Disorders of Early Development - Mechanisms of Early Pregnancy Loss Tutorial Flashcards
What fraction of fertilised eggs are estimated to spontaneously miscarry in the early stages of pregnancy? (before implantation / pregnancy detection)
40-50% but uncertain
Can range between 30-75% loss before implantation
Total loss between fertilisation and birth estimated to be between 46-90%
Monthly probability of conception = 15-25%
So very high estimates (>80%) of loss are unlikely
What proportion of pregnancies are lost after a pregnancy has been biochemically confirmed?
10% of all clinically recognised pregnancies
80% of those losses occur in the first trimester
What is likely to be the major contributor to pregnancy loss before 12 weeks’ gestation?
Major driver = aneuploidy (chromosomal errors) in embryo
50% of lost early pregnancies display chromosomal errors
Other factors include:
Untreated increased TH (i.e. hyperthyroidism) = increased BP / hypertension = risk to embryo
Increased stress / cortisol
Chromosomal abnormalities (untolerated trisomies, monosomies)
Alcohol and smoking
How does maternal age affect the chance of miscarriage? Considering your answer to the previous question, why might this be the case, and what are the molecular mechanisms that underpin this?
As women get older, incidence of chromosomally abnormal eggs increases
Risk of miscarriage lowest at 25-29 (10%)
Risk of miscarriage increases from aged 33 onwards, reaching 53% >45 y/o
Caused by loss of cohesion between homologous chromosomes in oocytes with increasing age
Loss of proteins (cohesions) holding homologues together
Drifting of cohesions means spindle fibres cannot capture the chromosomes
Spindle fibres struggle to attach to chromosomes - lead to chromosomal abnormalities e.g. trisomy
What are recurrent miscarriage and recurrent implantation failure and what is the key difference between them?
Recurrent miscarriage = loss of pregnancy during the first 23 weeks; loss of 3 or more consecutive prognancies, affects 1% of couples trying to conceive - blastocyst and progress of actual embryo cannot be tracked
Recurrent implantation failure = refers to cases in which women have had 3 failed IVF attempts with good quality embryos; blastocyst hatches but fails to implant onto endometrial lining of uterus
Failure to implant or sustain pregnancy by natural conception (recurrent miscarriage) versus failure of transferred embryo to implant/sustain pregnancy (RIF)
What potential common/overlapping causes would you explore in the first instance for patients experiencing these conditions?
Substance use - drugs, excess caffeine Stress Anaemia Hypertension T2DM Thyroid dysfunction Abnormal structure of the uterus Placental issues Chromosomal abnormality in embryo (little or excess genetic material) - risk increased with maternal age
Initial diagnostic approaches are the same: what are they?
Check for uterine anatomical defects - fibroids/polyps that might disrupt implantation
Determine presence of auto-immune antibodies (anti-nuclear or antiphospholipid antibodies) attacking to embryo, preventing implantation / leading to miscarriage
Test paternal DNA for sperm integrity / fragmentation
Using your knowledge of reproductive endocrinology (BRS1/2 endocrinology), what signalling pathway(s) might underpin recurrent miscarriage or RIF?
LIF = leukemia inhibitory factor
Normal embryo development but failed implantation in LIF-deficient mouse models
LIF promotes decidualisation of human endometrial stromal cells in culture
Reduced LIF in the uterine secretions of subfertile women would cause recurrent miscarriage / RIF
LIF and progesterone promote decidualisation, lack of LIF or progesterone (/abnormal corpus luteum) = compromised implantation
What is endometrial scratching and how might it help a patient experiencing RIF?
Use of pipette or hysteroscope to damage endometrial mucosa before embryo transfer in IVF
Mechanism unknown but thought to stimulate immune cell infiltration and wound healing cytokine production = creation of more favourable environment for egg to implant
Evidence in support variable - possible benefit in selected groups e.g. RIF
Although large NZ study suggests no benefit of scratching in any group
Histologically, how is the fallopian tube adapted to support transit of the fertilised embryo to the uterus?
Fimbriae catch the embryo
Cilia and peristalsis by the smooth muscle contractions of the tubes = migration of embryo down the fallopian tube
Cilia = promotes fluid movement
What happens if a fertilised egg moves up the peritoneum?
Leads to placenta attaching to the peritoneum and is impossible to remove without severe fatal bleeding
Thinking about your answer to the previous question, how might this help explain how cigarette smoking increases the risk of ectopic pregnancy? Can you find experimental evidence to support this?
PROKR1 = regulator of fallopian tube smooth muscle contractility
Smoking dysregulates PROKR1 receptor = disrupt peristalsis of tube = embryo not moved along
Cotinine, present in cigarette smoke = increases expression of pro-apopotic proteins in fallopian tube explants
Tobacco smoke also likely to inhibit ciliary function, reducing transit of the embryo through the fallopian tube
Tube rupture
What are ectopic pregnancies?
Where do ectopic pregnancies usually occur?
What percentage of pregnancies are ectopic?
Ectopic pregnancies arise from the implantation of the embryo at a site other than the uterine endometrium
98% of these implantation events occur in the fallopian tube
Around 1-1.5% of pregnancies are ectopic
What is the treatments for ectopic pregnancies?
What can rupture of ectopic pregnancy lead to?
Ranges from chemotherapy (methotrexate) to surgery to remove the affected tube
Rupture of an ectopic pregnancy can lead to severe internal bleeding
Cannabis use is also believed to elevate the risk of ectopic pregnancy, but via a different mechanism to cigarette smoking. At the molecular level, how might cannabis use elevate the risk of a tubal pregnancy?
Fallopian tube exppresses CB1 and CB2 cannabinoid receptors
CB1 reduced in ectopic pregnancy patients, and CB1 KO mice causes embryo retention in the fallopian tubes
70% of women who use cannabis proceed with using it through their pregnancy
Levels of endocannabinoids elevated in ectopic pregnancy fallopian tubes
Components such as THC in cannabis may act directly on the fallopian tube (as it can get through to the fallopian tubes and affect there) = perturb transit or alter the balance of endocannabinoids in the fallopian tube = disrupted embryo environment
