Dev & Ageing - Disorders of Early Foetal Development Flashcards
What are the reasons for early pregnancy loss? (3)
- Failure in the embryo-foetal development
- Inability to sustain development of implanted embryo/foetus
- Failure of embryo implantation in endometrium
What is a miscarriage?
A loss of pregnancy prior to 23 weeks of gestation
What is an early clinical pregnancy loss
A loss of pregnancy prior to 12 weeks of gestation
What is a late clinical pregnancy loss
A loss of pregnancy after 24 weeks of gestation (stillbirth)
What classifies for recurrent miscarriages/pregnancy loss in the UK
3+ losses
What classifies for recurrent miscarriages/pregnancy loss in the US/Europe
2+ losses
How many pregnancies does recurrent loss affect?
0.8-1.4% of pregnancies
How frequent is clinical pregnancy loss?
Affects 15% of conceptions
What age group is most affected by clinical pregnancy loss?
40-44 year olds
What are the 2 types of clinical pregnancy loss
Live birth
Miscarriage
What are the 2 types of pre-clinical pregnancy loss?
Post-implantation
Pre-implantation
What is one of the major causes for early pregnancy loss?
Aneuploidy
How common is aneuploidy?
- It was found that 53% of IVF donor eggs embryos were aneuploid.
- 50% of lost early pregnancies displayed some chromosomal abnormality
How does maternal age vary with trisomy?
Increase in maternal age increases the risk of trisomy exponentially
Why does maternal age increase the risk of aneuploidy?
Maternal oocytes undergo prolonged meiotic arrest in prophase I
Explain how maternal age increases aneuploid incidence?
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.
What are examples of cohesin proteins?
REC8 and SMC2
What signalling in mice was shown to cause pregnancy loss?
Deficiency of LIF was shown to cause failed implantation despite normal embryo development
What is LIF?
Leukaemia inhibitory factor released from endometrial cells stimulates adhesion from the blastocyst to endometrial cells
How do LIF levels relate to sub fertile women’s uterine secretions?
Reduced levels of LIF were found in the uterine secretions of sub fertile women
What is the non selective uterine hypothesis?
The uterus will permit the implantation of poor quality embryos, but in women with RPL/RM there are changes in uterine mucin expression
What is genomic imprinting?
The balance between the maternal and the paternal genome in order to create a viable embryo, creating an intergenomic conflict
What does the paternal genome promote?
Embryo fitness at expense of the mother
What does the maternal genome promote?
Restricts embryo resources in order to save for future pregnancies
What genes are commonly involved in intergenomic conflict?
Genes involves with placentation and nutrition
What are GTDs?
Gestational trophoblastic disorders - a set of disorders characterised by trophoblastic overgrowth
What are hydatidiform moles?
Benign GTDs
What is a complete hydatidiform mole?
When no foetal tissue is involved there is just trophoblastic overgrowth
What is a partial hydatidiform mole?
When there is some foetal tissue involved with the trophoblastic overgrowth
What are malignant GTDs called?
Gestational trophoblastic neoplasias
What are the rare trophoblastic neoplasias?
Invasive mole
Carcinoma
What are the very rare trophoblastic neoplasias?
Placental site trophoblastic tumour
Epithelioid trophoblastic tumour
How may trophoblastic neoplasias arise?
20% are from hydatidiform moles after we try to remove them
How do complete hydatidiform moles arise?
When 2 spemr fertilise an empty egg, or one sperm fertilises but then replicates its genome
How do partial hydatidifrom moles arise?
2 sperm fertilise a haploid egg, or one sperm will fertilise the haploid egg and then duplicate its genome
What gene mutation may underly recurrent hydatidiform moles?
NLPR7
What is an ectopic pregnancy?
When there is a pregnancy arising from the embryo being implanted at a site other than the endometrium
Where do most ectopic pregnancies occur?
98% occur in the fallopian tube, but then they can also occur in the ovary, cervix or other intra-abdominal sites
How common are ectopic pregnancies?
They affect 1-1.5% of pregnancies
What are the treatments for ectopic pregnancy?
Expectant management
Chemotherapy (methotrexate)
Surgery to remove the trophoblast and/or tube
What can rupture of an ectopic pregnancy cause?
It can cause severe internal bleeding
How may smoking affect ectopic pregnancy?
Smoking increases the risk of a tubal pregnancy
What does continine do?
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
What does tobacco smoke do?
Inhibits ciliary function therefore may reduce tubal transit of embryo
What endocannabinoid receptors does the epithelium of the Fallopian tube express?
CB1 and CB2
What was found in a knockout mouse for CB1 and what does this show?
There was embryo retention in the Fallopian tube suggesting that endocannabinoids have a signalling effect on normal pregnancy
How may inhaling cannabinoids affect ectopic pregnancy?
There were elevated cannabinoid levels in ectopic pregnancy patients, and reduced levels of CB1 therefore cannabinoid tone is disrupted
How may THC affect ectopic pregnancy?
May act directly on the Fallopian tube to upset embryo transit
What are the risk factors for ectopic pregnancy?
Prior ectopic pregnancy Prior Fallopian tube surgery Certain STIs Pelvic inflammatory disease Endometriosis
What are possible risk factors for ectopic pregnancy?
Cigarettes Cannabis 35+ years old Infertility history Use of assisted reproductive technology e.g. IVF
