(dev&age) disorders of early development Flashcards
what are three causes of pregnancy loss?
errors in embryo-fetal development
failure of the embryo to interact with the maternal endometrium and implant in the uterine lining
inability to sustain development of an implanted embryo/fetus
define miscarriage
loss of a pregnancy prior to 23 weeks gestation
what are the two classifications of miscarriage?
early clinical pregnancy loss (<12 weeks gestation)
late clinical pregnancy loss (>24 weeks gestation)
why is miscarriage classified based on a 23-24 week window?
as after 24 weeks there is a baseline levels of foetal viability outside the womb
(in case the fetus needs to be delivered)
what is early clinical pregnancy loss?
pregnancy loss before 12 weeks (i.e. in the first trimester)
what is late clinical pregnancy loss?
pregnancy loss after 24 weeks (i.e. in the second/third trimester)
how can a pregnancy be detected?
either by detected hCG in the mother’s urine OR by detecting the fetal heartbeat on an ultrasound scan
what is recurrent miscarriage?
recurrent pregnancy loss
in the UK = three or more pregnancy loss (either consecutive or non-consecutive)
what is recurrent miscarriage alternatively known as?
recurrent pregnancy loss
how many miscarriages must a woman have to be diagnosed with RM/RPL?
three or more consecutively OR non-consecutively
what are the two classifications of pregnancy loss?
pre-clinical pregnancy loss
clinical pregnancy loss
what is pre-clinical pregnancy loss?
the loss of a conceptus prior to implantation (pre-implantation) OR following implantation but before the missed menstrual period, approx 3-4 weeks gestation (post-implantation)
what is clinical pregnancy loss?
the loss of a conceptus following implantation but after the missed menstrual period (3-4 weeks gestation)
differentiate between pre-clnical and clinical pregnancy loss
pre-clinical pregnancy loss is either pre-implantation or post-implantation but before the missed menstrual period (i.e. 3-4 weeks gestation)
whereas clinical pregnancy loss is post-implantation after the missed menstrual period (i.e. after 3-4 weeks gestation)
how common is pre-clinical pregnancy loss?
pre-implantation = approx 30%
post-implantation (up to 3-4 weeks gestation) = another 30% approx
how common is clinical pregnancy loss?
approx 10%
how does the risk of clinical pregnancy loss change with maternal age?
as maternal age increases, the risk of clinical pregnancy loss also increases
what proportion of conceptions actually end up in successful live births?
approx 30%
what is the main cause of early pregnancy loss?
aneuploidy (chromosomal number errors)
what is aneuploidy?
having missing or extra chromosomes
what percentage of embryos are likely to be aneuploid?
approx 50%
what is the relationship between trisomic pregnancy risk and maternal age?
as maternal age increases, the risk of trisomic pregnancies increases exponentially
what is a trisomic pregnancy?
wherein the fetus has an extra chromosome in either some or all of the body cells
explain how oocytes undergo meiosis in the developing foetus
- eggs in ovary enter meiosis
- maternal and paternal copy pair up and DNA is replicated so there are two chromatid per chromosome
- homologous chromosomes lin up
- exchange material in recombination
- become arrested (do not proceed through to the first meiotic division)
- paternal and maternal chromosomes remain arrested in this linked state (i.e. dictyate state) all through life until the point at which the specific oocyte is about to get ovulated
- once ovulated THEN first meiotic division resumes
how is genetic material exchanged between homologous chromosomes?
homologous chromosomes line up and crossing over takes place between the chromatids of the chromosomes = genetic recombination
when do the foetal chromosomes in the developing ovary become arrested?
become arrested just after genetic recombination takes place and just before the first meiotic division can occur
what is dictyate arrest?
the prolonged resting phase in oogenesis wherein the oocytes become arrested in prophase I just before the first meiotic division until ovulation
for how long do the oocytes remain in dictyate arrest?
up to 50 years between the creation of an egg in foetal life TO point of oocyte ovulation = until then oocytes remain in dictyate arrest
describe the structure of the replicated chromosome in the ovary of the developing foetus
chromosomes, once replicated, are made up of two chromatids, joined together by cohesin proteins
how are chromatids held together?
cohesin proteins
what are cohesion proteins?
proteins that hold together sister chromatids of homologous chromosomes and provide cohesion
when does meiosis commence in oocytes?
during foetal life
post DNA replication, how many chromatids are there per chromosome?
two chromatids per chromosome
how long does dictyate arrest last?
the oocytes become arrested in prophase I just before the first meiotic division until ovulation
i.e. depending on when ovulation takes place, dictate arrest can last up to 50 years
compare the cohesion proteins in a young oocyte to that of an older oocyte
in young oocytes = many cohesion proteins link the chromatids of homologous chromosomes together
in older oocytes = cohesion proteins are lost and not replaced so the cohesion between chromatids is also lost
how do the first and second meiotic divisions occur in oocytes post ovulation?
when the oocyte is ovulated, the first meiotic division occurs as the spindle fibres separate the homologous chromosomes
the second meiotic division occurs when the spindle fibres separate the chromatids of a homologous chromosome
what separates in the first meiotic division?
the paired homologous chromosomes
what separates in the second meiotic division?
the (joined) chromatids of a homologous chromosome
what happens to the cohesion proteins as the oocyte gets older?
cohesion proteins are gradually lost and not remade or replaced so cohesion between the chromatids is also lost with increasing age of the oocyte
how are lost cohesion proteins replaced?
the lost cohesion proteins are not remade or replaced
what happens to cohesion proteins with increasing maternal age?
as the oocyte gets older, cohesion proteins are gradually lost and not replaced so there is a loss of cohesion between the chromatids
how does the loss of cohesion proteins impact meiosis?
as there is a loss of cohesion between the chromatids of the homologous chromosome, the chromatids can separate and drift randomly during meiotic division
= are not segregated accurately + do not line up properly
= can lead to aneuploidy
what is the impact of cohesion proteins not being replaced?
cohesion between the chromatids is lost
why does increasing maternal age lead to increased risk of aneuploidy?
increased maternal age = older oocytes = greater loss of cohesion proteins between the chromatids
greater loss of cohesion between chromatids so during spindle fibre anaphase in meiosis, less likely to be segregated accurately and will drift randomly
= can lead to aneuploidy
how does the lack of cohesion proteins with age lead to aneuploidy?
greater loss of cohesion between chromatids so during spindle fibre anaphase in meiosis, less likely to be segregated accurately and will drift randomly
= can lead to aneuploidy
what essential structure do cohesion proteins form and why is this important?
cohesion proteins form a ring structure that holds the two chromatids of a chromosome together
= if it is lost, chromatids cannot be held together properly and will drift apart
why is an increased maternal age risky for pregnancies?
increased maternal age = older oocytes = greater loss of cohesion proteins between the chromatids
greater loss of cohesion between chromatids so during spindle fibre anaphase in meiosis, less likely to be segregated accurately and will drift randomly
= increased risk of aneuploidy
what signalling pathway underpins recurrent pregnancy loss?
Lif pathway
what has been seen in Lif-deficient mouse models that can tell us about RPL/RM in humans?
while there is normal embryo development, there is failed implantation in Lif-deficient mouse models
define subfertile
women that can conceive normally but take longer than normal
(i.e. delay in conceiving)