Disorders of Early Foetal Development

Question 1

What are the 3 causes of pregnancy loss?

Answer 1

Errors in embryo-foetal development
Failure of the embryo to implant in the uterine lining
Inability to sustain development of an implanted embryo/ foetus

Question 2

What is a recurrent miscarriage?

Answer 2

UK: 3 or more pregnancy losses (consecutive/ non-consecutive)

USA/ Europe: 2 or more pregnancy losses (consecutive/ non-consecutive)

Question 3

How frequent is pregnancy loss?

Answer 3

preclinical pregnancy loss
- 30% conceptions lost prior to implantation
-30% following implantation but before the menstrual period

clinical pregnancy losses
- 15% of conceptions
10% 20-24 y/o
51% in 40-44 y/o

Question 4

What is the major cause of early clinical pregnancy loss?

Answer 4

Aneuploidy (chromosome number errors) in embryo
Exponential increase in the risk of trisomic pregnancy with increasing maternal age

Question 5

Why increasing maternal age increases risk of miscarriage (pathophysiological detail)?

Answer 5

Loss of cohesion between homologous chromosomes in oocyte, due to cohesins degrading as you get older (and are not replaced)

If cohesion has been lost, chromatids can separate and drift during meiotic division, rather than being segregated accurately by the spindle

Question 6

Name 2 examples of cohesion proteins.

Answer 6

REC8 and SMC2

Question 7

Oocyte experience prolonged meiotic arrest, explain this?

Answer 7

The waiting at a particular stage of meiosis by the oocyte until some stimulus is received, usually the entry of the sperm
- the prophase of the first meiotic division

Question 8

When is meiosis resumed after the meiotic arrest?

Answer 8

just before ovulation

Question 9

Embryos require maternal and paternally derived genomes to be viable, i) state a two-word phrase which explains the cause of this, ii) using one word, describe which type of embryo arises when we have 2 sets of the maternal genome fertilising an egg, iii) using one word, describe which type of embryo arises when we have 2 sets of the paternal genome fertilising an egg

Answer 9

i) Genomic imprinting

ii) Maternal genome x2 = parthenogenetic embryo (small placenta)

iii) Paternal genome x2= androgenetic embryo (big placenta)

Question 10

What are gestational trophoblastic diseases?

Answer 10

a collection of disorders characterised by overgrowth of trophoblastic tissue

Question 11

What two broad types of gestational trophoblastic diseases are there?

Answer 11

benign or malignant

Question 12

What are example(s) of benign gestational trophoblastic diseases?

Answer 12

Hydatidiform mole- overgrowth of trophoblastic cells

NLRP7 mutations may underlie recurrent hydatidiform mole

2 types of hydatidiform moles:

• Complete hydatidiform mole (empty egg fertilised by 1x sperm then sperm genome duplicated
  or 2x sperm (no duplication)); foetal tissue absent
• Partial hydatidiform mole (normal egg fertilised by 1x sperm then sperm genome duplicated
  or 2x sperm (no duplication)); foetal tissue present

Question 13

What are example(s) of malignant gestational trophoblastic diseases?

Answer 13

rare:
invasive mole
choriocarcinoma

very rare:
placental site trophoblastic tumour (PSTT)
epithelioid trophoblastic tumour

Question 14

What is an ectopic pregnancy?

Answer 14

Implantation of the embryo at a site other than the uterine endometrium (usually in the fallopian tube)
1-1.5% of pregnancies are ectopic

Question 15

How are ectopic pregnancies treated?

Answer 15

chemotherapy (methotrexate)
surgery to remove the affected tube

Question 16

What can the rupture of fallopian tubes lead to?

Answer 16

Severe internal bleeding and high risk of death

Question 17

Describe 2 adaptations of the fallopian tubes.

Answer 17

Smooth muscle contraction which facilitates the movement of the embryo along the uterine tube

Epithelium coated in cilia to promote fluid movement

Question 18

What are some risk factors fro ectopic pregnancies?

Answer 18

maternal cigarette smoking
cannabis use
prior ectopic pregnancy
prior fallopian tube surgery
certain STIs: chlamydia and gonnoreahea
pelvic inflammatory disease (PID)
endometriosis
history of infertility
use of assisted reproductive technology, such as IVF
age (older than 35)

Question 19

Why is maternal cigarette smoking a risk factor for ectopic pregnancies?

Answer 19

Cotinine- component of cigarette smoke, regulates the expression of PROKR1, a regulator of fallopian tube smooth muscle contractility; may inhibit action of smooth muscle= failure to transit

Increase expression of pro-apoptotic proteins in fallopian tube explants, cilia can block the tube -BAD gene

Tobacco smoke likely to inhibit ciliary function- reducing transit of the embryo

Question 20

Why is cannabis a risk factor for ectopic pregnancy?

Answer 20

Fallopian tube expresses CB1 and CB2 cannabinoid receptors

CB1 reduced in ectopic pregnancy patients, and CB1 knock-out mice causes embryo retention in the fallopian tubes

Levels of endocannabinoids elevated in ectopic pregnancy fallopian tubes

THC in cannabis may act directly on the fallopian tubes to disturb transit or alter the balance of endocannabinoids in the tube leading to disrupted embryo environment