Disorders of Early Development Flashcards
what is the definition of a miscarriage
why is this
loss of pregnancy before 23 weeks gestation
before 23 weeks because this it the time period where the fetus is not viable to sustain life outside of the uterus
(after 24 weeks fetus could have some chance of viability)
how can miscarriage be further defined
early clinical pregnancy loss - before 12 weeks gestation (1st trimester loss)
late clinical pregnancy loss - between 12-24 weeks gestation (2nd trimester loss)
what are broad causes of miscarriage
errors in embryo fetal development
failure of embryo to implant in uterine lining
inability to sustain development of implanted embryo/fetus
(remember pregnancy can only be detected when embryo has implanted in uterus and is producing beta HCG)
what are broad causes of miscarriage
errors in embryo fetal development
failure of embryo to implant in uterine lining
inability to sustain development of implanted embryo/fetus
(remember pregnancy can only be detected when embryo has implanted in uterus and is producing beta HCG)
how is recurrent pregnancy loss/recurrent miscarriage defined
UK - 3 or more pregnancy losses (consecutive or non consecutive)
USA/Europe - 2 or more pregnancy losses (consecutive or non consecutive)
to classify a pregnancy as “lost” it needs to have been detectable - e.g. by beta HCG, fetal heartbeat, ultrasound
happens in 0.8%-1.4% of pregnancies (remember majority of miscarriages are spontaneous not recurrent)
what is the major cause of early clinical pregnancy loss
loss that occurs before 12 weeks (but after 3-4 weeks)
chromosomal abnormalities/aneuploidy
what is a pre-clinical pregnancy loss
how common is it
a pregnancy which was undetectable has been lost
too early to be detected either biochemically (2 weeks gestation) or by foetal heartbeat (3-4 weeks gestation)
difficult to determine how common it is because they are undetectable
30% of conceptions are lost prior to implantation
another 30% of conceptions are lost following implantation but before the missed menstrual period
in total around 60% of conceptions are lost before they were detectable biochemically or by fetal heartbeat (are pre-clinical pregnancy losses)
(NOTE: after heartbeat is detected another 10% are lost through miscarriage so in total only 30% of all conceptions make it to live birth)
what is a clinical pregnancy loss
pregnancy that is lost after it is detectable - either biochemically (2 weeks) or by ultrasound/heartbeat (3-4 weeks)
would be classed as early if before 12 weeks
how common is clinical pregnancy loss
15% of all conceptions are lost after they are detectable
age has large effect:
occurs in 10% of pregnancies in women 20-24 years old
occurs in 51% of pregnancies in women 40-44 years old
how common is aneuploidy
aneuploidy = chromosomal number errors
53% embryos created using donor eggs in IVF are aneuploid
50% of lost early pregnancies display chromosomal errors
exponential increase in trisomic pregnancy risk with increasing maternal age
why does maternal age increase risk of aneuploidy
primary oocytes are arrested in meiotic prophase I (dictyate arrest) until ovulation of a few of these oocytes during each menstrual cycle
possible that meiosis can be arrested for up to 50 years
the primary oocytes are diploid → each homologous chromosome is made up of 2 identical sister chromatids due to DNA replication
during the meiotic arrest the sister chromatids of homologous chromosomes are held together by cohesin proteins
in “young” eggs there are lots of cohesin proteins, as egg gets older cohesin proteins are lost and are not remade or replaced → loss of cohesion between sister chromatids → both sister chromatids (that make up a homologous chromosome) are not captured by spindles, only one is and the other drifts
loss cohesin with age → age-related loss of cohesion between sister chromatids → inaccurate segregation of chromosomes → increased aneuploidy risk with age
what do these images highlighting cohesins REC8 and SMC2 show
much less REC8 and SMC2 in aged oocyte compared to young
almost all REC8 is lost and SMC2 is markedly decreased (can tell by the decreased luminescence)
old oocyte has less cohesion between sister chromatids of homologous chromosomes → increased risk of aneuploidy due to inaccurate segregation
what signalling pathways might underpin recurrent pregnancy loss
normally LIF (leukaemia inhibitory factor) and IL11 are secreted by uterine lining to allow embryo implantation
in LIF-deficient mice there is normal embryo development but failed implantation and there are reduced levels of LIF in the uterine secretions of subfertile women
suggests low levels of LIF could be reason for recurrent pregnancy loss (but not conclusive)
non-selective uterus hypothesis:
the uteri of women who experience recurrent pregnancy loss are highly permissive → they permit implantation of poor quality embryos (normal uteri would not)
as the embryos are of poor quality → they can’t develop → pregnancy loss
evidenced by the changes in uterine mucin expression in women with RPL (mucin is involved in uterine selectivity)
what is the importance of having maternal and paternal DNA in an embryo
why
embryo NEEDS to have both maternally + paternally derived genomes in order to be viable
need to have both to balance the development of embryo/fetus with development of placenta
genomic imprinting - the exclusive expression of specific gene copies from one parent
(NOTE: normally both copies of a gene, one from mother and one from father are active/switched)
in certain genes only the paternally-inherited copy is active/expressed - these genes promote the fitness of the embryo at the expense of the mother (large placenta)
and in other certain genes only the maternally inherited copy is active/expressed - restricts embryo fitness to conserve maternal resources for future pregnancies (small placenta)
there is inter-genomic conflict between maternal and paternal genes involved in placentation and nutrition
what is the clinical relevance of genomic imprinting
if genomic imprinting does not occur properly → gestational trophoblastic disease
formation of complete or partial hydatidiform moles
and in rare cases they can become malignant
what are gestational trophoblastic diseases
how common are they
what are their main features
how do hydatidiform moles form
an empty egg has no DNA
molar pregnancy can be carried to around 12 weeks gestation
explain the appearance of the hydatidiform mole
grape-like structure - each large fluid filled sac arises from chorionic villus
what are the risk factors for ectopic pregnancy
how does cannabis cause increased risk of ectopic pregnancy
receptors:
fallopian tubes express cannabinoid receptors CB1 and CB2
CB1 levels are reduced in ectopic pregnancy patients + in mice with the CB1 gene removed they display embryo retention in tubes
therefore endocannabinoid signaling has a role in normal embryo transit along fallopian tube and when this is disrupted → embryo becomes stuck → ectopic pregnancy
cannabinoids:
endocannabinoids levels are increased in ectopic pregnancy
exogenous cannabinoids in cannabis e.g. THC bind to and stimulate CB1 and CB2 receptors → this displaces endogenous endocannabinoids and overwhelms the normal endocannabinoid signalling
the displaced endocannabinoids result in increased presence of endocannabinoids in fallopian tube → disrupts the delicate endocannabinoid tone (balance) → disrupts embryo environment + fallopian tube epithelium
overall disruption in embryo transit → more likely to implant locally
