development and ageing Flashcards
1
Q
how is development related to cancer?
A
usual processes: proliferation, apoptosis, migration, responsiveness to local signals and neighbouring cells
unrestrained processes underpin cancer pathophysiology
2
Q
how is development related to common/ chronic diseases?
A
potential opportunities for tissue repair
3
Q
what is the Barker hypothesis?
A
impact of the uterine environment ‘programmes’ foetus for postnatal life
e.g. low birth weight or premature birth associated with risk of cardiovascular disease in adulthood
4
Q
what are some stressors that affect the uterine environment?
A
endocrine (cortisol)
nutritional (e.g. high fat low protein)
extrinsic toxicants (e.g. smoking)
5
Q
how do stressors in the uterine environment affect health across the life course?
A
epigenetic modification – heritable changes to the DNA which do not alter the sequence of bases (i.e. genes are switched on and off)
6
Q
how is child development charted (0-5 years)?
A
gross motor control
fine motor control
cognitive development
language development
social and emotional development
7
Q
where does fertilisation occur?
A
fallopian tube
8
Q
what does fertilisation trigger?
A
cortical reaction
9
Q
what does the release of molecules from cortical granules cause?
A
degrade Zona Pellucida (e.g. ZP2 and 3)
therefore prevents further sperm binding (no receptors)
10
Q
how does the conceptus develop?
A
continues to divide as it moves down fallopian tube to uterus (3-4 days)
receives nutrients from uterine secretions
free-living phase can last for 9-10 days
11
Q
what is the attachment phase of implantation?
A
outer trophoblast cells contact uterine surface epithelium
12
Q
what is the decidualisation phase of implantation?
A
changes in underlying uterine stromal tissue within a few hours of attachment phase
13
Q
what hormonal change does implantation require?
A
progesterone domination in the presence of oestrogen
14
Q
what is the function of leukaemia inhibitory factor (LIF) (and interleukin-11 (IL11)) in the attachment phase of implantation?
A
stimulates adhesion of blastocyst to endometrial cells
15
Q
where are leukaemia inhibitory factor (LIF) and interleukin-11 (IL11) released from?
A
endometrial cells
16
Q
what endometrial changes occur due to progesterone during the decidualisation phase of implantation?
A
glandular epithelial secretion
glycogen accumulation in stromal cell cytoplasm
growth of capillaries
increased vascular permeability (leads to oedema)
17
Q
what factors are involved in the decidualisation phase of implantation?
A
interleukin-11 (IL11)
histamine
certain prostaglandins
TGFb (promotes angiogenesis)
18
Q
how is time divided in embryo-foetal development?
A
fertilisation/conceptual age
gestational age
carnegie stage
19
Q
when is fertilisation/conceptual age measured from?
A
time of fertilization (assumed to be +1 day from last ovulation)
difficult to know time of fertilization exactly (unless IVF)
20
Q
when is gestational age calculated from?
A
beginning of last menstrual period (LMP)
determined by fertilization date (+14 days) if known, or early obstetric ultrasound and comparison to embryo size charts
21
Q
how is the carnegie stage divided up?
A
23 stages of embryo development based on embryo features not time
22
Q
what does the carnegie stage allow?
A
comparison of developmental rates between species
23
Q
how long is the carnegie stage?
A
0-60 days fertilization age in humans
24
Q
what 2 stages of embryo-foetal development make up the first trimester of pregnancy?
A
embryogenic stage
embryonic stage
25
how long does the embryogenic stage last?
14-16 days post-fertilization
26
what happens during the embryogenic stage?
establishing the early embryo from the fertilized oocyte
determining two populations of cells:
- pluripotent embryonic cells
- extraembryonic cells
27
what do pluripotent embryonic cells contribute to?
foetus
28
what do extraembryonic cells contribute to?
support structures (e.g. placenta)
29
how long does the embryonic stage last?
16-50 days post-fertilisation
30
what 2 things happen during the embryonic stage?
establishment of the germ layers and differentiation of tissue types
establishment of the body plan
31
what stage of embryo-foetal development makes up the second and third trimester of pregnancy?
foetal stage
32
how long does the foetal stage last?
~8 - ~38 weeks
33
what happens during the foetal stage?
major organ systems now present
migration of some organ systems to final location
extensive growth and acquisition of foetal viability (survival outside the womb)
34
how does the ovulated oocyte develop after fertilisation?
zygote (1 cell, fertilised)
cleavage stage embryos (2-8 cells)
morula (16+ cells)
blastocyst (200-300 cells)
35
when does maternal-to-zygotic transition happen?
4-8 cell stage
36
what 3 things happen during maternal-to-zygotic transition?
transcription of embryonic genes (zygotic genome activation)
increased protein synthesis
organelle maturation
(mitochondria, Golgi)
37
what does the embryo depend on during the first divisions?
maternal mRNAs and proteins synthesized and stored during oocyte development (i.e. pre-ovulation)
38
what can impair embryonic development (impacts first divisions specifically)?
failure to synthesise, store or interpret maternal mRNAs and proteins during oogenesis
39
what starts the formation of the first two cell types?
compaction
40
what 5 changes occur during the 8 cell stage or later?
outer cells become pressed against zona (compaction)
change from spherical to wedge-shaped
outer cells connect to each other through tight gap junctions and desmosomes
forms barrier to diffusion between inner and outer embryo
outer cells become polarised
41
what are the 2 distinct cell populations in a compacted morula?
inner
outer
42
how are the inner and outer cells of the morula change over time?
reorganisation with formation of blastocoel cavity (blastocyst)
43
what is the zona pellucida?
hard protein shell inhibiting polyspermy
protects early embryo
44
what is the blastocoel?
fluid-filled cavity formed
osmotically by
trophoblast pumping
Na+ ions into cavity
45
what makes up the inner cell mass of a blastocyst?
pluripotent embryonic cells (contribute to final organism)
46
what is the trophoectoderm?
(outer cells)
extra-embryonic cells (contribute to extraembryonic structures that support development)
47
what process must occur for implantation to take place?
hatching (day 5-6)
blastocyst must escape zona pellucida
48
how does hatching occur for the blastocyst to escape the zona pellucida?
enzymatic digestion
cellular contractions
49
what 2 lineages are produced from the inner cell mass of the blastocyst during peri-implantation events (day 7-9)?
epiblast (from which the foetal tissues will be derived)
hypoblast (forms yolk sac - extraembryonic structure)
50
what 2 lineages are produced from the trophoectoderm of the blastocyst during peri-implantation events (day 7-9)?
cytotrophoblast
syncitiotrophoblast
51
why do cytotrophoblast cells remain individual?
provide source of syncitiotrophoblast cells
52
how does the separation of the trophoectoderm aid implantation?
trophoblast cells fuse to form syncitiotrophoblast
syncitiotrophoblast invasion destroys local maternal cells in endometrium
creates interface between embryo and maternal blood supply
53
what is the final stage before gastrulation?
bilaminar embryonic disc formation
54
what hormone is secreted by syncitiotrophoblasts?
hCG
| detection of beta hCG subunit in blood/urine is basis of pregnancy testing
55
how is the bilaminar embryonic disc formed?
some cells become separated from the epiblast by the formation of a new cavity (amniotic cavity)
two-layer disc of epiblast and hypoblast remains sandwiched between cavities (blastocoel and amniotic cavity)
56
what do amnion cells contribute to?
extra-embryonic membranes
57
what is gastrulation (day 15-16)?
bilaminar embryonic disc reorganised to form trilaminar disc
layers formed are precursors to foetus organs
58
what occurs during gastrulation?
thickened structure forms along midline of epiblast near caudal end of bilaminar embryonic disc (primitive streak)
primitive streak expands at cranial end to create primitive node containing circular depression (primitive pit)
primitive pit continues along primitive streak towards caudal end to form primitive groove
cells from epiblast migrate inwards towards primitive streak, detach and slip beneath into interior of embryo (invagination)
invaginating cells invade hypoblast and eventually fully displace cells - forms definitive endoderm
remaining epiblast cells = ectoderm (most distal layer)
invaginated epiblast cells remain in between endoderm and ectoderm (forms mesoderm)
epiblast cells no longer migrate towards primitive streak
59
what does the primitive streak define?
cranial and caudal ends
left and right sides of embryo
60
which direction does gastrulation occur in?
cranial to caudal end
61
which organs are formed from the endoderm?
GI tract
liver
pancreas
lung
thyroid
62
which organs are formed from the ectoderm?
CNS and neural crest
skin epithelia
tooth enamel
63
which organs are formed from the mesoderm?
blood (endothelial cells, red and white blood cells)
muscle (smooth, skeletal and cardiac)
gonads, kidneys and adrenal cortex
bone, cartilage
64
what is the function of the notochord?
acts as a key organizing centre for neurulation and mesoderm development
65
what is the notochord?
rod-like tube structure formed of cartilage-like cells
forms along the embryo midline, under the ectoderm (opposite direction to primitive streak)
66
what occurs during neurulation?
notochord signals direct neural plate ectoderm to invaginate forming neural groove
creates two ridges (neural folds) running along cranio-caudal axis
neural crest cells specified in neural folds
neural folds move together over neural groove, fuse to form hollow tube
neural tube overlaid with epidermis (ectoderm)
migration of neural crest cells from folds
neural tube closure
- head end day 23 (closure at head end precedes formation of brain structures)
- tail end day 27
67
what is anencephaly?
absence of most of the skull and brain
68
what causes anencephaly?
failure of neural tube closure at head end
69
what is spina bifida?
open neural tube at birth (usually lower spine - failure to close neural tube at tail end))
70
what is neurulation?
formation of neural tube and CNS
71
how do neural crest cells contribute to development?
ectoderm-derived
plastic and migrate extensively during development to form various structures
72
what structures are formed from cranial neural crest cells?
cranial neurones
glia
lower jaw
middle ear bones (ossicles)
facial cartilage
73
what structures are formed from cardiac neural crest cells?
aortic arch/pulmonary artery septum
large artery wall musculoconnective tissue
74
what structures are formed from trunk neural crest cells?
dorsal root ganglia
sympathetic ganglia
adrenal medulla
aortic nerve clusters
melanocytes
75
what structures are formed from vagral and sacral neural crest cells?
parasympathetic ganglia
enteric nervous system ganglia
76
what are some defects that can arise as a result of neural crest migration/specification defects?
pigmentation disorders
deafness
cardiac defects
facial defects
failure to innervate gut
77
what is somitogenesis?
segmentation of body axis
formation of somites
78
what are somites?
arise from paired blocks of paraxial mesoderm flanking the neural tube and notochord
79
what occurs during somitogenesis?
blocks of paraxial mesoderm condense and bud off in somite pairs (one of each pair either side of the neural tube)
rate of ‘budding’ or appearance of somite pairs is species-specific, as is the number of pairs
(humans 1 pair/90 min, 44 pairs)
80
what direction does somitogenesis take place in?
commences at the head end
progresses down the long axis of the embryo
81
what are the 2 forms of embryonic tissue initially derived from somites?
sclerotome
dermomyotome
82
what does the sclerotome give rise to?
vertebrae, rib cartilage
83
the dermomyotome is subdivided into what 2 forms of embryonic tissue?
dermatome
myotome
84
what does the dermatome give rise to?
dermis of the skin
some fat
connective tissues of neck and trunk
85
what does the myotome give rise to?
muscles of the embryo
86
what 2 types of folding in the embryo give rise to the primitive gut (day 16+)?
ventral folding (head and tail ends curl together)
lateral folding (2 sides of embryo roll)
87
how does folding form the primitive gut?
pinches off part of yolk sac to form primitive gut
patterned into foregut, midgut and hindgut
88
what structures are derived from the foregut?
oesophagus
stomach
upper duodenum
liver
gallbladder
pancreas
89
what structures are derived from the midgut?
lower duodenum and remainder of small intestine
ascending colon
first two-thirds of transverse colon
90
what structures are derived from the hindgut?
last third of the transverse colon
descending colon
rectum and upper anal canal
91
what are the notable stages of the development of the heart?
begins as tube of mesoderm (~ day 19)
beating and pumping blood commences ~ day 22
foetal heartbeat detectable from ~6 weeks gestational age
92
what are the notable stages of the development of the lungs?
arise from the lung bud, and endodermal structure adjacent to the foregut (4th week of development)
lung bud splits into two at the end of the 4th week, progressively branches through development
93
what are the notable stages of the development of the gonads in XY embryos?
forms from mesoderm as bipotential (i.e. not committed to testis or ovary) structures known as gonadal/genital ridges
presence of SRY gene on Y chromosome directs gonadal cells to become Sertoli cells
triggers testis development, Leydig cell formation and testosterone production
94
what are the notable stages of the development of the gonads in XX embryos?
forms from mesoderm as bipotential (i.e. not committed to testis or ovary) structures known as gonadal/genital ridges
absence of SRY leads to gonadal cells adopting a granulosa cell fate and ovary development
requires reinforcement by FOXL2
95
what is likely to be the major driver of early pregnancy loss?
aneuploidy
exponential increase in risk of trisomic pregnancy with increasing maternal age
96
why does increasing maternal age increase risk of miscarriage?
loss of cohesion between homologous chromosomes in oocyte with increasing age
loss of proteins (cohesins) holding homologues together
97
how is recurrent miscarriage defined?
loss of 3+ consecutive pregnancies
98
how is recurrent implantation failure defined?
3 failed IVF attempts with good quality embryos
99
what is the key difference between recurrent miscarriage and recurrent implantation failure?
failure to implant or sustain pregnancy by natural conception vs. failure of transferred embryo to implant/sustain pregnancy (RIF)
100
what is the initial diagnostic approach for recurrent miscarriage and recurrent implementation failure?
check for uterine anatomical defects or presence of fibroids/polyps that might disrupt implantation
determine presence of auto-immune antibodies (anti-nuclear, anti-phospholipid antibodies)
test for paternal DNA sperm integrity/fragmentation?
101
what signalling pathways may underpin recurrent miscarriage or recurrent implementation failure?
LIF - leukaemia inhibitory factor (cytokine) promotes decidualisation of human endometrial stromal cells in culture
normal embryo development but failed implantation in LIF-deficient mouse models
reduced LIF in uterine secretions of subfertile women
102
what is endometrial scratching?
use of pipette or hysteroscope to damage endometrial mucosa before embryo transfer in IVF
103
what is thought to be the benefit of endometrial scratching?
thought to stimulate immune cell infiltration and wound healing cytokine production
104
is endometrial scratching effective?
some studies suggest no benefit
possible benefit in selected group (e.g. recurrent implementation failure)
105
what are some adaptations of the fallopian tube that aid function?
smooth muscle – contractions drive embryo along fallopian tube
epithelium coated in cilia (microvilli) -promote fluid movement
106
how does smoking impact the fallopian tube and therefore pregnancy?
cotinine (component of cigarette smoke) regulates PROKR1 expression - regulator of fallopian tube smooth muscle contractility
cotinine increases expression of pro-apoptotic proteins in fallopian tube explants
tobacco smoke inhibits ciliary function - reducing transit of the embryo through the tube
increased risk for tubal pregnancy in smokers
107
how does cannabis impact the fallopian tube and therefore pregnancy?
fallopian tube expresses CB1 and CB2 cannabinoid receptors
CB1 reduced in ectopic pregnancy patients, and CB1 KO in mice causes embryo retention in the fallopian tubes
levels of endocannabinoids elevated in ectopic pregnancy fallopian tubes
some components (e.g. THC) disrupt embryo environment by acting directly on the fallopian tube to:
- perturb transit
- alter balance of endocannabinoids (‘endocannabinoid tone’)
108
what is foetal growth acceleration associated with?
changes in support
| growth relatively limited during 1st trimester, increases after 2nd trimester
109
what kind of support is present during the first trimester/early embryo?
histiotrophic
reliant on uterine gland secretions and breakdown of endometrial tissues
110
what kind of support begins at the beginning of the 2nd trimester?
haemotrophic
achieved in humans through a haemochorial-type placenta - maternal blood directly contacts the foetal membranes
111
what are the 2 key foetal membranes that lead to formation of the placenta?
chorion
amnion
112
what is the connecting stalk?
links developing embryo unit to the chorion
113
what are the trophoblastic lacunae?
large spaces filled with maternal blood
114
how are trophoblastic lacunae formed?
breakdown of maternal capillaries and uterine glands
115
what do trophoblastic lacunae develop into?
intervillous spaces
aka maternal blood spaces
116
what are the foetal membranes?
extraembryonic tissues
form tough, flexible sac encapsulating foetus
forms basis of the maternal-foetal interface
117
what is the function of the amnion?
arises from epiblast (does not contribute to foetal tissues)
forms closed, avascular sac with the developing embryo at one end
begins to secrete amniotic fluid from 5th week – forms a fluid filled sac to encapsulate and protect foetus
118
what is the function of the chorion?
formed from yolk sac derivatives and the trophoblast
highly vascularized
gives rise to chorionic villi – outgrowths of cytotrophoblast from the chorion that form the basis of the foetal side of the placenta
119
what is the allantois?
grows along the connecting stalk from embryo to chorion
becomes coated in mesoderm, vascularizes to form umbilical cord
120
how is the amniotic sac formed?
expansion of the amniotic sac by fluid accumulation forces the amnion into contact with the chorion, which fuse, forming the amniotic sac
2 layers; amnion inside, chorion outside
121
what are the primary chorionic villi?
```
cytotrophoblast forms
finger-like projections
through
syncitiotrophoblast layer
into maternal
endometrium (surface area for exchange)
```
undergo branching
122
what occurs during the primary phase of chorionic villi development?
outgrowth of the cytotrophoblast
branching of these extensions
123
what occurs during the secondary phase of chorionic villi development?
growth of foetal mesoderm into the primary villi
124
what occurs during the tertiary phase of chorionic villi development?
growth of the umbilical artery and umbilical vein into the villus mesoderm, providing vasculature
125
how can terminal villus microstructure be described?
convoluted knot of vessels and vessel dilation
structure coated with trophoblast
126
how does terminal villus microstructure change between early and late pregnancy?
early pregnancy: wider diameter, more trophoblast thickness between capillaries and maternal blood
late pregnancy: villi thin, vessels move within villi to leave minimal trophoblast separation from maternal blood
127
how does maternal blood supply to the endometrium develop?
uterine artery branches give rise to a network of arcuate arteries
arcuate arteries branch into radial arteries
radial arteries branch further to form basal arteries
basal arteries form spiral arteries during menstrual cycle endometrial thickening
128
how does implantation affect spiral arteries?
spiral arteries stabilised
provide maternal blood supply to foetus
129
how does lack of implantation affect spiral arteries?
loss of endometrium
regression of spiral arteries
130
when happens to spiral arteries during implantation and placental development?
extensive remodelling
131
how are spiral arteries remodelled during implantation and placental development?
extra-villus trophoblast (EVT) cells coating villi invade down into the maternal spiral arteries
outgrowth of trophoblast - grow into spiral arteries
forms endovascular EVT
132
what is the role of endovascular EVT (extra-villus trophoblast)?
replace maternal endothelium of blood vessels
133
how does endovascular EVT (extra-villus trophoblast) form a new endothelial layer (conversion)?
breaks down maternal endothelium and underlying smooth muscle
134
why is conversion important during placental development?
replacement of endothelium causes conversion of spiral arteries into relatively straight arteries
results in low pressure, high capacity conduit for maternal blood flow
135
what conditions may conversion underly?
pre-eclampsia
uterine growth retardation
136
how can the structure of the placenta be described?
maternal unit - maternal arteries give rise to spiral arteries, supply intervillous spaces (lacunae) with blood (some drained through venous system)
foetal unit - formation of chorionic villi, trophoblast invades branch and become vascularised
invasion of foetal circulatory system into chorionic villi provides surface for exchange
137
what are the 3 different ways that substances cross the placenta?
simple diffusion
facilitated diffusion (through formation of concentration gradients or via transporter proteins)
active transport (blood flow or energy dependent co-transporters)
138
how does oxygen cross the placenta?
simple diffusion - high maternal oxygen tension and low foetal oxygen tension causes diffusional gradient
139
how does glucose cross the placenta?
facilitated diffusion - via transporters on maternal side and foetal trophoblast cells
140
how does water cross the placenta?
majority via diffusion
some local hydrostatic gradients
(placenta is main site of exchange but some crosses amnion-chorion)
141
how do electrolytes cross the placenta?
large traffic of sodium and other electrolytes across placenta
combination of diffusion and active energy-dependent co-transport
142
how does calcium cross the placenta?
active transport against concentration gradient by magnesium ATPase calcium pump
143
how do amino acids cross the placenta?
reduced urea excretion as pregnancy progresses
active transport of amino acids across placenta
144
what physiological changes occur maternally in maternal-foetal oxygen exchange?
cardiac output increases 30% during first trimester (increased rate and stroke volume)
peripheral resistance decreases up to 30%
blood volume increases to 40% near term - increase in erythrocytes, increased plasma volume (20-30% erythrocytes, 30-60% plasma)
pulmonary ventilation increases 40%
145
what physiological changes occur in the placenta and foetus in maternal-foetal oxygen exchange?
placenta itself consumes 40-60% glucose and oxygen supplied
although foetal oxygen tension is low, oxygen content and saturation are similar to maternal blood.
embryonic and foetal haemoglobins: greater affinity for oxygen than maternal haemoglobin
146
how does the circulatory system act in late foetal development?
placenta acts as site of gas exchange (not lungs)
ventricles act in parallel, not in series (blood driven around same circulatory loop)
147
how can ventricles act in parallel rather than in series during late foetal development?
vascular shunts allow circulatory system to bypass pulmonary and hepatic circulation
permits heart to drive oxygenated blood from placenta around body more efficiently - delivers nutrients and gas supply, especially to the head
shunts close at birth to give standard circulatory system
148
how does the respiratory system act in late foetal development?
lungs begin as a bud around foregut - branches during first trimester to give lung structure
primitive air sacs form around week 20, vascularised from week 28
surfactant produced around week 20 - upregulated towards term
foetus spends 1-4 hours a day making rapid respiratory movements during REM periods
149
why may the foetus spend 1-4 hours a day making rapid respiratory movements during REM periods?
within amniotic sac - lungs are not site of gas exchange
probably practice for breathing reflex once leaving the uterus
may be important for diaphragm development
150
how does the gastrointestinal system act in late foetal development?
gut tube formed in early embryo development from endoderm and some contribution from yolk sac
second trimester - functional endocrine pancreas, secretes insulin from mid pregnancy
liver progressively develops, glycogen progressively deposited (accelerates towards term)
151
how is the first stool after birth (meconium) produced?
foetus inhales and swallows large amounts of amniotic fluid in utero
debris from fluid, bile acids and cells sloughing from inside of developing intestine form the meconium
152
how does the nervous system act in late foetal development?
movements begin late in first trimester, detectable by mother from ~week 14
stress responses present from week 18 but thalamus-cortex connections only present from week 24 (sensory inputs probably only processed from mid-pregnancy onwards)
no conscious wakefulness - mostly in slow-wave or REM sleep
153
how is organ maturation co-ordinated?
increase in foetal corticosteroid towards end of pregnancy
triggers production of surfactant from lungs, deposition of liver glycogen etc. (increases in parallel with corticosteroid)
154
what are the 3 aims of labour?
safe expulsion of foetus at correct time
expulsion of placenta and foetal membranes (empty for future reproductive events)
uterus has gone through extensive tissue remodelling and distension - resolution and healing period needed to ensure uterus is suitable for future pregnancy
155
what are the 2 characteristics of a pro-inflammatory reaction that can be seen in labour?
immune cell infiltration into tissues of reproductive tract
inflammatory cytokine and prostaglandin secretion (probably to orchestrate timing and sequence of events during labour)
156
what occurs during the first phase of labour? (quiescence)
prelude to parturition
uterus not contracting but some cervical changes (cervical softening)
late first trimester onwards
157
what occurs during the second phase of labour? (activation)
preparation for labour
preparing uterus for labour, cervical ripening (ready to dilate to allow delivery)
158
what occurs during the third phase of labour? (stimulation)
processes of labour
3 stages: uterine contraction, cervical dilation, expulsion of foetus and placenta
159
what occurs during the fourth phase of labour? (involution)
parturient recovery
restoration of uterus to original size (involution), cervical repair, onset of lactation
160
what happens during the first stage of labour (during stimulation)?
contractions begin, cervical dilation
latent phase - slow dilation of cervix to 2-3 cm
active phase - rapid dilation of cervix to 10cm
161
what happens during the second stage of labour (during stimulation)?
delivery of foetus
begins at full dilation of cervix (10cm)
intense and frequent myometrial contractions
162
what happens during the third stage of labour (during stimulation)?
delivery of placenta
expulsion of placenta and foetal membranes
allows onset of postpartum repair
163
how long is the entire delivery process?
8-18 hours (first delivery)
5-12 hours (subsequent deliveries)
0-8 hrs - latent stage 1
8-14 hrs - active stage 1 (equal parts acceleration, maximum slope and deceleration)
14-16 hrs - stage 2
16+ hrs - stage 3
164
what is the role of the cervix during pregancy?
retains foetus within uterus
165
what features of the cervix allow it to carry out its function?
high connective tissue content
keeps cervix closed - provides rigidity, stretch resistant
properties caused by collagen fibres embedded in proteoglycan matrix - changes to collagen bundle underlie softening (exact mechanism unclear)
166
what happens during the first phase of cervical remodelling? (softening)
begins in first trimester
changes in compliance (less stretch resistant)
retains cervical competence (cervix remains closed, keeps foetus inside uterus)
167
what happens during the second phase of cervical remodelling? (ripening)
weeks and days before birth
monocyte infiltration, IL-6 and IL-8 secretion
extensive immune cell infiltration of cervix (macrophages, neutrophils)
hyaluron deposition
168
what happens during the third phase of cervical remodelling? (dilation)
increased elasticity (cervix needs to open up to allow transit of foetus)
increased hyaluronidase expression - breaks down hyaluron (deposited during ripening phase)
influx of immune cells leads to production of matrix metalloproteinases (collagen breakdown, allows increased tissue elasticity)
169
what happens during the fourth phase of cervical remodelling? (post-partum repair)
recovery of tissue integrity and competency
170
how does the foetus determine the time of parturition according to current thinking?
changes in foetal HPA axis
corticotrophin-releasing hormone (CRH) levels rise exponentially towards end of pregnancy
concomitant decline in CRH binding proteins increases CRH bioavailability
171
what is the function of corticotrophin-releasing hormone (CRH) during labour)?
increased CRH levels act on foetal adrenal cortex - promotes foetal ACTH and cortisol release
increased cortisol drives placental CRH production (positive feedback)
CRH stimulates dehydroepiandrosterone sulphate (DHEAS) production by foetal adrenal cortex - substrate for increased placental oestrogen production
172
how do oestrogen and progesterone change during pregnancy?
both concentrations increase during pregnancy (oestrogen : progesterone ratio may shift in favour of oestrogen in association with onset of labour, unclear)
173
what is the function of progesterone in pregnancy?
maintains pregnancy
maintains uterine relaxation until labour
174
what is progesterone produced by?
placenta
175
how does progesterone signalling change as term approaches?
switch in progesterone receptors
moves from PR-A isoform (activating) expression in uterus to PR-B and PR-C isoforms (repressive)
causes functional progesterone withdrawal
176
what is the effect of functional progesterone withdrawal on oestrogen?
rise in oestrogen receptor expression within uterine tissues
although both progesterone and oestrogen levels stay high, uterus becomes 'blinded' to progesterone action and sensitised to oestrogen action
causes local shift in oestrogen : progesterone ratio in uterine tissue
177
what kind of hormone is oxytocin?
nonapeptide (9aa)
178
where is oxytocin synthesised?
predominantly in pituitary
also mainly in utero-placental tissues
179
what is increased oxytocin release driven by?
sharp increase in uterine oxytocin production at onset of labour
expression promoted by increased oestrogen levels
Ferguson reflex for main production of oxytocin from maternal pituitary
180
what is the Ferguson reflex?
neuroendocrine stretch reflex to promote oxytocin release
stretch receptors in cervix and vagina signal hypothalamus
firing of hypothalamus onto posterior pituitary triggers release of oxytocin from pituitary into maternal circulation
181
by what method does oxytocin signal?
through G-protein coupled oxytocin receptor (OTR/OXTR)
progesterone inhibits OXTR expression pre-labour (for uterus relaxation)
rise in oestrogen near term promotes increased OXTR expression
182
what are the functions of oxytocin?
increased connectivity of myocytes in myometrium (promotes formation of extensive gap junctions, myometrium can act as syncytium)
destabilise membrane potentials, lower threshold for contraction
enhance liberation of intracellular Ca2+ stores (aid contraction)
183
oxytocin acts in conjunction with what key effectors of labour?
prostaglandins
PGE₂, PGF₂ alpha, PGI₂: primary prostaglandins synthesised during labour
184
how do rising oestrogen levels affect prostaglandins in the uterus?
drives synthesis during labour
increased oestrogen activates phospholipase A2 enzyme, generates arachidonic acid for prostaglandin synthesis
oestrogen stimulation of oxytocin receptor (OXTR) expression promotes some prostaglandin release through oxytocin signalling
185
what is the primary function of PGE₂ during pregnancy?
cervix remodelling
promotes leukocyte infiltration into cervix, IL-8 release - allows remodelling of collagen bundles and therefore cervix ripening
186
what is the primary function of PGF₂ alpha during pregnancy?
acts on myometrium to promote contraction
destabilises membrane potential, promotes connectivity of myocytes (with oxytocin)
187
what is the primary function of PGI₂ during pregnancy?
acts on myometrium
promotes smooth muscle relaxation, relaxation of lower uterine segment
relaxation allows blood flow into uterus and placenta for foetus
188
what factors (other than prostaglandins) are implicated in cervix remodelling?
peptide hormone relaxin (levels increase sharply towards term)
nitric oxide (NO)
189
how can an integrated hypothesis for the endocrine regulation of labour be described?
production of CRH (corticotrophin releasing hormone) by foetal pituitary acts on foetal adrenal gland to produce cortisol and DHEAS
cortisol transferred to placenta - triggers increased CRH production (positive feedback)
DHEAS converted to oestrogen in placenta
oestrogen acts on myometrium to promote oxytocin receptor expression in uterus (previously inhibited by progesterone)
uterus sensitised to maternal pituitary oxytocin - triggers contraction
oestrogen promotes local production of oxytocin - oxytocin stimulates contraction, promotes placental prostaglandin production
prostaglandins (e.g. PGF₂ alpha) mediate contractions, soften cervix, stimulate placenta to produce more prostaglandins (positive feedback)
(in non-labouring state - prostaglandins inhibit oxytocin receptors to prevent premature contraction - positive feedback)
190
how can the uterus be divided up into functional segments?
fundus (top of uterus) (active)
upper segment (active)
lower segment (passive)
cervix (passive)
191
how do myometrial contractions take place?
myometrial muscle in fundus and upper segment form syncytium (extensive gap junctions) so contractions can be transmitted across whole muscle
contractions start in the fundus, spread down upper segment (active contraction)
lower segment and cervix pulled upwards (passive contraction)
formation of larger, open birth canal
192
what characteristic of myometrial contractions aids formation of the birth canal?
brachystatic contraction - muscle fibres do not return to full length upon relaxation (retain some shortening)
therefore each contraction progressively opens cervix and lower segment more until full dilation
193
what are the stages of foetal delivery?
foetus head engages with pelvic space/cervix 34-38 weeks (final weeks of pregnancy)
onset of labour - myometrial contractions puts pressure on foetus, causing flexion (chin pressed against chest)
foetus rotates (stomach faces mother's spine)
head expelled first after full cervical dilation
sequential delivery of shoulders (upper shoulder first), followed by torso
194
what is the process of placental expulsion?
rapid shrinkage of uterus after foetal delivery causes:
- shrinkage of area of contact between placenta and endometrium
- folding of foetal membranes, causing them to peel off the endometrium
clamping umbilical cord stops foetal blood flow to placenta, causing villi to collapse
haematoma formation between decidua and placenta triggered
myometrial contractions expel placenta and foetal tissues
195
how does uterine repair happen?
uterus remains contracted after placental delivery - facilitates thrombosis and healing of uterine vessels (prevents intrauterine bleeding)
eventual involution of uterus and repair of cervix to restore non-pregnant state
196
why is restoration of the uterus important?
shields uterus from commensal bacteria in reproductive tract
restore endometrial cyclicity in response to hormones (ready to allow future embryo implantation)
197
when does a mother's emotional state have a long lasting effect on a child?
during pregnancy
early postnatal period
(can have as many symptoms of depression and anxiety during pregnancy as postnatally)
198
why may pregnancy cause strain when expecting?
increased domestic abuse
increased relationship strain
199
what is foetal programming?
concept that environment of the womb during different sensitive periods for specific outcomes (e.g. caused by mother's emotional state) affects development of foetus and potentially all the way through to adulthood
200
how can foetal programming be counteracted?
sensitive early mothering
helps attachment
counteracts some of what happens in utero
201
how can the foetal brain be considered "under construction" and how does this continue during its lifetime?
250 000 neurons a minute through gestation
proliferation - 5 weeks gestation to 18 months after birth
(migration, differentiation, synaptogenesis)
neural pruning - continues through puberty
202
what are some types of prenatal stress reportedly associated with increased risk of changes in a child's cognitive development and behaviour?
(not just extreme/toxic stress, diagnosed mental illness)
maternal anxiety and depression
maternal daily hassles
pregnancy specific anxiety
domestic abuse; partner or family discord (lack of support too)
distress caused by war
experience of acute disasters, e.g. freezing ice storm, hurricane or 9/11
203
what are some neurological/emotional conditions for which risk is increased by associated prenatal stress?
increased levels of anxiety, depression
behavioural issues - ADHD, conduct disorder
impaired cognitive development
neonatal behaviour
more difficult infant temperament
victimisation in childhood (are bullied)
schizophrenia (only very severe stress in first trimester)
autism spectrum
personality disorder
204
why may schizophrenia be caused by stress in the first trimester?
altered pattern of migration of neurones during first trimester - gestation period affected
205
what are some physical conditions for which risk is increased by associated prenatal stress?
reduced birthweight and gestational age
preterm delivery
mixed handedness
decreased telomere length (decreased longevity)
asthma
altered immune function
altered microbiome (in meconium)
206
how can we tell that there is a causal relationship between the womb environment and later events (rather than genetic or postnatal factors?
animal studies - research literature shows direct effects, translatable to humans
effects of natural disasters - children all affected (no possibility of genetic transmission, children were all exposed to same event)
studies allow for confounders
underlying mechanisms (investigation)
207
what is an example of a study investigating the effects of the uterine environment?
ALSPAC (Avon Longitudinal Study of Parents and Children)
large prospective birth cohort (~14 000 pregnant women recruited 1990-1991)
complete data obtained n=~7000
208
what did ALSPAC show?
top 15% of most anxious/depressed women in pregnancy - rate of probable mental disorder doubled (6 to 12%) at 13 years
(after multivariate analysis allowing for a wide range of possible confounders)
attributable load of probable mental disorder in whole population due to prenatal anxiety/depression
~10%
209
why are some children affected by womb environment and not others?
gene-environment interactions
different genetic predispositions
- e.g. COMT gene inactivate catecholamines (dopamine, adrenaline, noradrenaline), some COMT variations mean more vulnerability to anxiety in conjunction with womb environment
210
what is the underlying mechanism behind maternal stress affecting uterine environments?
maternal stress, anxiety, mental illness triggers increased levels of cortisol, pro-inflammatory cytokines
transplacental passage of cortisol affects foetus
211
how does the foetus control levels of cortisol received from the mother?
foeto-placental unit rich in placental 11beta-HSD2 enzyme (convers cortisol to cortisone)
(more anxious mothers have lower 11beta-HSD2 expression - significant correlation with state of anxiety, trend with depression)
212
how does stress affect how much cortisol moves from a mother to the foetus?
stress downregulates 11beta-HSD2
more cortisol moves across placenta to foetus
