Development and Ageing Flashcards
state 3 types of prenatal stresses that are associated with increased risk of changes to cognitive development and behaviour in the child?
Anxiety and depression Maternal daily hassles Pregnancy specific anxiety Domestic abuse Distress caused by war Acute disasters eg. hurricane
State 3 different effects on the child of prenatal stress.
- Anxiety and depression
- ADHD, conduct disorder and other behavioural problems
- Impaired cognitive disorder
- Schizophrenia
- Victimisation in childhood
- Autism spectrum
- Personality disorder
- Preterm delivery
What is the effect of 11-βHSD2 release in mother?
Breaks down cortisol in placenta and allows more cortisol to pass to fetus
What patterns are observed in children with increased in utero cortisol?
fMRI studies show: Reduced attention, Increased anxiety
BSID2 - Lower cognitive function
Sensitive early mothering can reverse effects of high in utero cortisol
State 2 other MRI studies and the changes shown for children with increased prenatal stress
- Structural MRI: Thinner cortex ( associated with depression and cognitive problems), Enlarged amygdyla ( associated with increased anxiety)
- Diffusion MRI: Alterations in uncinate fasciculus which connects amygdyla with frontal cortex ( associated with mood disorders and antisocial behaviour)
what is the effect of breastfeeding on child development?
- Exclusive breastfeeding at one month improves, IQ ( 3 points) and hyperactivity at 8 years
- but not emotional problems and conduct disorder after allowing for confounders
How is preeclampsia diagnosed?
New onset hypertension (>140/90) + proteinuria or end organ dysfunction (order LFTS and kidney function tests) after 20th week of pregnancy
what are the symptoms and signs of preeclampsia?
- Reduced fetal movement and or amniotic fluid volume (by ultrasound)
- Oedema common but not discriminatory for PE
- Headache, abdominal pain
- visual disturbances, seizures and breathlessness associated with severe PE
What are the different forms of preeclampsia? distinguish between them
Early onset <34 weeks -> fetal and maternal symptoms, changes in placental structure
Late onset > 34 weeks -> more common, mostly maternal symptoms, no placental changes, less fetal risk
What maternal risk factors may predispose to developing PE?
- Pre-existing hypertension/gestational, diabetes, CKD, autoimmune disorders, age >40, race, BMI >30, PCOS, subfertility,
- family history, previous pregnancy with pre-eclampsia
- multiple pregnancy, first pregnancy, new paternity
- IVF
What are the risks of PE to the fetus and the mother during pregnancy?
- Placental abruption
- coagulopathy, renal failure, pulmonary oedema, uteroplacental insufficiency
- May lead to Eclampsia (PE + seizures), HELLP Syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets).
- Fetal growth restriction, preterm birth, still birth
What structural/developmental changes in the placenta are believed to underpin pre-eclampsia?
Abnormal placenta spiral arteries/reduced conversion -> endothelial dysfunction, vasoconstriction and ischemia
EVT invasion of maternal spiral arteries is limited to decidual layer -> restricted placental perfusion
How might soluble Flt1 (aka soluble VEGF1R) and PLGF contribute to the maternal symptoms of pre-eclampsia?
Increased levels of placental Flt1 trap circulating vascular endothelial growth factor (VEGF), placental growth factor (PLGF) and transforming growth factor β (TGFβ) decreasing their free levels, leading to endothelial dysfunction by preventing their interaction with endothelial cell surface receptors.
describe tests carried out to predict the likelihood of Pre-eclampsia
PLGF <100 pg/ml is abnormal. Increased risk of preterm delivery.
PLGF >100 pg/ml is normal. Unlikely to progress to delivery within 14 days of the test.
sFlt-1/PLGF ratio > 38 = increased risk of preeclampsia
What management options are available for women who develop PE during pregnancy?
- Antihypertensives
- IV magnesium sulfate to prevent seizures.
- Immediate delivery - eclampsia, HELLP syndrome
<34 weeks -> try and maintain pregnancy. Give corticosteroids to promote fetal lung development before delivery
> 37 weeks -> delivery preferable
In between 34-37 -> case by case
Are there preventative measures that can be taken to avoid PE developing?
Weight loss
Exercise throughout pregnancy
Low-dose aspirin from 11-14 weeks for high risk groups
Are there any ongoing risks to the mother after pregnancy with preeclampsia?
Elevated risk of cardiovascular disease, T2DM, renal disease.
Recurrence of PE in next pregnancy
Describe 3 ways in which humans adapt
Homeostasis
Developmental plasticity - changes in neural connections
Selection
What is the Barker hypothesis?
The seeds of most diseases are sown during organogenesis and periods of rapid cell division
Give 2 examples of challenges that a fetus may face in utero that may affect long term health
Infection Maternal malnutrition Maternal illness Maternal medication Environmental factors
State some adult diseases that are affected by foetal programming
Allergic and auto-immune diseases
Cancer
Lung disease
Diabetes type 2
give examples screening tests during or after pregnancy as part of the NHS screening programme
diagram in notes
How is COPD diagnosed?
FEV1/FVC ratio <70%
State some factors that affect FEV in children
More rapid FEV decline - born in winter, smoking mothers
Less rapid FEV decline - day-care attendance, pets
learn common genogram symbols
picture in notes
State 3 ways of measuring embryo-fetal development
Fertilization age
Gestational age
Carnegie Stage - uses 23 stages of embryo development based on embryo features. Covers 0-60 days fertilization
How do you calculate gestational age?
From the start of last menstrual cycle
It is fertilization age + 14
Can take early obstetric ultrasound and compare embryo size to charts
What are the stages in embryo-fetal development (starting with the earliest)?
Embryogenic
Embryonic
Fetal
What happens during the embryogenic stage?
Pluripotent embryonic cells form - contribute to fetus
Extraembryonic cells form - contribute to placenta
What happens during the embryonic stage?
Establishment of germ layers and differentiation of tissue types.
Establishment of body plan
What happens during the fetal stage?
Major organs systems now present
Organ systems can migrate
Growth and acquisition of fetal viability
What makes up the 1st trimester?
Embryogenic and embryonic stages
What makes up the 2nd and 3rd trimesters?
fetal stage
Describe the stages in blastocyst formation from an oocyte
Oocyte -> zygote -> cleavage stage embryos (2-8 cells) -> Morula 16+ cells and compaction of morula -> Blastocyst
What happens during the maternal-to-zygotic transition (4-8 cell stage)
Transcription of embryonic genes (zygotic genome activation)
Increased protein synthesis
Organelle (mitochondria, Golgi) maturation
What happens during compaction?
Outer cells become pressed against zona
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
what is the main goal of compaction?
start the formation of 1st two cell types:
- inner cell mass - gives rise to pluripotent embryonic cells
- trophectoderm - gives rise to extraembryonic cells
The first 2 distinct cell types that can be recognised in the developing embryo are?
inner cell mass and trophectoderm
The fluid filled cavity in the blastocyst is called the ___. It forms because the trophoblast pumps __ into cavity
blastocoel
Na+
___ is the escape of the blastocyst from the zona pellucida. It as achieved through the use of ___ ____ and ___ ____.
Hatching
Enzymatic digestion
Cellular contraction
What separation takes place during peri-implantation?
- Trophoectoderm lineage separates to form syncytiotrophoblast and cytotrophoblast
- Inner cell mass separates into epiblast and and hypoblast
During peri-implantation, ___Invades and destroys maternal cells in the endometrium. It also creates an interface between embryo and maternal blood supply.
Syncytiotrophoblast
___ divides to form syncytiotrophoblasts.
Cytotrophoblast
During peri-implantation, the fetal tissues are derived from ___
epiblast
During peri-implantation __ forms the yolk sac - an extraembryonic structure.
hypoblast
What happens during bilaminar embryonic disc formation? (day 12+)
Epiblast cells become separated in two by the formation of a new cavity – the amniotic cavity.
The cells above the amniotic cavity - amnion cells will contribute to the extra-embryonic membranes.
This leaves a two-layer disc of epiblast and hypoblast, sandwiched between cavities.
Embryo is now ready for gastrulation
Syncytiotrophoblast starts secreting hCG
What subunit in hCG in blood/urine is detected during pregnancy?
beta
What is gastrulation?
The process whereby the bilaminar embryonic disc undergoes reorganization to form a trilaminar disc. Three primary germ layers form.
How do the 3 germ layers form in gastrulation?
Primitive streak forms in epiblast -> primitive groove -> invagination of cells into primitive streak -> hypoblast cells replaced by definitive endoderm -> remaining cells of epiblast now called ectoderm (exterior layer) -> some of the invaginated epiblast cells remain in space between ectoderm and endoderm and form mesoderm
What defines the head-tail and left-right axes of an embryo?
Primitive streak formation
draw a diagram showing the separation of embryonic cell lineages from morula all the way to 3 germ layers
(refer to notes for answer)
what structures does the ectoderm give rise to?
external body systems + nervous system
- CNS and neural crest
- Skin epithelia (epidermis)
- tooth enamel
what structures does the mesoderm give rise to?
Things between digestive system and skin:
- circulatory system - blood
- MSK - muscle, bone, cartilage, connective issue
- dermis
And also gonads, kidneys and adrenal cortex.
what structures give rise to the endoderm?
Digestive system + systems budding off:
- Gi tract
- Liver, pancreas
- lungs
- thyroid
what is a notochord?
A tube structure elongating from primitive streak. It forms along the embryo midline, under the ectoderm.
function of notochord?
Organizing centre for neurulation and mesoderm development
How does the notochord direct neurulation?
Uses signals to direct neural plate (thickened ectoderm) to form neural tube
How specifically does the neural tube form?
Notochord sends signals directing neural plate to invaginate forming neural groove. Two ridges are created on the sides (neural folds)
Neural folds contain neural crest cells
Neural folds migrate and fuse over neural groove -> neural tube
In order for brain structures to develop, __ of neural tube at head end must occur
closure
State 2 developmental defects resulting from neural tube closure
Anencephaly - failure to close at head end
Spina bifida - usually lower spine due to failure to close tail end
State 4 different types of neural crest cells
Cranial NC
Cardiac NC
Trunk NC
Vagal & Sacral NC
State 3 types of defects of neural crest migration/specification
Pigmentation disorders
Deafness
Cardiac and facial defects
Failure to innervate gut
what is somitogenesis?
Paired Blocks of MESODERM condense and bud off and subsequently differentiate into sclerotome and dermomyotome
Form form head -> tail
What 2 types of embryonic tissue do somites give rise to?
- Sclerotome - form vertebrae and rib cartilage
- Dermomyotome which divides into:
- Dermatome - gives dermis of skin, some fat and connective tissues to neck and trunk
- Myotome
How does the gut tube form?
Ventral and lateral folding -> pinches off part of the yolk sac
The gonads form from ___ as bipotential. In XY embryos, the presence of SRY gene on Y chromosome directs gonadal cells to become ___ cells.
Mesoderm
Sertoli
using arrows, draw out the sequence of events from fertilisation to week 8
Fertilization -> morula -> blastocyst (blastocyst sticks at day SIX) -> bilaminar disc (epiblast & hypoblast) in week 2 -> primitive streak-> gastrulation (3 layers forming in week 3 -> germ layers -> neural tube forms and closes by week 4. organogenesis
What fraction of fertilised eggs are estimated to spontaneously miscarry in the early stages of pregnancy? What proportion of pregnancies are lost after a pregnancy has been biochemically confirmed?
~40% before implantation/pregnancy detection
Loss after clinically determined pregnancy 10%
Total loss between fertilization and birth between 46%-90%
What is likely to be the major contributor to pregnancy loss before 12 weeks’ gestation?
Chromosomal errors in embryo/aneuploidy
How does maternal age affect the chance of miscarriage? what are the molecular mechanisms that underpin this?
loss of cohesin proteins holding homologous chromsomes in oocytes together with increasing age
What are recurrent miscarriage and recurrent implantation failure and what is the key difference between them?
What potential common/overlapping causes would you explore in the first instance for patients experiencing these conditions?
Recurrent miscarriage = loss of three or more consecutive pregnancies by natural pregnancies
Recurrent implantation failure = women have had 3 failed IVF attempts with good quality embryos
Overlapping causes - uterine anatomical defects (fibroids/polyps), paternal DNA sperm integrity/fragmentation,
auto-immune antibodies (anti-nuclear, anti-phospholipid antibodies)
what signalling pathway(s) might underpin recurrent miscarriage or RIF?
Reduced LIF (Leukemia inhibitory factor) in the uterine secretions of subfertile women.
LIF promotes decidualization of human endometrial stromal cells in culture
LIF promotes adhesion of blastocyst to endometrial cells
What is endometrial scratching and how might it help a patient experiencing RIF?
Use of pipette or hysteroscope to damage endometrial mucosa before embryo transfer in IVF
It may stimulate immune cell infiltration and wound healing cytokine production - unsure if it works
Histologically, how is the fallopian tube adapted to support transit of the fertilised embryo to the uterus?
Smooth muscle - contractions drive embryo along the fallopian tube
Epithelium coated in cilia(microvilli) to promote fluid movement
why might cigarette smoking increases the risk of ectopic pregnancy?
Continine - a component of cigarette smoke regulates expression of PROKR1 (a regulator of fallopian tube smooth muscle contraction)
Continine also increases expression of pro-apoptotic proteins in fallopian tube explants
Tobacco smoke also likely to inhibit ciliary function - reducing transit of embryo through tube
Cannabis use is also believed to elevate the risk of ectopic pregnancy. what is the described mechanism?
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
Components such as THC in cannabis may act directly on the fallopian tube to perturb transit, or alter the balance of endocannabinoids in the tube leading to a disrupted embryo environment.
Early embryo nutrition is ___. There is a switch to _ support at the start of the 2nd trimester.
Histiotrophic (breakdown of endometrial tissues by syncytiotrophoblast, breakdown of maternal capillaries, uterine gland secretions)
Haemotrophic
Humans have what type of placenta?
Haemochorial-type
When the fetal membranes are created, what other structures then develop?
connecting stalk, trophoblastic lacunae(maternal blood will flow through)
The amnion is the _ fetal membrane and arises from the _
Inner
Epiblast
The chorion is the ___ fetal membrane. It is derived from the __ __ and ___. Unlike the amnion it is highly ___. It gives rise to __ ___ which are outgrowths of cytotrophoblast that form the basis of the fetal side of the placenta.
Outer Yolk sac Trophoblast Vascularised Chorionic villi
What forms the amniotic sac?
Fusion of amnion and chorion due to accumulation of amniotic fluid
Like the chorion, the ___ is another fetal membrane derived from yolk sac. It grows along the connecting stalk and forms the __ ___.
Allantois
Umbilical cord
What are the 3 phases of chorionic villi development?
Primary - outgrowth of cytotrophoblasts from chorion to form finger-like projections
Secondary - mesoderm cells invade into the cytotrophoblasts /primary villi
Tertiary - Growth of blood vessels from umbilical artery and vein into villus to provide blood supply
What slows blood flow enabling exchange between maternal and fetal blood?
Convoluted knot of vessels and vessel dilation in chorionic villi
What coats the vessels in chorionic villi?
Trophoblast
Describe the maternal blood supply to the endometrium and its branches
Ovarian artery-> uterine artery -> arcuate artery -> radial artery -> basal artery -> spiral artery
When do maternal spiral arteries form?
During menstrual cycle and endometrial thickening
How does the endovascular EVT form? What is the process called?
EVT cells coating the villi invade into maternal spiral arteries
Conversion - from high pressure spiral arteries to low pressure arteries with increased capacity
How do amino acids reach the fetus?
Reduced excretion of maternal urea and active transport of amino acids to fetus
State 2 differences in circulatory system of fetus vs adult
Placenta acts as a site of gas exchange for fetus not lungs
Ventricles act in parallel rather than series (vascular shunts bypass pulmonary & hepatic circulation-> close at birth)
what is the meconium?
First stool - formed from debris (from swallowed amniotic fluid) and bile acids
What coordinates organ maturation in the fetus?
Fetal cortico-steroids
Give two pieces of evidence to show that pregnancy is a pro-inflammatory reaction
Immune cell infiltration
Cytokine and prostaglandin secretion
State and describe the different phases of labour
Phase 1 - quiescence - cervical softening
Phase 2 - activation - uterine prepared for labour, cervical ripening
Phase 3 - stimulation - uterine contraction, cervical dilation, fetal and placenta expulsion
Phase 4 - involution - uterine involution, cervical repair, breastfeeding
During phase 3, what are the 3 stages of labour?
Stage 1 - contraction starts, cervix dilation (latent and active phase)
Stage 2 - delivery of fetus
Stage 3 - delivery of the placenta
What enables the cervix to retain the fetus in the uterus?
High connective tissue content -> Bundles of collagen fibres embedded in proteo-glycan matrix
Cervical __ is marked by monocyte infiltration
ripening
Cervical dilation is marked by increased __ expression and ___
Hyaluronidase
MMPs
How might the fetus determine the timing of/ cause labour?
- Increase in CRH production by fetus and decline in CRH binding protein levels
- Promotes fetal ACTH and cortisol release
- Increasing cortisol drives placental production of CRH (+ve)
- CRH also stimulates DHEAS production by the fetal adrenal cortex -> estrogen production by placenta -> induces oxytocin receptor expression and oxytocin production -> oxytocin stimulates contractions and stimulates placenta to make PGs -> vigorous contractions
High __ level through pregnancy maintains uterine relaxation by inhibiting OXTR expression
progesterone
Which progesterone receptors are more present during labour?
PR-B and PR-C (repressive) isoforms -> functional progesterone withdrawal
Estrogen receptors alpha expression __ during pregnancy
rises
What 2 things prompt oxytocin production?
Estrogen
Stretch receptors in cervix signal to hypothalamus, pituitary oxytocin release -> ferguson reflex
What inhibits OXTR expression pre-labour? What increases expression?
Decreases = progesterone Increases = estrogen
State 3 functions of oxytocin
Increases connectivity of myocytes in myometrium
Destabilizes membrane potentials to lower threshold for contraction
Enhances liberation of intracellular Ca2+ stores
Describe 2 ways in which rising estrogen drives prostaglandin action
Rising estrogen activates phospholipase A2 enzyme, generating more arachidonic acid for PG synthesis
Estrogen stimulation of oxytocin receptor expression promotes PG release
What is the role of PGE2?
Cervix remodelling: promotes leukocyte infiltration
What is the role of PGF2alpha?
Myometrial contractions: destabilises membrane potentials and promotes connectivity of myocytes
What is the role of PGI2?
Myometrium: promotes myometrium SMC relaxation and relaxation of lower uterine segment
Other than PGS, what other molecules may be implicated in cervix remodelling?
Relaxin
NO
State ways in which PG inhibition can prevent pre-term labor
Inhibits leukocyte recruitment
Inhibit interleukin release
Inhibit membrane destabilization
Inhibit myocyte connectivity
Inhibit uterine lower segment relaxation
Which part of myometrium do contractions start? What are the gap junctions that muscle cells form called?
Fundus, spread down
Syncytium
Muscle contractions in labour are __ this causes the lower segment to be pulled up forming birth canal
brachystatic
What 3 factors bring about placental expulsion?
Uterine shrinkage - fetal membranes fold off, area of contact of placenta with endometrium decreases
Clamping of umbilical cord after birth
Contractions
what are the WHO guidelines for breastfeeding?
6 months exclusively
Up to 2 years and beyond
What is the full duration of breastfeeding per child?
between 4 and 7 years
what are the positive impacts of breastfeeding?
Reduced risk Postnatal depression
Reduced risk ovarian and endometrial cancer
Reduced risk of breast cancer
How often do babies feed?
8-12 times per 24 hours
What are the key barriers to breastfeeding and how can these be overcome?
attitudes/cultural norms
Physical discomfort and inconvenience
Readily available formula
where can doctors be signposted for breastfeeding support?
UNICEF the baby friendly initiative
Hospital infant feeding network
functions of pre-frontal cortex?
Executive function and concentration
Can be impaired in ADHD
state and describe the 4 key domains of child neurodevelopment
Gross motor skills - position, head lag, sitting, walking, running
Fine motor skills - use of hands, grasp and fine pincer, bricks, crayon, puzzles
Speech and language skills - vocalization, words, understanding, imaginative play
Social skills - interaction, stranger reaction, eating skills, dressing
When an infant is unable to raise its head to 45 degrees when prone by 2 years limit, what are some signs of cerebral palsy?
Unable to lift head or push up on arms
Stiff extended legs
Pushing back with head
Constantly fisted hand and stiff leg on one side
When an infant is unable to sit properly by the 6 years limit, what are some signs of cerebral palsy?
Unable to left head when sitting up, floppy trunk, stiff arms, extended legs
Arms flexed and held back, stiff crossed legs
what does the Healthy Child Program in the UK include?
Name some commonly used assessment tools for child development
Screening
Examination and immunisation
Health education/promotion
- Bailey developmental scale
causes of developmental impairments in a child?
Prenatal - iron, folate deficiency
Perinatal - delivery/oxygen deprivation
Postnatal - trauma, meningitis
Factors influencing developmental delay?
sensory/motor impairments
Ill health
Lack of physical/psychological stimuli
Reduced inherent potential
causes of global developmental delay?
Chromosomal abnormalities - downs syndrome, fragile X
Chronic illness
Metabolic - hypothyroidism
Antenatal and perinatal factors - infections, drugs, toxins, trauma, folate def, anoxia
Environmental-social issues
Causes of motor delay in a child?
Cerebral palsy
DMD
Hydrocephalus
Neural tube defects
Congenital dislocation of hip
Global delay e.g. Downs syndrome
Social deprivation
causes of language delay in a child?
Hearing loss
Stammer
Learning disability
Autism spectrum disorder
Impaired comprehension of language - developmental dysphasia
Lack of stimulation
state the 3 primary vesicles in the developing brain (3-4 weeks)
Forebrain - prosencephalon
Midbrain - Mesencephalon
Hindbrain -rhombencephalon
What are the 3 flexures in the embryo at 4 weeks?
Cephalic flexure
Pontine flexure
Cervical flexure
Describe the 5 secondary vesicles of the brain at 5 weeks and how they arise
Forebrain -> telencephalon and diencephalon(give rise to cerebral hemispheres)
Midbrain -> Midbrain (cerebral aqueduct also later develops)
Hindbrain -> metencephalon (gives rise to pons and cerebellum) and myelencephalon(gives rise to medulla)
Positive impacts of breastfeeding on baby
Brain development
Metabolic programming
Antiviral functions of human milk - contains cytokines, vitamin A, etc
Variance in gut microbiome
__ feeding involves a mother responding to her babies cues about when he/she wants to be fed. What is it associated with?
Responsive feeding
Higher prolactin, longer duration of breastfeeding, fewer breastfeeding difficulties, increased milk supply, lower risk of being overweight, satiety responsiveness
Factors that decrease supply of milk to baby?
Using a dummy
Supplementing with formula
Sleep training, trying to follow a routine, separating mother and baby
At the physiological level, what developmental changes are thought to occur to the fetus during its development in response to these challenges that may predispose to health issues in later life?
Altered endocrinology/metabolism
Changes in foetal bone, lean and fat mass
Altered blood flow/vascular loading
Altered immune responses
What inactivates catecholamines and has gene variants associated with ADHD and working memory?
COMT
What are some evolutionary benefits of changes caused by prenatal stress?
impulsive - more willing to explore new environments
- conduct disorder- more willing to break rules
autism spectrum - understand things in different ways
Define decidualisation
What interleukin is involved?
Endometrial changes due to high PROGESTERONE.
IL-11
What links developing embryo to the chorion?
Connecting stalk
Allantois grows along the connecting stalk and becomes the umbilical cord
What are trophoblastic lacunae?
Large spaces filled with maternal blood formed from breakdown marker all capillaries
