fetal development and pregnancy Flashcards
(571 cards)
1
Q
Which organ is the first to develop in the fetus?
A
The placenta
2
Q
What does the phrase haemochorial villous organ mean?
A
Maternal blood comes into direct contact with placental trophoblast cells
3
Q
List diseases in which disordered placental development is the primary defect in major diseases
A
-Pre-eclampsia
-fetal growth restriction
-Recurrent miscarriage
-preterm birth
-still-birth
4
Q
What does the placenta develop from?
A
The trophectoderm
5
Q
Which part of the trophectoderm attaches to the surface of the uterine mucosa?
A
The polar trophectoderm
6
Q
Describe the development of the placenta at the implantation stage
A
- 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.
7
Q
Describe the development of the placenta in the lacunar stage
A
▪ 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.
8
Q
Describe the villous stage of placental development (before days 17-18dpf)
A
- 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.
9
Q
Describe placental development from day 17 dpf
A
-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.
10
Q
How do the primary villi form in the villous stage of placental development?
A
Trophoblast cells under the syncytium are called the cytotrophoblast, they rapidly proliferate into the primary syncytium forming the primary villi
11
Q
What is the maternal-fetal interface?
A
Maternal-fetal Interface: Where the
cytotrophoblast (CTB) is in contact with
the decidua
12
Q
When is the blueprint for the placenta established?
A
By the end of the 1at trimester
13
Q
What does EMT stand for in the context of maternal-fetal interface?
A
Epithelia-mesenchymal transition
14
Q
Describe what cytotrophoblast cells do in epithelial-mesenchymal transition (EMT)
A
Individual cytotrophoblast cells leave the shell to invade the decidua as extravillous trophoblast
15
Q
For villous stem cell cytotrophoblast, what are the 3 possible cells that they can differentiate into?
A
-Endovascular trophoblast
-placental bed giant cells
-syncytiotrophoblast
16
Q
What are the pathways that villous stem cells (cytotrophoblasts) can take when differentiating?
A
-Extravillous
-villous
17
Q
Describe the extravillous pathway for cytotrophoblast differentiation
A
-Cytotrophoblast cell columns and shell
-endovascular trophoblast or interstitial trophoblast
-interstitial trophoblast becomes placental bed giant cells
18
Q
Describe the villous pathway in cytotrophoblast differentiation
A
villous cytotrophoblast
-syncytiotrophoblast
19
Q
what is the role of endovascular trophoblasts?
A
Remodels uterine arteries
20
Q
What is the role of placental bed giant cells
A
migrates into the decidua and myometrium
21
Q
What is the purpose of the syncytiotrophoblast?
A
Primary site of placental transport, protective and endocrine functions
22
Q
What are the 4 functions of the placenta?
A
-Gas exchange
-Transport and metablism
-protection
-endocrine functions
22
Q
Where does gas exchange in the placenta take place?
A
maternal-fetal interface
23
Q
How does oxygen pass from mother to fetus?
A
-passive diffusion
-pressure gradient between maternal blood in the intervillous space and umbilical artery of the fetus
24
What is the pressure difference and net O2 transfer in the placenta?
Pressure difference 4 kPa
Net O2 transfer= 10%
25
How does CO2 pass from fetus to mother?
passive diffusion
26
What is the PCO2 pressure difference between the umbilical artery and uterine artery?
1.8kPa
27
What is the main carbohydrate transferred in the placenta?
-Glucose
28
Why is the fetus dependent on maternal glucose?
It has a low capacity for gluconeogenesis
29
How is glucose transferred to the fetus in the placenta?
-facilitated diffusion using glucose transporters
30
Where are glucose transporters present in the placenta?
On both the apical and basal surfaces on the syncytiotrophoblast and villous endothelial cells
31
What produces lactate and how is it transported?
The placenta and via the placenta
32
Why does the fetus require amino acids?
Protein synthesis
33
Where can the fetus aquire amino acids from?
it can metabolise its own but it can also get them from the mother
34
How are amino acids transferred between mother and fetus?
active transport through amino acid transporters in the syncytiotrophoblast
35
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
36
What specific lipids does the fetus require?
-fatty acids
-cholesterols
37
what does the fetus use lipids for?
synthesis of
-signalling molecules
-cell membranes
-myelin sheath
38
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
39
What does the fetal liver synthesise?
Cholephilic compounds such as bile acids and heme-related biliary pigments such as bilirubin
40
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
41
How is water transferred between mother and fetus?
passive diffusion
-hydrostatic pressure and osmotic pressure gradients
42
How are Na+ and cl- transferred between mother and fetus?
passive diffusion and active transport
43
How are k+,ca2+ and PO43- transferred between fetus and mother?
active transport using ion pumps such as Na/K ATPase and Ca ATPase
44
Name 3 methods that the placenta uses in immune defence against pathogens
-physical barrier
-secretory factors
-passive immunity
45
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
46
What type of pathogen does the membrane composition of the placenta protect against?
-parasites
-Toxoplasma gondii
47
Name 4 types of secretory factors involved in the immune defense function of the placenta
-Interferons
-TLRs
-Chemokines
-miRNAs
48
which antibodies provide passive immunity to fetuses?
IgG
49
How are antibodies transferred from mother to fetus?
Neonatal Fc receptors for IgG facilitate the transfer of iGg in the placenta
50
When does transplacental passage of maternal humoral immunity begin?
16th wk of gestation, peaking at term
51
How do the concentrations of igG in fetal and maternal circulation compare at birth?
-they're higher in the fetus
52
How is the developing Festus considered immunologically by the mother?
semi-allograft
53
What is the failure of maternal tolerance associated with?
-pre-eclampsia, miscarriage, preterm birth
54
Describe generally how maternal tolerance is achieved
Restriction and modulation of leukocytes at the maternal-fetal interface
55
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
56
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
57
What triggers apoptosis in leukocytes? (maternal immune tolerance)
-Synctiotrophoblast secretes exosomes contains TRAIL and Fas ligand
58
How does the STB avoid detection by circulating maternal immune cells?
-Doesn't express any human leukocyte antigen
59
How is the trophoblast protected from NK-mediated cytolysis?
Placental extravillous trophoblast expresses HLA-G, which binds to NK inhibitory receptors
60
How do the placenta, mother and fetus communicate?
-hormones
-growth factors
-cytokines
61
Name 5 hormones produced by the placenta
1) Human chorionic gonadotrophin
2) progesterone
3) oestrogens
4) placental lactogen
5) placental growth hormone
62
what type of hormone is hCG?
glycoprotein
63
what produces hcG?
Syncytiotrophoblast
64
when does hCG production peak?
8 weeks gestation
65
name 3 functions of hCG
-stimulates the corpus luteum to produce progesterone and oestrogens
-cytotrophoblast cell fusion
-differentiation of villous trophoblasts
66
when does the corpus luteum atrophy?
8 weeks gestation
67
What type of hormones are Oestrogen and progesterone?
-steroid
68
which placental cells produce esotrogen and progesterone?
STB cells
68
When does the placenta take over the production of progesterone and oestrogens?
8 weeks gestation
68
what are the roles of progesterone during pregnancy?
inhibit uterine contractions
suppresses LH release, stopping ovulation
68
What is the role of oestrogen during pregnancy?
-specialised growth hormones for the mothers reproductive organs (breasts, uterus, cervix and vagina)
69
What type of hormone is human placental lactogen?
polypeptide
70
which cells make human placental lactogen?
STB
71
when is human placental lactogen present in maternal circulation?
appears from 3-6 wks gestation, increasing throughout and disappears at delivery
72
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
73
What type of hormone is placental growth hormone?
single-chain peptide
74
what makes placental growth hormone?
STB
75
which hormone is placental growth hormone structurally similar to?
pituitary growth hormone
76
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
77
What is a major function of placental growth hormone?
regulate maternal blood glucose to give the fetus an adequate supply
78
when does the bilaminar disc form?
during the 2nd week post fertilisation
79
when does the trilaminar disc form and what does is contain?
week 3 post fertilisation
-ectoderm, mesoderm, endoderm
80
What organs come from the endoderm?
1) digestive system
2) liver
3)pancreas
4) lungs (inner layers)
81
What organs come from the mesoderm?
1) circulatory system
2) lungs (epithelial layers)
3) skeletal system
4) muscular system
82
what organs come from the ectoderm?
1) hair
2) nails
3) skin
4) nervous system
83
When is the fetal stage of development?
9th week of gestation up until birth
84
when do the sex organs differentiate?
during the 3rd month of gestation
85
what is the role of insulin in fetal development?
-late gestation, growth in normal and adverse nutritional cicumstances
86
How does hyperinsulinemia in DM affect a fetus?
macrosomia due to excessive fat deposition
87
how can low insulin affect a fetus?
growth restriction
88
what is the purpose of thyroxine in fetal development?
-required in late gestation for normal growth
89
How can a thyroxine deficiency affect a fetus?
-deficiency in skeletal and cerebral maturation (cretinism)
-delayed surfactant production in the lungs
90
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
91
what does the umbilical vein do?
carries oxygenated blood from placenta to fetus
92
what do the umbilical arteries carry, and where do they arise from?
-carry deoxygenated blood from fetus to placenta
-common iliac arteries
93
What does the ductus venosus allow?
passage of the umbilical vein through theliver and into the inferior vena cava
94
what does the presence of the foramen ovale allow for?
right to left atrium shunt whilst some blood is pumped into the right ventricle
95
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
96
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
97
when does the ductus arteriosus close after birth?
within 96 hours
98
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
99
what is the name of the remnant of the ductus arteriosus?
ligamentous arteriosum
100
what causes the foramen ovale to close after birth?
increased left atrial pressure when pulmonary circulation is established
101
what is the remnant of the foramen ovale called?
fossa ovale
102
when does the ductus venosus close?
after cord clamping, due to decreased umbilical venous pressure
103
what is the remnant of the ductus venosus called?
ligamentum venosum
104
what is the name of the remnant of the umbilical vein?
round ligament of the liver
105
what are the names of the remnants of the umbilical arteries?
medial umbilical ligaments
106
what shunt is seen in a patent ductus arteriosus?
left to right
107
what may the presentation of patent ductus arteriosus be?
respiratory distress and hypoxaemia
108
what can the consequences of patent ductus arteriosus be?
brain damage and cardiac dysfunction
109
what type of shunting is caused by a patent foramen ovale?
right to left shunting of deoxygenated blood
110
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
111
when and where is the first fetal blood cell formed?
the yolk sac from 14-19 days after conception
112
when does haemopoiesis in the yolk sac stop?
3rd month of development
113
in the 5th week of embryonic life, where does haemopoiesis begin?
liver and spleen
114
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
115
Describe the structure of haemoglobin F
2 alpha and 2 gamma chains
116
describe the structure of adult haemoglobin
2 alpha and 2 beta chains
117
when does the switch from fetal to adult haemoglobin occur?
from week 28-34
118
describe HbF affinity for O2 and why this is advantageous
-higher affinity for O2 than HbA, helps with O2 exchange across the placenta
119
when do the gestational pulmonary capillaries of the fetal lung fully develop?
by week 20
120
when doe the alveoli develop?
after week 24
121
when and where is surfactant produced?
-type 2 alveolar cells
-maximum production will be after 28 weeks
122
How can the incidence and severity of respiratory distress syndrome be reduced antenatally?
-steroids to mothers at risk of preterm delivery
123
when does fetal Gi development begin?
by the 3rd week of pregnancy
124
when does peristalsis begin?
from the 2nd trimester
125
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
126
where does the renal collecting system (ureters and collecting ducts) derive from?
the metanephros
127
where does the renal secretory system (glomeruli, convoluted tubes, loop of henle) derive from?
mesenchyme of the nephrogenic cord
128
when is nephrogenesis complete?
36th week
129
what are the implications of having an immature kidneys in premature babies?
abnormal water, glucose, sodium and acid-base homeostasis
130
what is the result of renal agenesis?
-severe oligohydramnios
131
what infections may a fetus encounter?
intrauterine and perinatal infections
132
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
133
what immunoglobulin provides passive fetal immunity?
IgG
134
what immunoglobulins does the fetus produce?
IgM and IgA, small amounts, dont cross the placenta
135
what may indicate a fetal infection in the newborn?
presence of IgM and IgA without IgG
136
Describe the general immunological defences of the fetus
- amniotic fluid, lysosomes IgG
-placenta, lymphoid cells, phagocytes, barrier
- liver and bonemarrow, granulocytosis
-interferon from lymphocytes
137
what layers make up the amniotic membrane?
-epithelium
-basement membrane
-stroma
138
how does the chriodecidua layer contribute to the initiation of labour?
prostaglandin E2 and F2a production
139
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
140
Define monozygotic
identical twins (from a single zygote)
141
Define dizygotic
non-identical (from two different zygotes)
142
Define monoamniotic
single amniotic sac
143
Define diamniotic
two separate amniotic sacs
144
define monochorionic
share a single placenta
145
Define dichorionic
two separate placentas
146
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.
147
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
148
what is observed on US in monochorionic diamniotic twins?
Monochorionic diamniotic twins have a membrane between the twins, with a T sign
149
what is observed in monochorionic monoamniotic twins?
Monochorionic monoamniotic twins have no membrane separating the twins
150
what are the risks to mother in multiple pregnancy?
Anaemia
Polyhydramnios
Hypertension
Malpresentation
Spontaneous preterm birth
Instrumental delivery or caesarean
Postpartum haemorrhage
151
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
152
what is twin-twin transfusion syndrome called in pregnancies with more than 2 fetuses?
feto-fetal transfusion syndrome
153
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
154
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
155
How is twin-twin transfusion syndrome treated?
laser treatment
156
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).
157
How is anaemia monitored in multiple pregnancies?
extra FBC's at the booking clinic, 20 wks and 28wks
158
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
159
when is planned birth offered for uncomplicated monochorionic monoamniotic twins?
32- 33+6 weeks
160
when is planned birth offered for uncomplicated monochorionic diamniotic twins?
36-36+6 weeks
161
when is planned delivery offered for uncomplicated dichorionic diamniotic twins?
37-37+6 weeks
162
when is planned delivery offered for triplets?
before 35+6 weeks for triplets
163
what type of delivery is required for monoamniotic twins?
-elective caesarean section between 32 and 33+6 weeks
164
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
165
Describe antepartum haemorrhage
bleeding from the genital tract from 24 wks up until the birth of the baby
166
What are the usual causes of antepartum haemorrhage?
-placenta praevia
-placental abruption
167
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
168
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
169
How can post partum haemorrhage be subdivided
-minor: 500-1000ml
-major: more than 1000ml
- major-moderate: 1001-2000ml
-major-severe: more than 2000ml
170
Define secondary postpartum heamorrhage
abnormal or excessive bleeding from the birth canal between 24 hours and 12 weeks postnatally
171
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
172
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
173
How much blood on average is lost during vaginal births and caesarean sections?
300-500ml for vaginal, 750ml for caesarean sections
174
what is autotransfusion in the context of labour
-Compensation for blood loss by contracting the uterus
175
How is clotting during pregnancy and how does this affect bleeding times?
-Hypercoagulable state
-clotting and bleeding times are normal however
176
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
177
Which clotting factors increase during pregnancy?
2, 7,8,10,11 and 12
178
Describe primary homeostasis in pregnancy
-vasoconstriction (immediately)
-platelet adhesion (seconds)
-platelet aggregation (minutes)
Formation of white blood clot or platelet plug
179
Describe secondary homeostasis in pregnancy
-activation of coagulation factors
-formation of fibrin (minutes)
formation of stable red blood clot
180
describe fibrinolysis in pregnancy
activation of fibrinolysis (minutes)
lysis of the clot
181
Describe changes in physiology during haemorrhage
- increased HR
-Increased force of contraction
-Vasoconstriction
- Less urine is produced
182
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
183
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
184
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
185
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
186
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
187
What are the risk factors for atonic bleeding?
-Prolonged labour
-Overdistended uterus, twins, large baby, polyhydramnios
188
What tissues may cause obstetric haemorrhage?
-Retained placenta
-Retained products of conception
-Placenta praevia
-placental adhesive disorders (accreta, increta, percreta)
189
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
190
List acquired coagulopathy in pregnancy
-Sepsis
-Pre-eclampsia/eclampsia
-Placental abruption
-HELLP syndrome
-Retained dead fetus
-amniotic fluid embolus
-DIC
-Liver disease
191
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
192
Name 4 drugs which can be used as uterotonic agents
-syntocinon iv
-ergometrine Iv/im
-carboprost im
-misoprostol pr
193
How can tranexamic acid be useful in obstetric haemorrhage?
reduction of fibrinolysis
194
How can obstetric haemorrhage caused by tone be managed?
-uterine massage
-B lynch suture
-Bakri balloon insertion
195
How should a haematological obstetric haemorrhage be treated?
-Replace circulating volume
- replace blood: cell salvage/allogenic
-correct coagulation with blood products
196
Define normal small fetuses
Normal small fetuses- no structural abnormality, normal umbilical artery Doppler
& liquor. Not at risk. No special care needed.
197
Define abnormal small fetuses
have chromosomal or structural abnormalities.
198
Define growth restricted fetuses
result from placental dysfunction. Appropriate
treatment or timely delivery may improve prospects.
199
Define small for gestational age
Fetus ≤ 10th weight percentile for age (wks)
200
Define intrauterine growth restriction
Fetus unable to achieve genetically predetermined size
201
Define low birth weight and what can cause it
birth weight less than 2500gms
❑ SGA or
❑ Prematurity
Digital register check-in: CI-QY-DO
202
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
203
describe symmetrical FGR and its causes
*fetal head and body proportionately
small.
*fetal insult during early
development - affect growth
processes and cell hyperplasia
204
Describe asymmetrical FGR and its causes
*fetal brain disproportionately large
compared to liver.
*Fetal insult during later
development
205
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
206
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
207
Describe specific placental and cord abnormalities which may contribute to FGR
-placental insufficiency
-incorrect cord insertion
-placental tumour
-single umbilical artery
-circumvallate placenta
208
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
209
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
210
name 3 drugs associated with FGR
-marijuana
-heroin
-cocaine
-cigarette
-alcohol
-lithium
-phenytoin
211
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
212
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
213
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
214
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
215
Define epigenteic alterations
-stable alterations through covalent modifications of DNA and core histones
216
Name 2 methods of epigenetic modification
-DNA methylation
-Histone modification
217
How does FGR affect the risk of late-fetal death?
10-fold increase in risk among very small fetuses
218
Describe the perinatal implications of FGR
-Stillbirth
-prematurity
-asphyxia
-congenital malformations
219
What complications are premature babies more at risk of?
-Necrotising enterocolitis
-thrombocytopenia
-temperature instability
-renal failure
-metabolic problems like hypoglycaemia and hypothermia
220
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
221
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
222
How many minor risk factors would someone have for FGR that would merit reassessment at 20 weeks?
3
223
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
224
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
225
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
226
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)
227
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.
228
when does a uterine artery doppler happen in someone with 3 or more minor risk factors for FGR?
20-24 weeks
229
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
230
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
231
How can symphysio-fundal height measurements be improved?
-Customised fundal height charts which take into account maternal height, weight, parity, ethnicity
232
What fetal biometry measures can be seen on US?
-Biparietal diameter
-Head circumference
- Transverse cerebellar diameter
-Femure length
- abdominal circumference
-estimated fetal weight
233
What investigations can be done using ancillary invasive tests
-fetal karyotyping
-fetal blood sampling
-amniocentesis for lecithin-to-sphingomyelin ratio
234
what may a low ponderal index indicate?
-Hypoglycemia
-Hyperbilirubinemia
-Necrotising entercoliting
-Hyperviscosity syndromes
235
How can IUGR be prevented?
-Low dose aspirin and miniheparin
-maternal smoking cessation
-antibiotics to prevent/rx UTIs
-antimalarial prophylaxis
236
How is IUGR managed?
-Fetal surveillance until the risk of in utero demise exceeds the risk of delivery and prematurity
237
Define large for gestational age
above the 90th centile for that gestation
238
Define macrosmia
BW above 4000g regardless of gestational age
239
How is morbidity and mortality estimated in macrosomia?
relates to absolute bw rather than centiles
240
List RF for macrosomia
obesity
gestational/T2DM
postterm gestation
multiparity
large size parents
advancing maternal age
previous macrosomic infant
racial and ethnic factors
241
what are the complications with fetal overgrowth?
-maternal diabetes
-fetal demise
-birth trauma-shoulder dystocia, nerve palsies
-neonatal hypoglycaemia
242
a birth weight above 4500g identifies pregnancies at an increased risk of what?
morbidity
243
a birth weight above 5000g identifies pregnancies at an increased risk of what?
mortality
244
What is the greatest risk factor for accelerating fetal growth and altering body proportions?
maternal hyperglycaemia
245
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
246
When does normal labour occur?
between 37 and 42 weeks gestation
247
when is estimated date of delivery?
estimated date of delivery (EDD) is 280 days from the first day of the last menstrual period
248
What are the changes required for the expulsion of the fetus?
-Cervical ripening
-myometrial tone change
249
What is the effect of hCG on the formation of myometrial gap junctions?
-Inhibits formation
250
What is the effect of progesterone on circulating oestrogen and on the formation of MGJ?
-inhibits oestrogen
-stimulates the formation of myometrial gap junctions
251
What is the role of relaxin in pregnancy?
-acts on all smooth muscle
252
What is the role of oxytocin in pregnancy?
stimulate synthesis of relaxatory prostaglandins until hCG levels
at onset of labour
253
How is myocyte activity coordinated in labour?
-gap junctions
254
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
255
How many muscle layers are in the uterus?
3
-outer longitudinal
-inner circular
-middle spiral
256
When do myometrial gap junctions appear?
from 32 weeks gestation
257
what are myometrial gap junctions made of?
symmetrical portions of plasma membranes from adjacent cells
258
Which hormones stimulate the formation of myometrial gap junctions? and when do these hormones peak?
-oestrogen, prostaglandin, melatonin
-end of pregnancy
259
what hormones inhibit the formation of myometrial gap junctions? and when are these hormone present?
-progesterone, hCG, relaxin
- increase throughout pregnancy
260
Which hormone promotes the formation of oxytocin receptors?
-oestrogen
261
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
262
What is fundal dominance?
progressive conductance of electrical activity from the fundus to cervix
263
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
264
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
265
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
266
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
267
Describe the progesterone block hypothesis
progesterone supresses effective uterine activity by blocking the formation of oxytocin receptors and gap-junctions
268
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
269
In labour what is responsible for the release of prostaglandins?
the increased ratio of oestrogen: progesterone
270
Which prostaglandins are necessary for labour and where are they produced?
F and E
-placenta, membranes, decidua
271
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
272
What is the role of cytokines in labour?
cytokines: stimulates synthesis of prostaglandins
273
What is the role of interleukins in labour?
interleukins : increases collagenolytic activity of cervix
274
What is the role of nitric oxide in labour?
nitric oxide : stimulates release of PGE2 from fetal membranes
275
How can labour be characterised?
* Involuntary
* Intermittant and regular
* Painful (usually)
276
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
277
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
278
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
279
Describe fetal axis pressure
Fetal axis pressure- This is the force transmitted by the uterine contractions down the fetal spine to its head.
280
Which position optimises fetal axis pressure?
upright
281
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
282
How common are chromosomal abnormalities in pregnancy?
1/300
283
what are the 95% most common chromosomal abnormalities?
trisomy 21,18, 13 or changes in X and Y
284
What factor increases the risk of all chromosomal abnormalities?
maternal age
285
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
286
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
287
when is nuchal translucency measured?
11-14+1
288
what nuchal translucency would be considered as elevated?
above 3.5 mm
289
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
290
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
291
when is amniocentesis recommended?
after 15 weeks
292
what is the most common way of carrying out chorionic villus sampling?
abdominal
293
Name 3 invasive fetal chromosome testing methods
-amniocentesis
-chorionic villus sampling
-fetal blood sampling
294
what chromosomal aberrations can be checked through invasive methods?
-trisomy,
-monosomy,
-polyploidy,
-deletion,
-duplication,
-inversion,
-translocation,
-ring chromosome
295
Other than chromosomal aberrations, what can be checked through invasive testing?
* Genetic aberrations
* Infectious disease
* Biochemical markers (eg chorioamnionitis, raised IL-6)
296
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
297
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
298
Mosaicism may be indicated by chromosomal tests, what can mosaicism affect?
-fetal only mosaicism
-confined placental mosaicism
-placental and fetal mosaicism
299
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
300
Why is amniocentesis not recommended until after 15 weeks?
mosaicism increases with gestational age due to somatic mosaicism
301
what can each element of chorionic villus sampling results indicate?
*cytotrophoblast: more representative of placenta
*mesenchymal core: more representative of the fetal karyotype
302
why are pregnancies with confined placental mosaicism required to have growth scans?
Confined placental mosaicism (fetus normal) still associated with FGR: warrants growth scans
303
what are the 3 mechanisms that can lead to uniparental disomy?
1) Trisomy rescue
2) monosomy rescue
3) mitotic crossing over
304
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
305
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
306
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
307
Give 2 examples of imprinting disorders
-pradder willy syndrome
-anglemans syndrome
308
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
2. Amniotic fluid suggests that at least one fetal tissue may be affected
3. Fetal blood sampling confirms the diagnosis of chromosomal mosaicism
4. Ultrasound findings +/- presence/absence of uniparental disomy
5. Previous case reports known in the literature (for guidance)
309
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
310
What does non-invasive prenatal testing assess?
Measures cell-free DNA from apoptotic trophoblastic cells
311
what can reduce the accuracy of non-invasive prenatal testing
Reduced accuracy: low fetal fraction, maternal malignancy, vanishing twin, high BM
312
What may a persistent low fraction in non-invasive testing indicate?
-higher risk of T18 and T13
313
What is the commonest cause of a false positive and non-invasive prenatal testing?
placental mosaicism
314
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%)
315
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
316
In dizygotic twins how many placentas are there?
2
317
what percentage of monozygotic twins are dichorionic diamniotic and when does the division happen?
~25%
- days 0-3
318
what percentage of monozygotic twins are monochorionic diamniotic and when does the division happen?
~75%
days 4-7
319
what percentage of monozygotic twins are monchorionic monomniotic and when does the division happen?
~1-2%
days 7-14
320
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
321
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
322
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
323
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)
324
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
325
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
326
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
327
What can disrupted inflammation lead to in pregnancy?
adverse outcomes:
-Preeclampsia
-Preterm birth
-Miscarriage
-Still birth
-FGR
328
Name 3 cells that make up part of the innate immune repsonse
-Dendritic
-macrophage
-mast cells
-natural killer cell
-basophil
-eosinophil
-neutrophil
329
Which cells in the innate immune system are granulocytes?
-Natural killer cells
-basophils
-eosinophils
-neutrophils
330
Which cells make up the adaptive immune response?
- B cells
- T-cells
331
What cell is a member of both types of immunity?
Natural killer cells
332
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)
333
Which cells make up the decidual inflammatory cells after implantation?
Leukocytes-
70% NKs
20-25% macrophages
1.7% dendritic cells
3-10% T cells
334
What processes do the decidua inflammatory cells play an active role in?
-Implantation
-placentation
-Immune tolerance
335
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.
336
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
337
What types of cells are crucial for early implantation and placentation?
CD11c and DC's
338
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.
339
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
340
How do macrophages contribute during fetal growth?
dMφ -> M2 type, release anti-inflammatory cytokines. Tissue renewal during placental development
341
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.
342
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.
342
How is the TH2 type inflammation maintained during fetal growth?
-Soluble factors maintain the Th2 type inflammation
-Fetal factors maintain the Th2 type inflammation
343
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.
344
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
345
Which pathway initiates and executes labour and delivery?
NF-κB signalling
346
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.
347
What does activation of NF-KB signalling do?
-increases the production of pro-inflammatory cytokines
348
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.
349
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)
350
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.
351
How does pathological intrauterine inflammation or infection affect progesterone?
Pathological intrauterine inflammation or infection reduces progesterone function by its
functional withdrawal.
352
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
353
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.
354
Name a key hormone in stimulating uterine contraction during partruition
-Oxytocin
355
How is the oxytocin receptor regulated?
Positively by inflammatory mediators of parturition
356
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
357
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
358
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
359
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)
360
How is apoptosis in leukocytes triggered at the maternal-fetal interface?
STB secrete exosomes containing TRAIL and Fas ligand which trigger apoptosis in leukocytes.
361
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’.
362
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.
363
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
364
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
365
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
366
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.
367
What are the clinical features of pre-eclampsia?
Clinical features:
▪ Hypertension,
▪ Proteinuria,
▪ HELLP- Haemolysis, Elevated Liver enzymes, and Low Platelets,
▪ Visual disturbances.
368
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
369
What are the fetal complications of preeclampsia?
Fetal complications: PE pregnancies are at higher risks for stillbirth, FGR and other neonatal complications
370
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.
371
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
372
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.
373
Does the time of onset of preeclampsia change thee outcome?
No, however the pathophysiology is slightly different, but still results in placental hypoxia
374
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
375
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
376
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.
377
What is the effect of progesterone on smooth muscle?
relaxation
378
What is the effect of progesterone on oxytocin?
Inhibits receptor expression
379
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
380
What produces HCG? what does it do and what is a side effect?
-STB
-maintains corpus luteum
-responsible for hyperemesis gravidarum
381
Where is prolactin produces and what does it do?
-ant pituitary
- milk production
382
What changes happen to skin during pregnancy?
* Hyperpigmentation (linea nigra)
* Striae gravidarum (stretch marks)
383
What changes happen to breast in pregnancy?
* Increased size (& sensitivity)
* Darkened areolas
* Colostrum production
384
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
385
For how long postpartum does hypercoagulation persist for ?
Hypercoagulation persists for the first 3 weeks after delivery and resolves by 6–8 weeks postpartum
386
How much does oxygen consumption increase by during pregnancy?
+30-50ml/min
387
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
388
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:
1. Excretion of HCO3 through kidneys
2. O2 more available to the fetus
3. Easier breathing for the mother
389
How does the mass of the heart change during pregnancy?
ventricular muscle mass
size of left ventricle and atrium
390
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
391
How does pregnancy affect the position of the appendix?
It will be displaced higher up
392
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.
393
what condition affects 50-80% of pregnant women?
Reflux esophagitis and heartburn
symptoms affect 50–80% of
pregnant women
394
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
395
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.
396
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)
397
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
398
What changes occur to the vagina during pregnancy?
Venous congestion (blue/purplish tint)
399
How can fetal growth be estimated in low risk pregnancies?
Symphysis fundal height (SFH) is used to estimate fetal growth in low risk pregnancies
400
What are the effects of aortocaval compression in pregnancy?
* Oedema
* Pregnant people high risk for
VTE
401
How does CPR differ in pregnancy?
-Lateral uterine displacement
-perimortem caesarean delivery
402
Describe postpartum changes
* Involution of the uterus
* Cervical changes to return to
normal
* Lactation
* Perineal health
* Mental health
Hormones postpartum
403
How does the name of breast milk change with time?
Day 1-3 Colostrum
Day 3-14 Transitional milk
>14 days Mature milk
404
What vitamins is breast milk rich in?
A and K
405
Which immunoglobulin is present in breast milk?
IgA
406
How is iron bound in breast milk?
To lactoferrin
407
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
408
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!
409
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
410
How can breast feeding act as contraception?
Suppresses the release of gonadotrophin,
therefore inhibits ovulation (Lactational
amenorrhea LAM)
411
How are prolactin receptor sites opened?
expulsion of the placenta
412
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
413
What can hinder the oxytocin reflex?
-anxiety
-stress
-pain
-doubt
414
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
415
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)
416
How can preterm birth be defined by weight?
Low BW <2.5kg
Very low BW <1.5kg
Extremely low BW <1kg
417
What factors can lead to preterm birth?
-Uterine overdistension
-decidual haemorrhage
-cervical insufficiency
-cervical remodelling
-infection and inflammation
418
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
419
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
420
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)
421
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)
422
Other than multiple gestation what may cause uterine overdistension?
-polyhdramnios
-uterine anomalies
423
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
424
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
425
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
426
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
427
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
428
How can tertiary prevention be done in preterm birth
Tertiary prevention
◦ Treatment after diagnosis of preterm
labour
◦ Aims to reduce morbidity and mortality
429
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
430
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
431
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
432
What drug can be used to reduce the risk of cerebral palsy in PTB?
*MgSO4
433
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
434
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.
435
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.
436
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)
437
What are the congenital anomalies of the uterus?
-Unicornuate
-Bi cornuate
-Septate uterus
-uterus didelphys
-arcuate uterus
438
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
439
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
440
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
441
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
442
Give an example of a genetic condition which can cause obesity
Prader willi syndrome
443
Give examples of medical reasons which can cause obesity
● Hypothyroidism
● Cushing's syndrome
● Corticosteroids
● Anti psychotics
444
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
445
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
446
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
447
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
448
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
449
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
450
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
451
What dosage of folic acid should obese pregnant women be prescribed?
5mg
452
Which women should be screened for gestational diabetes?
BMI over 30
453
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
454
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
455
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
456
Name 5 in vitro models of pregnancy
-2D cell culture
-Transwell system
-explant culture
-spheroid/organoid
-organ on chip
456
Describe a transwell system
Transwell System:
monolayer cells with
ability to migrate
457
Describe explant culutre
Explant Culture: fresh
placental tissue supported
in culture
458
Describe spheroid/organoid
Spheroid/Organoid:
Multiple cell types grown in
aggregates
459
What develops from the endoderm?
-alveolar cells
-thyroid cells
-pancreatic cells
460
What develops from the mesoderm?
cardiomyocytes
-skeletal muscle
-tubule cells of the kidney
erythrocytes
smooth muscle cells of the gut
461
What develops from the ectoderm?
skin cells of the epidermis
neurons of the brain
melanocytes
462
What gestational weeks can major defects in CNS structure?
wk3 -wk 16
463
What gestational weeks can major defects in heart structure occur?
wk3 -end of week 6
464
What gestational weeks can major defects in limb structure occur?
start of week end of wk 6
465
What gestational weeks can major defects in eye structure occur?
mid wk 4- mid week 8
466
What gestational weeks can major defects in teeth structure occur?
mid wk 6- start of week 12
467
What gestational weeks can major defects in palate structure occur?
towards the end of wk 6 and the end of wk 8
468
What gestational weeks can major defects in external genitalia structure occur?
mid wk 7 towards the end of wk 12
469
What gestational weeks can major defects in ear structure occur?
start of week 4 to mid wk 12
470
What gestational weeks can major functional defects and minor structural in CNS structure occur?
Wks 20-36
471
What gestational weeks can major defects in heart and minor defects structural occur?
from wk 6 to end of wk 8
472
What gestational weeks can major defects in the limbs and minor structural defects occur?
start of wk 7 -end of week 8
473
What gestational weeks can major defects in the eyes and minor structural defects occur?
Halfway through wk 8 to wk 38
474
What gestational weeks can major defects in the teeth and minor structural defects occur?
wk 12- wk 38
475
What gestational weeks can major defects in the palate and minor structural defects occur?
wk 12-wk16
476
What gestational weeks can major defects in the external genitals and minor structural defects occur?
end of week 12-week 38
477
What gestational weeks can major defects in the ears structural defects occur?
halfway through week 12 -wk 20
478
What is the chance of survival at 24 wks birth?
50%
479
what time period is spontaneous loss of pregnancy counted as miscarriage?
up until week 24
480
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.
481
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
482
What is an ectopic pregnnacy?
A pregnancy located outside of the uterine cavity, usually in the fallopian tube.
483
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.
484
What are the common signs of ectopic pregnancy?
Common signs:
➢ pelvic tenderness
➢ adnexal tenderness
➢ abdominal tenderness
485
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.
486
How is recurrent miscarriage defined?
➢ Loss of three or more consecutive pregnancies
487
What are the RF for an ectopic pregnancy?
Maternal age, previous miscarriages, advanced
paternal age, obesity, alcohol ,smoking, excessive caffeine
488
What haematological conditions should be considered in cases of recurrent miscarriage?
antiphospholipid syndrome, thrombophilia
489
What genetic factors may contribute to recurrent miscarriage?
balanced translocation, chromosomal abnormalities
490
What anatomical factors may contribute to recurrent miscarriage?
➢ Anatomical factors: Uterine malformations, Cervical weakness
491
What endocrine factors can lead to recurrent miscarriage?
Uncontrolled Diabetes, Thyroid dysfunction, PCOS.
492
How can the aetiologies of hydatidiform moles be?
Benign (80%)
Invasive mole (10-15%)
Choriocarcinoma- malignant 2-3%
493
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)
494
What is a complete mole in molar pregnancy?
2 sets of paternal genes, no maternal genes, no fetus
495
What is a partial mole
3 sets of genes 1 maternal, 2 paternal and a non-viable fetus
496
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
497
How can molar pregnancy be diagnosed clinically?
Vaginal bleeding after amenorrhea
Hyperemesis gravidarum, hyperthyroidism
Passing of grape like vesicles
498
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
499
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
500
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
501
What are the short-term complications of respiratory distress syndrome?
* Death
* Air leaks
– Pneumothorax
– Pulmonary interstitial emphysema
– Pneumomediastinum
– Pneumopericardium
– Pneumoperitoneum
* Uncontrollable hypoxia
502
How can respiratory distress syndrome lead to chronic lung disease?
-Chronic inflammation
-impaired lung growth
503
What are the signs of chronic lung disease of prematurity?
* Severe inflammatory
changes
* Fibrosis
* Atelectasis
* Hyperexpansion
504
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
505
506
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
507
How can an ischaemic - reperfused bowel lead to perforation?
Mural oedema
intra mural gas
perforation
508
How are prebiotics used in preterm birth?
Used to populate the gut microbiome to prevent NEC
509
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
510
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
511
Name 3 pro quiescence molecules
Pro - quiescent molecules
➢ Progesterone
➢ Gs / cAMP / PKA
➢ CRH
➢ PGE2
➢ PKC
➢ cGMP
➢ NO
➢ Ion Channels (K+)
512
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-)
513
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
514
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
515
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
516
What are the 3 stages of partruition?
1) Cervical dilatation (remodelling)
2) Fetal expulsion (myometrial contraction)
3) Placental delivery and haemostasis
517
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
518
What factors promote cervical ripening?
Promoted by release of:
➢ PGE from cervical mucosa
➢ Relaxin
➢ Placental oestrogens
➢ Regulated inflammation – NF-B-mediate
519
What does increased expression of gap junction proteins in the fundal myometrium allow?
cells to communicate with each other
520
Describe functional progesterone withdrawal
Reduced uterine sensitivity to progesterone
521
How is myometrial muscle cell membrane potential different in labour?
➢ Differential ion permeabilities
➢ Plasma membrane oscillator function
522
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+]
523
What ion is the major determinant of myocyte membrane potential?
K+
524
Describe myometrial membrane potential during quiesence
* Em strongly –ve (net K+ exit)
* Membrane is hyperpolarised
* Few regular contractions
525
Describe myometrial membrane potential in myometrial contraction
Myometrial contraction
* Membrane can depolarise
❑ Em strongly +ve (net Na+/Ca2+ entry)
* Increasing rhythmical depolarisation –
hyperpolarisation cycles
526
How does Ca2+ affect myometrial contractility?
Increases it
527
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?
528
How does nifedipine work?
Nifedipine – Ca2+ channel blocker
➢ Inhibits premature myometrial contractions
529
How does oxytocin stimulate myometrial contractions?
By elevating Ca2+, through releasing intracellular stores
530
What pathway increases the number of ocytocin receptor numbers seen at term in the fundal myometrium?
NF-KB
531
How is oxytocin released?
-made in hypothalamus
-stored in posterior pituitary
-cervical/myometrial stretch initiates secretion and positive feedback mechanism
532
What mechanisms allow for placental delivery?
Mechanisms:
* Increase clotting efficiency
* Reduce clot dissolution efficiency
* Rapid uterine contraction
533
What factors change in order to make the mothers blood hypercoaguable?
* Plasma fibrinogen levels
* Erythrocyte sedimentation rate
* Clotting factors (VII, VIII, X)
534
How much fibrin is used initially when placenta detaches?
➢ 5-10% of circulatory fibrinogen used
535
What may cause a depletion of fibrinogen reserve during placental delivery?
* Inadequate myometrial contraction (placenta near lower segment)
* Incomplete placental separation
536
How is atosiban used in premature labour?
Prevents uterine contraction, oxytocin receptor antagonist
536
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
536
How is reduced clotting dissolution achieved in placental delivery?
Plasminogen Activator Inhibitor
537
538
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
539
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)
540
How are maternal cells marked?
➢ All nucleated cells - MHC-I (HLA-A, B, C)
➢ Antigen Presenting Cells (APC) MHC-II
❖ (Lymphocytes, macrophages
541
How are extra-villus trophoblasts marked?
➢ Only MHC-I (HLA-C, E and G)
542
How are syncytiotrophoblast cells marked?
No HLA-A or HLA-B self:non-self markers
543
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
544
545
Which cells make up the majority of the decidual immune cells?
70%
546
how are MHC-I proteins bound?
By uNK cells expressing Ig-Like receptors
547
Which cells facilitate EVTB invasion?
uNK
548
What pathologies may uNK play a role in?
Pre-eclampsia?
IUGR?
Recurrent miscarriage?
Placentation?
549
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
550
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
551
Which cell markers on the EVT interact with uNK cells?
-HLA-G
-HLA-C1/HLA-C2
-HLA-E
552
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?
553
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?
554
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
555
556
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
557
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
558
Whar conditions may a lack of TH2 bias in pregnancy lead to?
* Pre-eclampsia?
* Re-current miscarriage?
* IUGR
559
Which cells promote B cell activation in order for plasma cells to cross the placenta, and which antibody crosses the placenta?
TH2 cells
IgG
560
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
561
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
562
What type of genetic profile leads to haemolytic disease of the newborn?
➢ Rh-ve mother (dd) X Rh+ve father (DD or Dd)
563
