fetal development and pregnancy Flashcards
Which organ is the first to develop in the fetus?
The placenta
What does the phrase haemochorial villous organ mean?
Maternal blood comes into direct contact with placental trophoblast cells
List diseases in which disordered placental development is the primary defect in major diseases
-Pre-eclampsia
-fetal growth restriction
-Recurrent miscarriage
-preterm birth
-still-birth
What does the placenta develop from?
The trophectoderm
Which part of the trophectoderm attaches to the surface of the uterine mucosa?
The polar trophectoderm
Describe the development of the placenta at the implantation stage
- At ∼6-7 dpf, after attachment to the
endometrium, the TE fuses to form a
primary syncytium.
▪ Following implantation, the primary
syncytium quickly invades into the
underlying endometrium.
▪ This part is later transformed during
pregnancy into a specialised tissue known
as decidua.
Describe the development of the placenta in the lacunar stage
▪ Around ∼14 dpf, the blastocyst is completely
embedded in the decidua and is covered by the surface epithelium.
▪ Fluid-filled spaces (lacunae) then form within the syncytial mass that enlarge and merge.
▪ The syncytium also erodes into decidual glands, allowing secretions to bathe the syncytial mass.
Describe the villous stage of placental development (before days 17-18dpf)
- The trophoblast cells under the syncytium
(termed cytotrophoblast) rapidly proliferate to
form projections into the primary syncytium to
form primary villi.
▪ The villous trees are formed by further
proliferation and branching, and the lacunae
become the intervillous space.
Describe placental development from day 17 dpf
-Around day 17-18 dpf, extraembryonic
mesenchymal cells penetrate through the
villous core to form secondary villi.
▪ By day 18 dpf, fetal capillaries appear within
the core, marking the development of tertiary
villi.
▪ The villous tree continues to rapidly enlarge
by progressive branching from the chorionic
plate to form a system of villous trees.
How do the primary villi form in the villous stage of placental development?
Trophoblast cells under the syncytium are called the cytotrophoblast, they rapidly proliferate into the primary syncytium forming the primary villi
What is the maternal-fetal interface?
Maternal-fetal Interface: Where the
cytotrophoblast (CTB) is in contact with
the decidua
When is the blueprint for the placenta established?
By the end of the 1at trimester
What does EMT stand for in the context of maternal-fetal interface?
Epithelia-mesenchymal transition
Describe what cytotrophoblast cells do in epithelial-mesenchymal transition (EMT)
Individual cytotrophoblast cells leave the shell to invade the decidua as extravillous trophoblast
For villous stem cell cytotrophoblast, what are the 3 possible cells that they can differentiate into?
-Endovascular trophoblast
-placental bed giant cells
-syncytiotrophoblast
What are the pathways that villous stem cells (cytotrophoblasts) can take when differentiating?
-Extravillous
-villous
Describe the villous pathway for cytotrophoblast differentiation
-Cytotrophoblast cell columns and shell
-endovascular trophoblast or interstitial trophoblast
-interstitial trophoblast becomes placental bed giant cells
Describe the villous pathway in cytotrophoblast differentiation
villous cytotrophoblast
-syncytiotrophoblast
what is the role of endovascular trophoblasts?
Remodels uterine arteries
What is the role of placental bed giant cells
migrates into the decidua and myometrium
What is the purpose of the syncytiotrophoblast?
Primary site of placental transport, protective and endocrine functions
What are the 4 functions of the placenta?
-Gas exchange
-Transport and metablism
-protection
-endocrine functions
Where does gas exchange in the placenta take place?
maternal-fetal interface
How does oxygen pass from mother to fetus?
-passive diffusion
-pressure gradient between maternal blood in the intervillous space and umbilical artery of the fetus
What is the pressure difference and net O2 transfer in the placenta?
Pressure difference 4 kPa
Net O2 transfer= 10%
How does CO2 pass from fetus to mother?
passive diffusion
What is the PCO2 pressure difference between the umbilical artery and uterine artery?
1.8kPa
What is the main carbohydrate transferred in the placenta?
-Glucose
Why is the fetus dependent on maternal glucose?
It has a low capacity for gluconeogenesis
How is glucose transferred to the fetus in the placenta?
-facilitated diffusion using glucose transporters
Where are glucose transporters present in the placenta?
On both the apical and basal surfaces on the syncytiotrophoblast and villous endothelial cells
What produces lactate and how is it transported?
The placenta and via the placenta
Why does the fetus require amino acids?
Protein synthesis
Where can the fetus aquire amino acids from?
it can metabolise its own but it can also get them from the mother
How are amino acids transferred between mother and fetus?
active transport through amino acid transporters in the syncytiotrophoblast
Name 3 amino acid transporters found in the syncytiotrophoblast
-Sodium-independent transporter of catonic amino acids
-sodium-dependent transporters of neutral amino acids
-sodium-independent transporter of neutral amino acids
What specific lipids does the fetus require?
-fatty acids
-cholesterols
what does the fetus use lipids for?
synthesis of
-signalling molecules
-cell membranes
-myelin sheath
How are lipids and fatty acids transferred from mother to fetus?
- Fatty acids and cholesterol bind to plasma proteins to form lipoprotein complexes
-maternal side of the placenta contains lipoprotein lipase which releases free fatty acids from lipoprotein complexes - simple diffusion and fatty acid binding complexes
What does the fetal liver synthesise?
Cholephilic compounds such as bile acids and heme-related biliary pigments such as bilirubin
How are excess bile acids and biliary pigments excreted?
- small amounts via fetal kidney into amniotic fluid
-majority transferred to mother through the placenta via solute-carrier transporters
How is water transferred between mother and fetus?
passive diffusion
-hydrostatic pressure and osmotic pressure gradients
How are Na+ and cl- transferred between mother and fetus?
passive diffusion and active transport
How are k+,ca2+ and PO43- transferred between fetus and mother?
active transport using ion pumps such as Na/K ATPase and Ca ATPase
Name 3 methods that the placenta uses in immune defence against pathogens
-physical barrier
-secretory factors
-passive immunity
Describe the physical barrier of the placenta against pathogens
- Synctytiotrophoblast forms a continuous layer over the chorionic villi, with no cell-cell junctions
-dense actin filament network under the brush border of the apical surface of the syncytiotrophoblast
What type of pathogen does the membrane composition of the placenta protect against?
-parasites
-Toxoplasma gondii
Name 4 types of secretory factors involved in the immune defense function of the placenta
-Interferons
-TLRs
-Chemokines
-miRNAs
which antibodies provide passive immunity to fetuses?
IgG
How are antibodies transferred from mother to fetus?
Neonatal Fc receptors for IgG facilitate the transfer of iGg in the placenta
When does transplacental passage of maternal humoral immunity begin?
16th wk of gestation, peaking at term
How do the concentrations of igG in fetal and maternal circulation compare at birth?
-they’re higher in the fetus
How is the developing Festus considered immunologically by the mother?
semi-allograft
What is the failure of maternal tolerance associated with?
-pre-eclampsia, miscarriage, preterm birth
Describe generally how maternal tolerance is achieved
Restriction and modulation of leukocytes at the maternal-fetal interface
Describe the amounts of immune cells in the decidua in terms of maternal tolerance
-abundance of NK cells
-low dendritic cells and T-effector cells
In the maternal-fetal interface how does the abundance of IL-10 and TGF-B affect immune cells?
-Anti-inflammatory
- circulating monocytes differentiate into M2 type monocytes
-T-cells differentiate into T-regulatory cells
What triggers apoptosis in leukocytes? (maternal immune tolerance)
-Synctiotrophoblast secretes exosomes contains TRAIL and Fas ligand
How does the STB avoid detection by circulating maternal immune cells?
-Doesn’t express any human leukocyte antigen
How is the trophoblast protected from NK-mediated cytolysis?
Placental extravillous trophoblast expresses HLA-G, which binds to NK inhibitory receptors
How do the placenta, mother and fetus communicate?
-hormones
-growth factors
-cytokines
Name 5 hormones produced by the placenta
1) Human chorionic gonadotrophin
2) progesterone
3) oestrogens
4) placental lactogen
5) placental growth hormone
what type of hormone is hCG?
glycoprotein
what produces hcG?
Syncytiotrophoblast
when does hCG production peak?
8 weeks gestation
name 3 functions of hCG
-stimulates the corpus luteum to produce progesterone and oestrogens
-cytotrophoblast cell fusion
-differentiation of villous trophoblasts
when does the corpus luteum atrophy?
8 weeks gestation
What type of hormones are Oestrogen and progesterone?
-steroid
which placental cells produce esotrogen and progesterone?
STB cells
When does the placenta take over the production of progesterone and oestrogens?
8 weeks gestation
what are the roles of progesterone during pregnancy?
inhibit uterine contractions
suppresses LH release, stopping ovulation
What is the role of oestrogen during pregnancy?
-specialised growth hormones for the mothers reproductive organs (breasts, uterus, cervix and vagina)
What type of hormone is human placental lactogen?
polypeptide
which cells make human placental lactogen?
STB
when is human placental lactogen present in maternal circulation?
appears from 3-6 wks gestation, increasing throughout and disappears at delivery
what is the role of human placental lactogen?
-regulates maternal lipid and carbohydate metabolism
-maternal insulin resistance in mid t late gestation to ensure nutritional support for the fetus by raising circulating glucose levels
What type of hormone is placental growth hormone?
single-chain peptide
what makes placental growth hormone?
STB
which hormone is placental growth hormone structurally similar to?
pituitary growth hormone
Describe the levels of different growth hormones in maternal circulation throughout pregnancy
Fist 15-20 weeks pituitary growth hormone is the main one
from 15 weeks onwards placental growth hormone gradually replaces pituitary GH
What is a major function of placental growth hormone?
regulate maternal blood glucose to give the fetus an adequate supply
when does the bilaminar disc form?
during the 2nd week post fertilisation
when does the trilaminar disc form and what does is contain?
week 3 post fertilisation
-ectoderm, mesoderm, endoderm
What organs come from the endoderm?
1) digestive system
2) liver
3)pancreas
4) lungs (inner layers)
What organs come from the mesoderm?
1) circulatory system
2) lungs (epithelial layers)
3) skeletal system
4) muscular system
what organs come from the ectoderm?
1) hair
2) nails
3) skin
4) nervous system
When is the fetal stage of development?
9th week of gestation up until birth
when do the sex organs differentiate?
during the 3rd month of gestation
what is the role of insulin in fetal development?
-late gestation, growth in normal and adverse nutritional cicumstances
How does hyperinsulinemia in DM affect a fetus?
macrosomia due to excessive fat deposition
how can low insulin affect a fetus?
growth restriction
what is the purpose of thyroxine in fetal development?
-required in late gestation for normal growth
How can a thyroxine deficiency affect a fetus?
-deficiency in skeletal and cerebral maturation (cretinism)
-delayed surfactant production in the lungs
what are the roles of cortisol on fetal development?
-limited role in stimulating growth
-lung maturation by stimulating surfactant release
-liver maturation via beta receptor and glycogen depositing, maintaining glucose supply after delivery
-gut maturation via villous proliferation and induction of digestive enzymes
what does the umbilical vein do?
carries oxygenated blood from placenta to fetus
what do the umbilical arteries carry, and where do they arise from?
-carry deoxygenated blood from fetus to placenta
-common iliac arteries
What does the ductus venosus allow?
passage of the umbilical vein through theliver and into the inferior vena cava
what does the presence of the foramen ovale allow for?
right to left atrium shunt whilst some blood is pumped into the right ventricle
what does the ductus arteriosus allow for?
the right ventricle pumps blood into the descending aorta, bypassing the lungs via the ductus arteriosus, supplying the lower body parts
How is blood supplied to the brain, heart and upper lower parts?
blood entering the left atrium is pumped to the left ventricle and then to the ascending aorta
when does the ductus arteriosus close after birth?
within 96 hours
what factors cause the ductus arteriosus to close?
-reduced pulmonary artery pressure
-raised aortic pressure
-decreased hypoxia-induced prostacyclin production which leads to vasoconstriction
-increased bradykinin production by the heart which leads to increased vasoconstriction
what is the name of the remnant of the ductus arteriosus?
ligamentous arteriosum
what causes the foramen ovale to close after birth?
increased left atrial pressure when pulmonary circulation is established
what is the remnant of the foramen ovale called?
fossa ovale
when does the ductus venosus close?
after cord clamping, due to decreased umbilical venous pressure
what is the remnant of the ductus venosus called?
ligamentum venosum
what is the name of the remnant of the umbilical vein?
round ligament of the liver
what are the names of the remnants of the umbilical arteries?
medial umbilical ligaments
what shunt is seen in a patent ductus arteriosus?
left to right
what may the presentation of patent ductus arteriosus be?
respiratory distress and hypoxaemia
what can the consequences of patent ductus arteriosus be?
brain damage and cardiac dysfunction
what type of shunting is caused by a patent foramen ovale?
right to left shunting of deoxygenated blood
how many people are affected by a patent foramen ovale
about 25% of people, can be asymptomatic and may not need treatment however does have an increased risk of stroke, heart attack and blood clots
when and where is the first fetal blood cell formed?
the yolk sac from 14-19 days after conception
when does haemopoiesis in the yolk sac stop?
3rd month of development
in the 5th week of embryonic life, where does haemopoiesis begin?
liver and spleen
when does the bone marrow become the predominant site of haemopoiesis?
- production begins at week 7-8 and becomes predominant at week 26 of gestation
Describe the structure of haemoglobin F
2 alpha and 2 gamma chains
describe the structure of adult haemoglobin
2 alpha and 2 beta chains
when does the switch from fetal to adult haemoglobin occur?
from week 28-34
describe HbF affinity for O2 and why this is advantageous
-higher affinity for O2 than HbA, helps with O2 exchange across the placenta
when do the gestational pulmonary capillaries of the fetal lung fully develop?
by week 20
when doe the alveoli develop?
after week 24
when and where is surfactant produced?
-type 2 alveolar cells
-maximum production will be after 28 weeks
How can the incidence and severity of respiratory distress syndrome be reduced antenatally?
-steroids to mothers at risk of preterm delivery
when does fetal Gi development begin?
by the 3rd week of pregnancy
when does peristalsis begin?
from the 2nd trimester
why is swallowing of the amniotic fluid necessary, and what abnormalities way it be caused by and cause?
-maintains the right volume of fluid in the amniotic sac
-neurological abnormalities like anencephaly or gut obstruction may result in polyhydramnios
where does the renal collecting system (ureters and collecting ducts) derive from?
the metanephros
where does the renal secretory system (glomeruli, convoluted tubes, loop of henle) derive from?
mesenchyme of the nephrogenic cord
when is nephrogenesis complete?
36th week
what are the implications of having an immature kidneys in premature babies?
abnormal water, glucose, sodium and acid-base homeostasis
what is the result of renal agenesis?
-severe oligohydramnios
what infections may a fetus encounter?
intrauterine and perinatal infections
When do fetal immune cells appear and where do they come from?
-lymphocytes appear from week 8
-all phagocytic cell, t and b cells and the complements can mount an immune response from the middle of trimester 2
what immunoglobulin provides passive fetal immunity?
IgG
what immunoglobulins does the fetus produce?
IgM and IgA, small amounts, dont cross the placenta
what may indicate a fetal infection in the newborn?
presence of IgM and IgA without IgG
Describe the general immunological defences of the fetus
- amniotic fluid, lysosomes IgG
-placenta, lymphoid cells, phagocytes, barrier - liver and bonemarrow, granulocytosis
-interferon from lymphocytes
what layers make up the amniotic membrane?
-epithelium
-basement membrane
-stroma
how does the chriodecidua layer contribute to the initiation of labour?
prostaglandin E2 and F2a production
Name 4 functions of amniotic fluid
-protects the fetus from mechanical injury
-permits fetal movement and prevents limb contracture
-prevent adhesion between fetus and amnion
-permit fetal lung development
Define monozygotic
identical twins (from a single zygote)
Define dizygotic
non-identical (from two different zygotes)
Define monoamniotic
single amniotic sac
Define diamniotic
two separate amniotic sacs
define monochorionic
share a single placenta
Define dichorionic
two separate placentas
what type of multiple pregnancy has the best outcomes and why?
The best outcomes are with diamniotic, dichorionic twin pregnancies, as each fetus has their own nutrient supply.
what is bserved on US in dichorionic diamniotic twins?
Dichorionic diamniotic twins have a membrane between the twins, with a lambda sign or twin peak sign
what is observed on US in monochorionic diamniotic twins?
Monochorionic diamniotic twins have a membrane between the twins, with a T sign
what is observed in monochorionic monoamniotic twins?
Monochorionic monoamniotic twins have no membrane separating the twins
what are the risks to mother in multiple pregnancy?
Anaemia
Polyhydramnios
Hypertension
Malpresentation
Spontaneous preterm birth
Instrumental delivery or caesarean
Postpartum haemorrhage
what are the risks to babies in preterm birth?
Miscarriage
Stillbirth
Fetal growth restriction
Prematurity
Twin-twin transfusion syndrome
Twin anaemia polycythaemia sequence
Congenital abnormalities
what is twin-twin transfusion syndrome called in pregnancies with more than 2 fetuses?
feto-fetal transfusion syndrome
Describe the pathology of twin-twin transfusion syndrome?
-Connection in blood supply between the 2 fetuses, so the recipient receives the majority of blood and the donor doesn’t receive enough blood
what are the complications with twin-twin transfusion syndrome?
-Recipient is fluid overloaded, has heart failur and polyhramnios
-donor has growth restriction, anaemia and oligohydramnios
-Discrepancy in fetus sizes
How is twin-twin transfusion syndrome treated?
laser treatment
Describe twin anaemia polycythemia sequence
Twin anaemia polycythaemia sequence is similar to twin-twin transfusion syndrome, but less acute. One twin becomes anaemic whilst the other develops polycythaemia (raised haemoglobin).
How is anaemia monitored in multiple pregnancies?
extra FBC’s at the booking clinic, 20 wks and 28wks
How are fetal growth restriction, unequal growth and twin0twin transfusion syndrome monitored for?
additional US
-2 weekly scans from 16 weeks in monochorionic twins
-4 weekly scans from 20 weeks in dichorionic twins
when is planned birth offered for uncomplicated monochorionic monoamniotic twins?
32- 33+6 weeks
when is planned birth offered for uncomplicated monochorionic diamniotic twins?
36-36+6 weeks
when is planned delivery offered for uncomplicated dichorionic diamniotic twins?
37-37+6 weeks
when is planned delivery offered for triplets?
before 35+6 weeks for triplets
what type of delivery is required for monoamniotic twins?
-elective caesarean section between 32 and 33+6 weeks
How can diamniotic twins be delivered?
-vaginal if the first twin has cephalic presentation
-caesarean section may be required after the birth of the 1st baby
-elective caesarean when the 1st twin is not in cephalic presentation
Describe antepartum haemorrhage
bleeding from the genital tract from 24 wks up until the birth of the baby
What are the usual causes of antepartum haemorrhage?
-placenta praevia
-placental abruption
How can antepartum haemorrhage be subdivided?
-minor: blood loss of less than 50ml
-major: 50-1000ml
-massive: more than 1000ml of blood loss or clinical signs of shock
Define primary post partum haemorrhage
-loss of 500 ml or more of blood from the genital tract within 24 hours of the birth of a baby
How can post partum haemorrhage be subdivided
-minor: 500-1000ml
-major: more than 1000ml
- major-moderate: 1001-2000ml
-major-severe: more than 2000ml
Define secondary postpartum heamorrhage
abnormal or excessive bleeding from the birth canal between 24 hours and 12 weeks postnatally
How does blood volume change during pregnancy?
-total volume goes up from 70ml/kg to 100ml/kg
-plasma volume increases 40-50%
-Red cell mass increases 20-305 producing a relative anaemia
why is increased blood volume beneficial in pregnancy?
-facilitates maternal and fetal exhanged of respiratory gases, nutrients and metabolites
-reduces impact of maternal blood loss at delivery
How much blood on average is lost during vaginal births and caesarean sections?
300-500ml for vaginal, 750ml for caesarean sections
what is autotransfusion in the context of labour
-Compensation for blood loss by contracting the uterus
How is clotting during pregnancy and how does this affect bleeding times?
-Hypercoagulable state
-clotting and bleeding times are normal however
what changes in blood prevent excessive bleeding at delivery?
-Fibrinogen is increased
-clotting factors increase
-platelets increase but are still within normal ranges
-D-dimer levels increase
Which clotting factors increase during pregnancy?
2, 7,8,10,11 and 12
Describe primary homeostasis in pregnancy
-vasoconstriction (immediately)
-platelet adhesion (seconds)
-platelet aggregation (minutes)
Formation of white blood clot or platelet plug
Describe secondary homeostasis in pregnancy
-activation of coagulation factors
-formation of fibrin (minutes)
formation of stable red blood clot
describe fibrinolysis in pregnancy
activation of fibrinolysis (minutes)
lysis of the clot
Describe changes in physiology during haemorrhage
- increased HR
-Increased force of contraction
-Vasoconstriction - Less urine is produced
Describe class 1 of haemorrhagic shock classification and treatment
-up to 15% blood loss
-Normal HR
-Normal BP
-Normal RR
-Normal Urine output
-mental status: slightly anxious
-Treatment: crystalloid
Describe class 2 of haemorrhagic shock classification and treatment
-15%- 30% blood loss
-mild tachycardia
-Normal-decreased BP
-mild tachypnea
-0.5-1ml/kg/h Urine output
-mental status: mildly anxious
-Treatment: crystalloid
Describe class 3 of haemorrhagic shock classification and treatment
-30-40% blood loss
-moderate tachycardia
-decreased BP
-moderate tachypnea
-0.25-5ml/kg/h Urine output
-mental status: anxious/confused
-Treatment: crystalloid and blood
Describe class 4 of haemorrhagic shock classification and treatment
-more than 40% blood loss
-severe tachycardia
-decreased BP
-severe tachypnea
-negligible Urine output
-mental status: confused/lethargic
-Treatment: crystalloid and blood
What are the 4 T’s of obstetric haemorrhage?
-Tone, abnormalities of uterine contraction
-Tissue, retained products of conception
-Trauma, of the genital tract
-Thrombin, abnormalities of coagulation
What are the risk factors for atonic bleeding?
-Prolonged labour
-Overdistended uterus, twins, large baby, polyhydramnios
What tissues may cause obstetric haemorrhage?
-Retained placenta
-Retained products of conception
-Placenta praevia
-placental adhesive disorders (accreta, increta, percreta)
Describe causes of trauma which may lead to obstetric haemorrhage
uterine trauma
-inverted uterus
-ruptured uterus: Old C/S scars
-Surgical damage
Vaginal tears: 1st,2nd, 3rd,4th degree
List acquired coagulopathy in pregnancy
-Sepsis
-Pre-eclampsia/eclampsia
-Placental abruption
-HELLP syndrome
-Retained dead fetus
-amniotic fluid embolus
-DIC
-Liver disease
List platelet abnormalities which may contribute to the thrombin in the 4 T’s of obstetric haemorrhage
-Gestational thrombocytopenia
-idiopathic/immunological thrombocytopenic purpura
-HELLP syndrome
-sepsis
-DIC
Name 4 drugs which can be used as uterotonic agents
-syntocinon iv
-ergometrine Iv/im
-carboprost im
-misoprostol pr
How can tranexamic acid be useful in obstetric haemorrhage?
reduction of fibrinolysis
How can obstetric haemorrhage caused by tone be managed?
-uterine massage
-B lynch suture
-Bakri balloon insertion
How should a haematological obstetric haemorrhage be treated?
-Replace circulating volume
- replace blood: cell salvage/allogenic
-correct coagulation with blood products
Define normal small fetuses
Normal small fetuses- no structural abnormality, normal umbilical artery Doppler
& liquor. Not at risk. No special care needed.
Define abnormal small fetuses
have chromosomal or structural abnormalities.
Define growth restricted fetuses
result from placental dysfunction. Appropriate
treatment or timely delivery may improve prospects.
Define small for gestational age
Fetus ≤ 10th weight percentile for age (wks)
Define intrauterine growth restriction
Fetus unable to achieve genetically predetermined size
Define low birth weight and what can cause it
birth weight less than 2500gms
❑ SGA or
❑ Prematurity
Digital register check-in: CI-QY-DO
What percentage of SGA/FGR babies are at risk of potentially preventable perinatal death? and what does this result in?
-40%
-Sig. no. healthy SGA fetuses subjected to high-risk protocols and potentially iatrogenic prematurity
describe symmetrical FGR and its causes
*fetal head and body proportionately
small.
*fetal insult during early
development - affect growth
processes and cell hyperplasia
Describe asymmetrical FGR and its causes
*fetal brain disproportionately large
compared to liver.
*Fetal insult during later
development
What is the normal infant brain: liver ratio?
Normal infant brain:liver ratio >3. Asymmetrical FGR ratio > 6
FGR underlying cause of growth delay
duration of the insult
Describe specifically maternal factors that can contribute to FGR
-age
-small stature
-high altitude
-genotype
-stress
-pre-eclampsia
-substance use/abuse
-undernutrition
-overnutrition
-hypertension
-prior IUGR
Describe specific placental and cord abnormalities which may contribute to FGR
-placental insufficiency
-incorrect cord insertion
-placental tumour
-single umbilical artery
-circumvallate placenta
Describe specific fetal factors which may contribute to FGR
-congenital heart disease
-congenital diaphragmatic hernia
-trisomy 21
-trisomy 18 (edwards syndrome)
-trisomy 13 (patau syndrome)
-turners syndrome
What infections may cause fetal growth restriction?
T: Toxoplasmosis
O: Other diseases, such as syphilis, varicella-zoster, parvovirus B19, or HIV
R: Rubella
C: Cytomegalovirus (CMV)
H: Herpes simplex virus (HSV)
and malaria
name 3 drugs associated with FGR
-marijuana
-heroin
-cocaine
-cigarette
-alcohol
-lithium
-phenytoin
Name fetal risk factors for FGR
Multiple pregnancy – increased demands
Infections -TORCH, TB, Malaria, Parvo virus B19.
Congenital malformations
Extra-uterine pregnancy – e.g. abdominal
Placenta or umbilical cord defects.
Chromosomal abnormalities
describe the underlying mechanism of IUGR
- Insufficient gas exchange and nutrient delivery to fetus
- Maternal disease
- Decreased O2-carrying capacity eg cyanotic heart disease, smoking,
haemoglobinopathy) - Dysfunctional O2 delivery system - diabetes with vascular disease,
hypertension, autoimmune conditions - Placental damage - smoking, thrombophilia, autoimmune diseases
describe the role of the intrauterine environment in fetal development
- Recipient mother more important for fetal growth than egg donor for embryo
transfer - FGR twin more likely to develop Type 2 diabetes than well grown co-twin
Describe the role of maternal nutrition in fetal development
- Undernutrition reduces placental and fetal growth
- Growth most vulnerable to maternal dietary deficiencies during peri-implantation and period of rapid placental development
Define epigenteic alterations
-stable alterations through covalent modifications of DNA and core histones
Name 2 methods of epigenetic modification
-DNA methylation
-Histone modification
How does FGR affect the risk of late-fetal death?
10-fold increase in risk among very small fetuses
Describe the perinatal implications of FGR
-Stillbirth
-prematurity
-asphyxia
-congenital malformations
What complications are premature babies more at risk of?
-Necrotising enterocolitis
-thrombocytopenia
-temperature instability
-renal failure
-metabolic problems like hypoglycaemia and hypothermia
What are the long term consequences of FGR?
- HPA abnormalities
-CVR abnormalities such as decreased stroke volume, globular ventricles, high BP, Increased intima-media thickness
-insulin resistance
-metabolic syndrome
When screening for FGR through a history what things should you ask about?
-Smoking
-altitude
-malnutrition
-previous FGR
-Medications
-recreational drugs
-alcohol
-chronic maternal disease
-genetic abnormalities
-maternal age
-FH
-Habitual abortion
-alpha-fetoprotein
-environmental (lead, mercury, copper)
-1st trimester vaginal bleeding
-parents size
How many minor risk factors would someone have for FGR that would merit reassessment at 20 weeks?
3
How many major risk factors would someone have for FGR to be reassessed at 20 weeks from booking assessment? and what drug should be assessed to prevent/ minimise FGR?
1
-aspirin
Name 3 major risk factors for FGR
-maternal age above 40
-smoker of more than 11 cigarettes a day
-Cocaine
-daily vigorous exercise
-parental SGA
-previous SGA baby
Name 3 minor risk factors for FGR
-maternal age abover 35
-IVF singleton
-nulliparity
-BMI below 20
-BMI 25-34.9
-smoker 1-10 cigarettes a day
-low fruit intake pre-pregnancy
What assessments are done at 20 weeks in people at risk of FGR?
-PAPP-A (Helps the placenta implant in the womb, Helps maintain a healthy placenta, and Helps the baby grow healthily)
-Fetal echogenic bowel (a condition where a fetus’s bowel appears brighter than normal on an ultrasound scan. It’s often seen in the lower abdomen)
What may cause fetal echogenic bowel?
-Bleeding in the amniotic fluid: A baby may swallow blood from an early pregnancy bleed, which is not harmful.
-Infection: A congenital infection, such as cytomegalovirus (CMV), can cause echogenic bowel.
-Cystic fibrosis: A serious inherited disease that affects the lungs and digestion.
-Chromosomal conditions: Such as trisomy 21, 13, and 18, or Down syndrome.
when does a uterine artery doppler happen in someone with 3 or more minor risk factors for FGR?
20-24 weeks
What are the outcomes for a uterine artery doppler at 20-24 weeks when there’s risk of FGR?
Normal- assessment of fetal size and umbilical artery doppler in the 3rd trimester
abnormal- serial assessment of fetal size and umbilical artery doppler from 26-28 weeks
How reliable is Symphysio-fundal height when assessing IUGR?
-Poor
-sensitivity= 27%
-specificity= 88%
- high observer variability
-can be affected by the mothers fat levels
How can symphysio-fundal height measurements be improved?
-Customised fundal height charts which take into account maternal height, weight, parity, ethnicity
What fetal biometry measures can be seen on US?
-Biparietal diameter
-Head circumference
- Transverse cerebellar diameter
-Femure length
- abdominal circumference
-estimated fetal weight
What investigations can be done using ancillary invasive tests
-fetal karyotyping
-fetal blood sampling
-amniocentesis for lecithin-to-sphingomyelin ratio
what may a low ponderal index indicate?
-Hypoglycemia
-Hyperbilirubinemia
-Necrotising entercoliting
-Hyperviscosity syndromes
How can IUGR be prevented?
-Low dose aspirin and miniheparin
-maternal smoking cessation
-antibiotics to prevent/rx UTIs
-antimalarial prophylaxis
How is IUGR managed?
-Fetal surveillance until the risk of in utero demise exceeds the risk of delivery and prematurity
Define large for gestational age
above the 90th centile for that gestation
Define macrosmia
BW above 4000g regardless of gestational age
How is morbidity and mortality estimated in macrosomia?
relates to absolute bw rather than centiles
List RF for macrosomia
obesity
gestational/T2DM
postterm gestation
multiparity
large size parents
advancing maternal age
previous macrosomic infant
racial and ethnic factors
what are the complications with fetal overgrowth?
-maternal diabetes
-fetal demise
-birth trauma-shoulder dystocia, nerve palsies
-neonatal hypoglycaemia
a birth weight above 4500g identifies pregnancies at an increased risk of what?
morbidity
a birth weight above 5000g identifies pregnancies at an increased risk of what?
mortality
What is the greatest risk factor for accelerating fetal growth and altering body proportions?
maternal hyperglycaemia
How is labour divided into stages?
-Latent, irregular contractions, effacement and dilatation of the cervix
-First stage - onset of regular uterine contractions, accompanied by effacement and dilation of the cervical os to full dilatation
- Second stage- full dilation of the cervix to birth of the baby
- Third stage – birth of baby to expulsion of placenta and membranes
When does normal labour occur?
between 37 and 42 weeks gestation
when is estimated date of delivery?
estimated date of delivery (EDD) is 280 days from the first day of the last menstrual period
What are the changes required for the expulsion of the fetus?
-Cervical ripening
-myometrial tone change
What is the effect of hCG on the formation of myometrial gap junctions?
-Inhibits formation
What is the effect of progesterone on circulating oestrogen and on the formation of MGJ?
-inhibits oestrogen
-stimulates the formation of myometrial gap junctions
What is the role of relaxin in pregnancy?
-acts on all smooth muscle
What is the role of oxytocin in pregnancy?
stimulate synthesis of relaxatory prostaglandins until hCG levels
at onset of labour
How is myocyte activity coordinated in labour?
-gap junctions
How do the actin filaments in the myometrium act differently to every other area of the body?
-They interact with the entire length of the myosin filament
-greater shortening at each contraction
-produces efficient cervical defacement, dilation and delivery of fetus
How many muscle layers are in the uterus?
3
-outer longitudinal
-inner circular
-middle spiral
When do myometrial gap junctions appear?
from 32 weeks gestation
what are myometrial gap junctions made of?
symmetrical portions of plasma membranes from adjacent cells
Which hormones stimulate the formation of myometrial gap junctions? and when do these hormones peak?
-oestrogen, prostaglandin, melatonin
-end of pregnancy
what hormones inhibit the formation of myometrial gap junctions? and when are these hormone present?
-progesterone, hCG, relaxin
- increase throughout pregnancy
Which hormone promotes the formation of oxytocin receptors?
-oestrogen
how is oxytocin released during pregnancy? What is this known as?
- Stored in the post. pituitary
-secreted in short pulsatile manner in response to neuronal stimuli from the distension of the cervix and vagina
-Ferguson reflex
What is fundal dominance?
progressive conductance of electrical activity from the fundus to cervix
Relaxin
1) where is it produced?
2) what does it do in pregnancy ?
3) what does it do in labour?
4) what type of hormone is it?
1) initially by the corpus luteum, then by the placenta
2) uterine quiescence
3) Unknown
4) peptide
hCG
1) where is it produced?
2) what does it do in pregnancy ?
3) what type of hormone is it?
1)syncytiotrophoblast
2) promotes production of relaxin and supports the corpus luteum to maintain estrogen and progesterone production
3)glycoprotein
Corticotrophin-releasing hormone
1) when does it peak
2) what does it do
-end of pregnancy
-potentiates the effects of prostaglandins and oxytocin on uterine contractility and increases prostaglandin production by the decidua and membranes
what is the potential role of the fetal-hypothalamic pituitary adrenal axis and the initiation of labour?
-fetal hypothalamo-pituitary adrenal axis matures and is more sensitive to ACTH
-stimulates the production of cortisol, which initiates changes in the maternal uterus and prepares the fetus for extra-uterine life by promoting lung maturation
-stimulation of the fetal adrenal gland results in higher levels of oestrogen, due to higher levels of oestrogens precursor being made
Describe the progesterone block hypothesis
progesterone supresses effective uterine activity by blocking the formation of oxytocin receptors and gap-junctions
What is the relationship of oxytocin to calcium in labour?
-oxytocin is repsonsible for the activation of receptor-operated calcium channels and the release of calcium in the myomtrial cells
-calcium necessary for actin and myosin interactions, which produce ATP, providing energy for contraction
In labour what is responsible for the release of prostaglandins?
the increased ratio of oestrogen: progesterone
Which prostaglandins are necessary for labour and where are they produced?
F and E
-placenta, membranes, decidua
How do prostaglandins act during labour?
-myometrial stimulants, enhance the effects of oxytocin and ripen the cervix
- administration can induce labour
-inhibition of prostaglandins will delay labour
What is the role of cytokines in labour?
cytokines: stimulates synthesis of prostaglandins
What is the role of interleukins in labour?
interleukins : increases collagenolytic activity of cervix
What is the role of nitric oxide in labour?
nitric oxide : stimulates release of PGE2 from fetal membranes
How can labour be characterised?
- Involuntary
- Intermittant and regular
- Painful (usually)
What are the average times of each stage of labour in primigravidae women?
- 1st stage 12-14 hours
- 2nd stage 1-2 hours
- 3rd stage 20-30 mins with 5-15 mins active management
What are the average times of each stage of labour in multigravidae women?
1st- 6-10 hours
2nd 30 mins- 1 hours
3rd 20-30 mins with 5-15 active management
What is effacement? why does it happen, when and what is it a sign of?
- May start 2-3 weeks before end of pregnancy
- Occurs because of changes in solubility of collagen in
cervix - Progressive dilation of the cervix is a definite sign of
labour
Describe fetal axis pressure
Fetal axis pressure- This is the force transmitted by the uterine contractions down the fetal spine to its head.
Which position optimises fetal axis pressure?
upright
What are the signs of the second stage of labour?
- Expulsive uterine contractions
- Rupture of the forewaters (Babies
may be born ‘en caul’ ) - Dilatation and gaping of the anus
- Anal cleft line
How common are chromosomal abnormalities in pregnancy?
1/300
what are the 95% most common chromosomal abnormalities?
trisomy 21,18, 13 or changes in X and Y
What factor increases the risk of all chromosomal abnormalities?
maternal age
what test is done for prenatal screening of chromosomal abnormalities in the 1st trimester?
First Trimester Screening (Combined) 11-14+1 weeks
* -Nuchal translucency (NT), hCG & PAPP
What test can be done in the 2nd trimester for chromosomal abnormalities? How does it compare to screening in the 1st trimester?
(Second trimester) Quadruple maternal serum screening (Quad/serum
integrated screening) 15-20 weeks
* -hCG, AFP, uE3, inhibin A
-less accurate
when is nuchal translucency measured?
11-14+1
what nuchal translucency would be considered as elevated?
above 3.5 mm
If a fetus has a rasied nuchal translucency but normal chromosomes what problems may be present?
With normal chromosomes:
* cardiac defects
* diaphragmatic hernia
* pulmonary defects
* skeletal dysplasias
* congenital infection
* metabolic/haem disorders
* rare single gene disorders
If a fetus has a rasied nuchal translucency but normal chromosomes what investigations should be done?
Diagnostic testing indicated + fetal echocardiogram indicated ~20
weeks (if NT>3.5mm) + detailed anatomy scan at 18-20 weeks + genetic
counselling
when is amniocentesis recommended?
after 15 weeks
what is the most common way of carrying out chorionic villus sampling?
abdominal
Name 3 invasive fetal chromosome testing methods
-amniocentesis
-chorionic villus sampling
-fetal blood sampling
what chromosomal aberrations can be checked through invasive methods?
-trisomy,
-monosomy,
-polyploidy,
-deletion,
-duplication,
-inversion,
-translocation,
-ring chromosome
Other than chromosomal aberrations, what can be checked through invasive testing?
- Genetic aberrations
- Infectious disease
- Biochemical markers (eg chorioamnionitis, raised IL-6)
How can chorionic villus sampling results be interpreted?
- Direct analysis examines placental trophoblasts (very rapidly dividing
cells) - Results in few hours
- greater vulnerability to mitotic error
- Cultured analysis examines the fibroblast-like cells of the villus
stroma or mesenchymal core - Approximately 10-14 days
- Accurately reflect the chromosomes of the fetus
what are the complications of invasive procedures?
- Pregnancy loss 1:100-1:200
- Increased risk with larger needle, multiple needle insertion and discoloration of the fluid
- Leakage of amniotic fluid (respiratory distress syndrome)
- Limb reduction (if CVS <9 weeks)
- Amnionitis (infection)
- Vaginal bleeding
- Potential isoimmunization (In HIV+, higher risk of vertical transmission, chemoprophylaxis essential, aim for viral load <50
Mosaicism may be indicated by chromosomal tests, what can mosaicism affect?
-fetal only mosaicism
-confined placental mosaicism
-placental and fetal mosaicism
what are the 3 scenarios that lead to fetal mosaicism?
1) mitotic non-disjunction (autosomes)
2) mitotic non-disjunction (sex chromosomes)
3)meiotic non-disjunction
Why is amniocentesis not recommended until after 15 weeks?
mosaicism increases with gestational age due to somatic mosaicism
what can each element of chorionic villus sampling results indicate?
*cytotrophoblast: more representative of placenta
*mesenchymal core: more representative of the fetal karyotype
why are pregnancies with confined placental mosaicism required to have growth scans?
Confined placental mosaicism (fetus normal) still associated with FGR: warrants growth scans
what are the 3 mechanisms that can lead to uniparental disomy?
1) Trisomy rescue
2) monosomy rescue
3) mitotic crossing over
Compare heterodisomy and isodisomy
Heterodisomy and isodisomy are both conditions that occur when a person inherits two copies of a chromosome from one parent. The difference is whether the two copies are identical or different.
hetero= 2 different alleles
iso= same allele twice
what are the health implications of uniparental disomy?
- Parental imprinting in the case of heterodisomy and isodisomy
- Unmasking of recessive conditions in some cases of isodisomy
Which chromosomes need to be tested for when testing for uniparental disomy and why?
Molecular UPD testing should be considered for certain chromosomes (including 6, 7, 11, 14, 15) that are known to have adverse phenotypic imprinting effect
Give 2 examples of imprinting disorders
-pradder willy syndrome
-anglemans syndrome
How can the clinical outcomes of mosacisim be estimated?
- Subject to the tissues affected and level of trisomy in those tissues (which cannot always be evaluated, only estimated)
- Method of ascertainment:
1. CVS shows that the placenta is affected
- Amniotic fluid suggests that at least one fetal tissue may be affected
- Fetal blood sampling confirms the diagnosis of chromosomal mosaicism
- Ultrasound findings +/- presence/absence of uniparental disomy
- Previous case reports known in the literature (for guidance)
High-risk women are offered non-invasive testing in the fetal anomaly screening programme; what is considered high risk? and when is this testing done?
1:150 chance of chromosomal abnormality or higher
combined with 1st trimester screening
What does non-invasive prenatal testing assess?
Measures cell-free DNA from apoptotic trophoblastic cells
what can reduce the accuracy of non-invasive prenatal testing
Reduced accuracy: low fetal fraction, maternal malignancy, vanishing twin, high BM
What may a persistent low fraction in non-invasive testing indicate?
-higher risk of T18 and T13
What is the commonest cause of a false positive and non-invasive prenatal testing?
placental mosaicism
what are the advantages of using cell free DNA in non-invasive screening?
-Reduces unnecessary procedures in borderline high-risk women
* Can give more equivocal risk assessment thanany of the options offered on NHS (sensitivity DS> 99%)
what are the disadvantages of using cell free DNA in non-invasive testing?
Currently not available on NHS → Costly
* Still classified as screening – NOT diagnostic
* Takes 7-10 working days
* Variable depending on the chromosome
affected and on the woman’s pre-test risk in 1stT screening (higher risk of false result in low-risk women) and whether there is presence or absence of fetal structural anomaly
In dizygotic twins how many placentas are there?
2
what percentage of monozygotic twins are dichorionic diamniotic and when does the division happen?
~25%
- days 0-3
what percentage of monozygotic twins are monochorionic diamniotic and when does the division happen?
~75%
days 4-7
what percentage of monozygotic twins are monchorionic monomniotic and when does the division happen?
~1-2%
days 7-14
what are the incidences of twins and triplets?
Hellin’s law: 1 in 89n-1 i.e. twins 1 in 89 singleton pregnancies, triplets 1 in 892
How do dizygotic twins occur?
Dizygotic twins result from multiple ovulation – two eggs reaching maturity at the same
time and being fertilized by two sperm
What are the risk factors associated with superovulation?
Risk factors therefore relate to risk of superovulation associated with raised FSH levels:
- Assisted Reproductive Techniques
- Ovarian stimulation
- Multiple embryo transfer
- Maternal age
- Parity
- Genetics (multiple mechanisms of inheritance described)
- Dietary sources of oestrogen
- Geography
- Seasonal light
What complications are associated with monozygotic twinning?
TTTS – Twin-to-twin transfusion syndrome
- TAPS – Twin anaemia polycythaemia sequence
- TRAP sequence – Twin reversed arterial perfusion sequence
- sFGR – Selective fetal growth restriction
- Anomalies
- Cord entanglement (MCMA)
