSC groups. ASC had one case of
repeated surgery in the group from Nosti et al. Regarding
LSC, Paraiso et al. reported one case of repeated surgery
for apical recurrence, and Nosti et al. also reported one
repeated surgery for apical recurrence in the LSC group(6-8).
Discussion
This systematic review found that the laparoscopic ap-
proach in sacrocolpopexy has the advantage of less blood
loss, shorter hospital stay, less postoperative ileus/SBO,
but a longer operation time compared with the abdominal
approach. The findings reveal that there is no difference
between the two methods regarding the need for further
surgery and the risk of bowel or bladder injury(6-8).
Our results were similar with other meta-analyses re-
garding blood loss, hospital stay and surgery duration(5,9).
According to a recent systematic review(10) which com-
pared ASC with LSC, the duration of surgery between the
two approaches was 87 minutes. In our systematic review,
38
Postoperative ileus/small
Hospital stay
bowel obstruction
(days)
(reported cases)
LSC ASC LSC ASC LSC
83 3.3 1.2 3 0
100 3 1 29 5
172 4 1,8 4 1
118 3.4 1.33 12 2
we found a smaller difference in the duration of surgery of
45 minutes. This difference may be explained by the fact
that surgeons with experience can perform the LSC much
faster than surgeons who are still in the learning curve.
There is good evidence to support the laparoscopic ap-
proach due to the advantage of a shorter hospital stay
and less blood loss, which can have a positive impact of
the patients’ expectations of hospital care and service.
Because the anatomical and combined outcomes were not
very different between LSC and ASC, it is important to
notice the fact that ASC had a shorter duration of surgery,
which leads to a shorter anesthesia time for the patient.
Conclusions
The present systematic review indicates that ASC and
LSC have similar clinical outcomes in prolapse surgery.
The abdominal approach has a shorter surgery time, but
is associated with greater blood loss, longer hospital stay,
and has greater risk of postoperative ileus and small bowel
obstruction. LSC represents a safe alternative to ASC, with
similar anatomical results and with all the aforementioned
advantages. n
Conflicts of interests: The authors declare no con-
flict of interests.
References
1. Luber KM, Boero S, Choe JY. The demographics of pelvic floor disorders: current
observations and future projections. Am J Obstet Gynecol. 2001; 184(7):1496–501.
2. Culligan PJ, Murphy M, Blackwell L, Hammons G, Graham C, Heit MH. Long-term
success of abdominal sacral colpopexy using synthetic mesh. Am J Obstet Gynecol.
2002; 187(6):1473–80, discussion; 1481–2.
3. Benson J, Lucente V, McClellan E. Vaginal versus abdominal reconstructive surgery for
the treatment of pelvic support defects: a prospective randomized study with long-
term outcome evaluation. Am J Obstet Gynecol. 1996; 175:1418–22.
4. Lo T, Wang A. Abdominal colposacropexy and sacrospinousligament suspension for
severe uterovaginal prolapse: a comparison. J Gynaecol Surg. 1998; 14:59–64.
5. Pan K, Zhang Y, Wang Y, Wang Y, Xu H. A systematic review and meta-analysis of
conventional laparoscopic sacrocolpopexy versus robot-assisted laparoscopic
sacrocolpopexy. Int J Gynecol Obstet. 2015; 132(3):284–91.
6. Hsiao K, Latchamsetty K, Govier F, et al. Comparison of laparoscopic and abdominal
sacrocolpopexy for the treatment of vaginal vault prolapse. J Endourol. 2007;
21:926–30.
7. Nosti P, Andy U, Kane S, et al. Outcomes of abdominal and minimally invasive
sacrocolpopexy: a retrospective cohort study. Female Pelvic Med Reconstr Surg. 2014;
20:33–7.
8. Paraiso M, Walters M, Rackley R, et al. Laparoscopic and abdominal sacral colpopexies:
a comparative cohort study. Am J Obstet Gynecol. 2005; 192:1752–8.
9. Campbell P, Cloney L, Jha S. Abdominal versus laparoscopic sacrocolpopexy. Obstet
Gynecol Survey. 2016; 71(7):435–42.
10. De Sa M, Claydon L, Whitlow B, et al. Laparoscopic versus open sacrocolpopexy for the
treatment of prolapse of the apical segment of the vagina: a systematic review and
meta-analysis. Int Urogynaecol J. 2016; 27:3–17.
Year VII • No. 26 (4/2019)
 gynecology

Sex cord-stromal tumors

of the ovary: granulosa-stromal
cell tumors. Case report
and literature review
Laura Mustaţă1, Abstract Rezumat
Gheorghe
Peltecu1,2, Background. Sex cord-stromal tumors of the ovary Introducere. Tumorile cordoanelor sexuale stromale ale
(SCSTO) are a rare pathology of the ovary, representing ova­­ru­­lui reprezintă o patologie rară, constituind mai puţin
Raluca less than 2% from the total primary ovarian cancer cases. de 2% din to­ta­lul cancerelor primare ovariene. Materiale şi
Chirculescu3, Materials and method. This paper describes a case of me­­to­­dă. Lu­crarea descrie un caz de tumoare de gra­nu­loasă de
Anca Maria granulosa tumor cell, juvenile type, in a young woman with tip juvenil la o femeie tânără cu amenoree se­cun­dară şi infer­
Panaitescu1,2, secondary amenorrhea and primary infertility. Results. ti­­li­­tate primară. Rezultate. Tumoarea de granuloasă de tip
Nicolae Gică1,2, Granulosa tumor cell, juvenile type, was suspicioned after ju­­ve­nil a fost suspicionată după ce s-au efectuat investigaţiile
clinical and paraclinical tests had been done, and MRI cli­­ni­ce şi paraclinice, iar RMN-ul a descris o tumoare ovariană.
Radu Botezatu1,2, de­scribed the ovarian tumor. This case emphasizes the Ca­zul prezentat arată im­por­tanţa abordării în echipă mul­ti­­dis­­
Ruxandra importance of multidisciplinary team approach, involving ci­pli­nară care să in­clu­dă ginecologul, specialistul în re­pro­
Gabriela Cigaran1, gynecologist, fertility specialist, oncologist, and radiologist. du­­ce­re medicală asis­ta­tă, oncologul medical şi spe­cia­lis­tul în
Corina Gică1, We have reviewed the available literature in this report. ima­gis­tică. Deşi tra­ta­mentul de bază îl reprezintă chi­rur­gia, cu
George Iancu1,2 Although most cases are treated with surgery alone fol­ res­pec­tarea prin­ci­piilor de siguranţă oncologică si­mi­lare celor
lowing oncological safety principles as in epithelial ovarian din can­ce­rul epitelial ovarian, este importantă in­di­vi­dualizarea
1. “Filantropia” Clinical
Hospital of Obstetrics cancer approach, it is important to discuss the follow-up tra­­ta­­men­­tului la pacientele care doresc con­ser­va­rea fer­ti­li­tă­
and Gynecology, Bucharest ap­proach, taking into consideration that this patient par­ ţii, situaţie în care se recomandă o chirurgie adaptată aces­tui
2. “Carol Davila” University ti­cularly wished to procreate, and fertility sparing surgery deziderat. Chimioterapia şi radioterapia sunt tra­ta­mente
of Medicine and Pharmacy, was performed. Chemotherapy and radiotherapy were com­ple­mentare, recomandate în caz de recidivă sau paliaţie,
Bucharest com­plementary treatments that were discussed in the în stadii avansate de boală. Urmărirea atentă este importantă
3. “Alessandrescu-Rusescu” multidisciplinary meeting, but as no adjuvant therapy was pentru a surprinde o eventuală recidivă, în cazul pacientei fiind
National Institute for Mother
and Child Health, Polizu
found to be effective, these adjuvant therapies are kept realizată prin RMN abdominală/pelviană. Concluzii. Datorită
Hospital, Bucharest for recurrence and palliative care for advanced disease. rarităţii acestor cazuri, este necesară o continuă in­for­mare a
Corresponding author: Close follow-up was arranged for the patient as clinical po­pu­laţiei feminine şi a medicilor de familie de a so­li­cita opinia
Nicolae Gică and pelvic/abdominal MRI surveillance. Conclusions. spe­cia­listului pentru o depistare precoce.
E-mail: nicolae.gica@gmail.com Given the rarity of this disease worldwide, it is important Cuvinte-cheie: tumoare ovariană stromală de cordoane
to raise awareness amongst medical staff and educate sexuale, tumoare cu celule granuloase, tumoare juvenilă cu
the general population to seek medical attention early. celule granuloase, chirurgie conservatoare a fertilităţii, cancer
Keywords: sex cord-stromal tumors of the ovary, ovarian
granulosa tumor cell, juvenile granulosa tumor cells, fertility
sparing surgery, ovarian cancer

Submission date:
23.09.2019 Tumorile cordoanelor sexuale stromale ale ovarului: tumoarea de granuloasă.
Acceptance date:
18.10.2019 Prezentare de caz şi revederea literaturii
Suggested citation for this article: Mustaţă L, Peltecu G, Chirculescu R, Panaitescu AM, Gică N, Botezatu R, Cigaran RG, Gică C, Iancu G. Sex cord-stromal tumors
of the ovary: granulosa-stromal cell tumors. Case report and literature review. Ginecologia.ro. 2019;26(4):40-43.

Introduction of the malignant SCSTO have a good prognosis, being

Sex cord-stromal tumors of the ovary (SCSTO) is a
group of ovarian tumors, either benign of malignant,
that usually develop from the division of the cells which
surround and support the oocytes, and they include cells
that produce hormones. SCSTO represent a rare pathol-
ogy of the ovary and they comprise less than 2% from
the total primary ovarian cancer cases(1). The majority
diagnosed in an early stage, and they are low-grade ma-
lignancies compared with epithelial ovarian cancer.
SCSTO are a group of tumors that include fibro-the-
comas, Sertoli-Leydig cells, and granulosa cell tumors.
Almost 70% of the sex cord-stromal cells are granulosa
stromal cells and these include fibromas (the most fre-
quent histology found), thecomas and granulosa cell

40 Year VII • No. 26 (4/2019)


tumors. Pre- or postmenopausal women account the
same percentage of granulosa stromal cells tumors(2).
Fibromas don’t produce any hormones compared with
theca or granulosa cells; the latter tumors show specific
hormonal profile and they have a malignant histology
in most of the cases. Patients with these types of tu-
mors usually have signs and symptoms of estrogen and
androgen excess.
Granulosa cell tumors are part of the group of sex cord-
stromal tumors of the ovary, being the most common
one and having a malignant potential(3). These tumors
represent less than 5% of all ovarian cancer, two types
being described, the juvenile and adult types. The latter
is specific for patients aged 50-55 years old, and this is
the vast majority of the granulosa cell tumors, compris-
ing 95%. These tumors are large ovarian masses, up to
15 cm(4). The juvenile type is very rare, and this is specific
for children, for women at puberty, or in their early 20s.
This subtype seems to be more aggressive, with early re-
currence compared with the adult subtype, that tends
to have low risk of late recurrence(5). Of the rare cases
of prepubertal tumors, 75% are associated with pseudo-
precocious puberty because of estrogen secretion(6).
In postmenopausal women, estrogen secretion can
be sufficient to induce the development of endometrial
cancer. Endometrial cancer is accompanying granulosa
cell tumor in at least 5% of cases and 25-50% of the cases
of granulosa cell tumors are associated with endometrial
hyperplasia(6,7).
Ascites could be present in 10% of cases and pleural
effusion is even much rarer(6,7). Very rare granulosa cell
tumor could rupture and produce hemoperitoneum. Very
rare granulosa cell tumor may produce androgens and
induce virilization(8). Granulosa cell tumors are bilateral
in only 2% of patients(8).
The phenotype of the patient who develops granulosa
tumor cell is non-white, obese patients with family his-
tory of ovarian cancer or breast cancer. Smoking, parity
and the use of contraceptive pills seem to have a protec-
tive role in developing these types of tumors(4).
However, a gene mutation was found to be the con-
stant in the adult type of granulosa cell tumor, and this
is mutant FOXL2(9), but no family cases were found.
Surgical approach as a first-line treatment brought
significant benefit on a long-term prognosis, since most
of these tumors are confined with one ovary and they can
be resected with oncological safety principles followed.
Moreover, chemotherapy is less needed, although recur-
rent disease usually responds poorly to chemotherapy.
Taking into consideration that patients are in an early
stage at diagnosis and surgery is usually done with a
curative approach, these bring excellent prognosis and
outcome for these patients, but the real prognosis and
the natural history are poorly known and understood
since these tumors are very rare in the population.
Clinical and paraclinical investigations
Early puberty, secondary amenorrhea and endocrino-
logic symptoms are the most common symptoms that
Year VII • No. 26 (4/2019)
ginecologia
brings the patients to medical advice and lead to early
diagnosis(10). Other nonspecific symptoms include ab-
dominal pain and enlargement of the abdomen for the
juvenile type. For the adult type, symptoms and signs
include menometrorrhagia or postmenopausal bleed-
ing, virilization, abdominal pain and a palpable mass(11).
Blood tests and hormonal profile should be included
in the investigation panel in order to check for the level
of testosterone and androstendione. Because these tu-
mors are very rare, the hormonal profile is not evalu-
ated currently preoperatively, therefore after surgery the
levels of these hormones are normal. Inhibin B is very
accurate as a tumor marker, more specific than inhibin
A, and is also useful to monitor recurrence. Imaging
shows pelvic/adnexal mass with polycystic aspect and
semisolid features (Figure 1). It was supposed that CT or
MRI could characterize more accurate these tumors and
bring more information than ultrasound, but the imag-
ing features are nonspecific and cannot discriminate
from the epithelial ovarian tumors(12).
As a diagnostic procedure, a complete surgical resec-
tion and staging are recommended for these cases. Only
histopathology can diagnose adequately these tumors
and can discriminate between epithelial ovarian tumors,
germ cell tumors or other cancer(13) (Figure 2, Figure 3).
The natural history of these tumors is different from
that of epithelial ovarian cancers, since these tumors
have a low malignant potential. These tumors are usu-
ally unilateral masses, have an estrogen secretion and
don’t relapse frequently. When this happens, these tu-
mors relapse as an abdomen or pelvic mass, and bone
metastases are rare as well(14,15).
The histopathological results describe a macroscopi-
cally cystic mass, with solid or hemorrhagic content or
gelatinous fluid. The microscopic analysis shows pale
grooved, “coffee bean” nuclei and a rosette arrangement
of cells around an eosinophilic fluid space (Figure 2).
The survival rate for patients with stage I disease is
95%, but up to 25% of these tumors will relapse within
5-6 years, sometimes even after decades. Poor prognos-
tic factor is stage II-IV tumors, with a five-year survival
rate between 30% and 50%(16).
Figure 1. Ultrasound aspect of granulosa tumor cell
41
gynecology
Treatment
The treatment with the best outcome for these tu-
mors is the complete surgical resection, with an excellent
prognosis for stage I disease. These tumors have a poor
response to chemotherapy and radiation therapy, there-
fore surgery is not just a diagnostic procedure, but aims
to resect completely the disease. When planning surgery,
fertility sparing surgery should be considered especially
for patients who have not completed their family and
wish to preserve fertility. Otherwise, for postmeno-
pausal women, hysterectomy with bilateral salpingo-
oophorectomy is recommended. Because of the risk of
hyperplasia of the endometrium and adenocarcinoma,
a risk due to estrogen exposure, it is recommended to
advise the patient about endometrium sampling. Adding
lymphadenectomy as a staging procedure did not show
any survival benefit. Laparoscopy used for staging did
not show any specific benefit, the laparotomy approach
being the chosen way to remove completely the tumor.
Follow-up is done as a clinical exam, pelvic ultrasound
and serum marker testing. Chemotherapy did not show
any benefit in stage I disease, however a big tumor,
poorly differentiated with clinical or other suspicious
feature, should be discussed by the multidisciplinary
team. Chemotherapy included bleomycin, etoposide and
cisplatin(17). More data is needed. However, the series is
still small, taking into consideration the fact that these
tumors have a very low incidence. Radiation therapy was
not found useful and is usually reserved for palliative
42
Figure 2.
Immunohistochemistry
of granulosa tumor cell
(VIM + staining)
Figure 3. Granulosa
tumor cell histo­
pathology (HE staining)
care and symptoms relief. No change of the approach
should be applied for pregnant patients and chemother-
apy is more often given after delivery.
For relapse management, chemotherapy is the chosen
treatment, and bevacizumab has shown to be effective.
Moreover, it is expected to see a new targeted therapy,
taking into consideration the gene mutation FOXL2(18).
The prognosis of these tumors is better when com-
pared with epithelial ovarian cancers, and depends on
the stage at diagnosis, size of the tumor, completeness
of surgical excision and residual disease.
Case report
We report the case of a 26-year-old woman, with a
three-year history of primary infertility and secondary
amenorrhea, with no other specific medical history. The
patient was admitted for a right ovarian mass discovered
during a routine pelvic ultrasound. The ovarian mass seen
on transvaginal ultrasound measured 7/5 cm, with regular
contour, with solid pattern; no other pathological findings
was seen. MRI was further recommended and described a
right para-uterine pelvic mass, measuring up to 6 cm, with
solid content and important contrast uptake. There was
no right ovary structure found; the left ovary and uterus
were normal; no ascites or other pathological features.
All blood tests performed, including tumor markers such
as CA125, HE4, beta-HCG, alpha-fetoprotein, inhibine A
and B, LDH and testosterone level, were within normal
range. The level of estrogen was normal.
Year VII • No. 26 (4/2019)

Surgical approach was decided, and a right salpingo-
oophorectomy was performed. Frozen section raised
suspicion of granulosa tumor cell, juvenile type. Dur-
ing surgery, the evaluation of uterus and contralateral
ovary, peritoneal cavity and of abdominal and pelvic
organs was macroscopically normal. Taking into con-
sideration the age of the patient, the intraoperative
findings and the wish to procreate, surgery was limited
to a conservative approach, keeping the uterus and the
left adnexa.
Postoperatively, the patient had a good recovery, with
no complications, and she was discharged two days after
surgery. The final histopathology and immunohisto-
chemistry confirmed a granulosa cell tumor, juvenile
type, with VIM difuse positive, AE1/AE3 negative, CRO-
MO negative, calretinine and inhibin positive, Ki67 10%
positive.
The case was discussed in the multidisciplinary meet-
ing and the patient was recommended to have close
follow-up, fertility advice and pelvic MRI every three
months, to check for recurrences. The first follow-up
was clear, with no pathological finding on the clinical
exam and pelvic MRI. The patient is currently under
the care of the infertility team in order to complete her
family, and she will continue the follow-up protocol as
discussed in the MDT meeting.
1. Young RH. Sex cord-stromal tumors of the ovary and testis: their similarities and
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Year VII • No. 26 (4/2019)
ginecologia
Discussion
Although granulosa cell tumors are a very rare type of
ovarian tumors, they have an important malignant and
spreading potential, and represent the most common
type of malignant ovarian sex cord tumors. Granulosa
cell tumor, the juvenile type, is the rarest type, compris-
ing less than 5% of these malignancies. These tumors
develop before puberty, and they have a higher prolifera-
tive rate, but a lower late recurrence rate compared with
the adult type(5).
It is important to emphasize that the juvenile type
occurs in young and very young female patients, and
the surgical approach should take into consideration
fertility sparing techniques, informed consent and fer-
tility advice prior to treatment. As most of the cases are
diagnosed in an early stage, fertility sparing surgery is
an achievable target and close follow-up can be a good
long-term approach. Moreover, clinical and imaging
follow-up should both be part of the follow-up strategy
as recurrence rate is low, but it is important to determine
the recurrence very early in order to facilitate the ap-
propriate treatment. n
Conflicts of interests: The authors declare no con-
flict of interests.
The authors contributed equally for this article.
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43
 interdisciplinary

Uropathogenic Escherichia coli

and the related virulence
Benyamin Salmani
Pour Noghlbari,
Mahsa Mozaffari
Department of Microbiology,
College of Basic Sciences,
Shahr-e-Qods Branch,
Islamic Azad University,
Tehran, Iran
Corresponding authors:
Benyamin Salmani Pour Noghlbari
E-mail: benyaminsp1@gmail.com
Mahsa Mozaffari
E-mail: mahsa.mozaffari97@
gmail.com
factors
Abstract
Uropathogenic strains of Escherichia coli (UPEC) are the
most common cause of non-hospital-acquired urinary
tract infections (UTIs). The most common UTIs occur
mainly in women and affect the bladder and urethra,
leading to infections of the bladder (cystitis). Uro­patho­
genic Escherichia coli have genes and virulence factors
in association with adhesion, biofilm formation and
colonization. These genes are: mrk, kpsM, foc, auf, C, Kps,
chuA, hma, ireA, iha, iutA, fliC, ompA, upab, upaC, upaG,
and upaH. Doctors typically treat UTIs with a wide range of
different antibiotics, such as fosfomycin, nitrofurantonin,
pivmecillinam, trimethoprim, sulfamethoxazole, cipro­
flo­xacin, levofloxacin and prulifloxacin. However, some
strains of E. coli, called extended-spectrum beta-lactamase
(ESBL) E. coli, are resistant to most antibiotic treatments.
Keywords: urinary tract infections, Escherichia coli, ESBL
Rezumat
Tulpinile uropatogene de Escherichia coli sunt cea mai frec­ven­
tă cauză de infecții non-intraspitaliceşti ale tractului uri­nar.
Infecţiile de tract urinar apar mai frecvent la femei și afec­
tea­ză vezica urinară și uretra. Infecția vezicii urinare poartă
de­nu­mirea de cistită. Escherichia coli uropatogen prezintă
fac­tori de virulență şi gene responsabile de aderare, formarea
bio­fil­mu­lui și colonizare. Principalele gene sunt: mrk, kpsM, foc,
auf, C, Kps, chuA, hma, ireA, iha, iutA, fliC, ompA, upab, upaC,
upaG şi upaH. Pentru tratarea infecţiei, medicii apelează în
mod obișnuit la o gamă largă de antibiotice diferite, cum ar fi
fos­fo­mi­cină, nitrofurantonină, pivmecilinam, trimetoprim, sul­
fa­­me­to­xazol, ciprofloxacină, levofloxacină şi prulifloxacină. Cu
toa­te acestea, unele tulpini de E. coli, denumite beta-lactamaze
cu spectru extins (ESBL) E. coli, sunt rezistente la majoritatea
tra­ta­mentelor cu antibiotice.
Cuvinte-cheie: infecții de tract urinar, Escherichia coli, ESBL

Submission date:
18.07.2019 Escherichia coli uropatogenă și factorii de virulență înrudiți
Acceptance date: Suggested citation for this article: Pour Noghlbari BS, Mozaffari M. Uropathogenic Escherichia coli and the related virulence factors.
5.08.2019 Ginecologia.ro. 2019;26(4):44-48.

Introduction
Despite many progresses in the field of medical
microbiology, urinary tract infections (UTIs) are still
known as a big concern for microbiologists and stay
as the second ranking infectious diseases all over the
world. The most important problem with the UTIs is
related to their multimicrobial spectrum. Either bacte-
rial or fungal agents involve lower part (cystitis) and/or
upper part (pyelonephritis) of urinary tract. Escherichia
coli strains and in particular the uropathogenic patho-
types are recognized as the most important bacterial
etiology of the UTIs, while the fungal agent of Candida
albicans has the same role; however, C. albicans may
cause different types of candidiasis, including UTIs.
E. coli bacteria are divided into two groups of in-
tra-intestinal and extra-intestinal strains. The intra-
intestinal strains may be categorized into two sub-
groups of commensal strains and the pathotypes. On
the other hand, the extra-intestinal strains include
different types of pathotypes such as uropathogenic
E. coli (UPEC). UPEC pathotypes are known as invalu-
able genomic treasures of a wide range of diverse viru-
lence factors which each one has its own importance
regarding UTIs. Antigens of Flagella (H), Soma (O) and
Capsule (K) are common criteria for UPEC strains clas-
sification. In addition to varieties of virulence factors,
the feature of antibiotic resistance in UPEC pathotypes
is a big deal to be concerned for. The progression of mul-
ti-drug resistant (MDR) and extensively drug resistant
(XDR) strains of UPEC worldwide has complicated the
treatment of the UTIs, too(1-12).
As mentioned before, the treasure of virulence fac-
tors and genes within the pan-genome of UPEC strains
is amazingly widespread. But, in this review, some of
them which are involved in biofilm formation have been
studied (Table 1 and Figure 1)(6,11-13).
Materials and method
In silico studies have been done for this article. Data-
bases such as NCBI and GenBank in parallel with Google
Scholar were searched to find and study various review
articles about UPEC genes from the year 2000 to 2018.
We have also used reference books to improve our data.
Genes involved in biofilm formation
As indicated in Table 1, genes which have contributed
in biofilm formation can be divided into two groups:
biofilm formation in catheher and the host’s body. Some

44 Year VII • No. 26 (4/2019)

 ginecologia

Table 1
Uropathogenic Escherichia coli (UPEC) genes and virulence factors in association
with adhesion, biofilm formation and colonization
Genes Virulence factors References

Mrk Type 3 fimbriae (13)

kps Capsule (13, 14)
Foc F1C (15)
Auf Auf fimbriae (13)
C F9 fimbriae (13)
chuA, hma, ireA,
Hemin uptake system (15)
iha, iutA
flic H antigen (Flagella protein) (13)
ompA, upab, upaC,
(16)
upaG, upaH

Figure 1. Uropatho­ge­nic Escherichia coli (UPEC) genes and virulence factors

of the most important virulence genes of UPEC strains 1. mrk

which are associated with biofilm formation are, mrk,
kpsM, foc, auf, C, Kps, chuA, hma, ireA, iha, iutA, fliC, ompA,
upab, upaC, upaG and upaH. Among them, mrk and kpsM
can form biofilms on indwelling catheters and others in
the host’s body. Specific virulent properties of each gene
have been analyzed in this study.
Catheter-associated urinary tract infection (CAUTI)
had been relatively abandoned in clinical research un-
til recently. CAUTIs occur from the growth of bacterial
biofilms on the inner surface of the urinary catheter.
The urinary catheters are tubular latex or silicone de-
vices, which when inserted, biofilms can be formed on

Year VII • No. 26 (4/2019)

45
interdisciplinary
the inner or outer surfaces(17). Biofilm formation is typi-
cally facilitated by fibrillar structures such as fimbriae
or pili. In Escherichia coli, the production of determined
types of fimbriae (e.g., type 3 fimbriae) increases biofilm
formation. One of the genes that are deeply associated
with biofilm formation has been named as mrk gene. The
genetic structures in a cell which can replicate indepen-
dently of the chromosomes are called plasmids. Plasmids
are circular DNA in the cytoplasm of a bacterium. Mrk
gene located in plasmid (pMAS2027) encodes the type
3 fimbriae. The precise position of mrk gene is on a seg-
ment (5,536-bp) with G+C content of 56.6%. It has been
demonstrated that mrk genes are located on a mobile
genetic element and on upstream and downstream of the
mrk cluster; they are genes encoding proteins associated
with transposition(18).
2. kpsM
Capsule (also known as K antigen) is a large structure
of some prokaryotic cells such as bacteria. It is a poly-
saccharide layer that lies outside the cell envelope of
bacteria, and is thus deemed part of the outer envelope
of a bacterial cell. It is a layer which is not easily washed
off, and it can be the cause of various diseases. Capsule is
located immediately exterior to the peptidoglycan layer
of Gram-positive bacteria and the Lipopolysaccharide
layer of Gram-negative bacteria(19). In recent years, sev-
eral studies have examined the role of polysaccharide
capsules in the pathogenesis of UTI and polysaccharide
capsules have been identified, and they have been divi­
ded into three groups(20). Remarkably, kpsM gene encodes
a capsule transport protein which is one member of the
gene cluster responsible for type 2 capsular polysaccha-
ride synthesis. This gene is one of the reasons of biofilm
formation. It is recognized that the deletion of the gene
kpsM would cause a huge decrease in the virulence of the
UPEC strain both in vitro and in vivo. Many studies show
that kpsM was relatively highly conserved during the
evolution process of bacterial species, so we can conclude
that this gene is probably a molecular clock(21).
3. foc
Biofilm formation in bacteria including UPEC strains
has determined increase survival in natural environ-
ments and in the host’s body(22). Foc gene encodes F1C
fimbriae which is located on the bacterial surface and is
capable of adhesion to mucosal and endothelial cells(23).
F1C fimbriae are essential for biofilm formation on an
inert surface. Among three genes encoding for fimbrial
adhesive systems (fimH, pap and sfa/foc), the prevalence
of sfa/foc gene had been found 23%(24). Many antibiotics
have proven to be effective for the clinical symptoms
of UTIs, but recurrent and chronic infections continue
to afflict many people. Saira Bashir et al.(25) found that,
due to indiscriminate use of drugs in developing coun-
tries, the pathogenic bacteria are more battle-hardened
as compared with developed countries. Studies show
that the resistance of nalidixic acid can be related to
considerably decreased prevalence of the gene sfa/foc (S
and F1C fimbriae)(26). Daniël J. Wurpel et al. observations
along with the binding specificity of these organelles
46
proved that F1C pili may impact the pathogenesis of a
remarkable number of UTI cases. β-GalNac-1, 4β-Gal
residues on glycolipids expressed by epithelial cells of
the distal tubules and collecting ducts of the kidney and
also by bladder and kidney endothelial cells. F1C pili are
encoded by approximately 14% of UPEC isolates and can
bind β-GalNac-1 and 4β-Gal residues(27).
4. auf
Buckles et al.(28) determined that auf gene cluster
was significantly associated with uropathogenic E. coli
isolates. The role of auf genes is in biofilm formation
and adhesion. Auf fimbriae (encoded by auf gene) are
encoded by 67% of UPEC strains and 27% fecal E. coli
strains (commensal isolates)(29). Furthermore, auf can
cause all types of UTIs. Each type of UTI may result
in more-specific signs and symptoms, depending on
which part of the urinary tract is infected. Acute py-
elonephritis usually occurs with upper back and side
(flank) pain, high fever, shaking and chills, nausea and
vomiting signs(30). Cystitis can be recognized with signs
and symptoms such as pelvic pressure, lower abdomen
discomfort, frequent, painful urination, and blood in
urine(31). Urethritis are often seen with burning with
urination and discharge(32).
5. C
F9 Fimbriae of uropathogenic Escherichia coli mediates
biofilm formation which encodes by C gene. F9 fimbriae
expression was indicated at 20c, representing the first
proof of functional F9 fimbriae expression by wild-type
E. coli. However, for binding directly to the f9 promoter,
the f9 gene expresses at 37c(27). Besides of UTIs, this
fimbriae can be effective at the clinical symptoms of
pyelonephritis. Pyelonephritis is a common infection in
adult women, but there is a paucity of controlled trials
of its treatment and the optimum duration of antibi-
otic treatment has not been properly defined(33). UPEC
strains have different specific genomes, for example the
UPEC strain CFT073 genome contains ten gene loci that
share sequence identity with the chaperone-usher class
of fimbriae. In this strain, the f9 has c number named
c1931-c1936 and the genes are c1936-34-ydeSRQ, and
these information in other strains can be various(34).
6. Kps
Biofilms are the microbial communities of the surface-
attached cells which are embedded in a self-produced ex-
tracellular polymeric matrix. Kps genes encode K1, K2,
K3, K5, K12, K13, K20 and K51/KspMT capsular poly-
saccharides. Among the K group, k1 and k2 are more
outstanding. The K1 capsule on the surface of UPEC
strains is a key virulence factor and its expression may
be important in the beginning and development of UTIs
and cystitis(35). Similar to other bacterial polysaccharide
capsules, K1 capsule has two classical roles which contain
inhibition of phagocytosis by granulocytes/monocytes
and serum resistance. It has been recognized that the
polysialic acid K1 capsule may not only protect UPEC from
natural immunity, but also form an IBC matrix compo-
nent which facilitates the aggregation of the bacterial
communities, which in turn precludes infiltration of host
Year VII • No. 26 (4/2019)

inflammatory mediators and environmental stressors(36).
While K1 played an insignificant role in conferring serum
resistance, the K2 antigen is mildly important. In the
presence of whole blood, both K1 and K2 antigens pro-
vided a survival advantage to the UPEC strains tested(37).
7. chuA, hma, ireA, iha, iutA
UPEC, the famous cause of urinary tract infection,
uses specific outer membrane receptors, facilitating the
import of iron-chelating siderophores and iron from
host cells. For the colonization of the urinary tract by
uropathogenic Escherichia coli, iron attainment mediated
by special outer membrane receptors is essential. Heme
is an essential source of iron for UPEC in the kidney.
Siderophores are small, iron-chelating molecules which
bind and transport iron in microorganisms. Many distin-
guished types of siderophores are produced by bacteria.
For the synthesis of a siderophore after many steps in
E. coli, the completed molecules are discharged instantly
from the cytoplasm to the extracellular space through
a complex named TolC. ChuA, hma, ireA, iha, and iutA
genes work together for UPEC iron uptake system and
chuA performs the task of heme transport. The tran-
scriptional regulators influence on the expression of iron
uptake genes. The expression of chuA is also regulated by
RfaH(38). Iha is an abbreviation of the IrgA homolog ad-
hesin which transport both enterobactin and dihydroxy
benzoylserine (DHBS) and also help UPEC to fitness in
the urinary tract(39).
8. filC
The structure of the flagellum is free at one end and
attached to the cell at the other end. The bacterial fla-
gella with a diameter of about 20 nm move the bacteria
towards nutrients and other attractants. The flagellated
Escherichia coli spp. are common causes of urinary tract
infections and the flagella help the bacteria by propelling
up the urethra into the bladder. There are four types of
flagellar arrangement: monotrichous, amphitrichous,
lophotrichous and peritrichous(40). FliC gene encodes the
H antigen or flagella protein. The expression of fliC gene
in vitro is optimal and increasing osmolarity combined
with lowering pH represses fliC activity which is the
similar condition to the environment of the bladder(41).
According to a study by M.R. Karam Asadi et al.(42), about
70% of clinical isolates obtained from patients with UTI
harbored fliC gene, so we conclude that fliC is another
conserved gene among UPEC strains.
9. ompA, upab, upaC, upaG, upaH
The pathogenic roles of OmpA proteins, including
adhesion, invasion or intracellular survival, have been
expected. Features of the outer membrane protein A
(OmpA) encoded by ompA gene are monomeric, main,
integral, porin and heat-modifiable component of the
bacteria. The ompA functions as an intracellular viru-
lence for UPEC and also within bladder epithelium it
causes persistent infection. It has been demonstrated
that the deletion of the ompA gene did not disrupt the
initial epithelial binding and invasion by UPEC, whereas
it did preclude completion of the intracellular bacterial
community (IBC) pathway(43).
Year VII • No. 26 (4/2019)
ginecologia
The formation of the extracellular matrix (ECM) re-
quires cells to secrete ECM proteins(44). UpaB is located
at the bacterial cell surface. The function of upaB is cell
adhesion and upaB can mediate the adherence to several
ECM proteins, so the deletion of upaB can reduce the early
colonization of the bladder.
The upaB gene is common among UPEC strains and
is present in all available UPEC genomes, but absent or
disrupted in all diarrheagenic E. coli genomes(45). UpaC
AT-encoding gene is common in E. coli. Autotransporter
(AT) proteins have their independent transport across
the bacterial membrane system and final routing to
the cell surface which facilitates by special structural
properties. Several AT proteins have been characterized
from UPEC, and these include the upaC protein which
encodes by upaC gene(46). UpaG is a member of the tri-
meric autotransporter family of adhesins in UPEC and
is strongly associated with other E. coli strains. UpaG
proteins encoded by upaG genes mediates adhesion to
human bladder epithelial cells(47). UpaH is a identified
autotransporter protein that contributes to biofilm for-
mation and bladder colonization by UPEC. UpaH encodes
a large cell surface-located AT protein that contributes
to biofilm formation(48). As we mentioned before, ompA,
upaB, upaC, upaG, and upaH genes encode various pro-
teins, such as ag43, upaB, upaC, upaG and upaH proteins,
with biofilm formation, adhesion and chronic infection
tasks, causing chronic UTIs.
Effective antibiotics on UPEC
For the treatment of urinary tract infections, the first
and second lines of the treatment can be used in a variety
of antibiotics, for example: fosfomycin, nitrofurantonin,
pivmecillinam, trimethoprim, sulfamethoxazole, cipro-
floxacin, levofloxacin, and prulifloxacin(49).
It is noteworthy that ciprofloxacin, levofloxacin and
prulifloxacin should not be used as the first line of treat-
ment due to their high side effects(49).
Conclusions
Urinary tract infections are demonstrated to be one
of the most controversial infections all over the world.
The commonest cause of UTI is uropathogenic Escheri-
chia coli, with different virulence factors encoding by
virulence genes, such as mrk (encoding type 3 fimbriae),
kpsM (encoding type 3 fimbriae), foc (encoding F1C), auf
(Auf fimbriae), C (F9 fimbriae), Kps (encoding K antigen
group), chuA, hma, ireA, iha, iutA (encoding Hemin up-
take system), fliC (encoding H antigen), and ompA, upaB,
upaC, upaG and upaH. Among these virulence factors,
genes by encoding make the course of treatment harder.
More studies are also need to find the most appropriate
treatment for this issue, but we searched and found some
antibiotics group for the treatment, such as: fosfomycin,
nitrofurantonin, pivmecillinam, trimethoprim, sulfameth-
oxazole, ciprofloxacin, levofloxacin and prulifloxacin. n
Conflict of interests: The authors declare no con-
flict of interests.
47
interdisciplinary
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urinary tract infection. Infection and Immunity. 2005; 73(2):965-71.
40. Kojima S, Blair DF. The bacterial flagellar motor: structure and function of a
complex molecular machine. International Review of Cytology. 2004; 233:93-135.
41. Schwan WR, Lee JL, Lenard FA, Matthews BT, Beck MT. Osmolarity and pH
growth conditions regulate fim gene transcription and type 1 pilus expression
in uropathogenic Escherichia coli. Infection and Immunity. 2002; 70(3):1391-402.
42. Asadi KM, Oloomi M, Habibi M, Bouzari S. Cloning of fimH and fliC and
expression of the fusion protein FimH/FliC from Uropathogenic Escherichia coli
(UPEC) isolated in Iran. Iranian Journal of Microbiology. 2012; 4(2):55.
43. Nicholson TF, Watts KM, Hunstad DA. OmpA of uropathogenic Escherichia coli
promotes postinvasion pathogenesis of cystitis. Infection and Immunity. 2009;
77(12):5245-51.
44. Sottile J, Hocking DC. Fibronectin polymerization regulates the composition
and stability of extracellular matrix fibrils and cell-matrix adhesions. Molecular
Biology of the Cell. 2002; 13(10):3546-59.
45. Allsopp LP, Beloin C, Ulett GC, Valle J, Totsika M, Sherlock O, et al. Molecular
characterization of UpaB and UpaC, two new autotransporter proteins of
uropathogenic Escherichia coli CFT073. Infection and Immunity. 2012; 80(1):321-
32.
46. Allsopp LP, Beloin C, Moriel DG, Totsika M, Ghigo J-M, Schembri MA. Functional
heterogeneity of the UpaH autotransporter protein from uropathogenic
Escherichia coli. Journal of Bacteriology. 2012; 194(21):5769-82.
47. Valle J, Mabbett AN, Ulett GC, Toledo-Arana A, Wecker K, Totsika M, et al.
UpaG, a new member of the trimeric autotransporter family of adhesins in
uropathogenic Escherichia coli. Journal of Bacteriology. 2008; 190(12):4147-61.
48. Allsopp LP, Totsika M, Tree JJ, Ulett GC, Mabbett AN, Wells TJ, et al. UpaH is a
newly identified autotransporter protein that contributes to biofilm formation
and bladder colonization by uropathogenic Escherichia coli CFT073. Infection
and Immunity. 2010; 78(4):1659-69.
49. Bartoletti R, Cai T, Wagenlehner FM, Naber K, Johansen TE. Treatment of urinary
tract infections and antibiotic stewardship. European Urology Supplements. 2016
Jul 1; 15(4):81-7.
Year VII • No. 26 (4/2019)
 Asociația Medicilor Independenți este COMUNITATEA MEDICILOR
ANTREPRENORI care pun pe primul loc pasiunea pentru
exercitarea profesiei și grija pentru pacient.
Asociația Medicilor Independenți este ȘANSA de a fi parte a unei
ELITE A MEDICILOR care împărtășesc aceleași principii și valori
profesionale și umane.
Asociația Medicilor Independenți este o ALTERNATIVĂ VIABILĂ
PENTRU PACIENȚII din România de a primi îngrijire coordonată și
pluridisciplinară, cu centralizarea întregului dosar al pacientului și prin
colaborarea unor echipe de medici specializați.

Valorile AMI:
• competență, profesionalism și probitate
• calitatea crescută a actului medical
• acces rapid și în beneficiul pacientului

Ești pacient? Programează-te pe www.mediciami.ro

Ești medic? Vrei să fii membru, intră pe www.mediciami.ro/membru

Comunitatea ta de încredere!
MEMBRI FONDATORI

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Dr. Leventer Centre Otomed Artro Sport Clinic Cardiomed

Dr. Ovidiu Palea Dr. Silviu Predoi Dr. Wargha Enayati

Provita Wellborn Intermedicas
events
December 2019 – February 2020
Calendar
PHOTO: SHUTTERSTOCK
EUROGIN 2019
4-7 December 2019, Monaco
https://www.eurogin.com/en/home.html
13th Winter Gynaecology Symposium
Munich 2019
14 December 2019, Munich, Germany
https://www.wintersymposium-
muenchen.de/
13th Joint Conference of the UK Fertility Societies:
the Association of Clinical Embryologists,
British Fertility Society and the Society
for Reproduction & Fertility 2020
9-11 January 2020, Edinburgh, UK
https://fertilityconference.org/
50
Masterclass in Cosmetic Gynaecology
Reclamă GIN(26)0107
23-24 January 2020, Bordeaux, France
https://invivox.com/training/detail/2847?utm_
source=conferenceservice&utm_
medium=conferencewebsite&utm_
campaign=cosmegyn_conferenceservice_231019
Arab Health Obs-Gyne Conference 2020
27-30 January 2020, Dubai, UAE
Reclamă GIN(26)0106
https://www.arabhealthonline.com/en/Home.html
International Society of Gynecological
Endocrinology 19th World Congress 2020
(ISGE 2020)
4-7 March 2020, Florence, Italy
https://www.isgesociety.com/congresses/isge-congresses/ n
Year VII • No. 26 (4/2019)
 ESMYA CONTINUĂ
SĂ TRANSFORME
ABORDAREA
FIBROMULUI UTERIN
KEDP/DAC57Q

Tratamentul cu ESMYA oferă singura alternativă pe

termen lung, aprobată, pentru femeile de vârstă fertilă,
cu fibrom uterin simptomatic, pentru care chirurgia
nu este o opțiune.1
Aprobat pentru tratamentul intermitent al FU¹
Controlează rapid, eficient și susținut sângerarea²
Reduce clinic semnificativ volumul FU²
Îmbunătățește calitatea vieții²
Bine tolerat²
1. ESMYA ® RCP Iulie 2018
2. Donnez J, et al. Fertil Steril. 2016; 105: 165-73.e4.

Acest material promoţional este destinat profesioniștilor din domeniul sănătăţii.

Acest medicament se eliberează pe bază de prescripţie medicală.

Pentru mesaje de siguranţă și informaţii medicale:
E-mail: pharmacovigilance@gedeon-richter.ro, Tel./Fax: +40-265-257-011
 DATE NOI
DESPRE HPV
CU RISC
RIDICAT

Gel vaginal

PRIMUL TRATAMENT PENTRU PREVENIREA

ȘI TRATAMENTUL LEZIUNILOR COLULUI
UTERIN INDUSE DE HPV*
Recomandat pentru:1
• Controlul și reepitelizarea zonei de transformare a
colului uterin pentru a preveni riscul de apariție a
leziunilor (LSIL) cauzate de HPV.
• Tratamentul coadjuvant al leziunilor intraepiteliale
cauzate de HPV.
• Refacerea și reepitelizarea leziunilor mucoasei
cervico-vaginale.
• Tratamentul uscăciunii mucoasei cervico-vaginale.
• Reechilibrarea microflorei vaginale.
• Îmbunătățirea sănătății vaginale.
• Crearea condițiilor pentru o vindecare rapidă a leziunilor
cauzate de grataj datorită senzației de arsură și prurit.
Instrucțiuni de utilizare: 1
Se inseră canula mono-doză în vagin, de preferat seara
la culcare. Tratamentul se începe după menstruație.

PRIMA URMĂTOARELE

LUNĂ 5
LUNI

Prima lună : Lunile 2 până la 6:

în fiecare zi timp de o dată la 2 zile, apoi
21 de zile consecutive, pauză în timpul
apoi 7 zile pauză menstruației
(sau în timpul menstruației)

FORMULĂ
TEHNOLOGIA ÎNCAPSULĂRII PENTRU CREȘTEREA INOVATOARE
BIODISPONIBILITĂȚII ȘI ELIBERARE CELULARĂ ȚINTITĂ PATENTATĂ

ASCUS: Celule scuamoase atipice cu semnificaţie nedeterminată; LSIL: Leziune intraepitelială scuamoasă de grad scăzut; HPV: Virusul Papiloma uman.
* Leziuni de grad scăzut: ASCUS/LSIL
Referință: 1. Instrucțiuni de utilizare Papilocare Gel Vaginal.
Acest material este destinat exclusiv profesioniștilor din domeniul sănătății.
KEDP/DAC617

PROCARE HEALTH IBERIA, S.L.

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46450 Benifaió (Valencia)
Spania