Dev & Ageing - Disorders of Early Foetal Development

Question 1

What are the reasons for early pregnancy loss? (3)

Answer 1

1. Failure in the embryo-foetal development
2. Inability to sustain development of implanted embryo/foetus
3. Failure of embryo implantation in endometrium

Question 2

What is a miscarriage?

Answer 2

A loss of pregnancy prior to 23 weeks of gestation

Question 3

What is an early clinical pregnancy loss

Answer 3

A loss of pregnancy prior to 12 weeks of gestation

Question 4

What is a late clinical pregnancy loss

Answer 4

A loss of pregnancy after 24 weeks of gestation (stillbirth)

Question 5

What classifies for recurrent miscarriages/pregnancy loss in the UK

Answer 5

3+ losses

Question 6

What classifies for recurrent miscarriages/pregnancy loss in the US/Europe

Answer 6

2+ losses

Question 7

How many pregnancies does recurrent loss affect?

Answer 7

0.8-1.4% of pregnancies

Question 8

How frequent is clinical pregnancy loss?

Answer 8

Affects 15% of conceptions

Question 9

What age group is most affected by clinical pregnancy loss?

Answer 9

40-44 year olds

Question 10

What are the 2 types of clinical pregnancy loss

Answer 10

Live birth

Miscarriage

Question 11

What are the 2 types of pre-clinical pregnancy loss?

Answer 11

Post-implantation

Pre-implantation

Question 12

What is one of the major causes for early pregnancy loss?

Answer 12

Aneuploidy

Question 13

How common is aneuploidy?

Answer 13

• It was found that 53% of IVF donor eggs embryos were aneuploid.
• 50% of lost early pregnancies displayed some chromosomal abnormality

Question 14

How does maternal age vary with trisomy?

Answer 14

Increase in maternal age increases the risk of trisomy exponentially

Question 15

Why does maternal age increase the risk of aneuploidy?

Answer 15

Maternal oocytes undergo prolonged meiotic arrest in prophase I

Question 16

Explain how maternal age increases aneuploid incidence?

Answer 16

During oogenesis, maternal and paternal chromosomes will pair up with their homologues and replicate their DNA.
This will in turn give us 2 chromatids per chromosome, and a pair of each of these chromosomes from the mum and dad.
Genetic material is exhanged between the maternal and paternal homologues via recombination, and they are then held in dictyate arrest until menarche, via cohesin proteins.
With age, we lose cohesins therefore are more likely to split chromosomes, meaning that chromatids drift and will enter eggs in uneven numbers.

Question 17

What are examples of cohesin proteins?

Answer 17

REC8 and SMC2

Question 18

What signalling in mice was shown to cause pregnancy loss?

Answer 18

Deficiency of LIF was shown to cause failed implantation despite normal embryo development

Question 19

What is LIF?

Answer 19

Leukaemia inhibitory factor released from endometrial cells stimulates adhesion from the blastocyst to endometrial cells

Question 20

How do LIF levels relate to sub fertile women’s uterine secretions?

Answer 20

Reduced levels of LIF were found in the uterine secretions of sub fertile women

Question 21

What is the non selective uterine hypothesis?

Answer 21

The uterus will permit the implantation of poor quality embryos, but in women with RPL/RM there are changes in uterine mucin expression

Question 22

What is genomic imprinting?

Answer 22

The balance between the maternal and the paternal genome in order to create a viable embryo, creating an intergenomic conflict

Question 23

What does the paternal genome promote?

Answer 23

Embryo fitness at expense of the mother

Question 24

What does the maternal genome promote?

Answer 24

Restricts embryo resources in order to save for future pregnancies

Question 25

What genes are commonly involved in intergenomic conflict?

Answer 25

Genes involves with placentation and nutrition

Question 26

What are GTDs?

Answer 26

Gestational trophoblastic disorders - a set of disorders characterised by trophoblastic overgrowth

Question 27

What are hydatidiform moles?

Answer 27

Benign GTDs

Question 28

What is a complete hydatidiform mole?

Answer 28

When no foetal tissue is involved there is just trophoblastic overgrowth

Question 29

What is a partial hydatidiform mole?

Answer 29

When there is some foetal tissue involved with the trophoblastic overgrowth

Question 30

What are malignant GTDs called?

Answer 30

Gestational trophoblastic neoplasias

Question 31

What are the rare trophoblastic neoplasias?

Answer 31

Invasive mole | Carcinoma

Question 32

What are the very rare trophoblastic neoplasias?

Answer 32

Placental site trophoblastic tumour | Epithelioid trophoblastic tumour

Question 33

How may trophoblastic neoplasias arise?

Answer 33

20% are from hydatidiform moles after we try to remove them

Question 34

How do complete hydatidiform moles arise?

Answer 34

When 2 spemr fertilise an empty egg, or one sperm fertilises but then replicates its genome

Question 35

How do partial hydatidifrom moles arise?

Answer 35

2 sperm fertilise a haploid egg, or one sperm will fertilise the haploid egg and then duplicate its genome

Question 36

What gene mutation may underly recurrent hydatidiform moles?

Answer 36

NLPR7

Question 37

What is an ectopic pregnancy?

Answer 37

When there is a pregnancy arising from the embryo being implanted at a site other than the endometrium

Question 38

Where do most ectopic pregnancies occur?

Answer 38

98% occur in the fallopian tube, but then they can also occur in the ovary, cervix or other intra-abdominal sites

Question 39

How common are ectopic pregnancies?

Answer 39

They affect 1-1.5% of pregnancies

Question 40

What are the treatments for ectopic pregnancy?

Answer 40

Expectant management Chemotherapy (methotrexate) Surgery to remove the trophoblast and/or tube

Question 41

What can rupture of an ectopic pregnancy cause?

Answer 41

It can cause severe internal bleeding

Question 42

How may smoking affect ectopic pregnancy?

Answer 42

Smoking increases the risk of a tubal pregnancy

Question 43

What does continine do?

Answer 43

Continine from cigarette smoke regulates PROKR1, which in turn regulates contractility of Fallopian tube smooth muscle. Continine also induces pro-apoptosis protein expression in Fallopian tube explants

Question 44

What does tobacco smoke do?

Answer 44

Inhibits ciliary function therefore may reduce tubal transit of embryo

Question 45

What endocannabinoid receptors does the epithelium of the Fallopian tube express?

Answer 45

CB1 and CB2

Question 46

What was found in a knockout mouse for CB1 and what does this show?

Answer 46

There was embryo retention in the Fallopian tube suggesting that endocannabinoids have a signalling effect on normal pregnancy

Question 47

How may inhaling cannabinoids affect ectopic pregnancy?

Answer 47

There were elevated cannabinoid levels in ectopic pregnancy patients, and reduced levels of CB1 therefore cannabinoid tone is disrupted

Question 48

How may THC affect ectopic pregnancy?

Answer 48

May act directly on the Fallopian tube to upset embryo transit

Question 49

What are the risk factors for ectopic pregnancy?

Answer 49

``` Prior ectopic pregnancy Prior Fallopian tube surgery Certain STIs Pelvic inflammatory disease Endometriosis ```

Question 50

What are possible risk factors for ectopic pregnancy?

Answer 50

``` Cigarettes Cannabis 35+ years old Infertility history Use of assisted reproductive technology e.g. IVF ```