Pregnancy

Question 1

What are the terms used to describe the timing of pregnancy?

Answer 1

Last menstrual period

• convention
• counted from the first day of the last mentrual period

Gestational age

• LMP + 2 weeks
• start from the point of fertilisation - right after ovulation

Accurate dating → importance in preterm babies

• in UK a baby with GA > 24 weeks would always be revived and treated a very positively
• whereas a baby of lower gestation (eg 22 weeks) would be considered borderline for survival, and a clinical decision whether to treat or not would be taken.

Question 2

What is the 1st trimester?

Answer 2

Weeks 0-13

Question 3

Define the features and risks of the first trimester.

Answer 3

1. Maternal changes

• N+V “morning sickness”
• Hard to tell someone is pregnant
• Increased urinary frequnecy due to hormonal changes

2. Most embryological development takes place in this period - focus on structural development not growth
3. Risks - Most dangerous time for the foetus, due to:-

• Most susceptible to insult/ teratogens - congenital abnormalities
  
  • e.g. Spina bifida, Cleft palate

NOTE: main development of lungs, the digestive system, the immune system and the brain happens late in pregnancy (they do start developing in early stages though)

• Chromosomal abnormalities - miscarriage
  
  • e.g. Turner’s (XO), YO inviable, Kelinfelter’s XYY, Down’s trisomy 23
• Placental problems - miscarriage
  
  • e.g. weeks 10-12 when placenta becomes less anchored as cytotrophoblast plug breaks down
• Miscarriage risk highest - 1/3 of all conceptions do not complete the first trimester

Question 4

What is the 2nd trimester?

Answer 4

Weeks 14-26

Question 5

Define the features and risks of the second trimester.

Answer 5

1. The foetus becomes viable (foetus can survuve if born) in this trimester

• 24 weeks = Viability limit
• 25 weeks = 50% survival
• 26-27 weeks (end of trimester) = without intensive care
• However, survivial of preterm birth is often associated with morbidity in premature infants

2. Foetal changes
   * Focuses on foetal growth (though less than 3) - clear cut increase in foetal weight from 1 → 2
3. Maternal changes

• Urinary frequency normalises from first trimester
• Mother starts to feel baby moving

4. Risks

• Stillbirth
• Increase in maternal blood clotting tendency
• Maternal blood pressure is lowest during the second trimester, and increases the risk of maternal fainting – so pregnant women should not stand for prolonged periods of time

Question 6

What is the 3rd trimester?

Answer 6

Weeks 27-39

Question 7

Define the features and risks of the third trimesters.

Answer 7

1. CONCENTRATED foetal growth (~2kg)
2. Maturation of brain, immune system, lungs and digestive tract (BILD)
3. Maternal changes

• Increased urinary frequency as uterus pushes on bladder
• Increases in weight (concentrated particularly in the third trimester - to feed the baby after delivery)

4. Risks

• Highest risk to mother at this time
  
  • Gestational diabetes
  • Preeclampsia - less blood to foetus - less growth
• Foetal
  
  • Preterm labour
  • Preterm premature rupture of membranes
  • Placental previa + placental abruption
  • Intrauterine growth restriction

Question 8

Define term in pregnancy.

Answer 8

• Term (39-40 weeks) is the expected timing of delivery.
• Covers gestational ages from 37 – 41 weeks of gestation, with deliveries either side of these limits being ‘preterm’ or ‘post-term’ respectively

Question 9

Define the following terms:-

• Conceptus
• Embryo
• Fetus
• Infant

Answer 9

• Conceptus – everything resulting from the fertilised egg (baby, placenta, fetal membranes, umbilical cord)
• Embryo – the baby before it is clearly human
• Fetus – the baby for the rest of pregnancy
• Infant – less precise, normally applied after delivery

Question 10

What are the main risk in pre-term infants and why?

Answer 10

• In a preterm infant, the 4 main organs or systems (lungs, the digestive system, the immune system and the brain) may not function correctly, and thereby cause illness or death to the infant
• This is because the fetus has limited need of them in utero - so they develop relatively late in pregnancy, during the last few weeks

Question 11

What are the maternal anatomical and physiological changes associated with pregnancy?

Answer 11

KNOW CHANGES EXPLANATION FOR UNDERSTANDING

First Trimester

1. Altered emotional state - changes in hormone levels within the maternal system
2. Altered endocrine system
3. Altered brain function - high levels of progesterone (well established that many steroids affect brain function in humans generally)
4. Altered Immune system - need to accomodate non-self entity
   
   • factors produced at the utero-placental interface to suppress the maternal immune system
   • placenta expresses invariant (unlike the others which are highly polymorpic),and structurally simplistic HLA-G:-
   • immunological signal that shows that the tissue is human – but little or no information on which human it is from (not as being ‘non-self’) in addition
   • suppress the activity of some leukocytes and can down-regulate the maternal immune system within the uterus.
5. Altered appetite
   
   • increase size of uterus imposes increasing pressures on GI - decrease the distensibility of the stomach
6. N and V
   
   • co-incides with the highest levels of hCG in the maternal circulation
   • decline in hCG during second trimester improves symptoms
7. Increased Breast size
   
   • increased hormone levels in the maternal circulation (human placental lactogen, prolactin, and ostrogens are all involved)
   • start in the first trimester and continues through
8. Fluid balance + urination frequency
   
   • enlarged uterus will be exerting pressure on the bladder, decreasing the maximum size and volume of urine
9. Increased basal body temp

Second Trimester

1. Decreased Blood pressure - increases the risk of maternal fainting
2. Increased blood clotting tendency
   
   • starts early in pregnancy, and is greatest at term
   • protective against losing too much blood at delivery
   • also due to interactions between the placenta and maternal blood throughout pregnancy

Third Trimester

1. Increased Weight
   
   • weight of the fetus, amniotic fluid and placenta, increased fluid retention, increased nutritional stores
2. Joints
   
   • maternal pelvis changes to make the connections between the bones more flexible and permit the delivery
   • same permanent modification in other maternal joints (persist after pregnancy)

Question 12

Draw a graph showing the hormonal changes in pregnancy.

Answer 12

DIAGRAM (past question)

Human Chorionic Gonadotrophin (hCG)

• shows peak levels in maternal plasma in the first trimester, and declines thereafter
• produced by placenta
• rescues the corpus luteum
• acts at the LH receptor to produce oestrogen and progesterone

Steady Increase

Human placental lactogen

• parallel the increased size of the placenta

Progesterone

• very high levels → of particular importance in allowing the pregnancy to continue.
• low progesterone levels, or administration of a progesterone antagonist, will lead to loss of the pregnancy at all gestational ages.

Porgesterone + Oestrogen

• high levels suppress HPG
• very low levels of LH and FSH throughout pregnancy
• no cyclic ovarian or uterine functions

Question 13

How is steroidogenesis an example of the three-way interaction in pregnancy?

Answer 13

NOTE: this answer also covers what the sources of progesterone and oestrogens are during pregnancy

• First 9 weeks*
• HcG produced by the placenta rescues the corpus luteum and acts on the LH receptors to produce oestrogen and progesterone

Luteal-placental shift (week 6-9)

After 9 weeks

• Placenta produces an excess of progesterone

Oestrogen formation required all 3 components - (1) maternal adrenal glands (pregnenolone), (2) foetal adrenal glands and/or liver, (3) maternal placenta

• Placenta lacks CYP17 (17αhydroxylase) for conversion of pregnenolone to androgens
• The pregnenolone passes into the foetus - its adrenal gland has CYP17, which converts pregnenolone → dehydroepiandrosterone (DHEA) —sulphation→ DHEAS
• DHEAS can be either:-
  
  • (1) deconjugated in the placenta and form oestradiol and oestrone or
  • (2) hydroxylated in the foetal liver to form 16α-hydroxy DHEAS → converted into oestriol in the placenta

Question 14

Describe the main structural features of the human placenta.

Answer 14

1. 30-60 cotylendons on the maternal side of the placenta
   
   • Each cotyledon contains one or more villi, with larger cotyledons containing more villi.
   • The variability in the shape and size of cotyledons does not affect placenta function.
2. Placental villous tree - complex branched structure
   
   • provides large SA for exchange between the maternal and fetal vascular systems
   • provides anchorage to the maternal decidualised endometrium
3. Complex blood supply within each villus - countercurrent flow
   
   • spiral arteries → blood supply
   • umbilical arteries (de-oxygenated blood); umbilical veins (oxygenated)
   • these larger vessels are connected to smaller capillaries in the terminal portions of each villus
4. Despite being in close proximity, maternal and fetal blood supplies are separated from each other

Question 15

What are the functions of the placenta?

Answer 15

1. Separation
   
   • prevents mixing of maternal and foetal blood despite the close contact between the tissues
2. Exchange of nutrients (maternal to fetal) and waste products (fetal to maternal)
3. Biosynthesis
   
   • Hormones and Growth factors are actively produced
   • Functions as a “transient hypothalamo-pituitary-gonadal axis
4. Immunoregulation
   
   • ensures that there is no rejection of the conceptus
   • placenta (rather than the uterus) is the key tissue → occasional survival of ectopic pregnancy until delivery shows that the uterine lining is not completely essential for pregnancy
5. Connection (or anchorage)
   
   • placenta makes strong connections with the underlying maternal decidua to last for the 9 months of pregnancy.
   • anchorage is essential as the placenta is in contact with maternal arterial blood

Question 16

Summarise the development of the human embryo.

Answer 16

I.e. 1st TRIMESTER

1st week after fertilisation

• mitotic (cleavage) division deriving their nutrients from the secretions of the Fallopian tube (by day 6)

2nd week

• • Implantation of conceptus (by day 10)

3rd week

• • “Development of villi and anchoring”
• • Contact with maternal tissues
• Hypertrophy of decidual glands
  
  • histotrophic nutrition (before haemotrophic when cyctotrophic plug break down during late 1st trimester)

6th week

• • Start of spiral artery remodelling (1st wave > last up to 2nd wave during late 1st trimester > end with invasion up to decidua)

Start = 12-14 week (2nd wave of spiral artery remodelling), End within 4 weeks

• Invasion up to the myometrium
• Break down of cytotroblast plugs and haemotrophic nutrition

Question 17

Detail the development of the placenta.

Answer 17

1. Implantation of conceptus
   • trophoblast → placenta
     
     • cytotrophoblast is surrounded by syncitioblast
2. Development of villi and anchoring - CONCEPTUS INVASION
   
   • primary villi = cytotrophoblast invades into synctioblasts
   • secondary villi = extra-embryonic mesoderm (NOT OF FOETUS!!!) invades into cytotrophoblast layer
   • tertiary villi = branches of the umbilical artery and umbilical vein grow into the mesoderm → vascularization
3. Endometrium undergoes decidualisation
   
   • Hypertrophy of decidual glands
   • histotrophic nutrition = nutrition form the maternal decidual gland until end of 1st trimester as conceptus is not in contatc with maternal aterial blood
4. Spiral arteries
   
   • Spiral arteries open to form funnel shaped openings to allow trophoblast entry
   • Decidualised endometrium also mediates the invasiveness of trophoblast cells and triggers remodelling of spiral arteries
   • Cytotrophoblasts
     
     • invade spiral arteries (same molecular mechanisms as tumors, but are highly regulated and controlled)
     • remodel:
       
       1. destroy the smooth muscle and elastic layers and replace them with fibrinoid material → no longer vasoconstricts → narrow vessels widen to carry more blood to placenta
       2. line vessels with trophoblast
5. Contact with maternal tissues
   
   1. endometrial contact
   2. brieft contact with maternal capillaries and then cut off by cytotrohphoblastic shell
6. Cytotrophoblast plug gradually breaks down to expose placenta to maternal blood → haemotrophic nutrition (end of 1st trimester)

Question 18

Describe a pathology regarding spiral artery remodelling and its consequences.

Answer 18

• Spiral arteries do not open properly
• Invasion depth up to decidua
• 30–50% of the spiral arteries of the placental X undergo remodeling
• Poor placental perfusion
• Clotting in the uterine arteries
• Vessel contraction
• Causing →
  
  • maternal : hypertension (BP > 140/90, 300mg protein/ day measured in 2 occasion); eclampsia (>1 convulsions from high blood pressure, often followed by coma)
  • foetal : IUGR, HELLP syndrome, preterm birth

Question 19

What regulates the growth of the placenta?

Answer 19

• Autocrine - regulated by placenta
• Maternal decidual tissues seem to restrain growth - protective to mother
• NOT much is known (ethics)

Question 20

Comment on the neurological structure of the placenta.

Answer 20

• The placenta has no nervous system, so it is not regulated by such systems at any stage of pregnancy.
• This means that it can feel no pain during delivery, and the umbilical cord can be cut after delivery without any impact on the infant.

Question 21

Outline the development of the placenta.

Answer 21

Day 9 PF:

• Blastocyst implants into decidualising endometrium
• Surrounded by inner cytotrophoblast and outer synctiotrophoblast which has fluid filled spaces called lacunae

Day 13-20 PF:

• STB in contact with maternal blood supply transiently - Slow flow of blood into lacunae
• Rapidly proliferating CTB begins to invade into the STB to form a primary villus and trophoblastic plug, blocking the spiral arteries and isolating conceptus from maternal blood

Day 21- 28 PF:

• CTB eventually reaches outside to cut off maternal blood supply
• Creating a low oxygen tension environment (~3%)

8 weeks PF

• CTB plugs gradually break down, beginning with those at the periphery of the placenta, and ending with those near the centre
• Spiral arteries start to
  
  1. provide maternal blood to the placenta, and hence forming the main supply of nutrients to the developing placenta and fetus
  2. be remodelled by cytotrophoblast cells - vascular endothelium, and underlying smooth muscle cells are lost, and replaced by cytotrophoblast from first trimester to weeks 16-18 of gestation.

8 weeks onwards

• Most of the placental growth is due to increased size and branching of the villi (increases from 5 cm to 20cm in diameter - key structural components do not change)
• During first trimester, there is endometrial glandular hypertrophy which provides histotrophic nutrition for the placenta and developing baby - source of the nutrients (glands: histotrophic nutrition) rather than maternal blood (haemotrophic nutrition)

Question 22

What is the relationship between syncytiotrophoblast and cytotrophoblast?

Answer 22

The syncytiotrophoblast forms as a result of differentiation and fusion of the underlying cytotrophoblast cells which continues throughout placental development.

• It contributes to the barrier function of the placenta.

Question 23

What is the clinical significance of the time when spiral arteries start to provide maternal blood to the placenta?

Answer 23

• This is one of the risky time-frames of pregnancy
• if the placenta is not fully anchored to maternal decidua, the increase in pressure as it is exposed to the maternal arterial supply can detach the placenta and lead to miscarriage (late first trimester).

Question 24

What is the significance of the remodelling of the spiral arteries by the cytotrophoblasts?

Answer 24

• This remodelling is critical for later growth of the fetus
• This is because it converts the narrow, vasoactive spiral arteries to wide-bore vessels that can transport very large volumes of maternal blood to the placenta, and hence provide the quantities of nutrients needed.
• The lack of smooth muscle cells in these remodelled vessels is important, as this means that the blood flow remains high as these arteries cannot respond to vasoconstrictors.

Question 25

When does spiral artery remodelling start?

Answer 25

Week 6 PF

Question 26

What is the difference between miscarriage and stillbirth?

Answer 26

Foetus expelled * \<24 weeks = miscarriage * most happen in 1st trimester (\<12 weeks = early miscarriage) - highest risk to foetus * causes = unknown, chromosomal/genetic abnormality, placental insult/failure of placenta to develop * \>24 weeks = still birth * causes = IUGR, maternal medical condition * HENCE NEED foetal monitoring of movement and blood flow (US, Doppler US) - may indicate risk but cannot predict

Question 27

How are ultrasound imaging and foetal dopplers used in foetal assessment?

Answer 27

* Confirming pregnancy * Dating pregnancy * Assessment of suspected early pregnancy failure or ectopic pregnancy * Estimating date of delivery * Checking placenta