Human Embryo Mortality

Question 1

What are the problems with current estimates of human embryo mortality?

Answer 1

1. Drawn entirely from old studies - of which they are misinterpreted and contradict themselves
2. Too many assumptions -assuming a rate of coitus, rate of unprotected sex, assume 1/2 sex result in fertilisation, assume how much sex is happening around ovulation - any insubstantial assumptions multiplying, so making the situation worse. Minimal adjustments of any of these values can yield any plausible outcome.
3. Different definitions used - fecundity (probability of live birth within a given cycle) vs embryo survival.
4. Source - clinical pregnancy vs biochemical pregnancy (days 0-6 undetectable)
5. Have no data on failure of fertilisation - so how do you judge?
   Accuracy
   Precision

Question 2

What is the shit study called?

Answer 2

Robert and Lowe - a ‘hypothesis’

Question 3

What is the statistic the lecturer uses to quote for pregnancy loss? Evidence?

Answer 3

hCG studies
33%
20% occult loss before patient knows she is pregnant
15% clinical loss
Metaanalysis of women with no known fertility problem trying to get pregnant. Daily urinary samples tested for hCG over an extended period of time.
Wilcox, Zinaman, Wang

Question 4

What was the problem with Wilcox’s cycle by cycle analysis?

Answer 4

Within each cycle, the proportion of sub-fertile couples increases as pregnant women drop out. This will underestimate the number for normal fertile couples

Question 5

What did Rock and Hertig do?

Answer 5

Rock and Hertig
Looked for earliest products of conception in surgically removed fallopian tubes and uteri.
‘The Harvard Egg’
Did a visual search for ova in uteri/fallopian tubes of fertile women presenting for hysterectomy. 34 embryos, 24 normal 10 abnormal in 210 women in 15 years.
Shut down as started to be seen as termination of pregnancy by surgery.

Question 6

How were anatomical studies tried to be used to elucidate pregnancy loss rates?

Answer 6

Look at the proportion of normal to abnormal fertilised ova at the start (i.e. just post ovulation)
Assume this proportion should stay the same.
Then compare to proportion at the end
The difference is the loss.
?
PROBLEM this is just 4 out of 8 good eggs
confidence interval invalidates?

Question 7

So what are the 4 main types of data on pregnancy loss and what are their estimates?

Answer 7

1. Robert and Lowe hypothesis nothing useful
2. Clinical pregnancy loss 15-20% depending on definition
3. Biochemical pregnancy loss 20% occult 15% clinical Wilcox
4. Anatomical 31% pre-implantation .

Question 8

What can cause miscarriage?

Answer 8

Embryonic (aneuploidy)
Uterine (developmental aneuploidies, other disorders, prolapse, infection etc)
Cervical abnormalities
Hormonal insufficiency
Drugs/teratogens
Immune rejection

Question 9

How common is aneuploidy?

Answer 9

Assume:
10-15% clinical preg lost P(lost) so P(born) 85-90%
50-60% losses are aneuploidy P(AN/Lost)
0.3% live newborns aneuploidy P(AN/Born)
P(AN)=P(AN/lost)P(lost) + P(AN/born)P(born)
Gives 5.3%-9.3%
BUT don’t know about pre-clinical embryos, pre-implantation blastocysts, newly fertilised zygotes etc

Question 10

What is the problem with using IVF studies?

Answer 10

Particular to IVF population
Ovarian stimulation and IVF culture conditions can both influence rates of chromosome abnormalities
Gives a massive rate of aneuploidy

Question 11

Is aneuploidy always abnormal?

Answer 11

Mosaic embryos may self correct by eliminating aneuploidy cells, so not necessarily going to be abnormal
Aneuploidy in cytotrophoblast may be an important component of normal placentation
Implication for Pre-implantation genetic diagnosis - if you take one single cell that cell could still be normal