Age + Dev - Disorders Of Early Development Flashcards
What are some common causes of pregnancy loss in humans?
→ Errors in embryo-fetal development
→ Failure of the embryo to implant in the uterine lining
→ Inability to sustain development of an implanted embryo/fetus
What is a miscarriage?
loss of a pregnancy prior to ~23 weeks gestation
What is counted as early clinical pregnancy loss?
< 12 weeks gestation
What is counted as late clinical pregnancy loss?
> 24 weeks gestation
What is categorised as recurrent miscarriage / recurrent pregnancy loss?
→ UK: three or more pregnancy losses (consecutive or non-consecutive)
→ USA/Europe: two or more pregnancy losses (consecutive or non-consecutive)
What is counted as pre-clinical pregnancy loss?
→ pre-implantation
→ post-implantation
What is counted as clinical pregnancy loss?
→ miscarriage
How frequent are pre-clinical early pregnancy loss?
→ pre-implantation = 30%
→ post-implantation before the missed menstrual period = 30%
How frequent are clinical early pregnancy loss?
→ miscarriage = 10% - 15%
What are some of the major causes of early 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
→ Exponential increase in risk of trisomic pregnancy with increasing maternal age
How common are clinical pregnancy losses in 20-24 year olds?
10% of pregnancies
How common are clinical pregnancy losses in 40-44 year olds?
51% of pregnancies
How do oocytes end up experiencing prolonged meiotic arrest?
→ Meiosis commences in oocytes during fetal life
→ Paternal and maternal homologous chromosomes pair up, and DNA is replicated generating two chromatids per chromosome.
→ Genetic material is exchanged between homologues through recombination
→ 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
What signalling pathways underpin RPL + RM?
→ 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
What is non-selective uterus hypothesis?
→ Uterus permits implantation of poor quality embryos
→ Changes in uterine mucin expression in women with RM/RPL
What are molar pregnancies?
molar pregnancy (hydatidiform mole) = rare complication of pregnancy characterised by the abnormal growth of trophoblasts (cells that normally develop into the placenta)
What can cause molar pregnancies?
imprinted genes (commonly genes involved in placentation and nutrition) → some genes only express the paternal-inherited or maternal-inherited copy
What is a GTD?
→ gestational trophoblastic diseases
→ collection of disorders characterised by overgrowth of trophoblastic tissue
What are the 2 main types of GTD?
→ benign = hydatidiform moles
→ malignant = gestational trophoblastic neoplasias
What are the 2 types of benign hydatidiform moles?
→ complete hydatidiform mole = fetal tissue absent
→ partial hydatidiform mole = fetal tissue present
What are some rare types of malignant GTDs?
→ invasive mole
→ choriocarcinoma
What are some very rare types of malignant GTDs?
→ placental site trophoblastic tumour (PSTT)
→ epithelioid trophoblastic tumour
What causes a complete hydatidiform mole to form?
Empty egg fertilised by:
→ 1x sperm then sperm genome duplicated
→ or 2x sperm (no duplication)
What causes a partial hydatidiform mole to form?
Normal egg fertilized by:
→ 1x sperm then sperm genome duplicated
→ or 2x sperm (no duplication)
What could be the cause to underlying recurrent hydatidifirm moles?
→ NLRP7 mutations
→ failure to recognise + clear failed pregnancies
What is an ectopic pregnancy?
Implantation of the embryo at a site other than the uterine endometrium
Where does the extra-uterine implantation often occur?
→ 98% of these implantation events occur in the fallopian tube
→ Other sites include ovary, cervix, other intra-abdominal sites
What are the consequences of a rupture of an ectopic pregnancies?
severe internal bleeding
How can you treat an ectopic pregnancy?
→ expectant management
→ chemotherapy (methotrexate)
→ surgery to remove the trophoblast and/or tube
What are some lifestyle risk factors of an ectopic pregnancy?
→ smoking → cannabis → age > 35 → history of infertility → use of assisted reproductive technology, such as IVF
What is the impact of smoking of 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?
How might cannabis affect 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
