12. Cytogenetics of miscarriage

Question 1

What is the definition of a miscarriage?

Answer 1

Spontaneous end of pregnancy at a stage when embryo/fetus is incapable of surviving independently

Question 2

Up to how many weeks is defined as a miscarriage?

Answer 2

Prior to 24 weeks

After 24 weeks = stillbirth

Question 3

What are the two common causes of miscarriage at the morula/blastocyst stage?

What happens?

Answer 3

Autosomal monosomy or polyploidy

Fail to implant or lost following transient implantation with little disruption of menstrual cycle

Question 4

At what stage do the majority of miscarriages in the first trimester take place? Why?

Answer 4

End of first trimester

When placenta takes over nourishment

Question 5

Of the cases with a chr abnormality that miscarry, what is the cause in the majority?

Answer 5

Single trisomy accounts for 60%

Question 6

Other than T13, T18, T21, what is the most common trisomy? Is it viable?

Answer 6

T16 in 1% of conceptuses - not viable unless mosaic or CPM

Question 7

What is the cause of the majority of trisomies? What are the exceptions?

Answer 7

Non-disjunction in maternal meiosis I

T18 - maternal meiosis II
T15 - maternal meiosis I or II

Question 8

What abnormalities are most commonly seen in second trimester miscarriages?

Answer 8

Viable trisomies (13, 18, 21)

Question 9

When does Turner syndrome end in miscarriage?

Answer 9

True monosomy X is lethal, conceptions die in utero - Turner patients are mosaic or were in early development

Question 10

What is the cause of tetraploidy? What are the most common karyotypes?

Answer 10

Failed early mitotic division

92, XXXX and 92, XXYY

Question 11

What is the cause of the majority of triploidies? What is it called?

Answer 11

2/3 due 2x paternal chromosome sets due to dispermy

Diandry

Question 12

What is the cause of the minority of triploidies?

Answer 12

2x maternal chromosome sets due to diploid egg

Digyny

Question 13

What is the consequences of diandric triploidy?

Answer 13

Form partial hydratiform mole

Abort in 1st/2nd trimester, risk of gestational trophoblastic neoplasia

Question 14

What are the consequences of digynic triploidy?

Answer 14

Non-molar pregnancy, abort early

Question 15

What is the result of diandric diploidy?

What risk is associated with it?

Answer 15

Complete mole - no embryo

High risk of choriocarcinoma

Question 16

What is the result of digynic diploidy?

Answer 16

Ovarian teratoma - fatal

Question 17

What is the definition of recurrent miscarriage?

Answer 17

3 or more miscarriages before 24 weeks

Question 18

What chromosomal abnormalities cause recurrent miscarriage?

Answer 18

In 2-5% of couples, one partner carries a balanced rearrangement

Most commonly balanced reciprocal translocation or Robertsonian

Question 19

What 3 types of referral are accepted for testing for miscarriages?

Answer 19

1. Pregnancy loss or termination with significant fetal abnormalities
2. Pregnancy loss at >24 weeks
3. Miscarriage at <24 weeks for 3rd and subsequent

Question 20

When should parents be karyotyped for RM?

Answer 20

Only if an unbalanced rearrangement is identified in POC

Question 21

Why should POC be karyotyped before parents?

Answer 21

1. To identify unbalanced rearrangment –> allows parents to be tested for balanced translocations
2. May also detect causes of sporadic miscarriage (aneuploidy, polyploidy) –> better prognosis for next pregnancy

Question 22

What tests are generally used for POC?

Answer 22

QF-PCR as first line for aneuploidies (13, 15, 18, 21, 22, X, Y)

Microarray

Question 23

When does maternal blood need to be tested when testing tissue by QF-PCR?

Answer 23

Normal female result from ESPL or placenta sample

Could represent maternal genotype so mum tested to confirm sample represents the fetus

Question 24

How does gestation impact the testing available for POC?

Answer 24

<24 weeks IUD - no testing unless recurrent

24-27 weeks IUD - QF-PCR only

> 27 weeks IUD - array (no QF-PCR) as usually cord sample so represents fetal genotype

Question 25

How are recurrent miscarriage referrals tested?

Answer 25

Must be >3 consecutive miscarriages

QF-PCR prior to array if ESPL or placenta - may require maternal blood

Array if cord/organ/skin

Question 26

How are POC referrals with fetal abnormality tested?

Answer 26

QF-PCR prior to array if ESPL or placenta - may require maternal blood

Array if cord/organ/skin

Unless isolated neural tube defect –> QF-PCR only

Question 27

How are positive QF-PCR results followed up?

Answer 27

Karyotype POC to determine nature of aneuploidy and whether there’s a recurrence risk

i.e. due to a familial translocation (high recurrence risk) or non-disjunction (sporadic)

Request parental bloods to determine if they carry a balanced translocation