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 extravillous 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)
Pregnancy involves controlled heterogenous inflammation, what is the balance of T-helper cells in implantation and placentation and how can this be described?
more TH2 production than TH1
pro-inflammatory
Pregnancy involves controlled heterogenous inflammation, what is the balance of T-helper cells in fetal growth and how can this be described?
More TH1 weighted and anti-inflammatory
Pregnancy involves controlled heterogenous inflammation; what is the balance of T-helper cells in parturition, and how can this be described?
More TH2 weighted and pro-inflammatory
What can disrupted inflammation lead to in pregnancy?
adverse outcomes:
-Preeclampsia
-Preterm birth
-Miscarriage
-Still birth
-FGR
Name 3 cells that make up part of the innate immune repsonse
-Dendritic
-macrophage
-mast cells
-natural killer cell
-basophil
-eosinophil
-neutrophil
Which cells in the innate immune system are granulocytes?
-Natural killer cells
-basophils
-eosinophils
-neutrophils
Which cells make up the adaptive immune response?
- B cells
- T-cells
What cell is a member of both types of immunity?
Natural killer cells
What are the different types of T regulatory cells and how do they differentiate?
-Adaptive Treg ( naive T cell)
- Natural T reg (directly from thymus)
Which cells make up the decidual inflammatory cells after implantation?
Leukocytes-
70% NKs
20-25% macrophages
1.7% dendritic cells
3-10% T cells
What processes do the decidua inflammatory cells play an active role in?
-Implantation
-placentation
-Immune tolerance
Why is implantation and placentation a pro-inflammatory process?
-Implantation and placentation require active
breakdown and restructuring of the decidua by the invasive trophectoderm.
▪ This process resembles the tissue injury and
subsequent repair driven by Th1 type pro-
inflammatory response.
Name 3 key inflammatory cytokines released by endometrial stroma and infiltrating inflammatory cells at the site of inflammation
TNF-α, IL6, IL8,
IL15, GM-CSF, CXCL1, CCL4
What types of cells are crucial for early implantation and placentation?
CD11c and DC’s
What processes does the specific inflammatory environment in implantation allow for
-Transfer and expression of new adhesion molecules to the cell surface of the uterus lumen.
▪ Removal of the pre-existing mucin layer from the luminal epithelial surface of the uterus that prevent blastocyst adhesion.
▪ Increase affinity of adhesion molecules on the uterine epithelium, such as L-selectin.
▪ Reorganization of adhesion molecules on the apical surface of the epithelium of the lumen to ensure blastocyst attachment.
Which cells contribute to the anti-inflammatory microenvironment required during fetal growth?
Macrophages, dNK cells and Treg cells contribute to provide this anti-inflammatory microenvironment
How do macrophages contribute during fetal growth?
dMφ -> M2 type, release anti-inflammatory cytokines. Tissue renewal during placental development
How do natural killer cells contribute to fetal growth?
dNK -> Different than peripheral NK cells with low cytotoxicity. Interacts with CD14+ dMφ and induce generation of Treg cells.
How do T regulatory cells contribute to fetal growth?
Treg -> Key players in the tissue repair process due to their anti-inflammatory and anti-apoptotic capacities.
Treg cells prevent Teff immune responses against paternal antigens.
How is the TH2 type inflammation maintained during fetal growth?
-Soluble factors maintain the Th2 type inflammation
-Fetal factors maintain the Th2 type inflammation
Describe how Soluble factors maintain the Th2 type inflammation in fetal growth
▪ IL10, TGF-β, IDO released by decidual M2
macrophages and differentiates into tolerogenic DCs.
▪ Decidual γδ T cells release IL10, TGF-β, PIBF which provide an anti-inflammatory microenvironment.
Describe how Fetal factors maintain the Th2 type inflammation in fetal growth
HLA-E and HLA-G expressed on trophoblast cells dampen the immune response by interacting with inhibitory receptors on NK cells and T cells
Which pathway initiates and executes labour and delivery?
NF-κB signalling
What induces NF-KB signalling?
NF-κB signalling is induced as a result of TLR-4
activation by surfactant protein A and endogenous damage-associated molecular patterns (DAMPs), which appear in high levels at the end of the pregnancy.
What does activation of NF-KB signalling do?
-increases the production of pro-inflammatory cytokines
Which cells shape the immunological microenvironment in implantation and placentation, and how do they do this?
-Trophoblast cells
-Trophoblast cells constitutively secrete CXCL12, CXCL8, CCL2 and
TGF-β.
-These chemokines and cytokines recruit peripheral monocytes, neutrophils, NK cells, T cells and Treg cells at the site of implantation.
How are recruited immune cells converted into favourable phenotypes during implantation and placentation?
Trophoblast secreted IL10, IL15, TGF-β differentiate recruited immune cells into favourable phenotypes to induce immune
tolerance such as:
NK cells -> Less cytotoxic NK cells
CD14+ Monocytes -> M2 type anti-inflammatory phenotype T cells -> Treg cells providing tolerance. (Mor et al 2017)
How does progesterone act as an immunomodulator?
Progesterone is a potent immunomodulator:
▪ It blocks lymphocyte proliferation,
▪ Prolongs allograft survival,
▪ Modulates antibody production,
▪ Decreases the oxidative burst of monocytes,
▪ Reduces the production of proinflammatory cytokines by macrophages,
▪ It upregulates TLR-4 expression but suppresses TLR-2 response to intrauterine infection, resulting in a protective role in preterm delivery,
▪ It inhibits MMP-1 and MMP-3 expression in decidual cells providing protection against preterm delivery.
How does pathological intrauterine inflammation or infection affect progesterone?
Pathological intrauterine inflammation or infection reduces progesterone function by its
functional withdrawal.
Why is the balance of oestrogen and progesterone important in parturition?
The balance between the relaxing actions of progesterone and the stimulatory
actions of estrogens is pivotal in determining the contractile state of the myometrium
during pregnancy and the timing and process of parturition
What are the immunomodulatory roles of oestrogen?
Immunomodulatory roles of oestrogen:
▪ It inhibits Th1 proinflammatory cytokines, such as IL12, TNF-α, and IFN-γ,
▪ It stimulates Th2 anti-inflammatory cytokines, such as IL10, IL4, and TGF-β.
Name a key hormone in stimulating uterine contraction during partruition
-Oxytocin
How is the oxytocin receptor regulated?
Positively by inflammatory mediators of parturition
Which signalling pathways have binding sites on the OTR promoter? and how are they activated?
C/EBP
and NF-kB
These transcription factors are activated by proinflammatory cytokines
IL1β and IL6 and increases OTR expression and potentiate oxytocin action
on labour
What is failure of maternal tolerance associated with?
Failure of maternal tolerance is associated with various adverse pregnancy outcomes including pre-eclampsia, miscarriage and
preterm birth
What is the general principle how immune tolerance is achieved?
In general, the tolerance is achieved by the restriction and modulation of leukocytes at the maternal-fetal interface
How do the anti-inflammatory factors at the maternal-fetal interface affect circulating monocytes and T cells?
Maternal circulating monocytes and T cells that appear at the maternal-fetal interface differentiate into M2 type MØ and Treg cells, respectively due to abundance of IL-10 and TGF-β (anti-inflammatory)
How is apoptosis in leukocytes triggered at the maternal-fetal interface?
STB secrete exosomes containing TRAIL and Fas ligand which trigger apoptosis in leukocytes.
How do cells of the syncytiotrophoblast remain undetected by the immune system?
STB cells never express any human leukocyte
antigen (HLA) molecules; therefore, maternal
circulating immune cells do not detect the STB as ‘non-self’.
How are trophoblasts protected from NK-mediated cytolysis?
Placental EVTs express HLA-G, which binds to
dNK inhibitory receptors (KIR2DL4, LILRB) to
protect the trophoblasts from NK-mediated
cytolysis.
How do decidual macrophages contribute to maternal tolerance?
dMØ produce IDO (indoleamine 2, 3-dioxygenase), which hinders T cell activation and phagocytosis of apoptotic trophoblasts
How does the HLA matching between mother and fetus affect the initiation of pregnancy?
Category - 1: Low-level matching between
maternal and fetal HLA I antigen= Initiating a successful pregnancy
Category - 2: High-level matching between
maternal and fetal HLA I antigen Leading to fetal loss in women with recurrent
spontaneous abortion
How can immunotherapy treat patients with recurrent spontaneous abortion?
-Male partner’s lymphocytes injected
to female partner
▪ Paternal HLA I is presented to CD8+
T cells
▪ CD8+ T cells differentiated into
CD8+TFLC
▪ CD8+TFLC stimulate
transdifferentiation of B cells into
Plasma cells
▪ Plasma cells produce IgG against
paternal HLA I
▪ The IgG blocks the fetal/trophoblasts
HLA I to inhibit cytotoxic CD8+ T cell
mediated cell killing
What is preeclampsia?
Preeclampsia (PE) is a multisystem obstetric disorder that presents as new onset of hypertension in conjunction with evidence of end-organ dysfunction beyond the 20th week of gestation.
What are the clinical features of pre-eclampsia?
Clinical features:
▪ Hypertension,
▪ Proteinuria,
▪ HELLP- Haemolysis, Elevated Liver enzymes, and Low Platelets,
▪ Visual disturbances.
How is preeclampsia treated?
Treatment: The only cure for PE is delivery of the fetal-placental unit, making PE a leading cause of premature birth
What are the fetal complications of preeclampsia?
Fetal complications: PE pregnancies are at higher risks for stillbirth, FGR and other neonatal complications
What is the immunomodulatory effect on uterine spiral arteries and how how is this different in preeclampsia?
▪ Normally, trophoblast and immune cells secrete proteases and angiogenic factors to progressively remodel uterine spiral arteries into high-capacity, low-resistance vessels.
▪ In PE, there is a breakdown in placental perfusion which ultimately results in placental ischemia.
What is effect of placental ischaemia in preeclampsia?
Placental ischemia induces the production of inflammatory modulators and antiangiogenic factors causing vascular dysfunction in the placenta and peripheral vessels
What is the effect of circulating placental factors in preeclampsia?
Circulating placental factors cause endothelial dysfunction and oxidative stress which contributes to hypertension and multi-organ
dysfunction.
Does the time of onset of preeclampsia change thee outcome?
No, however the pathophysiology is slightly different, but still results in placental hypoxia
How are tissue damage and vascular dysfunction induced during pre-eclampsia?
Cytolytic NK cells, macrophages, dendritic cells induce tissue damage and vascular dysfunction in PE while activating Th cells through antigen presentation
How are angiotensin 2 type 1 receptors involved in pre-eclampsia?
In PE, activated Th cells and B cells producing agonistic antibodies against the angiotensin II type 1 receptor which lead to antigen specific mechanisms of cell destruction and tissue damage
Describe the roles of dendritic cells and macrophages in the chronic inflammatory environment in preeclmapsia
Roles of dendritic cells and macrophages
▪ PE placentas show increased invading DCs and Mφ compared to normal placentas.
▪ These Mφ produce high levels of TNF-α and IFN-γ which induce apoptosis in trophoblasts.
▪ Excessive debris from dead trophoblasts lead to increased internalization and presentation
of fetal antigens by Mφ and DCs leading to inflammatory Th (TH1) response in PE.
What is the effect of progesterone on smooth muscle?
relaxation
What is the effect of progesterone on oxytocin?
Inhibits receptor expression
What produces oestrogen throughout pregnancy and what does it do?
Oestrogens: produced by corpus
luteum and then the placenta
* Breast, and nipple growth
* Uterine blood flow, myometrial
growth
* Promotes changes in the CV
system
What produces HCG? what does it do and what is a side effect?
-STB
-maintains corpus luteum
-responsible for hyperemesis gravidarum
Where is prolactin produces and what does it do?
-ant pituitary
- milk production
What changes happen to skin during pregnancy?
- Hyperpigmentation (linea nigra)
- Striae gravidarum (stretch marks)
What changes happen to breast in pregnancy?
- Increased size (& sensitivity)
- Darkened areolas
- Colostrum production
What haematological changes happen during pregnancy?
- Plasma volume
- Total blood volume
- Red cell mass
- White cell count (WCC)
NOTE that anaemia in
pregnancy is common
WCC elevated in pregnancy, is not always
a useful marker for
infection
For how long postpartum does hypercoagulation persist for ?
Hypercoagulation persists for the first 3 weeks after delivery and resolves by 6–8 weeks postpartum
How much does oxygen consumption increase by during pregnancy?
+30-50ml/min
What lung changes occur in pregnancy?
Progesterone increases minute
ventilation by relaxing smooth muscle
Note: changes in tidal volume rather
than changes in the respiratory rate
What is the acid base status in pregnancy and what adaptations occur to deal with this?
Pregnancy: Respiratory alkalosis
The lungs are (partly) responsible for
gas exchange and pH homeostasis
Adaptations mean:
- Excretion of HCO3 through kidneys
- O2 more available to the fetus
- Easier breathing for the mother
How does the mass of the heart change during pregnancy?
ventricular muscle mass
size of left ventricle and atrium
How do cardiac measurements change during pregnancy?
Cardiac output +40%
(4.5l/min to 6l/min)
Stroke volume +30%
Heart Rate +10-15%
BP and peripheral resistance decrease
How does pregnancy affect the position of the appendix?
It will be displaced higher up
What is the effect of progesterone during pregnancy on the GI system?
Cons
Constipation in pregnancy is very common.
Pros
The slowing down of the bowel allows for increased absorption.
what condition affects 50-80% of pregnant women?
Reflux esophagitis and heartburn
symptoms affect 50–80% of
pregnant women
why is pyelonephritis more common in pregnancy?
Pyelonephritis complicates 1–2% of
pregnancies due to the decreased ureteral
peristalsis and detrusor tone, mechanical
compression of the ureters, and incomplete
bladder emptying
How should the results of a urine dipstick in pregnant women be interpreted?
Proteinuria is common in pregnant women. A urine dipstick value of +1 is not evident of pathology. More than that requires investigation as it could be
preeclamspia.
What is the volume of the uterus in pregnancy and how is this achieved?
5000ml
How? smooth muscle hyperplasia and hypertrophy, increased elastic tissue, increased supportive fibrous tissue
Blood flow to uterus at term 500-800ml/min (from
50ml/min)
How does the cervix change during pregnancy?
Cervix
Increased vascularity and oedema, softening
↑ cervical glands and production of mucous plug Hyperplasia/eversion of endocervical epithelium
What changes occur to the vagina during pregnancy?
Venous congestion (blue/purplish tint)
How can fetal growth be estimated in low risk pregnancies?
Symphysis fundal height (SFH) is used to estimate fetal growth in low risk pregnancies
What are the effects of aortocaval compression in pregnancy?
- Oedema
- Pregnant people high risk for
VTE
How does CPR differ in pregnancy?
-Lateral uterine displacement
-perimortem caesarean delivery
Describe postpartum changes
- Involution of the uterus
- Cervical changes to return to
normal - Lactation
- Perineal health
- Mental health
Hormones postpartum
How does the name of breast milk change with time?
Day 1-3 Colostrum
Day 3-14 Transitional milk
>14 days Mature milk
What vitamins is breast milk rich in?
A and K
Which immunoglobulin is present in breast milk?
IgA
How is iron bound in breast milk?
To lactoferrin
Describe lysosyme in breast milk
- Bacteriocidal and anti-inflamatory action
- Contributes to the destruction of E Coli
and some salmonella strains - Production increases with age of infant
What are the risk factors for gastroenteritis associated with bottle feeding?
*Free iron in the gut (bacteria thrive on)
*No lactoferrin (mops up free iron)
*No bifidus factor (so ↑ pH conducive to bacterial growth)
*No oligosaccharides (to inhibit attachment of
pathogens)
*No secretory IgA (SIgA is disrupted by anything other than breastmilk and allows proteins to cross the gut wall)
*No entero/broncho-mammary pathway (for
antibody production)
* No white cells
* No lysozyme
* No epidermal growth factor (for gut maturation)
* No viral fragments (to stimulate antibody
response and trigger baby’s own immune
system)
* No anti-inflammatory molecules (to moderate response to pathogens)
* Possibility of contamination as every formula
feed requires expert preparation!
Describe the prolactin response
-Baby suckles
-sensory impulse pass from the nipple to the brain
-prolactin secreted by ant. pituitary goes via bloodstream to the breast
-lactocytes produce milk
How can breast feeding act as contraception?
Suppresses the release of gonadotrophin,
therefore inhibits ovulation (Lactational
amenorrhea LAM)
How are prolactin receptor sites opened?
expulsion of the placenta
Describe the oxytocin reflex
-Baby suckles
- sensory impulses pass from the nipple to the brain
-oxytocin secreted by posterior pituitary gland and goes to breasts via blood stream
-myo-epithelial cells contract and expel milk
What can hinder the oxytocin reflex?
-anxiety
-stress
-pain
-doubt
Describe feedback inhibitor of lactation
- Breast milk contains a protein (FIL) that causes the lactocytes to ignore the signals from prolactin when the breast is full.
- If only a little milk is removed or there is a long gap between feeds, milk production will slow down
- More frequent sucking/feeds (the more milk baby removes) – the less effect the FIL will have
Frequent, effective breastfeeding will help to ensure sufficient milk production
How can preterm birth be defined by gestational age?
Extreme PTB (<28 weeks)
Very PTB (28-31 weeks)
Moderate PTB (32-33 weeks)
Late PTB (34-37 weeks)
How can preterm birth be defined by weight?
Low BW <2.5kg
Very low BW <1.5kg
Extremely low BW <1kg
What factors can lead to preterm birth?
-Uterine overdistension
-decidual haemorrhage
-cervical insufficiency
-cervical remodelling
-infection and inflammation
What are the routes of intrauterine infection and what is the most common one?
- Ascending commonest
route of infection - Haematogenous via
placenta - Retrograde seeding via
fallopian tubes - Iatrogenic, following
invasive procedures
What cytokines are important in the mechanisms of preterm labour due to infection?
Cytokines play an
important role:
◦ IL-1β – proinflammatory
◦ TNFα – proinflammatory
◦ IL-10 – anti-inflammatory
Describe inherent defences against infection in the reproductive tract?
Inherent defences against infection in reproductive tract:
◦ Acid vaginal pH (secondary to lactobacilli)
◦ Cervical mucus
◦ Epithelial barriers
◦ Innate immune system receptors (TLRs)
What is more likely to happen with cervical insufficiency and where is cervical insufficiency most likely to occur?
*Premature cervical ripening: classically leads to mid-trimester pregnancy loss
*More likely to occur in patients with anatomically disrupted cervices (e.g. post LLETZ or congenital abnormalities)
Other than multiple gestation what may cause uterine overdistension?
-polyhdramnios
-uterine anomalies
How is preterm birth currently predicted?
History based risk assessment
Ultrasound cervical length screening
Predictive bedside tests:
◦ Actim Partus
Infection screening – HVS/MSU
Clinical diagnosis
What are the risk factors for preterm birth?
*Previous preterm birth
*Multiple pregnancy
*Previous cervical surgery
*Uterine anomalies
*Smoking
*Race
*Age
*Bacterial vaginosis
*Short cervix on ultrasound
Describe the actim partus test
Phosphorylated form of insulin-like
growth factor binding protein-1
(phIGFBP-1)
PhIGFBP-1 produced in the fetal
decidua, leaks into the cervix when
the decidua and chorion detach
How does primary prevention of preterm birth work?
Primary prevention
◦ Aim to reduce population risk
◦ Effective interventions not yet
demonstrated
-Smoking cessation, reducing multiple pregnancy
How can secondary prevention be used in preterm birth?
Secondary prevention
◦ Select those at increased risk for
surveillance + prophylaxis
- cervical length screening,cervical cerclage and progesterone
How can tertiary prevention be done in preterm birth
Tertiary prevention
◦ Treatment after diagnosis of preterm
labour
◦ Aims to reduce morbidity and mortality
what are the different types of cervical cerclage?
*History-indicated cerclage - risk factor
based prophylactic insertion, usually at
12-14/40
*Ultrasound-indicated cerclage -
therapeutic insertion in response to
cervical length shortening on TVUSS
but no exposed fetal membranes in
vagina
*Rescue cerclage – insertion as
therapeutic salvage measure after
cervical dilation with exposure of fetal
membranes, usually following
symptomatic presentation
What infections are antibiotics targeting when used to prevent ptb?
*Asymptomatic bacteriuria
* Incidence in pregnant women 2-10%. If untreated, rates of pyelonephritis ~30%
*Bacterial vaginosis
*Periodontal disease
* Most recent studies: treatment does not reduce incidence PTB
*Group B Strep
How do antenatal corticosteroids work when preparing for ptb?
Antenatal corticosteroid treatment:
◦ Use significantly reduces neonatal death, RDS, IVH
◦ 24+0 to 34+6/40.
◦ Accelerates development of type 1 and 2 pneumocytes in fetal lung
◦ Increases alveolar epithelial sodium channels, allowing fluid resorption from
fetal lung
◦ Increases surfactant protein transcription and translation
What drug can be used to reduce the risk of cerebral palsy in PTB?
*MgSO4
Which drugs are used in tocolysis?
◦ Nifedipine – calcium channel blocker
◦ Atosiban – oxytocin receptor antagonist
◦ Similar efficacy and side effect profile in Cochrane review.
Atosiban expensive
Which ligament support the uterus?
The uterus is supported in the pelvic cavity by:
the broad ligaments round ligament
cardinal ligaments and rectouterine (relating to rectum and uterus) and vesicouterine
(relating to bladder and uterus) folds or ligaments.
What can sonohysterography used for?
Sonohysterography allows for a more in-depth investigation of the uterine cavity. These exams are typically performed to detect:
uterine anomalies
uterine scars
endometrial polyps
fibroids
cancer, especially in patients with abnormal uterine bleeding
Some physicians also use sonohysterography for patients with infertility.
How does a doppler ultrasound work?
Doppler ultrasound, a special application of ultrasound, measures the direction and speed of blood cells as they move through vessels. The movement of blood cells causes
a change in pitch of the reflected sound waves (called the
Doppler effect)
What are the congenital anomalies of the uterus?
-Unicornuate
-Bi cornuate
-Septate uterus
-uterus didelphys
-arcuate uterus
What scans happen throughout pregnancy?
- Early scan if clinical reason
- 12 week dating scan and nuchal thickness
- 20 week anomaly scan
- Additional scans depending on clinical need
What is assessed at the 12 week dating scan?
- Heart beat to assess viability
- Crown rump length to date the pregnancy
- Number of fetuses
- Nuchal translucency
What is assessed in a 20 wk anomaly scan
- To detect any abnormality
– Detailed whole body scan - To assess the nature of the abnormality
– Viable or not - To assess the extent of the abnormality
– Referral to fetal maternal specialist - Assess placenta and its location
what are the definitions of death related to pregnancy?
Definitions
* Direct death; due to disorder directly linked to pregnancy
* Indirect; death from a previous existing disease or diseases that developed during pregnancy that are not
due to a direct obstetric cause but aggravated by pregnancy
* Coincidental; incidental or accidental death not due to pregnancy
* Late; between 42 days up to 12 months after delivery
Give an example of a genetic condition which can cause obesity
Prader willi syndrome
Give examples of medical reasons which can cause obesity
● Hypothyroidism
● Cushing’s syndrome
● Corticosteroids
● Anti psychotics
List the risks of obesity for the mother
● Type 2 Diabetes
● Insulin resistance
● Hypertension
● Dyslipidemia
● Sleep apnoea
● Pregnancy related
complications
● Anaesthetic risk
● Gallbladder disease
● Coronary heart disease
● Osteoarthritis
● Cancer – colon, breast,
endometrium
● PCOS
List the maternal risks of obesity in pregnancy
● Gestational diabetes (GDM)
● Pre-eclampsia
● Thromboembolism
● Dysfunctional labour
● Higher caesarean section rates
● General anaesthesia
● Higher risk of postpartum haemorrhage
● Wound infections
● Longer stay in hospital
● Lower breastfeeding rate
What are the intrapartum risks of obesity in pregnancy?
●Women with obesity are more likely to:
○require induction of labour
○fail to progress in labour
○require operative delivery
What are the risks of maternal obesity to the baby
● Miscarriage
● Congenital anomalies
● Stillbirth
● Neonatal death
● Prematurity
● Macrosomia, shoulder dystocia and brachial plexus injury
● Fetal growth restriction
● Hypoglycaemia
● Hyperbilirubinaemia
● Respiratory distress syndrome
What are the long term consequences oof maternal obesity for the child?
● Obesity
● Cardiovascular dysfunction : higher blood pressure
● Increased risk of diabetes
● Cognitive and behaviour disorders : ADHD, eating disorders and psychotic
disorders
What are the possible mechanisms for how maternal obesity is related to subsequent child obesity?
Obesity in pregnancy is associated with:
● Peripheral and hepatic insulin resistance
● Increase in metabolic fuels, glucose, lipids, leptins and aminoacids
● Inflammatory state
● Altered adipocyte function
● Increased adiposite size
● Increased mRNA expression of genes involved in adipocyte differentiation
What are the possible explanations for epigenetic mechanisms involved in subsequent childhood obesity?
● Maternal over-nutrition and obesity leads to:
○ long term modification of specific fetal genes
○ persistently altered gene expression
○ altered organ function
What dosage of folic acid should obese pregnant women be prescribed?
5mg
Which women should be screened for gestational diabetes?
BMI over 30
What are the moderate risk factors for pre-eclampsia?
Moderate risk factors for pre-eclampsia are:
○ BMI of 35 kg/m2 or greater,
○ first pregnancy/ pregnancy interval > 10 years
○ maternal age of more than 40 years,
○ family history of pre‐eclampsia
○ multiple pregnancy
When would you be concerned about a ladys risk of preeclampsia and what should the intervention be?
● Women with a booking BMI 35 have an increased risk of
pre-eclampsia
● If more than one moderate risk factor 150 mg aspirin daily to
commence prior to 16 weeks of gestation beneficial
In women with high BMI, how should fetal growth be assessed?
●Symphisis-fundal height measurement unreliable when BMI> 35
●Serial Ultrasound scans for growth assessment from:
○28 weeks if BMI> 40
○32 weeks BMI > 35
Name 5 in vitro models of pregnancy
-2D cell culture
-Transwell system
-explant culture
-spheroid/organoid
-organ on chip
Describe a transwell system
Transwell System:
monolayer cells with
ability to migrate
Describe explant culutre
Explant Culture: fresh
placental tissue supported
in culture
Describe spheroid/organoid
Spheroid/Organoid:
Multiple cell types grown in
aggregates
What develops from the endoderm?
-alveolar cells
-thyroid cells
-pancreatic cells
What develops from the mesoderm?
cardiomyocytes
-skeletal muscle
-tubule cells of the kidney
erythrocytes
smooth muscle cells of the gut
What develops from the ectoderm?
skin cells of the epidermis
neurons of the brain
melanocytes
What gestational weeks can major defects in CNS structure?
wk3 -wk 16
What gestational weeks can major defects in heart structure occur?
wk3 -end of week 6
What gestational weeks can major defects in limb structure occur?
start of week end of wk 6
What gestational weeks can major defects in eye structure occur?
mid wk 4- mid week 8
What gestational weeks can major defects in teeth structure occur?
mid wk 6- start of week 12
What gestational weeks can major defects in palate structure occur?
towards the end of wk 6 and the end of wk 8
What gestational weeks can major defects in external genitalia structure occur?
mid wk 7 towards the end of wk 12
What gestational weeks can major defects in ear structure occur?
start of week 4 to mid wk 12
What gestational weeks can major functional defects and minor structural in CNS structure occur?
Wks 20-36
What gestational weeks can major defects in heart and minor defects structural occur?
from wk 6 to end of wk 8
What gestational weeks can major defects in the limbs and minor structural defects occur?
start of wk 7 -end of week 8
What gestational weeks can major defects in the eyes and minor structural defects occur?
Halfway through wk 8 to wk 38
What gestational weeks can major defects in the teeth and minor structural defects occur?
wk 12- wk 38
What gestational weeks can major defects in the palate and minor structural defects occur?
wk 12-wk16
What gestational weeks can major defects in the external genitals and minor structural defects occur?
end of week 12-week 38
What gestational weeks can major defects in the ears structural defects occur?
halfway through week 12 -wk 20
What is the chance of survival at 24 wks birth?
50%
what time period is spontaneous loss of pregnancy counted as miscarriage?
up until week 24
What are the different types of miscarriage and how are they defined?
Biochemical- before pregnancy can be seen on USS
Early pregnancy loss- before 13 wks
Late pregnancy loss- between 14 and 24 wks
Threatened- a pregnancy that could possibly end in miscarriage due to mild vaginal bleeding with or without abdominal pain or cramping
Inevitable- a miscarriage that can’t be avoided because you’re bleeding, cramping and your cervix is open.
incomplete- you lose most of your pregnancy through bleeding but you still have some tissue left in your womb
complete- Complete miscarriage — when all the products of conception have been expelled from the uterus, and bleeding has stopped
septic- pregnancy loss accompanied with intrauterine infection
anembryonic- It’s also called an ‘anembryonic pregnancy’ as there is no embryo (developing baby). In this type of miscarriage, a sac and placenta grow, but there is no baby
missed miscarriage- occurs when a fetus is no longer alive, but the body does not recognize the pregnancy loss or expel the pregnancy tissue.
What is the USS criteria for diagnosis of miscarriage?
➢ Crown-rump length of at least 7 mm and no heartbeat.
➢ Mean gestational sac diameter of at least 25 mm and no embryo.
➢ Absence of embryo with heartbeat at least 2 weeks after an ultrasound scan
that showed a gestational sac without a yolk sac.
➢ Absence of embryo with heartbeat at least 11 days after an ultrasound scan
that showed a gestational sac with a yolk sac
What is an ectopic pregnnacy?
A pregnancy located outside of the uterine cavity, usually in the fallopian tube.
What are the symptoms of an ectopic pregnancy?
Other symptoms:
➢ dizziness, fainting or syncope
➢ shoulder tip pain
➢ urinary symptoms
➢ passage of tissue
➢ rectal pressure or pain on defecation.
Common symptoms:
➢ abdominal or pelvic pain
➢ amenorrhoea or missed period
➢ vaginal bleeding with or without clots.
What are the common signs of ectopic pregnancy?
Common signs:
➢ pelvic tenderness
➢ adnexal tenderness
➢ abdominal tenderness
What are the less common signs of ectopic pregnancy?
Other signs:
➢ cervical motion tenderness
➢ rebound tenderness or peritoneal signs
➢ pallor
➢ abdominal distension
➢ enlarged uterus
➢ tachycardia or hypotension
➢ shock or collapse
➢ orthostatic hypotension.
How is recurrent miscarriage defined?
➢ Loss of three or more consecutive pregnancies
What are the RF for an ectopic pregnancy?
Maternal age, previous miscarriages, advanced
paternal age, obesity, alcohol ,smoking, excessive caffeine
What haematological conditions should be considered in cases of recurrent miscarriage?
antiphospholipid syndrome, thrombophilia
What genetic factors may contribute to recurrent miscarriage?
balanced translocation, chromosomal abnormalities
What anatomical factors may contribute to recurrent miscarriage?
➢ Anatomical factors: Uterine malformations, Cervical weakness
What endocrine factors can lead to recurrent miscarriage?
Uncontrolled Diabetes, Thyroid dysfunction, PCOS.
How can the aetiologies of hydatidiform moles be?
Benign (80%)
Invasive mole (10-15%)
Choriocarcinoma- malignant 2-3%
What is a hydratiform mole?
Hydatidiform mole (HM) is a rare mass or growth that forms inside the womb (uterus) at the beginning of a pregnancy. It is a type of gestational trophoblastic disease (GTD)
What is a complete mole in molar pregnancy?
2 sets of paternal genes, no maternal genes, no fetus
What is a partial mole
3 sets of genes 1 maternal, 2 paternal and a non-viable fetus
What are the risk factors for a molar pregnancy?
Higher incidence in Asian women
Extremes of age increases risk
Previous molar pregnancy
Diets low in protein, folic acid, and carotene
Defects in the egg, abnormalities of uterus etc
Women with Blood Group A
How can molar pregnancy be diagnosed clinically?
Vaginal bleeding after amenorrhea
Hyperemesis gravidarum, hyperthyroidism
Passing of grape like vesicles
How can molar pregnancies be diagnosed radiologically?
Complete Mole : Absent gestational sac & a complex echogenic
intrauterine mass with cystic spaces(snow storm)
Partial Mole: May resemble a normal conception
What are the 3 factors that may lead to a baby being born prematurely?
- Maternal illnesses
– Pregnancy induced hypertension - Placental failure
– Poor growth
– Abruption - Preterm labour
– Mechanical
– Inflammation/infectio
What are the stages of lung development?
- Pseudoglandular phase
– 6 to 16 weeks gestation - Canalicular phase
– 16 to 26 weeks gestation - Saccular phase
– 26 to 32 weeks gestation - Alveolar stage
What are the short-term complications of respiratory distress syndrome?
- Death
- Air leaks
– Pneumothorax
– Pulmonary interstitial emphysema
– Pneumomediastinum
– Pneumopericardium
– Pneumoperitoneum - Uncontrollable hypoxia
How can respiratory distress syndrome lead to chronic lung disease?
-Chronic inflammation
-impaired lung growth
What are the signs of chronic lung disease of prematurity?
- Severe inflammatory
changes - Fibrosis
- Atelectasis
- Hyperexpansion
How should RDS be managed?
start off with the least amount of intervention and level it up
* Less is more
– Intubation and ventilation, then
– CPAP therapy, then
– High flow oxygen
Describe the pathophysiology of retinopathy of prematurity
-blood vessels in the eye grow towards areas of hypoxia
- If there is hyperoxic insult, then there will be arrest of normal vascular growth
-fibrous ridge forms
How can an ischaemic - reperfused bowel lead to perforation?
Mural oedema
intra mural gas
perforation
How are prebiotics used in preterm birth?
Used to populate the gut microbiome to prevent NEC
Describe the 3 muscular layers of the uterus
- Uterine smooth muscle – MYOMETRIUM
- Three major layers of smooth muscle:
➢ Inner circular layer
❖ underlies endometrium
❖ “junctional zone”
➢ Interlocking middle layer
➢ Outer longitudinal layer
Which contractile proteins are expressed in the myometrium of pregnant women and where are they mainly expressed?
❑ Gap junctions (Connexin-43; Cx-43)
❑ NF-B family members
❑ RNA splicing proteins
Mainly the upper section of the uterus
Name 3 pro quiescence molecules
Pro - quiescent molecules
➢ Progesterone
➢ Gs / cAMP / PKA
➢ CRH
➢ PGE2
➢ PKC
➢ cGMP
➢ NO
➢ Ion Channels (K+)
name 3 pro contractile molecules
Contractile - associated molecules
➢ Oestrogen
➢ CRH
➢ Gq
➢ Oxytocin
➢ PGE2
➢ PGF2
➢ Ca2+
➢ Inositol-1,4,5-triphosphate (IP3)
➢ Ion Channels (Na+, Ca2+, Cl-)
How does G alpha s relate to myometrial quiescence?
-Quiescence is an active process, so certain pathways need to be closed off
-G alpha s is a GTP binding protein, activation elevates cAMP and protein Kinase A activity
-PKA causes phosphorylation of intracellular proteins, causing inactivation of acto-myosin ATPase
- Repressed acto-myosin ATPase causes uterine smooth muscle relaxation
Describe the theory of placental clock
placental clock
Increased placental corticotrophin-releasing hormone
Stimulates fetal pituitary release of ACTH
ACTH increases fetal adrenal DHEA secretion
DHEA is a major oestrogenic precursor
Oestrogens stimulate increases in myometrial gap junction protein numbers
Facilitates regular coordinated uterine contractions
How might messaging from the fetus initiate labour?
▪ ACTH? (previous slide)
▪ Fetal surfactant proteins – (SpA)?
Increased SpA secretion at term activates
amniotic fluid-derived (AF) macrophages
AF macrophages migrate to uterine wall
Activation of inflammatory gene expression
What are the 3 stages of partruition?
1) Cervical dilatation (remodelling)
2) Fetal expulsion (myometrial contraction)
3) Placental delivery and haemostasis
Describe cervical ripening
- Growth and remodelling of the cervix prior to labour
-Effacement and dilatation due muscular action of cervix and uterus:
➢ “brachystasis”
First Phase of Labour – Cervical ripening
What factors promote cervical ripening?
Promoted by release of:
➢ PGE from cervical mucosa
➢ Relaxin
➢ Placental oestrogens
➢ Regulated inflammation – NF-B-mediate
What does increased expression of gap junction proteins in the fundal myometrium allow?
cells to communicate with each other
Describe functional progesterone withdrawal
Reduced uterine sensitivity to progesterone
How is myometrial muscle cell membrane potential different in labour?
➢ Differential ion permeabilities
➢ Plasma membrane oscillator function
What 4 things contribute to myometrial contraction in labour?
Increased expression of gap junction proteins in fundal myometrium
Functional Progesterone Withdrawal
Change in myometrial muscle cell membrane potential (Em)
Elevated [Ca2+]
What ion is the major determinant of myocyte membrane potential?
K+
Describe myometrial membrane potential during quiesence
- Em strongly –ve (net K+ exit)
- Membrane is hyperpolarised
- Few regular contractions
Describe myometrial membrane potential in myometrial contraction
Myometrial contraction
* Membrane can depolarise
❑ Em strongly +ve (net Na+/Ca2+ entry)
* Increasing rhythmical depolarisation –
hyperpolarisation cycles
How does Ca2+ affect myometrial contractility?
Increases it
Describe sources of calcium
➢ Extracellular sources
❑ Via voltage-gated Ca2+ channels
❑ T- and L-type
➢ Intracellular stores
❑ Store operated Ca2+ channels on sarcoplasmic reticulum
❑ Trigger role?
How does nifedipine work?
Nifedipine – Ca2+ channel blocker
➢ Inhibits premature myometrial contractions
How does oxytocin stimulate myometrial contractions?
By elevating Ca2+, through releasing intracellular stores
What pathway increases the number of ocytocin receptor numbers seen at term in the fundal myometrium?
NF-KB
How is oxytocin released?
-made in hypothalamus
-stored in posterior pituitary
-cervical/myometrial stretch initiates secretion and positive feedback mechanism
What mechanisms allow for placental delivery?
Mechanisms:
* Increase clotting efficiency
* Reduce clot dissolution efficiency
* Rapid uterine contraction
What factors change in order to make the mothers blood hypercoaguable?
- Plasma fibrinogen levels
- Erythrocyte sedimentation rate
- Clotting factors (VII, VIII, X)
How much fibrin is used initially when placenta detaches?
➢ 5-10% of circulatory fibrinogen used
What may cause a depletion of fibrinogen reserve during placental delivery?
- Inadequate myometrial contraction (placenta near lower segment)
- Incomplete placental separation
How is atosiban used in premature labour?
Prevents uterine contraction, oxytocin receptor antagonist
What is the role of administering tranexamic acid in labour?
Tranexamic acid is used in labor to prevent or treat postpartum hemorrhage (PPH), a condition where a woman experiences excessive bleeding after childbirth, by inhibiting the breakdown of blood clots, effectively reducing blood loss; it is most effective when administered within a few hours of delivery.
Prevents plasminogen activation by tPA/uPA
How is reduced clotting dissolution achieved in placental delivery?
Plasminogen Activator Inhibitor
Describe the primary decidual reaction that allows human blastocyst implantation
Primary decidual reaction:
➢ Uterine stromal cell enlargement
➢ Uterine Natural Killer (uNK) cells prominent
➢ Other adaptations of maternal immune system
The cytotrophoblast is a progenitor cell, what can it differentiate into and what primary roles do these cells do?
Fusion – multinucleate syncytiotrophoblast
Invasive phenotype: Extra-villus trophoblast (EVT)
How are maternal cells marked?
➢ All nucleated cells - MHC-I (HLA-A, B, C)
➢ Antigen Presenting Cells (APC) MHC-II
❖ (Lymphocytes, macrophages
How are extra-villus trophoblasts marked?
➢ Only MHC-I (HLA-C, E and G)
How are syncytiotrophoblast cells marked?
No HLA-A or HLA-B self:non-self markers
Out of cells derived from the cytotrophoblast which are most likely to stimulate a modified maternal immune response?
Extra-villus trophoblast, the syncytiotrophoblast has no HLA markers
Which cells make up the majority of the decidual immune cells?
70%
how are MHC-I proteins bound?
By uNK cells expressing Ig-Like receptors
Which cells facilitate EVTB invasion?
uNK
What pathologies may uNK play a role in?
Pre-eclampsia?
IUGR?
Recurrent miscarriage?
Placentation?
What is endovascular invasion and which cells play a role in it?
Endovascular Invasion (acquisition of maternal blood supply)
➢ Driven by EVT and uNK cells
➢ Taps maternal blood supply
➢ Completes ~10-12wks
How does decidua remodelling post partum multiparity differ between pregnancies?
Decidua remodelling post partum in multiparity is more efficient in the 2nd pregnancy due to possible memory in the innate system
Which cell markers on the EVT interact with uNK cells?
-HLA-G
-HLA-C1/HLA-C2
-HLA-E
EVTB expresses HLA-G, what does this do when it interacts with uNK?
- Immunomodulation
- IL8, IL10 INF-g, VEGF, PGF
- Pregnancy-associated inflammation
- Placenta derives its own blood supply?
EVTB expresses HLA-C, what does this do when it interacts with uNK?
HLA-C:
* Polymorphic
* Paternal specificity
* Combinations of HLA-C:KIR
determine implantation outcome?
EVTB expresses HLA-E, what does this do when it interacts with uNK?
HLA-E:
* Presents HLA-G leader peptide
* Inhibits NK cell cytotoxicity
* Prevents EVTB death
How do cell markers contribute to reproductive failure?
The optimum matching between the EVTB and uNK is HLA-C1 and maternal KIR2DS, this allows for appropriate decidual invasion and uNK activation
The worst combination is EVTB to express HLA-C2 and the uNK cell to have KIR2DL, as this inhibits uNK cells, causes poor EVT invasion and possible pathology such as pre-eclampsia
How can clinical observations lead us to consider the balance of TH cells in pregnancy?
Pregnancy favours TH2
➢ Th1-cell-mediated autoimmune disease – rheumatoid arthritis
❖ Symptoms improve during pregnancy
➢ Th2-cell-mediated autoimmune disease – systemic lupus erythematosus
❖ Symptoms become worse during pregnancy
Whar conditions may a lack of TH2 bias in pregnancy lead to?
- Pre-eclampsia?
- Re-current miscarriage?
- IUGR
Which cells promote B cell activation in order for plasma cells to cross the placenta, and which antibody crosses the placenta?
TH2 cells
IgG
Describe maternal antibodies cross-reacting with paternal HLAs
- Maternal immune system retains ability to produce antibodies against paternal HLA-
A, B and C antigens
➢ 15% of first pregnancy
➢ 60% of subsequent pregnancies with same father - Maternal IgG transported across syncitiotrophoblast
- IgG cross-reacting with paternal HLAs are removed
➢ Paternal HLAs presented on
❖ Placental Macrophages
❖ Chorionic villus - Immune complexes then removed by macrophages
In haemolytic disease of the newborn, which antigens may maternal Ig’s form against and which is most common?
➢ A, B,O and Rhesus-C, -D or -E
➢ Most common Rhesus-D
What type of genetic profile leads to haemolytic disease of the newborn?
➢ Rh-ve mother (dd) X Rh+ve father (DD or Dd)
