Newborn at High Risk of Brain Damage: Euraibi International Workshop, Siena, April 2001 (Biology of the Neonate)

205 Pages·2001·4.23 MB·English

by  G. Bunoncore

The Newborn at
High Risk of Brain Damage
EURope Against Infant Brain Injury (EURAIBI)
International Workshop
Siena, Italy, April 5–7, 2001
Guest Editor
G. Buonocore, Siena
38 figures and 22 tables, 2001
Basel(cid:1)Freiburg(cid:1)Paris(cid:1)London(cid:1)New York(cid:1)
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This publication was supported by grants from Chiesi Group
and Monte dei Paschi di Siena.
It is dedicated to Rodolfo Bracci, my teacher of neonatology
and life. I also wish to thank Jean-Pierre Relier, who made this
issue possible.
Giuseppe Buonocore
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Vol. 79, No. 3–4, 2001
Contents
149 Foreword
Relier, J.-P. (Paris)
150 Human Placenta as a Source of Neuroendocrine Factors
Reis, F.M.; Florio, P.; Cobellis, L.; Luisi, S.; Severi, F.M.; Bocchi, C.; Picciolini, E.;
Centini, G.; Petraglia, F. (Siena)
157 Maternal Risk Factors for Fetal and Neonatal Brain Damage
Terzidou, V.; Bennett, P. (London)
163 Fetal Endocrine Signals and Preterm Labor
Challis, J.R.G. (Cambridge/Toronto); Smith, S.K. (Cambridge)
168 Influence of Maternal Stress on Fetal Behavior and Brain Development
Relier, J.-P. (Paris)
172 Caspase-3 Activation after Neonatal Rat Cerebral Hypoxia-Ischemia
Wang, X. (Göteborg/Zhengzhou); Karlsson, J.-O. (Göteborg); Zhu, C.
(Göteborg/Zhengzhou); Bahr, B.A. (Storrs, Conn.); Hagberg, H.; Blomgren, K. (Göteborg)
180 Free Radicals and Brain Damage in the Newborn
Buonocore, G.; Perrone, S.; Bracci, R. (Siena)
187 Effect of Graded Hypoxia on Cerebral Cortical Genomic DNA Fragmentation
in Newborn Piglets
Akhter, W.; Ashraf, Q.M.; Zanelli, S.A.; Mishra, O.P.; Delivoria-Papadopoulos, M.
(Philadelphia, Pa.)
194 Is Periventricular Leucomalacia a Result of Hypoxic-Ischaemic Injury?
Hypocapnia and the Preterm Brain
Greisen, G. (Copenhagen); Vannucci, R.C. (Hershey, Pa.)
201 Chorioamnionitis and Fetal/Neonatal Brain Injury
Toti, P.; De Felice, C. (Siena)
205 New Insights into the Pathogenesis of Pulmonary Inflammation in Preterm
Infants
Speer, C.P. (Würzburg)
210 Red Blood Cell Involvement in Fetal/Neonatal Hypoxia
Bracci, R.; Perrone, S.; Buonocore, G. (Siena)
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213 Early Markers of Brain Damage in Premature Low-Birth-Weight Neonates
Who Suffered from Perinatal Asphyxia and/or Infection
Fotopoulos, S.; Pavlou, K.; Skouteli, H.; Papassotiriou, I.; Lipsou, N.; Xanthou, M. (Athens)
219 Prevention of Bilirubin Encephalopathy
Bertini, G.; Dani, C.; Pezzati, M.; Rubaltelli, F.F. (Florence)
224 Inflammatory Mediators and Neonatal Brain Damage
Saliba, E.; Henrot, A. (Tours)
228 The Biology of Erythropoietin in the Central Nervous System and Its
Neurotrophic and Neuroprotective Potential
Dame, C. (Gainesville, Fla.); Juul, S.E. (Seattle, Wash.); Christensen, R.D.
(Gainesville, Fla.)
236 Fetal and Neonatal Cerebral Infarcts
Marret, S.; Lardennois, C.; Mercier, A.; Radi, S.; Michel, C.; Vanhulle, C.; Charollais, A.
(Rouen); Gressens, P. (Paris)
241 Blood Pressure and Tissue Oxygenation in the Newborn Baby at Risk of
Brain Damage
Weindling, A.M.; Kissack, C.M. (Liverpool)
246 Monitoring of Antepartum and Intrapartum Fetal Hypoxemia:
Pathophysiological Basis and Available Techniques
Clerici, G.; Luzietti, R.; Di Renzo, G.C. (Perugia)
254 Glutamate in Cerebral Tissue of Asphyxiated Neonates during the First
Week of Life Demonstrated in vivo Using Proton Magnetic Resonance
Spectroscopy
Groenendaal, F.; Roelants-van Rijn, A.M.; van der Grond, J.; Toet, M.C.; de Vries, L.S.
(Utrecht)
258 Resuscitation of the Asphyxic Newborn Infant: New Insight Leads to New
Therapeutic Possibilities
Saugstad, O.D. (Oslo)
261 Six Years of Experience with the Use of Room Air for the Resuscitation of
Asphyxiated Newly Born Term Infants
Vento, M. (Valencia/Alicante); Asensi, M.; Sastre, J. (Valencia); García-Sala, F.
(Valencia/Alicante); Viña, J. (Valencia)
268 Psychological Prevention of Early Pre-Term Birth: A Reliable Benefit
Mamelle, N.J. (Lyon) for the PPPB Study Group
274 Pharmacotherapeutical Reduction of Post-Hypoxic-Ischemic Brain Injury in
the Newborn
Peeters, C.; van Bel, F. (Utrecht)
281 Author Index Vol. 79, No. 3–4, 2001
282 Subject Index Vol. 79, No. 3–4, 2001
283 Author Index Vol. 79, 2001
285 Subject Index Vol. 79, 2001
after 286 Contents Vol. 79, 2001
148 Biology of the Neonate Vol. 79, No. 3–4, 2001 Contents
Foreword
It is a great privilege for Biology of the Neonate to have been chosen to sequences of ‘oxygenation’ in all its aspects. His remarkable knowledge of
publish the proceedings of the conferences held by the leading specialists all the publications on the physiology as well as the pathology of this
in neonatology, particularly those concerned with the subject of brain aspect of fetal and neonatal life, associated with an extreme clinical pru-
damage in the newborn child. For easily understandable practical reasons, dence, allows him to bring us all the elements concerning changes in oxy-
it was unfortunately not possible to gather together the proceedings of all gen handling at birth.
the conferences in a single issue. The proceedings of the other conferences The presence of Felice Petraglia completes this group effectively, in at
will be published later in future issues. last introducing obstetrical research capabilities. Initially the young direc-
As editor in chief of this review for the last 20 years and neonatologist tor of a dynamic group in Udine, Felice Petraglia has traversed the world
for the last 37, it is my pleasant duty to introduce the principal protago- of developmental biology in Europe and on the American continent, tak-
nists of this meeting, particularly Rodolfo Bracci and Giuseppe Buono- ing an interest as much in studying the consequences of maternal stress as
core of the Università degli Studi di Siena, two research workers who, for the physiology of the fallopian tube or the complex mechanisms of nida-
30 years, have done so much to promote this difficult field of research on tion and placental organization. His choice of such capable speakers
‘the cerebral sequelae’ of abnormalities in pregnancy and birth. allows a more complete approach to all the phenomena leading to fetal
‘A tout Seigneur, tout honneur’, as the French say. There being no distress and premature birth, with all their consequences.
exact English equivalent, the nearest would perhaps be ‘give credit where It cannot be denied that the considerable progress in these areas has
credit is due!’ Indeed, Rodolfo Bracci was among the first to elucidate resulted in a simultaneous decrease in perinatal mortality and frequency
details of the oxygenation mechanisms in the fetus and the newborn child. of neurological handicap. Nonetheless, perinatal asphyxia is still responsi-
In 1970, Rodolfo Bracci and others published ‘Hydrogen peroxide genera- ble across the world for the death of a million newborn babies and a mil-
tion in the erythrocytes of newborn infants’ in Biology of the Neonate. In lion severely handicapped children each year. In Europe, out of 4 million
1981, again published in Biology of the Neonate, Bracci directed a magnif- births a year, 10,000 infants will suffer from cerebral palsy. The etiology
icent work on ‘Fatty acid pattern of the erythrocyte lipids and plasma of these cerebral complications is multifactorial. In addition to asphyxia
vitamin E in the first days of life’. at birth, which has become rare, it has been possible to demonstrate the
Without going into a detailed history of this essential aspect of fetal presence of other risk factors, such as psychological stress of the mother,
oxygenation and the disturbances of its physiology during birth, it seems poor management of minor abnormalities, oxygenation birth stress,
nevertheless right to cite the work of Maria Delivoria, who, after having inflammation, infection and environmental events during pregnancy or
elucidated the details of the gas exchanges of fetal haemoglobin, during even at birth, such as the pain suffered by the newborn child or the sudden
sojourns in Toronto and Denver, undertook a difficult and often thank- separation from the mother. These last two ‘birth accidents’, that is, sud-
less project on the cerebral sequelae of hypoxia-ischaemia at the Universi- den and lasting separation of the newborn child from the mother and the
ty of Philadelphia. Ever since 1985, her group certainly has been the most insufficient comprehension of pain experienced by the newborn child, are
prolific in the Western world, producing between 22 and 26 abstracts at doubtless the origin of postnatal neuropsychic complications that are not
the APS-SPR meetings each year, in addition to numerous original publi- possible to evaluate completely. With the daily ever-increasing under-
cations in the most prestigious reviews. standing of all these physiopathological mechanisms, it should be possible
The 1980s saw the arrival of young intelligent and dynamic re- to achieve better prevention, which nevertheless turns out to be difficult,
searchers who, in bringing the work of their precursors to fruition, allow in face of the particular physiopathological features specific to each preg-
the highest hopes for the future of perinatology. Three of these young nancy. The aim of the EURAIBI (Europe Against Infant Brain Injury)
researchers were very active in organizing this meeting and form part of association is to gather together the efforts of all centres of neonatology,
the Editorial Board: Giuseppe Buonocore, Ola Didrik Saugstad and a nursing care, doctors and scientists, in order to determine the elements
young obstetrician, Felice Petraglia. allowing a precise definition of these risk factors. Hopefully, these efforts
Giuseppe Buonocore is the one whom I know best and esteem for his will eventually lead to new preventive and therapeutic approaches.
great qualities. A faithful pupil of Rodolfo Bracci, he continues to Elements that seem to be important are the preparation for pregnancy,
improve our understanding of the consequences of hypoxia as much as respect for the exceptional creative power of the woman, understanding of
those of hyperoxia. Several stays in Maria Delivoria’s unit in Philadelphia the extraordinary power of the fetus for recovery and even of the newborn
have allowed him to make the best use of the extraordinary capacities of child, all these being conditional on a good parent-child interaction, espe-
certain fundamental researchers of the University of Siena, particularly in cially that between mother and child.
the study of the protein changes in hypoxia. Thus, he and others have just At a period when humankind has the impression of being able to dom-
published (1999) an article on ‘Hypoxic response of synaptosomal pro- inate technology, it is nevertheless common sense prevention which
teins in term guinea pig fetuses’ in the Journal of Neurochemistry. On the remains the most effective means to avoid the two great causes of cerebral
occasion of the retirement of Rodolfo Bracci, it was only right that his damage, prematurity and retardation of intrauterine growth. It is certain-
successor Giuseppe Buonocore be the principal organizer of a meeting of ly this elementary prevention applied from the moment of wanting a child
this quality, reviewing over 30 years of research and establishing the bases and the idea of the pregnancy that will assure a happy pregnancy and
of practical applications that appear to be possible at present. birth.
Moreover, it is this pragmatism which marks out Ola Didrik Saug- Jean-Pierre Relier, Paris
stad, well known for 20 years for his work on the physiopathological con-
ABC © 2001 S. Karger AG, Basel
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Biol Neonate 2001;79:150–156
Human Placenta as a Source of
Neuroendocrine Factors
FernandoM.Reis PasqualeFlorio LuigiCobellis StefanoLuisi
FilibertoM.Severi CaterinaBocchi EnricoPicciolini GiovanniCentini
FelicePetraglia
Chair of Obstetrics and Gynecology, University of Siena, Siena, Italy
Key Words rosteroids, monoamines) (table1). These products act as endocrine,
NeurohormonesW PlacentaW PregnancyW LaborW Gestational paracrine and autocrine factors to control the secretion of other regu-
diseases latory molecules, including the pituitary hormones of both mother
and fetus and their placental counterparts.
Several findings suggest a role of placental neurohormones in the
Abstract regulation of maternal and fetal physiology during pregnancy, rang-
Progress in the understanding of the physiological and pathological ing from the control of placental anchoring to fetal growth and matu-
functions of the placenta introduced the concept that the placenta is ration, fine regulation of uterine blood flow and/or initiation of labor.
a neuroendocrine organ, since it shows local production and release However, how placental hormones interact within the maternal uter-
of substances analog to neurohormones. These products act as us, and which precise functions they exert on the maintenance and/or
endocrine, paracrine and autocrine factors to control the secretion of interruption of pregnancy is still largely unknown. Recent studies
other regulatory molecules, including the pituitary hormones of have provided evidence for a decisive contribution of the placenta to
both mother and fetus and their placental counterparts. Further- all phases of gestation, through a range of substances largely exceed-
more, they may play a role in the regulation of maternal and fetal ing the classically known sex steroids and chorionic gonadotropin.
physiology during pregnancy, ranging from the control of placental The placenta and its accessory membranes, amnion and chorion,
anchoring to fetal growth and maturation, fine regulation of uterine although of fetal origin, actually undertake the role of intermediary
blood flow and/or initiation of labor. All this evidence underlines the barriers and active messengers in the maternal-fetal dialog. In the
decisive contribution of the placenta to all phases of gestation, present chapter, we will introduce the main families of placental neu-
through a range of substances largely exceeding the classically rohormones and summarize the cellular localization, the gestation-
known sex steroids and chorionic gonadotropin, throughout normal dependent changes and some putative functions attributed to these
pregnancy as well as in the presence of gestational diseases. substances by experimental and clinical studies.
Copyright © 2001 S. Karger AG, Basel
Thyrotropic Axis
Introduction
Thyrotropin-releasing hormone (TRH) is produced by the pla-
In the past three decades, there has been an accelerated progress centa from early pregnancy until term. The peptide is localized main-
in the understanding of the physiological and pathological functions ly in the syncytiotrophoblast but also in the fetal and maternal blood
of the placenta, much of which is owed to the discovery of new pla- vessels musculature as well as in the extravillous trophoblast cells [1].
cental signaling molecules. The developing concept is that the placen- Placental TRH is secreted into both the maternal and fetal circula-
ta is a neuroendocrine organ, since it shows local production and tion, but concentrations are higher in the latter compartment, proba-
release of substances analog to neurohormones (neuropeptides, neu- bly because the rapid degradation catalyzed by proteases is more
ABC © 2001 S. Karger AG, Basel Prof. Felice Petraglia, MD
0006–3126/01/0794–0150$17.50/0 Chair of Obstetrics and Gynecology, University of Siena
Fax [phone] Policlinico ‘Le Scotte’, viale Bracci
E-Mail [email protected] Accessible online at: I–53100 Siena (Italy)
www.karger.com www.karger.com/journals/bon Tel. [phone], Fax [phone], E-Mail [email protected]
Table 1. Neuropeptides, neurosteroids and
Brain peptides Pituitary-like Neurosteroids Monoamines and
monoamines produced by the human
peptides and proteins adrenal-like peptides
placenta
CRF ACTH progesterone epinephrine
TRH TSH allopregnanolone norepinephrine
GHRH GH pregnenolone sulfate dopamine
GnRH hPL 5·-dihydroprogesterone serotonin
Melatonin hCG adrenomedullin
Colecistokinin LH
Met-enkephalin FSH
Dynorphin ß-endorphin
Neurotensin prolactin
VIP oxytocin
Galanin leptin
Somatostatin activin
CGRP follistatin
NPY inhibin
Substance P
Endothelin
ANP
Renin
Angiotensin
Urocortin
VIP = Vasoactive intestinal polypeptide; CGRP = calcitonin gene-related peptide; ANP =
atrial natriuretic peptide; LH = luteinizing hormone; FSH = follicle-stimulating hormone.
active on the maternal side [1]. The possible paracrine effects of pla- showing some correlation with placental weight [6]. Because the half-
cental TRH remain unclear. There is very little passage of maternal life of hPL in maternal plasma is very short, the daily placental pro-
TRH across the placental barrier, but minimal amounts of TRH can duction of hPL has to be of great magnitude to maintain circulating
elicit an acute thyroid-stimulating hormone (TSH) release by the levels [6]. The secretion of hPL by the placenta is insensitive to sever-
fetal pituitary [2]. Since placental TRH is predominantly released al factors known to affect pituitary GH secretion. Like GH, however,
into the fetal circulation [1], this placental neuropeptide may be the levels of hPL have been reported to rise following hypoglycemia
involved in the regulation of thyroid function during fetal life. The [6]. The role of hPL in pregnancy is related to its metabolic proper-
placenta also produces a TSH-like peptide, named chorionic thyro- ties, rather than somatotropic or lactogenic effects. In the fasting
tropin (hCT) [3]. Although hCT was initially characterized as a state, the augmented release of hPL coupled with low insulin levels
bioactive thyrotropin [3], testing of better purified extracts demon- results in increased lipolysis and decreased glucose uptake by the
strated extremely low thyrotropic activity. The levels of hCT progres- mother, which protects the fetus from hypoglycemia.
sively increase from the first to third trimester, whereas the levels of Human placental GH, the product of the GH-V gene, is a GH-
TSH remain constant, suggesting an independent regulation of pitu- like peptide synthesized by the syncytiotrophoblast and released into
itary and placental thyrotropins. In addition, the injection of TRH in the maternal circulation, where it gradually replaces the pituitary GH
pregnant women produces an acute release of TSH but fails to induce from the second trimester of gestation. At least four splicing variants
placental release of hCT [4]. of the GH-V mRNA are expressed in the human placenta [7]. The
peptide exhibits both somatogenic and lactogenic activities and is
structurally distinguishable from pituitary GH by 13 amino acids [8].
Growth Hormone, Placental Lactogen and Insulin-Like It is released in a constant rather than pulsatile fashion, in contrast to
Growth Factor-I the episodic release of pituitary GH. This continuous secretion
appears to have important implications for physiologic adjustment
The classical placental hormone with growth hormone (GH)-like to gestation and especially the control of maternal insulin-like growth
activity is chorionic somatotropin, also named human placental lac- factor-I levels [8]. The placenta also expresses a GH-releasing hor-
togen (hPL) [5]. The dual nomenclature reflects its mammosomato- mone (GHRH), which is identical to the hypothalamic GHRH but is
tropic characteristics, due to the structural homology with GH and regulated by distinct mechanisms, including differential splicing of
prolactin (PRL). The hPL molecule is a polypeptide of 191 amino an untranslated exon and the activation of tissue-specific gene pro-
acids with 96% homology with GH but no more than 3% of the moters [9]. The role of placental GHRH in human pregnancy is still
somatotropic activity of GH. The levels of hPL in the maternal circu- unknown; the presence of GHRH receptor in the placenta [10] sug-
lation are very low in early pregnancy and increase progressively, gests a possible paracrine action.
Human Placenta as a Source of Biol Neonate 2001;79:150–156 151
Neuroendocrine Factors
Placental ACTH, also called chorionic corticotropin, is a product
of the proopiomelanocortin (POMC) gene and has the same structure
as pituitary ACTH, retaining its immunogenic and biologic activity
[18, 19]. Placental ACTH is localized to the cytotrophoblast in the
first trimester and to the syncytiotrophoblast in the second and third
trimesters [20]. There is a significant increase in POMC gene expres-
sion in the placenta with the advance of gestation, which is mani-
fested by increasing levels of POMC mRNA as well as immunoreac-
tive ACTH [20]. Among the possible local effects of placental ACTH
are the stimulation of placental steroidogenesis [21] and reduction of
vascular resistance [22].
Fig. 1. Paracrine control of hCG release by the placental syncytiotro- Gonadotropic Axis
phoblasts. The stimulatory effects of GnRH and activin and the
inhibitory effects of inhibin and follistatin resemble the control of Human chorionic gonadotropin (hCG), the most classic placental
pituitary follicle-stimulating hormone release. hormone, is a glycoprotein biologically equivalent to pituitary lutein-
izing hormone. Like all glycoprotein hormones, hCG is composed of
two subunits, · and ß. Since the immunological specificity of hCG is
conferred by the ß subunit, current clinical assays employ antibodies
Corticotropic Axis directed against the ß subunit in order to quantify hCG without
cross-reacting with luteinizing hormone. Produced by the syncytio-
The placenta produces corticotropin-releasing factor (CRF), cor- trophoblast, hCG is detectable in the maternal circulation 8–10 days
ticotropin (ACTH) and cortisol during the whole course of gestation. after ovulation, coinciding with the implantation of the blastocyst
These hormones have important roles in maternal adaptation and [23]. Although much is known about the mechanisms regulating hCG
fetal development, in addition to their local effects within the placen- secretion [23], the role of this hormone in the physiology of pregnan-
ta, fetal membranes and myometrium [11]. CRF is located predomi- cy is still a matter of controversy. Apart from its well-known luteo-
nantly in the syncytial layer of placental villi, but it is also present in tropic role in early pregnancy, it has been suggested that hCG may
the cytotrophoblast, in the epithelial cells and in some cells of the regulate steroidogenesis both at the placental level and in the fetal
subepithelial layer of the amnion, and in cells of the reticular layer of adrenals and testis [6]. It has also been noted that hCG stimulates
the chorion. Placental CRF secretion into maternal plasma progres- maternal thyroid function and this probably accounts for a transient
sively increases during pregnancy to reach the highest values at term. hyperthyroidism in the first trimester of gestation, particularly in
The local effects of CRF are mediated by two classes of receptors, twin or molar pregnancy [24].
named type 1 (CRF-R1) and type 2 (CRF-R2). CRF-R1 encompasses Gonadotropin-releasing hormone (GnRH) and its specific recep-
at least two isoforms of proteins, · and ß, while CRF-R2 has at least tor are expressed in the human placenta from the first trimester to
three splice variants characterized. By using reverse transcriptase term. Abundant expression of both hormone and receptor is ob-
polymerase chain reaction and in situ hybridization, the · variant of served in the cyto- and syncytiotrophoblast, where they are localized
CRF-R1 mRNA and the ß variant of CRF-R2 mRNA have been in identical cells [25]. Placental GnRH is likely to be one of the para-
identified in the placenta, chorion, amnion and decidua [12, 13]. crine regulators of hCG secretion, as suggested by evidence from in
Specifically, CRF-R1· was exclusively localized in syncytiotropho- vivo and in vitro experiments [26, 27]. Administration of GnRH to
blast cells which showed an intense hybridization, whereas CRF-R2ß pregnant women elicits a significant increase in hCG in the first tri-
was also present in the cytotrophoblast. There was no quantitative mester, a response seldom observed in the third trimester [27]. This
difference between placentas collected from vaginal delivery or different sensitivity may be explained by the downregulation of
cesarean section [13]. The CRF-R2ß mRNA signal was also present GnRH receptors in the term placenta [28]. In this regard, the
within the structure of the villi (blood vessels), chorionic trophoblast influence of local GnRH on hCG secretion is better explained by
and decidual cells, while a less intense or no signal was found in changes in GnRH receptor expression, which parallel the time course
amniotic epithelium. of hCG release during pregnancy [28]. The GnRH receptor expressed
Recently, a new peptide related to CRF has been found in human in the placenta is identical to the pituitary counterpart [29] and binds
placenta, named urocortin [14]. Due to its pharmacological charac- with high specificity to synthetic GnRH in vitro.
teristics and tissue distribution in the brain, urocortin may be consid- Resembling what occurs in the pituitary-ovary axis, the release of
ered a neuropeptide with high affinity to CRF-R2. The human pla- placental GnRH and hCG is modulated by inhibins, activins and the
centa and its related membranes produce urocortin throughout gesta- activin-binding protein follistatin (fig.1). Inhibin and activin are
tion [14, 15]. Placental and decidual cells collected in the first or third dimers composed of · and ß (inhibin) or two ß subunits (activin),
trimester express urocortin mRNA. Immunohistochemistry has lo- which are coexpressed with GnRH in placental villi at term [30].
calized urocortin in syncytial cells of the trophoblast, as well as in the Activin stimulates and inhibin antagonizes the activin-induced
amnion, chorion and decidua [14]. Studies in vitro have demon- GnRH and hCG secretion by cultured placental cells [31, 32]. In
strated that urocortin has CRF-like effects on placental cells and tis- turn, GnRH and hCG stimulate inhibin mRNA expression and
sue explants, such as stimulating ACTH and prostaglandin secretion immunoreactive inhibin release in cultured placental cells [33].
[16]. In addition, urocortin has a potent vasodilatory effect on the The human placenta is the source and target of inhibin-related
fetal-placental circulation [17]. proteins [34, 35]. Inhibin/activin subunits are present in placental
152 Biol Neonate 2001;79:150–156 Reis/Florio/Cobellis/Luisi/Severi/Bocchi/
Picciolini/Centini/Petraglia
cells, particularly in the syncytiotrophoblast. Dimeric activins and
inhibins are found in placental homogenates and dimeric activin A is
localized in both cyto- and syncytiotrophoblast cells from early to
term pregnancy. From early pregnancy, activin A levels are higher
than those measured during the menstrual cycle. Minimal changes
are seen during the first and second trimesters, but an exponential
increase comes with the beginning of the third trimester and is fol-
lowed by an additional increase toward term. Activin A, inhibin A
and inhibin B are also present in the amniotic fluid. Activin A is
increased in hypertensive complications of pregnancy, preterm labor
and gestational diabetes, and is particularly elevated in preeclampsia.
Alterations in maternal serum inhibin levels may be indicative of
several gestational diseases. For example, women with preeclampsia
have high circulating levels of inhibin A and its precursor subunit
pro-· C [35].
Fig. 2. Stress hormones in the maternal circulation at parturition.
The sharp increase in the concentrations of CRF, cortisol and NPY
Prolactin around the time of labor reflects acute placental release. The placenta
seems to participate in the stress response of human parturition.
The maternal decidua and placental trophoblast produce PRL,
which is carried through fetal membranes and released into the
amniotic fluid [36]. The levels of amniotic fluid PRL increase in par-
allel with decidual PRL secretion and reach a peak by the sixth diately after delivery [45]. Leptin levels are substantially increased in
month of pregnancy [37]. Although the decidua is the main site of women with severe preeclampsia, probably as a consequence of
PRL production in the pregnant uterus, PRL and its receptor are also increased placental leptin production [47]. The observation that lep-
expressed in the trophoblast throughout gestation [38]. The role of tin levels in arterial cord blood have a direct correlation with fetal
decidual/placental PRL in human pregnancy remains unclear, al- body weight and are lower in newborns with intrauterine growth
though some hypotheses regarding fluid homeostasis and fetal lung restriction (IUGR) suggests that leptin levels in the fetal circulation
maturation have been suggested [39]. are determined by the fetal adipose mass [46]; however, the placenta
is likely to contribute decisively to the fetal leptin pool, since leptin
levels are higher in venous than arterial cord plasma and decrease
Oxytocin shortly after birth [48]. The existence of leptin receptors in the pla-
centa supports the possibility of local effects, such as the regulation of
Oxytocin gene expression has been identified in the amnion, cho- other placental neuropeptides [49, 50]. Many aspects of the possible
rion and decidua, and to a lesser extent in the placental trophoblast. role of leptin in gestational diseases remain unclear. For example,
The levels of oxytocin mRNA in the decidua increase markedly placental leptin production is increased in preeclampsia and local
around the time of labor onset and do not correlate with oxytocin hypoxia may be an underlying mechanism [47], but this contrasts
levels in the maternal circulation [40]. A similar increase can be with the low leptin levels observed in IUGR [46].
induced in vitro by estradiol stimulation through an estrogen recep-
tor-mediated mechanism [41]. There appears to be no change in oxy-
tocin metabolism around the time of parturition, but oxytocin recep- Vasoactive Neuropeptides
tor gene expression is upregulated [42]. These observations indicate
that the onset of labor coincides with an increase in the paracrine A large number of vasoactive neuropeptides is present in human
rather than systemic release of oxytocin. This local oxytocin produc- placental tissues. An extensive immunohistochemical study has
tion seems to be regulated by other paracrine factors, such as CRF, revealed the presence of vasoactive intestinal polypeptide, calcitonin
activin A and prostaglandins [43]. gene-related peptide, neuropeptide Y (NPY), galanin, somatostatin,
metionine-enkephaline and substance P in the decidual layer, and
the expression of endothelin-1 in the trophoblast cells of the human
Leptin placenta at term [51]. Atrial natriuretic peptide is expressed at both
the mRNA and protein level in purified term trophoblasts, particu-
Leptin is a peptide secreted in the circulation by the adipose tis- larly in extravillous interstitial and cytotrophoblastic shell tropho-
sue that acts on the brain to regulate food intake and energy balance. blasts [52].
This peptide is also produced in nonadipose tissues such as the pitu- NPY is produced by the placenta, mainly by the cytotrophoblast
itary gland [44] and the placenta. Placental leptin is released into cells, and is found at high concentrations in maternal plasma with no
both maternal and fetal compartments, where its levels increase significant change from early to late gestation [53, 54]. NPY is also
steadily during late gestation [45, 46]. There is controversy about the present in epithelial amnion cells and in the chorionic cytotropho-
relative contribution of the placenta to the maternal plasma leptin blast, and is found at high concentrations in the amniotic fluid. The
content. The time course of maternal plasma leptin levels during levels of NPY in maternal plasma (but not in amniotic fluid) increase
pregnancy suggests that the placenta has a decisive role, since leptin by three-fold during labor [54], suggesting that this peptide may play
levels increase by more than two-fold up to 30 weeks and fall imme- a role in the stress response of parturition (fig.2).
Human Placenta as a Source of Biol Neonate 2001;79:150–156 153
Neuroendocrine Factors