PATHOPHYSIOLOGY OF
FETOPLACENTAL UNIT
VLA
April 3, 2018
PREGNANCY
 Pregnancy is marked by alterations in a
number of endocrine systems, including
activation of the renin–angiotensin–
aldosterone system and the hypothalamic–
pituitary–adrenal axis.
 Although rare, maternal adrenal disorders
are associated with considerable maternal
mortality and morbidity if not promptly
recognized and treated.
FETOPLACENTAL UNIT
 The placenta, the fetal adrenal glands and the
fetal liver constitute an interactive endocrine
entity, known as the fetoplacental unit.
 In the fetoplacental unit, the fetal adrenal
glands are the primary source of
dehydroepiandrosterone sulphate (DHEAS),
which is further metabolized by the fetal liver
and placenta to produce a variety of estrogens.
Cholesterol
Pregnenolon
Progesteron
11deoxykortiko
steron
Cortikosteron
18 hydroxycorti
kosteron
Aldosteron
17 hydroxy
pregnenolon
17 hydroxy
progesteron
11 deoxycortisol
Cortisol
DHEA
Androstendion
Estradiol
Testosteron
Desmolase
21 hydroxylase
11 hydroxylase
18 hydroxylase
21 hydroxylase
11 hydroxylase
11 hydroxylase
Steroidogenesis in adrenal glands
STEROID HORMONS
Suprarenal gland Aldosteron
Cortisol
Reproductive
hormons
Testes Testosteron
Ovaries Progesteron
Estrogens
Placenta Estrogens
Progesteron
1, Syncytiotrophoblast; 2,
fetal capillary with
erythrocytes; 3, MVM; 4,
BM; 5, umbilical vein; 6,
umbilical arteries; 7,
chorion plate; 8, decidua;
9, myometrium; 10,
intervillous space with
maternal blood; 11, veins;
12, spiral arteries; 13, villus
tree; 14,
syncytiotrophoblast cell
nuclei; 15, diffusion
distance between maternal
and fetal blood.
First trimester: the
villus has an intact
syncytioand
cytotrophoblast
layer. In the villus
interior there are
mesenchymal cells
with macrophages
and fetal capillaries.
In the middle third of the pregnancy
the capillaries migrate to the villus
surface. The cytotrophoblast layer
disappears slowly and the
syncytiotropho-blast layer becomes
thinner.
During the 6th month the nuclei of
the syncytiotrophoblast group
together in the so-called
proliferation knots. The other zones
of the syncythiothrophoblast lack
nuclei and are adjacent to the
capillaries (exchange zones).
1 Intervillous space
2 Syncytiotrophoblast
3 Cytotrophoblast
4 Villus mesenchyma
5 Fetal capillaries
6 Hofbauer macrophages
1 Intervillous space (with maternal blood)
2 Placental barrier of a terminal villus
3 Fetal capillaries
4 Merged basal membranes of the fetal capillary and of the syncythiothrophoblast
5 Endothelial cells
6 Rare cytotrophoblast cells
7 Basal membrane of the capillaries
8 Basal membrane of the trophoblast portion
9 Syncytiotrophoblast with proliferation knots (nuclei rich region)
Placental Barrier
1 Spiral arteries
2 Uterine veins
3 Intervillous spaces
A Basal plate
Maternal circulation system
Maternal blood arrives
at the intervillous space
via arteries that open
directly into the
intervillous space. At
the placental level, it
thus finds itself
temporarily outside the
vessel network.
STRESS SYSTEM AND THE FEMALE REPRODUCTIVE
SYSTEM
 The actions of the stress system and the female reproductive system are
bidirectionally interrelated.
 ACTH inhibits the secretion of gonadotropin hormone-releasing hormone
(GnRH) from the arcuate nuclei of the hypothalamus.
 Glucocorticoids inhibit both GnRH secretion and render resistance to sex
hormone tissues that are normally sensitive to them.
 Half estrogen-responsive elements have been shown on the promoter area of the
human CRH gene, while estrogens have been shown to directly regulate the
expression of the human CRH gene.
 A reciprocal relationship exists between the HPA axis and the
immune/inflammatory reaction. A dysregulated HPA response to stressors in
women might contribute to autoimmune phenomena, which are more frequent
in them.
 The epithelial cells of human endometrium produce CRH throughout the
menstrual cycle, while the stroma needs to undergo decidualization in order to
produce CRH. CRH-R1 alpha is present on both epithelial and stromal cells of
the human endometrium, and the human myometrium contains CRH-R1
receptors.
MATERNAL HPA AXIS IN PREGNANCY
 Pregnancy has been explored from the immunological point of view,
since it can be considered as a semiallograft situation. In this context,
locally produced embryonic and endometrial CRH plays a role in both
the aseptic inflammatory process of implantation and the antirejection
process that protects the fetus from the maternal immune system.
 It has been suggested that CRH of fetal and maternal origin regulates
FasL production, thus affecting the invasion process through a local
autoparacrine regulatory loop of cytotrophoblast cells and regulating
their own apoptosis. More particularly, CRH decreases FasL expression
in embryonic trophoblast and maternal decidua, and promotes
apoptosis of activated T lymphocytes.
MATERNAL HPA AXIS IN PREGNANCY
 During pregnancy, circulating immunoreactive CRH in plasma increases
exponentially up to a thousand times its nonpregnant level, from the eighth to
tenth week of gestation onward. This increase is the result of CRH production
by the placenta, decidua, and fetal membranes rather than of hypothalamic
origin.
 Placental CRH secretion is promoted by cortisol and supressed by estrogens.
 The CRHbp (bound to protein) plasma concentrations in pregnant women
remain similar to levels of nonpregnant women until the third trimester of
pregnancy. At that time its values fall to roughly one-third the levels of earlier
pregnancy or those of the nonpregnant state. Amniotic fluid CRHbp levels also
fall approaching term.
 The unbound fraction of CRH stimulates maternal ACTH secretion.
 CRH can induce vasodilation in the uterine arteries, and may regulate the
placental blood flow. Placental CRH does not exhibit a circadian rhythm.
MATERNAL HPA AXIS IN PREGNANCY
 Although during pregnancy the maternal pituitary gland enlarges
by about one-third (due to lactotroph cell hyperplasia), its
functions remain intact.
 The circadian rhythm of maternal ACTH plasma levels is
maintained during pregnancy, probably due to AVP secreted by
the parvicellular paraventricular nuclei. However, overall
pituitary ACTH secretion and plasma ACTH levels rise
(remaining, though, within normal limits) and follow in parallel
the rise of plasma-free and total cortisol levels. This rise of
maternal ACTH levels is due to circulating unbound placental
CRH.
 ACTH concentration in amniotic fluid rises during pregnancy,
peaking at the beginning of the third trimester, and then showing
a decline of the plasma levels of this hormone.
MATERNAL HPA AXIS IN PREGNANCY
 Elevated estrogen levels in pregnancy lead to a doubling of
corticosteroid-binding globulin (CBG) levels, resulting in low catabolism
of cortisol by the liver and a doubling of cortisol's half-life in plasma.
Moreover, during pregnancy maternal adrenal glands gradually become
hypertrophic as cortisol production in the adrenal zona fasciculata is
increased, because of the relatively increased maternal ACTH secretion.
Consequently, a steady rise in total and free plasma cortisol is noted,
peaking during the third trimester at about two and three times
nonpregnant values, respectively. These peak cortisol levels are
comparable to those observed in Cushing's disease, severe depression,
anorexia nervosa, and in athletes doing strenuous exercise.
 Thus, pregnancy is a transient, but physiologic, period of relative
hypercortisolism for the normal woman. The diurnal variation of
plasma cortisol levels is maintained in pregnancy. During pregnancy,
amniotic fluid cortisol levels follow the plasma levels of this hormone.
Yates N, Crew RC,
Wyrwoll C.
Vitamin D deficiency
and impaired placental
function: potential
regulation by
glucocorticoids
Reproduction. 2017 Jan
30. pii: REP-16-0647. doi:
10.1530/REP-16-0647.
[Epub ahead of print]
?
MATERNAL HPA AXIS AND PARTURITION
 During normal labor in humans, transient increases
in maternal plasma CRH, ACTH, and cortisol are
observed, the levels of which drop to prepartum
values within 1–4 days postpartum.
 Interestingly, neither correlation has been shown
between maternal ACTH and cortisol levels at this
stage, nor between maternal ACTH levels and parity,
weight of the newborn, or duration of the delivery.
 Primiparous women with uneventful pregnancies
that deliver spontaneously vaginally, show elevated
ACTH levels when their labor is not progressing
satisfactorily.
MATERNAL HPA AXIS AND PARTURITION
 It has been proposed that the HPA axis during pregnancy functions as a
biological clock, “counting” from the early stages of gestation. In this
model, placental CRH is the timing starter, determining the course of
pregnancy and culminating, accordingly, in a preterm, term, or postterm
labor.
 CRH-R 1 is considerably up-regulated at the time of labor in the human
myometrium and the fetal membranes. In the final hours before birth
the fetal adrenal cortisol production exceeds the CBG binding capacity,
leading to a sudden increase in fetal free cortisol concentration. Cortisol
competes with the action of progesterone in the regulation of placental
CRH gene at the end of gestation. Moreover, cortisol may also act as an
endogenous inhibitor of progesterone action on prostaglandininactivating
enzymes, thus playing a role in regulating the timing of
parturition.
 The fetal adrenals (at the level of the glands' fetal zone) respond to
pituitary ACTH and placental CRH with DHEAS production. The latter
is aromatized in the placenta to estrogen. An increase in local
concentration of estrogen (and more particularly in amniotic fluid) or of
the estrogen to progesterone ratio promotes myometrial contractility.
MATERNAL HPA AXIS IN THE POSTPARTUM PERIOD
 In the postpartum period, maternal plasma cortisol levels
show a decline toward normal levels, as the HPA axis
gradually returns to its prepregnant dynamic state.
Immediately after parturition, the maternal HPA axis is
mildly suppressed. Dynamic testing of the HPA axis shows
transiently suppressed hypothalamic CRH secretion at 3
and 6 weeks postpartum, and normal responses after 12
weeks. Although suppressed ACTH responses are noted in
the postpartum period, the total plasma cortisol levels are
within normal range.
MATERNAL HPA AXIS IN THE POSTPARTUM PERIOD
 Healthy lactating women show blunted HPA responses to
physical stress. In these women, estrogen levels were lower
and prolactin levels were higher compared to nonlactating
women.
 The HPA axis seems to influence the mother's psychological
status and the mother-infant relationship/bonding. More
particularly, among first-time mothers, those with higher
plasma cortisol levels recognize, in the early postpartum
period, their own infants' odors more easily and are more
attracted to them than women with low plasma cortisol
levels.
THE HPA AXIS IN PREGNANCY AND THE POSTPARTUM
PERIOD: PATHOPHYSIOLOGIC CONSIDERATIONS
 The HPA axis is involved in the response of pregnant
women to psychosocial stress; high plasma levels of
ACTH and cortisol have been measured in pregnant
women.
 Prenatal maternal stress is associated with premature
birth. Since the latter is also associated with elevated
maternal plasma CRH, it can be hypothesized that the
timing of birth can be modified via HPA axis activation.
Increased levels of corticosteriods (following physical or
emotional stress) can promote placental CRH secretion
and culminate in premature labor.
 ACTH-like products from the fetoplacental unit, may—
very rarely—induce Cushing's syndrome, which may
even resolve postpartum.
THE HPA AXIS IN PREGNANCY AND THE POSTPARTUM
PERIOD: PATHOPHYSIOLOGIC CONSIDERATIONS
 Almost half of postpartum women develop a
short-lived dysthymic disorder, called the
“postpartum blues,” while overt postpartum
depression is common and occurs in up to
18% of newly delivered mothers.
 Mood disorders after pregnancy can last up
to a year postpartum.
THE HPA AXIS IN PREGNANCY AND THE POSTPARTUM
PERIOD: PATHOPHYSIOLOGIC CONSIDERATIONS
 During pregnancy cell-mediated immune function and Th1 cytokine
production (e.g., IL-12, interferon-gamma) are suppressed, and humoral
immunity and Th2 cytokine production (e.g., IL-4, IL-10) are enhanced.
These cytokine patterns are reversed in the postpartum period.
 Thus, opposite Th1/Th2 cytokine profiles characterize pregnancy and
the postpartum period. Convincing evidence exists to indicate that
changes in the production of cortisol (as well as in progesterone and
estrogen) play major roles in modulating the balance between Th1 and
Th2 cytokines.
 In women with rheumatoid arthritis, pregnancy has an ameliorating
effect on disease activity, while the disease tends to flare in the
postpartum period. The prevalence of postpartum thyroiditis is 5–7%.
The increased postpartum vulnerability to such autoimmune diseases
could be attributed to the steroid withdrawal syndrome, the suppressed
hypothalamic CRH secretion, and the subsequent changes in cytokine
profiles.
FETAL-NEONATAL HPA AXIS
 The actions of the fetal HPA axis (in concert with those of the placenta)
are essential in fetal development, maturation, and homeostasis, and
eventually prepare for the survival of the neonate.
 The fetal pituitary matures first, with fetal HPA activity beginning at
midgestation. Fetal hypothalamic and placental CRH lead to fetal
pituitary ACTH secretion. The latter controls adrenocortical functional
development, including angiogenesis and expression of steroidogenetic
enzymes.
 The fetal adrenal gland is characterized by the presence of the fetal zone,
which is the principal localization of DHEAS synthesis, the substrate for
placental estrogen synthesis. Also in the fetal adrenal the definitive zone
is the main site of mineralocorticoid synthesis, while the transitional
zone synthesizes cortisol de novo after the 28th week of pregnancy.
Although about one-third of variations in fetal cortisol levels are
attributable to maternal cortisol levels, fetal stress responses are
independent of maternal responses.
Glucocorticoid signalling between mother, placenta and fetus. Figure shows interaction between maternal,
placental and fetal compartments during pregnancy leading to overexposure of the developing fetus to
glucocorticoids. Activation of the maternal HPA axis during pregnancy leads to increased circulating
levels of cortisol (filled circles). Placental CRH also directly stimulates the maternal pituitary and adrenal
to further increase cortisol levels, while maternal cortisol also stimulates placental CRH production.
Maternal cortisol passes through the placenta where it is broken down by the enzyme HSD2 into inactive
cortisone (grey triangles). The fetus can also signal to the placenta to increase production of placental CRH
when fetal metabolic demands increase. Overexposure of the developing fetus to excess cortisol leads to
fetal HPA axis activation which is associated with low birthweight and long term adverse programmed
outcomes including metabolic and brain sequelae. CRH – corticotropin releasing hormone, ACTH –
adrenocorticotropin hormone, HSD2 – 11β hydroxysteroid dehydrogenase type 2.
Psychoneuroendocrinology
38 (1), January 2013, Pages 1–
11
FETAL-NEONATAL HPA AXIS
 Birth is a very stressful situation for the neonate, and the
adequate adrenocortical secretion of steroids (mainly of
cortisol) enables adaptation to extrauterine life.
 Preterm and low-weight infants have adequate pituitary
function; however, they show decreased baseline cortisol
levels or low adrenocortical reserve after ACTH
stimulation. Cortisol precursors are elevated in these
infants, pointing to reduced steroidogenic enzymes'
activity due to adrenal immaturity. In these infants, an
inability to “recognize” stress or a failure of the
hypothalamus to secrete CRH in stressful situations has
been hypothesized.
PREGNANCY
 Pregnancy is a physiological state with a complex anatomical and
functional interaction between mother and fetus. When this interaction
is not a success, the mother, the fetus, or both exhibit functional
impairments.
 Complications of pregnancy are important causes of maternal mortality,
where gestational diabetes mellitus (GDM) and obesity of the mother in
pregnancy (OP) are major obstetric pathologies. Fetal-maternal
interaction could result in metabolic disturbances leading, for example,
to placental and endothelial dysfunction.
 Endothelial dysfunction in pregnancy is defined as an altered capacity
of the endothelium to take up and metabolize the cationic amino acid Larginine,
the substrate for nitric oxide (NO) synthesis via endothelial
NO synthases (NOS). Interestingly, it is reported that GDM and OP are
pathological conditions associated with altered L-arginine transport and
NO synthesis (i.e., the “L-arginine/NO signalling pathway”), probably
due to altered uptake and metabolism of adenosine, an endogenous
nucleoside acting as vasodilator in most vascular beds.
FETAL PROGRAMMING
 These pathophysiological characteristics are considered key in the
establishment of a “programmed state” of the developing fetus
(i.e., “fetal programming”). This concept refers to the impact of
abnormal intrauterine conditions on the development of diseases
in adulthood and becomes a key mechanism associated with
future development of chronic diseases including cardiovascular
disease (CVD), diabetes mellitus, and metabolic syndrome (a
concept globalizing clinical association of obesity, type II or noninsulin-dependent
diabetes mellitus, hypertension, and
dyslipidaemia) .
 Interestingly, GDM is a condition that also increases the risk of
obesity in children and adolescents , a phenomenon leading to
high incidence of type 2 diabetes mellitus (T2DM). OP is also
related to neonatal metabolic compromise, which is already
apparent in the offspring at birth, characterized by reduced
insulin sensitivity and higher concentrations of inflammatory
markers .
FETAL PROGRAMMING
 Adverse influences during fetal life alter the structure and
function of distinct cells, organ systems or homeostatic pathways,
thereby ‘programming’ the individual for an increased risk of
developing cardiovascular disease and diabetes in adult life.
 It can be caused by a number of different perturbations in the
maternal compartment, such as altered maternal nutrition and
reduced utero–placental blood flow.
 Perturbations in the maternal environment must be transmitted
across the placenta in order to affect the fetus. In IUGR
(intrauterine growth restriction) pregnancies, the increased
placental vascular resistance subjects the fetal heart to increased
work load, representing a possible direct link between altered
placental structure and fetal programming of cardiovascular
disease.
FETAL PROGRAMMING
 The placenta appears to function as a nutrient sensor
regulating nutrient transport according to the ability of
the maternal supply line to deliver nutrients. By directly
regulating fetal nutrient supply and fetal growth, the
placenta plays a central role in fetal programming.
Furthermore, perturbations in the maternal compartment
may affect the methylation status of placental genes and
increase placental oxidative/nitrative stress, resulting in
changes in placental function.
 A decreased activity of placental 11β-HSD-2 (type 2
isoform of 11β-hydroxysteroid dehydrogenase) activity
can increase fetal exposure to maternal cortisol, which
programmes the fetus for later hypertension and
metabolic disease.
GESTATIONAL DIABETES MELLITUS (GDM) AND
OBESITY IN PREGNANCY (OP)
 are pathological conditions associated with placenta
vascular dysfunction coursing with metabolic changes at
the fetoplacental microvascular and macrovascular
endothelium. These alterations are seen as abnormal
expression and activity of the cationic amino acid
transporters and endothelial nitric oxide synthase
isoform.
 GDM and OP prone placental endothelium to an “altered
metabolic state” leading to fetal programming evidenced
at birth, a phenomenon associated with future
development of chronic diseases, such as cardiovascular
disease, obesity, diabetes mellitus (including gestational
diabetes), and metabolic syndrome.
GESTATIONAL DIABETES MELLITUS
 Gestational diabetes mellitus (GDM) is a syndrome
characterized by glucose intolerance leading to maternal
hyperglycaemia first recognized during pregnancy.
 GDM is associated with abnormal fetal development and
perinatal complications, such as macrosomia and
neonatal hypoglycaemia .
 Alterations associated with GDM result from a change in
the amount of D-glucose available to the fetus due to
alterations in the physiology of the placenta (e.g.,
increased D-glucose transplacental transport) or by
hormone-induced dysfunction (e.g., altered insulin
signalling), phenomena that could lead to abnormal
growth of the fetus (macrosomia) and perinatal
complications.
GESTATIONAL DIABETES MELLITUS (GDM)
 Gestational diabetes mellitus (GDM) is a
syndrome compromising the health of the
mother and the fetus.
 Endothelial damage and reduced metabolism of
the vasodilator adenosine occur and fetal
hyperinsulinemia associated with deficient
insulin response is characteristic for this
pathology. These phenomena lead to
endothelial dysfunction of the fetoplacental
unit.
Endothelial L-arginine/NO signalling pathway in gestational diabetes
mellitus and obesity in pregnancy. In human endothelial cells L-arginine is
taken up via cationic amino acid transporters 1 (hCAT-1) accumulating this
amino acid in the intracellular compartment
HYPERTRIGLYCERIDEMIA IN PREGNANCY
 Pregnancy is a physiological condition
characterized by a progressive weeks of
gestation-dependent increase (reaching 100–
200%) in the maternal blood level of
triglycerides.
 These changes promote accumulation of
maternal fat stores in early and mid
pregnancy, so to metabolize and use it in late
pregnancy.
DYSLIPIDEMIA
 GDM is a pathological condition also characterized by
maternal dyslipidaemia, alteration directly affecting fetal
development and growth.
 Dyslipidaemia is defined as elevated levels of
triglycerides (hypertriglyceridemia) and total blood
cholesterol (hypercholesterolemia), including increased
low-density lipoprotein (LDL) and reduced high-density
lipoprotein (HDL) levels.
 Dyslipidaemia is the main risk factor for development of
CVD later in life in mother.
 GDM is a risk factor to fetal programming due apparently
to metabolic syndrome and, thus, predisposes to an
accelerated development of CVD in adult life.
L-Arginine metabolism in hypercholesterolaemia. In human endothelial cells,
L-arginine is taken up via cationic amino acid transporter 1 (hCAT-1) which is
then metabolized by either the endothelial nitric oxide synthase (eNOS) into Lcitrulline
and nitric oxide.
maternal supraphysiological hypercholesterolemiamaternal physiological hypercholesterolemia
Potential pathophysiological interaction between the mother, the placenta, and
the fetus in fetal atherosclerosis. Maternal factors, including reduced (↓)
catalase (CAT) activity, increased (↑) lipid peroxidation, and oxidized low
density lipoproteins.
MSPH= maternal supraphysiological
hypercholesterolemia
PREECLAMPSIA
 Preeclampsia is a multi-system disorder of pregnancy,
which is characterized by new onset hypertension
(systolic and diastolic blood pressure of ≥ 140 and 90 mm
Hg, respectively, on two occasions, at least 6 hours apart)
and proteinuria (protein excretion of ≥ 300 mg in a 24 h
urine collection, or a dipstick of ≥ 2+), that develop after
20 weeks of gestation in previously normotensive women
 Dependent on the systemic involvement, several other
symptoms, such as edema, disturbance of haemostasis,
renal or liver failure, and the HELLP syndrome
(hemolysis, elevated liver enzymes, and low platelet
counts) also complicate the clinical picture.
PREECLAMPSIA
 Preeclampsia can have an early onset (preeclampsia
starting before 34 weeks of gestation) or late onset
(preeclampsia starting after 34 weeks of gestation),
 can show mild or severe symptoms (systolic blood
pressure ≥ 160 mmHg or diastolic blood pressure ≥ 110
mmHg, proteinuria >5 g/24 hours, oliguria, neurological
symptoms, other clinical symptoms such as deranged
liver function, thrombocytopenia < 100 000 mm3, HELLP
syndrome)
 can evolve in eclampsia in the most severe cases.
 it can manifest as a maternal disorder only, with an
appropriate fetal growing, or
 it can present itself with a growth restricted fetus
(intrauterine growth restriction (IUGR)) or sudden fetal
distress.
PREECLAMPSIA
It is the main cause of maternal morbidity and mortality, and fetal
metabolic disturbances in developed and developing countries.
 Fetal complications in preeclampsia have been related with lower
placental blood flow. The placenta lacks of innervation, thus
vascular tone regulation depends on endothelial release of
vasoactive molecules such as adenosine and nitric oxide (NO).
Information about NO synthesis and its action in the fetoplacental
vasculature in preeclamptic pregnancies is controversial.
 A high plasma level of adenosine has been reported in umbilical
vein from preeclampsia compared with normal pregnancies.
Since this nucleoside is mainly involved in the regulation of
vascular tone and angiogenesis, perhaps through the modulation
of potassium channels, it is suggested that it would be involved in
the maintenance of normal fetoplacental function. A potential
adenosine-mediated, NO-dependent mechanism is hypothesized
accounting for the feto-placental reduced blood flow exhibited in
preeclampsia.
ANGIOTENSIN II TYPE I RECEPTOR AGONISTIC
AUTOANTIBODY
 AT1-AA interact with AT1 receptors on trophoblasts which
synergistically act with ANG II to impair placentation
 Normal RAS function and AT1 receptor activation is imperative
for normal placental development. AT1-AA, found in the serum of
preeclamptic women, functions as ANG II by activating AT1
receptors to increase production of sFlt-1, PAI-1 and NADPH
oxidase in trophoblast cells. The 7-AA peptide corresponds to a
sequence on the second extracellular loop of the AT1 receptor.
AT1-AA-mediated effects can be neutralized by 7-AA. AT1-AA:
Angiotensin II type I receptor agonistic autoantibody (AT1-AA).
This autoantibody can induce many key features of the disorder
and upregulate molecules involved in the pathogenesis of
preeclampsia.
POSTNATAL OUTCOME IN OFFSPRING IN OBESITY IN PREGNANCY
 Prepregnancy obesity and excessive gestational weight gain
have been implicated in an intergenerational “vicious cycle”
of obesity, since overweight or obese women give birth to
macrosomic girls, who are more likely to become obese
themselves and deliver large-sized neonates.
 Gestational weight gain and birth weight were directly
associated with the body mass index and the risk of obesity
in adolescence. The relationship described was independent
of parental characteristics, potentially mediating peripartum
factors, child obesogenic behaviour, and weight at birth,
suggesting a role of the intrauterine environment on longterm
offspring weight regulation.
POSTNATAL OUTCOME IN OFFSPRING IN OBESITY IN PREGNANCY
 Interestingly, an association between weight gain of
the mother during pregnancy and increased risk of
greater adiposity in the offspring has been shown
at ages of infancy as early as 7 or 3 years old.
Considering the high prevalence of OP and its
potential association with GDM, there is an
increasing interest in considering a potentially
negative influence of maternal overnutrition and
raised birth weight on the risk of disease in
childhood and adulthood.
POSTNATAL OUTCOME IN OFFSPRING IN OBESITY IN PREGNANCY
 Children of obese women exhibiting increased
risk of diabetes in pregnancy are more likely to
develop insulin resistance later in life.
 Women gaining more than recommended
weight during gestation have been found to be
more prone to have offspring with greater body
mass index, waist, fat mass, leptin, systolic
blood pressure, C-reactive protein, and
interleukin-6 levels, but lower HDL cholesterol
and apolipoprotein A levels than women with a
physiological weight gain.
POSTNATAL OUTCOME IN OFFSPRING IN OBESITY IN PREGNANCY
 Additionally, greater prepregnancy weight was independently
associated with greater offspring adiposity and adverse cardiovascular
risk factors.
 OP increases the incidence of metabolic syndrome in children .
Interestingly, OP is related to neonatal metabolic compromise already
apparent at birth, characterized by reduced insulin sensitivity and
increased serum inflammatory markers. Since OP effect on the
susceptibility to obesity in offspring is apparently independent of GDM,
as obese women with normal blood glucose have babies with increased
adiposity , OP and excessive maternal weight gain during pregnancy are
independent factors leading to increased risk of obesity, insulin
resistance, and early markers of CVD in the offspring.
 All this evidence shifts our attention towards the gestational period as
an extremely key interventional target in the prevention of obesity and
associated consequences such as insulin resistance and cardiovascular
risk.
MECHANISMS OF ADVERSE POSTNATAL OUTCOME
 During normal intrauterine life, maternal insulin does not
cross the placenta, whereas maternal D-glucose is actively
transferred to the fetus. The developing fetal pancreas
responds to a D-glucose load by increasing synthesis and
release of insulin, which acts as a fetal growth hormone.
This is the basic concept of the “Pedersen's
hyperglycaemia-hyperinsulinism hypothesis” (where fetal
overgrowth due to hyperinsulinemia in response to
increased transplacental D-glucose transfer is proposed,
explaining observations showing that offspring of diabetic
mothers exhibit high birth weight.
MECHANISMS OF ADVERSE POSTNATAL OUTCOME
 Maternal overnutrition produces hyperglycaemia,
which leads to increased fetal insulin secretion in a
similar manner as seen in GDM. Thus, secondary
fetal hyperinsulinemia is believed to be involved in
the intrauterine programming of obesity and
diabetes.
 Prospective studies indicate that at birth and at 6
years old the greatest increase in weight to height
relation (relative obesity) was seen in children who
experienced the greatest exposures to insulin in
uterus (as judged by amniotic fluid insulin
concentration) .
MECHANISMS OF ADVERSE POSTNATAL OUTCOME
 Leptin is also implicated in programming
obesity.
 In humans, leptin is increased in OP and
maternal diabetes and is reduced in intrauterine
growth restriction. Although the placental
transfer of leptin has been demonstrated in vivo,
it is believed that umbilical blood level of this
circulating peptide is a marker of neonatal
adiposity more than a relevant modulator of
fetal growth.
MECHANISMS OF ADVERSE POSTNATAL OUTCOME
 Additionally, several inflammatory cytokines
levels are elevated in obese pregnant women ,
changes that are proposed as potential
mediators of metabolic programming.
 Thus, altered metabolic phenotypes, such as
obesity and insulin resistance seen in offspring
in OP, could partially be explained by the
involvement of multiple mediators. Probably, a
multifactorial contribution of nutrient- (e.g., Dglucose,
fatty acids, amino acids) and hormone(e.g.,
insulin, leptin) triggered signals between
the obese mother and the developing fetus
would better describe the involved mechanisms.
Int J Eat Disord. 2016 Mar; 49(3): 276–292.
Changes in hormone levels in anorexia
ANOREXIA NERVOSA AND PREGNANCY
 AN, a state of severe energy deprivation, leads to changes in
many endocrine axes. Which is not functioning as necessary, is
 (1) energy conservation (through suppression of the
hypothalamic-pituitary-gonadal axis, thus avoiding energy
utilization in activities such as procreation)
 (2) activation of pathways that
 (a) cause an increase in energy intake (though an increase in
appetite stimulating hormones and a decrease in appetite
inhibiting hormones), or
 (b) mobilize substrates to increase energy availability for vital
functions (such as through activation of the glycogenolytic and
lipolytic pathways by cortisol and growth hormone respectively).
ANOREXIA NERVOSA AND PREGNANCY
 Hypothalamic-Pituitary-gonadal (HPG)
Axis
 The state of low energy availability in AN
has an inhibitory effect on the HPG axis,
resulting in varying degrees of menstrual
dysfunction, the most extreme being a state
of amenorrhea.
 Hypogonadism leads to low levels of the
gonadal steroids, estrogen and testosterone.
Front Neurosci. 2016; 10: 256
PATHOPHYSIOLOGY OF AN
 An integral pathophysiological scenario that fits to the natural
history of AN with the following steps an be porposed:
 (1) enhanced vulnerability to stress (genetic, epigenetic, or
environmental factors);
 (2) major stressing events activating the stress-axis, increased
intestinal permeability, and increased virulence of the microbiota;
 (3) bacterial proteins (e.g., ClpB) challenge the immune response
and due to molecular mimicry, cause increased production of Igs
cross-reactive with neuropeptides (e.g., α-MSH);
 (4) this results in altered food intake, anxiety, gastrointestinal
discomfort and other consequences of altered central and
peripheral melanocortin signaling;
 (5) global malnutrition and some specific macro- and micronutrient
deficiencies contribute to the perpetuation of gut barrier
and immune dysfunction as well as behavioral symptoms.
Front Neurosci. 2016; 10: 256
OREXIGENIC NEUROPEPTIDES
 Orexigenic neuropeptides including ghrelin, orexins
and 26RFa are up-regulated in AN and it is thought
that this orexigenic profile reflects an adaptive
mechanism of the organism to promote food intake
and thus to counteract undernutrition. However, this
adaptive mechanism is ineffective in increasing food
consumption leading to the concept of a global
resistance of AN patients to orexigenic signals.
 We can speculate that a chronic increase of the
activity of LHA orexigenic neurons expressing
orexins, MCH, or 26RFa could reinforce dopamineinduced
anxiety in the reward system of AN patients
and thus the aversion to ingest food.
Front Neurosci. 2016; 10: 256
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