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To cite this article: Neuroendocrinol Lett 2015; 36(2):101–105

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Neuroendocrinology Letters Volume 36 No. 2 2015

ISSN: 0172-780X; ISSN-L: 0172-780X; Electronic/Online ISSN: 2354-4716

Web of Knowledge / Web of Science: Neuroendocrinol Lett

Pub Med / Medline: Neuro Endocrinol Lett

Placental pathologic changes

in gestational diabetes mellitus

Patrycja Jarmuzek, Mirosław Wielgos, Dorota A. Bomba-Opon

1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Poland

Correspondence to: Assoc. Prof. Dorota A. Bomba-Opon, MD, Ph.D

1st Department of Obstetrics and Gynecology,

Medical University of Warsaw

Plac Starynkiewicza 1/3, 02-015 Warsaw, Poland.

tel: + 48225830301; fax: +48225830302; e-mail: dorota.bomba-opon@wum.edu.pl

Submitted: 2015-03-06 Accepted: 2015-03-12 Published online: 2015-05-18

Key words:

great obstetrical syndromes; gestational diabetes mellitus; placenta;

hypoxia; oxidative stress; VEGF

Neuroendocrinol Lett 2015; 36(2):101–105 PMID: 26071574 NEL360215R01 � 2015 Neuroendocrinology Letters • www.nel.edu

Abstract

Nowadays, the continuous rise of maternal obesity is followed by increased

gestational diabetes mellitus incidence. GDM is associated with adverse fetal and

neonatal outcome that often presents with macrosomia, birth trauma, neonatal

hypoglycemia, and respiratory distress syndrome. Inclusion of GDM into ‘the

great obstetrical syndromes’ emphasizes the role of the placenta in interactions of

the maternal and fetal unit.

The placenta acts as a natural selective barrier between maternal and fetal blood

circulations. Placenta is sensitive to the hyperglycemic milieu and responses with

adaptive changes of the structure and function. Alteration of the placental devel-

opment and subsequent vascular dysfunction are presented in 6 out of 7 women

with all ranges of diabetic severity.

Most placentas from GDM pregnancies present typical histological findings such

as villous immaturity, villous fibrinoid necrosis, chorangiosis, and increased

angiogenesis. The type of dysfunction depends on how early in pregnancy glycae-

mia disorders occurred. Generally, if impaired glucose metabolism is diagnosed

in the early pregnancy, mainly structural dysfunctions are observed. GDM that is

detected in late gestation affects placental function to a greater extent. Moreover

many studies suggest that diabetic placental changes are associated with inflam-

mation and oxidative stress that can lead to the chronic fetal hypoxia.

This article aims to review particular changes of the development, anatomy and

function of the placenta in the environment of abnormal glucose metabolism

which can establish the maternal-placental-fetal interface dysfunction as a poten-

tial source of adverse pregnancy outcomes. A detailed sequence of events that

leads from hyperglycemia to placental dysfunction and subsequent pregnancy

complications may become an important issue for further studies.

Abbreviations:

GDM

- gestational diabetes mellitus

VEGF

- endothelial growth factor

FGF

- fibroblast growth factor

PPAR

- peroxisome proliferator-activated receptor-gamma

PLGF

- placental growth factor

MAPK

- mitogen activated protein kinase

eNOS

- nitrogen oxide synthase

EPO

- erythropoietin

NRBCs

- nucleated red blood cell level

MDA

- malodialdehyde

- nitrogen oxide

ROS

- reactive oxygen species

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Patrycja Jarmuzek, Mirosław Wielgos, Dorota A. Bomba-Opon

INTRODUCTION

Gestational diabetes mellitus (GDM) is a metabolic

disease defined as progressively impaired glucose intol-

erance with the onset or first recognition during preg-

nancy (WHO 2013). The prevalence of GDM varies

between populations, ranging from 1.7% to 11.6%

(Schnaider et al. 2012). Numerous studies established

that GDM is associated with significantly higher risk

of short- and long-term maternal and fetal complica-

tions. Fetuses with intrauterine exposure to hyper-

glycemia more often present with macrosomia, birth

trauma, neonatal hypoglycemia, and respiratory dis-

tress syndrome (Nordin et al. 2006). Adverse long-term

outcomes of hyperglycemia are caused by intrauterine

fetal programming and consist in a higher prevalence

of metabolic-related diseases (Manderson et al. 2002;

D�rner et al. 2000). The development of subsequent

type 2 diabetes mellitus and cardiovascular diseases are

among widely discussed maternal complications (Kwak

et al. 2013; Kessous et al. 2013).

The underlying pathophysiology of GDM remains

a matter of much debate. Maternal insulin resistance

combined with the placental factor, are believed to play

an important role. Recent literature reports consider

GDM to be a part of the ‘great obstetrical syndromes’,

which include pregnancy-related disorders such as pre-

term labor, preterm premature rupture of membranes,

preeclampsia, spontaneous pregnancy loss, stillbirth,

and abnormally delayed or accelerated fetal growth

(Gabbay-Benziv & Baschat 2014; Bronsen et al. 2011).

The concept of the ‘great obstetrical syndromes’ desig-

nates the adverse interaction of the maternal- fetal unit

as the underlying etiology of pregnancy complications

which manifest mainly in the third trimester (Romero

2009). It differs from other theories by pointing to the

role of structural and functional changes of the placenta

in the development of GDM.

This article aims to review particular changes of the

development, anatomy and function of the placenta

in the environment of abnormal glucose metabolism

which can establish the maternal-placental-fetal inter-

face dysfunction as a potential source of adverse preg-

nancy outcomes.

IMPAIRED PLACENTAL DEVELOPMENT

The placenta acts as a natural selective barrier between

maternal and fetal blood circulations and is capable

of controlling nutrient and gas exchange. Moreover,

human placenta is responsible for important endocrine

function and local maternal immune tolerance. Due to

its location, this organ may be exposed to adverse intra-

uterine conditions and act as a target for maternal and/

or fetal metabolic alterations associated with pregnancy

pathologies.

According to the current diagnostic standards,

GDM may be diagnosed at any time in pregnancy

if one or more of the following criteria are met: fast-

ing plasma glucose of 5.1-6.9 mmol/l (92-125 mg/dl),

1-hour plasma glucose of >10.0 mmol/l (180 mg/dl),

and 2-hour plasma glucose of 8.5-11.0 mmol/l (153-

199 mg/dl) following a 75 g oral glucose load (Polish

Gynecological Society Standards 2014). The screening

model for GDM (between 24-28 gestational weeks) and

gradually decreasing insulin sensitivity during preg-

nancy lead to the diagnosis of diabetes mainly in late

gestation. According to Catalano, decreased insulin

resistance and the accompanying increase in insulin

response may be found already in the first trimester in

women who will develop GDM later in pregnancy (Cat-

alano 2014). According to the literature, performing a

screening test during the first trimester could detect

around 30-40% of all GDM cases before 24-28 gesta-

tional weeks (Bartha et al. 2000; Meyer et al. 1996). The

question how early in gestation the changes related to

hyperglycemia occur in the placenta remains to be elu-

cidated. In general, normal placental development can

be profoundly disturbed and followed by structural and

functional changes. If diabetes develops early in preg-

nancy it affects mainly the structure of the placenta,

whereas later disturbances in glucose metabolism are

more likely to affect its function (Madazli et al. 2008;

Laurini et al. 1987).

In the second half of pregnancy, placental villi

undergo extensive angiogenesis and vascularization. In

hyperglycemic environment both of them may remain

uncompleted. Placental development disorders such as

villous immaturity and alteration in villous branching

are suggested to be an adaptation to particular intra-

uterine conditions, mainly related to early onset of dia-

betes (Taricco et al. 2009; Daskalakis et al. 2008).

PLACENTAL ANATOMY IN DIABETIC

PREGNANCY

Macroscopically, a diabetic placenta is enlarged, thick

and plethoric and can be described by increased pla-

cental to fetal weight ratio (Lao et al. 1997; Taricco et al.

2003). Numerous studies determined that the placenta

grows first in a diabetic environment, thus precipitating

transport of glucose and other nutrients. This sequence

leads to accelerated fetal growth, which is proportional

to the degree of hyperglycemia (Gauster et al. 2012).

Various authors suggest that the degree of glucose

tolerance induces not only changes in the placental

weight but also its microanatomical morphology. In a

study by al-Okail et al. (1994), abundance of varying

histologic changes were observed in poorly controlled

GDM placentas. The typical changes included villous

edema, fibrin deposits in the syncytiotrophoblast,

and marked hyperplasia of the cytotrophoblast. Other

studies of diabetic placentas reveled alterations such

as fibrinoid necrosis and chorangiosis on histologic

examination (Madazli et al. 2008; Taricco et al. 2009;

Daskalakis et al. 2008).

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Placental changes in gestational diabetes mellitus

In general, a GDM placenta is characterized by a

higher number of transversal interconnections between

the villous brunches. Moreover, higher total length

volume and surface areas of villous capillaries are found

(Jirkovska et al. 2002)

FUNCTIONAL CHANGES IN A GDM

PLACENTA

Angiogenesis is considered to be a crucial process,

responsible for the correct function of the placenta.

The human placenta is a rich source of angiogenic sub-

stances which play an important role in maternal vascu-

lar adaptation to pregnancy. The villous vascularization

and formation of terminal villi is under constant control

of angiogenic factors such as endothelial growth factor

(VEGF), fibroblast growth factor-2 (FGF), peroxisome

proliferator-activated receptor–gamma (PPAR), and

placental growth factor (PlGF) (Reynolds& Redmer

2001; Khaliq et al. 1996). Increased angiogenesis of

feto-placental vessels is a typical feature of a placenta

exposed to hyperglycemic milieu. Vascular dysfunction

may be observed even in cases of well-controlled diabe-

tes mellitus (Leach et al. 2009; Mayhew 2002).

Many studies analyzed potential implications of an

imbalance of angiogenic factors in the placental envi-

ronment which can result in aberrant villous vascu-

larization. In general, VEGF is indicated as the most

important factor but a clear correlation between the level

of VEGF and impaired vascularization of the placenta

involves further investigation. Madazli et al. (2008)

examined maternal and cord plasma levels of VEGF

and revealed a tendency for lower values in GDM cases

and a negative correlation with villous immaturity. On

the contrary, Leach et al. (2009), suggest that in case

of hyperglycemia, a pseudohypoxic environment with

decreased levels of NO is created. These changes lead to

an increased production of VEGF and prostaglandin -

the leading factors of an inflammatory response.

The GDM placenta is also associated with lower

concentrations of adherence and tight junctional pro-

teins. In general, all placental lesions tend to change the

permeability of the maternal- fetal barrier. The feto-

placental vessels exhibit leakiness to macromolecules

larger than albumin as compared to non-diabetic pla-

centa. In a laboratory model, elevated levels of VEGF

and increased albumin permeation occurred after a 4h

hyperglycemic insult (Leach et al. 2009).

Another factor which may influence placental func-

tional disorders is increased level of insulin. Hyper-

insulinemia is the response of fetal pancreas to the

increased transplacental flux of glucose from the mater-

nal circulation. In case of poor diabetes control, fetal

hyperglycemia occurs and results in pancreatic B cells

hypertrophy to meet the demand for increased insulin

secretion. In the second and third trimester, insulin

receptor expression is switched to the luminal surface

of fetal capillaries, which suggests insulin as a regulator

factor of angiogenesis and vascular permeability (Hiden

et al. 2009; Desoye et al. 1994). Constantly higher cir-

culating level of insulin has direct access to maternal as

well as fetal endothelium. The important role of insulin

in angiogenesis has been shown by many studies. There

is evidence demonstrating that by stimulating several

pathways such as eNOS, mitogen activated protein

kinase (MAPK), small GTPase Racl and expression of

the matrix metalloproteinases, hyperinsulinemia is able

to influence the angiogenesis. High insulin level cor-

relates with increased endothelial VEGF and junctional

disruption and increased vascular leaks (Lucas et al.

2008; Nelson et al. 2009; Jahan et al. 2011).

FETAL CONSEQUENCES OF PLACENTAL

ALTERATION

Alteration of the placental development and subse-

quent vascular dysfunction are presented in 6 out of

7 women with all ranges of diabetic severity (Jones

& Fox 1976). The pivotal question is how placental

lesions such as villous fibrinoid necrosis, villous imma-

turity and chorangiosis may affect fetal development.

Maternal hyperglycemia directly stimulates metabolic

and hormonal changes in the fetus. Increased level of

insulin accelerates fetal metabolism and subsequently

enhances fetal oxygen demands. Both, placental abnor-

malities and increased oxygen consumption often lead

to chronic fetal hypoxia (Hytinantti et al. 2000; Taricco

et al. 2009). In the vast majority of cases, oxygen satura-

tion in the umbilical vein is significantly decreased as

compared to non-diabetic pregnancies. Fetal hypoxia

tends to increase erythropoiesis by induction of eryth-

ropoietin (EPO) secretion. Significantly elevated level

of EPO in cord blood is correlated with enhanced

nucleated red blood cell level (NRBCs) (Madazli et al.

2008; Daskalakis et al. 2008). Both of them are sug-

gested as markers of chronic intrauterine fetal hypoxia

(Ferber et al. 2005). Hypoxia is one of the basic triggers

for increased angiogenesis.

Another factor that can affect the physiology of

placental vasculature is oxidative stress. This assump-

tion can be confirmed by widely presented oxidative

stress markers such as 8-isoprostane, increased activity

of superoxide dismutase and glutation peroxidase, or

elevated levels of malodialdehyde (MDA) in diabetic

placentas (Madazli et al. 2008; Coughlan et al. 2004).

The transient dysregulation of NO and reactive oxygen

species (ROS) synthesis may induce vasoconstriction

of the placental vessels and activate synthesis of pro-

inflammatory cytokines. An increased expression of

antioxidant gene may be explained as an adaptation to

altered oxidative stress status.

Elevated total placental weight, low-grade inflam-

mation, and altered vascular permeability are followed

by increased materno-fetal nutrient transfer. Diabetic

milieu leads to upregulation of genes involved in lipid

pathways. Transport of triglyceride and cholesterol is

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Patrycja Jarmuzek, Mirosław Wielgos, Dorota A. Bomba-Opon

significantly enhanced in GDM placentas (Radaelli et

al. 2009). Placental amino acid exchange is also altered

in GDM. Interestingly, even in cases of well-controlled

glycaemia, the concentration of amino acids increases

in umbilical venous and arterial plasma as compared

to maternal circulation (Cetin et al. 2005). Generally,

enhanced nutrient transport and anabolic metabolism

induced by hyperinsulinemia contribute to an increased

fetal fat accumulation and, subsequently, accelerated

intrauterine fetal growth.

CONCLUSIONS

Gestational diabetes mellitus is associated with adverse

fetal and neonatal outcomes. Despite efforts to explain

the pathophysiology of GDM, effective screening and

prevention remain to be established. Nowadays, inclu-

sion of GDM into ‘the great obstetrical syndromes’

emphasizes the role of the placenta in materno-fetal

interaction. Particular location between the maternal

and fetal bloodstream makes the placenta a mediator in

the materno-fetal ‘dialogue’. On the one hand, the pla-

centa plays an important endocrine function and on the

other hand, it remains sensitive to adverse intrauterine

environment and presents anatomical and functional

adaptive changes. In pregnancies complicated by gesta-

tional diabetes mellitus, particular conditions of hyper-

glycemia and hyperinsulinemia are created. Adverse

metabolic milieu initiates a chain of events that, due to

placental dysfunction, may lead to increased neonatal

morbidity and mortality.

Most placentas from GDM pregnancies present

typical histological findings such as villous immaturity,

villous fibrinoid necrosis, chorangiosis, and increased

angiogenesis. The type of dysfunction depends on how

early in pregnancy glycaemia disorders occurred. Gen-

erally, if impaired glucose metabolism is diagnosed in

the early pregnancy, mainly structural dysfunctions are

observed. GDM that is detected in late gestation affects

placental function to a greater extent. Interestingly,

histologic changes are present in both, well and poorly

controlled GDM.

Many studies suggest that diabetic placental changes

are associated with inflammation and oxidative stress.

The role of this intrauterine environment in fetal devel-

opment remains unclear and further investigation is

needed. Despite normal umbilical artery flow presented

in most cases of GDM pregnancies, increased levels of

erythropoietin and nucleated red blood cells in cord

blood are very common. Elevated markers of chronic

fetal hypoxia may explain adverse neonatal outcome in

GDM pregnancies.

The continuous rise in the rate of maternal obesity

is followed by increased GDM incidence. A detailed

sequence of events that leads from altered glucose

metabolism to placental dysfunction and subsequent

pregnancy complications may become an important

issue for further studies. The concept of the ‘great

obstetrical syndromes’ points to the underlying etiol-

ogy of adverse interactions between the materno-pla-

cental and fetal unit. Ways to modify or even prevent

this sequence of changes remains a challenge for future

research.

Conflict of interest statement: The authors declare that

there are no conflicts of interest.

REFERENCES

1 Bartha JL, Martinez-Del-Fresno P, Comino-Delgado R (2000). Ges-

tational diabetes mellitus diagnosed during early pregnancy. Am

J Obstet Gynecol. 182: 346–50.

2 Brosens I, Pijnenborg R, Vercruysse L, Romero R (2011). The “great

obstetrical syndromes” are associated with disorders of deep

placentation. Am J Obstet Gyneacol . 204:193-201

3 Catalano PM (2014). Trying to understand gestational diabetes.

Diabet Med. 31:273-81

4 Cetin I, de Santis MS, Taricco E, Radaelli T, Teng C, Ronzoni S, et al:

(2005). Maternal and fetal amino acids concentrations in normal

pregnancies and in pregnancies with gestational diabetes mel-

litus. Am J Obstet Gynecol. 192: 610-7.

5 Coughlan MT, Vervaart PP, Permezel M, Georgiou HM, Rice GE

(2004). Altered placental oxidative stress status in gestational

diabetes mellitus. Placenta. 25: 78-94.

6 Daskalakis G, Marinopoulos S, Krielesi V, Papapanagiotou A,

Papantoniou N, Mesogitis S, et al. (2008). Placental pathology in

women with gestational diabetes. Acta Obstet Gynecol Scand.

87:403–7.

7 Desoye G, Hartman M, Blaschitz A, Dohr G, Hahn T, Kohnen G

et. Al (1994). Insulin receptors in syncytiotrophoblast and fetal

endothelium of human placenta. Immunohistochemical evi-

dence for development changes in distribution pattern. Histo-

chemistry. 101: 277-285.

8 D�rner G, Plagemann A, Neu A, Rosenbauer J (2000). Gestational

diabetes as possible risk factor for Type I childhood-onset diabe-

tes in the offspring. Neuro Endocrinol Lett. 21:355-359.

9 Ferber A, Minior VK, Bornstein E, Divon MY (2005). Fetal ‘nonreas-

suring status’ is associated with elevation of nucleated red blood

cell counts and interleukin- 6. Am J Obstet Gynecol. 192: 1427-

1429.

10 Gabbay-Benziv R, Baschat AA (2014). Gestational diabetes as one

of the “great obstetrical syndromes” - the maternal, placental,

and fetal dialog. Best Pract Res Clin Obstet Gynaecol. S1521-6934

11 Gauster M, Desoye G, Totsch M, Hiden U (2012). The placenta and

gestational diabetes mellitus. Curr Diab Rep. 12:16-23.

12 Hiden U, Glitzner E, Hartman M, Desoye G (2009). Insuline and

the IGF system in the human placenta of normal and diabetic

pregnancies. J Anat.215:60-8

13 Hytinantti TK, Koistinen HA, Teramo K, S, Karonen S-L, Koivisto

VA, and Andersson S (2000). Increased fetal leptin in type I

diabetes mellitus pregnancies complicated by chronic hypoxia.

Diabetologia. 43: 709–713

14 Jahan S, Ahmed CM, Zinnat R, Hasan Z, Habib SH, Saha S et al.

(2011). Influence of maternal diabetes on serum leptinemic

and insulinemic status of the offspring: a case study of selected

patients in a tertiary care hospital in Bangladesh. Diabetes and

Metabolic Syndrome: Clinical Research and Reviews, vol. 5, no.

1, pp. 33–37.

15 Jirkovska M, Kubinova L, Janacek J, Moravcov� M, Krejc� V, Karen

P (2002). Topological properties and spatial organization of

villous capillaries in normal and diabetic placentas. J Vasc Res.

39:268–78.

16 Jones CJ, Fox H (1976). Placental changes in gestational diabe-

tes. An ultrasound study. Obstet Gynecol. 48: 274-80.

17 Kessous R, Shoham- Vardi I, Pariente G, Sherf M, Sheiner E (2013).

An association between gestational diabetes mellitus and long-

term maternal cardiovascular morbidity. Heart. 99: 1118-1121.

Page 5

105

Neuroendocrinology Letters Vol. 36 No. 2 2015 • Article available online: http://node.nel.edu

Placental changes in gestational diabetes mellitus

18 Khaliq A, Li XF, Shams M, Sisi P, Acevedo CA, Whittle MJ et al.

(1996). Localization of placenta growth factor (PIGF) in human

term placenta. Growth Factors. 13:243–50.

19 Kwak SH, Choi SH, Jung HS, Cho YM, Lim S, Cho NH (2013). Clini-

cal and genetic risk factors for type 2 diabetes at early or late

post-partum after gestational diabetes mellitus. J Clin Endocri-

nol Metab. 98: E744-E752.

20 Lao TT, Lee CP, Wong WM (1997). Placental weight to birthweight

ratio is increased in mild gestational glucose intolerance. Pla-

centa. 18:227e30.

21 Laurini RN, Visser GHA, van Ballegooie E, Schoots CJ (1987). Mor-

phological findings in placentas of insulin-dependent diabetic

patients treated with continuous subcutaneous insulin infusion

(CSII). Placenta. 8:153e65

22 Leach L, Taylor A, Sciota F (2009). Vascular dysfunction in the

diabetic placenta: causes and consequences. J Anat. 215:69-76

23 Lucas J, Thomas R, Ikram A, Leach L (2008). The effect of fetal

hyperinsulinemia of human placental vascular function: Perfu-

sion of fetal microvascular bed results in increased vascular leak-

age and loss of junction B caterin. Microcirculation. 15: 672- 673.

24 Manderson JG, Mullan B, Patterson CC, Hadden DR, Traub AI,

McCance DR (2002). Cardiovascular and metabolic abnormalities

in the offspring of diabetic pregnancy. Diabetologia. 45: 991-6.

25 Madazli R, Tuten A, Calay Z, Uzun H, Uludag S, Ocak V (2008). The

incidence of placental abnormalities, maternal and cord plasma

malondialdehyde and vascular endothelial growth factor levels

in women with gestational diabetes mellitus and nondiabetic

controls. Gynecol Obstet Invest. 65:227e32.

26 Mayhew, TM (2002). Enhanced fetoplacental angiogenesis in

pre-gestational diabetes mellitus: the extra growth is exclusively

longitudinal and not accompanied by microvascular remodel-

ing. Diabetologia. 45:1434–1439.

27 Meyer WJ, Carbone J, Gauthier DW (1996). Early gestational

glucose screening and gestational diabetes. J Reprod Med.

41:675–9.

28 Nelson SM, Coan PM, Burton GJ, Lindsay RS (2009). Placental

structure in type 1 diabetes: relation to fetal insulin, leptin, and

IGF-I1. Diabetes 58: 2634-2641.

29 Nordin NM, Wei JWH, Naing NN, Symonds EM (2006). Com-

parison of maternal- fetal outcomes in gestational diabetes and

lesser degrees of glucose intolerance. J Obstet Gynaecol Res. 32:

107-114.

30 al-Okail MS, al-Attas OS (1994). Histological changes in placental

syncytiotrophoblasts of poorly controlled gestational diabetic

patients. Endocr J. 41:355–60.

31 Radaelli T, Lepercq J, Varastehpour A, Basu S, Catalano PM,

Hauguel-De Mouzon S (2009). Differential regulation of genes

for fetoplacental lipid pathways in pregnancy with gestational

and type 1 diabetes mellitus. Am J Obstet Gynecol. 201: 209

e201-209 e210.

32 Reynolds LP, Redmer DA (2001). Angiogenesis in the placenta.

Biol Reprod. 64:1033–40.

33 Romero R (2009). Prenatal medicine: the child is the father of the

man. 1996. J Maternal Fetal Neonatal Med. 22: 639-9.

34 Schneider S, Block C, Wetzel M, Maul H, Loerbroks A (2012). The

prevalence of gestational diabetes in advanced economies. J

Perinat Med. 40: 511-20.

35 Taricco E, Radaelli T, Nobile de Santis MS, Cetin I (2003). Foetal

and placental weights in relation to maternal characteristics in

gestational diabetes. Placenta. 24 :343e7.

36 Taricco E, Radaelli T, Rossi G, Nobile de Santis MS, Bulfamante GP,

Avagliano L et al. (2009). Effects of gestational diabetes on fetal

oxygen and glucose levels in vivo. Bjog. 116:1729–35.

37 Wender-Ozegowska E, Bomba-Opoń D, Brazert J, Celewicz Z,

Czajkowski K, Karowicz-Bilińska A (2014). Actualisation of Polish

Gyneacological Society standards of medical care in manage-

ment of women with diabetes. Ginekol Pol. 85:476-8.

38 Word Health Organization (2013). Diagnostic Criteria and Clas-

sification hyperglycemia first detected in pregnancy. Geneva