Disorders of Early development Flashcards
What can cause pregnancy loss?
Errors in embryo-fetal development
Failure of the embryo to implant in the uterine lining
Inability to sustain development of an implanted embryo/fetus
Define Miscarriage
Miscarriage: loss of a pregnancy prior to ~23 weeks gestation
Early clinical pregnancy loss (<12 weeks gestation)
Late clinical pregnancy loss (>24 weeks gestation)
What is the criteria for a recurrent miscarriage?
UK: three or more pregnancy losses (consecutive or non-consecutive)
USA/Europe: two or more pregnancy losses (consecutive or non-consecutive)
0.8-1.4% pregnancies
How common is preclinical pregnancy loss?
30% conceptions lost prior to implantation
30% following implantation but before the missed menstrual period (3-4wks gestation)
How common is clinical pregnancy loss?
~15% of conceptions
10% in 20-24 year olds
51% in 40-44 year olds
What is the major cause of pregnancy loss?
Major driver likely to be aneuploidy (chromosome number errors) in embryo
~53% embryos created using donor eggs in IVF are aneuploid
~50% of lost early pregnancies display chromosomal errors
What is the biggest risk factor in trisonomy pregnancy?
Exponential increase in risk of trisomic pregnancy with increasing maternal age
When does Meiosis begin?
Commences in Oocytes during foetal life
What happens during prophase in the first trimester
Paternal and maternal homologous chromosomes pair up, and DNA is replicated generating two chromatids per chromosome.
Genetic material is exchanged between homologues through recombination
What happens as you go from the first to second trimester?
Meiosis then arrests, resuming just before ovulation (up to 50 years later
Why does Aneuploidy increase with maternal age?
Throughout f meiotic arrest, the chromatids of homologous chromosomes are held together by cohesin proteins
These cohesin proteins are not replaced, leading to loss of cohesion between chromatids with increasing age of the oocyte
If cohesion has been lost, chromatids can separate and drift during meiotic division, rather than being segregated accurately by the spindle.
Which Cohesin Proteins are involved in maintaining cohesion between chromatids within chromosomes?
REC8 and SMC2
What signalling pathways underpin recurrent miscarriage?
Normal embryo development but failed implantation in Lif-deficient mouse models
Reduced levels of LIF in the uterine secretions of subfertile women
Non-selective uterus hypothesis
Uterus permits implantation of poor quality embryos
Changes in uterine mucin expression in women with RM/RPL
What is the cause of Molar pregnancy?
Imprinted genes
How do genes get imprinted?
Some genes only expressed from the paternally-inherited copy.
Promote embryo fitness at the expense of the mother
Some genes only expressed from the maternally-inherited copy.
Restrict embryo fitness to conserve resources for future pregnancies
Commonly genes involved in placentation and nutrition
What do embryos require to become viable?
Maternal and paternally derived genes
What are Gestational Trophoblastic diseases GTD’s?
GTDs are a collection of disorders characterized by overgrowth of trophoblastic tissue
What happens in benign GTD’s?
hydatidiform moles
Incidence of 1/500-1/1500 pregnancies, depending on geography.
Complete hydatidiform mole
Fetal tissue absent
Partial hydatidiform mole
Fetal tissue present
What happens in malignant GTD’s?
Gestational Trophoblastic Neoplasias
Arise following ~20% of cases of hydatidiform mole
Rare:
Invasive mole
Choriocarcinoma
Very rare:
Placental Site Trophoblastic Tumour (PSTT)
Epithelioid Trophoblastic Tumour
How do you form a Complete Hydatidiform mole?
Empty egg fertilised by:
1x sperm then sperm genome duplicated
or 2x sperm (no duplication)
How do you form a Partial Hydatidiform mole?
Normal egg fertilized by:
1x sperm then sperm genome duplicated
or 2x sperm (no duplication)
What could underpin recurrent hydatidiform mole formation?
NLRP7 mutations may underly recurrent HM
Failure to recognize and clear failed pregnancy?
What is an ectopic pregnancy?
Implantation of the embryo at a site other than the uterine endometrium.
Where do most ectopic pregnancies take place?
98% of these implantation events occur in the fallopian tube.
Other sites include ovary, cervix, other intra-abdominal sites.
What is the incidence of ectopic pregnancies?
1-1.5% of pregnancies
What is the treatment for ectopic pregnancies?
Treatment ranges from expectant management, through chemotherapy (methotrexate) to surgery to remove the trophoblast and/or tube.
What can happen if an ectopic pregnancy ruptures?
severe internal bleeding
What is the impact of smoking on the Fallopian tube?
Continine, a component of cigarette smoke, regulates the expression of PROKR1, a regulator of fallopian tube smooth muscle contractility.
Cotinine also induces pro-apoptosis protein expression in fallopian tube explants
Tobacco smoke inhibits ciliary function»_space; reduce tubal transit of the embryo?
Epidemiological studies: OR: 1.7-4 for tubal pregnancy in smokers
How can cannabis effect the Fallopian tube?
Fallopian tube expresses cannabinoid receptors CB1 and
CB1 levels are reduced in ectopic pregnancy patients,
CB1 knockout mice display embryo retention in the fallopian tubes.
Endocannabinoid levels are elevated in ectopic pregnancy fallopian tubes
Components such as THC in cannabis may act directly on the fallopian tube to peturb embryo transit,
or
alter the balance of endocannabinoids the ‘endocannabinoid tone’) in the tube leading to a disrupted embryo environment
What are the risk factors for ectopic pregnancy?
Prior ectopic pregnancy
Prior fallopian tube surgery
Certainsexually transmitted infections (STIs)
Pelvic inflammatory disease
Endometriosis
What factors increase the risk of ectopic pregnancy?
Cigarette smoking
Cannabis use?
Age older than 35 years
History of infertility
Use ofassisted reproductive technology, such asin vitro fertilization (IVF)
