L15: Multiple Pregnancy

Question 1

What are the different types of twins?

Answer 1

• Dizygotic (DZ)
• monozygotic (MZ)

Question 2

What are the differences between monozygotic and dizygotic twins?

Answer 2

monozygotic:
- 1/3 of twins
- one egg and one sperm
- zygotes are genetically nearly identical
- share all DNA
- twins appear identical
- always same sex

dizygotic:
- 2/3 of twins
- two eggs and two sperm
- zygotes have different genetic constitutions
- share 50% of DNA
- twins have no more resemblence than any brothers or sisters
- can be of different sex

Question 3

What is the frequency of monozygotic and dizygotic twins?

Answer 3

• monozygotic - 1/3 twins
• dizygotic - 2/3 twins

Question 4

How much are genetically monozygotic and dizygotic twins similar?

Answer 4

monozygotic - genetically nearly identical, share all DNA
dizygotic - different genetic constitutions, share 50% of DNA

Question 5

What are the possible sexes of monozygotic and dizygotic twins?

Answer 5

• monozygotic always same sex
• dizygotic can be same or different sex

Question 6

How can triplets be derived?

Answer 6

• one zygote and all be identical
• two zygotes, consisting of identical twins and a singleton
• three zygotes and be of the same sex or of different sexes

Question 7

How do twins develop in the uterus? (chorionicity)

Answer 7

• monochorionic monoamniotic (share chorion and amnion; MC/MA; share placenta)
• Monochorionic diamniotic (share chorion, but two amnions; MC/DA, share placenta)
• Dichorionic diamniotic (two chorions, two amnions; DC/DA; everything separate)

check L15, slide 6

Question 8

What is the most frequent chorionicity of monozygotic and dizygotic twins?

Answer 8

• for monozygotic most frequent is monochorionic diamniotic
• for dizygotic it’s always dichorionic diamniotic

Question 9

How is chorionicity determined?

Answer 9

The degree of splitting is determined by the timing of the split:
- at days 1-3 - DC/DA
- at days 4-8 - MC/DA
- at days 8-13 - MC/MA

Question 10

When does chorion and amnion post-fertilisation begin to form?

Answer 10

• chorion forms 4-5 days post-fertilisation
• amnion begins to form on day 8

Question 11

How are two complete and separate chorions/amnions determined?

Answer 11

Twins who have two complete and separate chorions indicates that separation occured before the formation of the trophoblast tissue on day 5

Question 12

How are separate amnions but same chorion determined?

Answer 12

In pregnancies where twins share a chorion, suggests that split occurred within the ICM after the trophoblast formed. If they have separate amnions: suggests the split occured before the formation of the amnion (day 9)

Question 13

How are shared amnion and chorion determined?

Answer 13

If separation of ICM comes after formation of chorion and after the formation of amnion then resulting embryos would have one chorion and one amnion

Question 14

What are conjoined twins?

Answer 14

The two fetuses will remain physically connected (most often at the chest, abdomen or pelvis), conjoined twins may also share one or more internal organs

Question 15

How does conjoined twinning occur?

Answer 15

if separation of an embryo occurs between day 13 & 15 & the inner cell mas does not completely separate, or if portions of the inner cell mass secondarily re-join, conjoined twins may result

Question 16

What’s the survival rate of conjoined twins?

Answer 16

Many are stillborn or die shortly after birth; some can be surgically separated

Question 17

What is twin-twin transfusion syndrome?

Answer 17

• TTTS occurs in around 10-15% of MC/DA pregnancies;
• placental vascular anastomoses form so that one twin receives most of the blood flow.
• Flow to the other twin is compromised.
• One twin is usually larger than the other

Question 18

What are mirror image twins?

Answer 18

• Mirror-image monozygotic twins have inverse laterality;
• suggests that twinning event took place after the cells of the embryonic plate were beginning to lateralise but before formation of the primitive streak.

Question 19

What are the examples of mirror image twins?

Answer 19

• whether the first tooth erupts on the right or let side
• which side cowlicks or hair whorls are present
• handedness
• wrinkles
• position of warts
• type and presence of neuralgias

Question 20

Why is the incidence of twins/triplets more common nowadays?

Answer 20

• The incidence of twins, triplets or more is common due to assisted reproductive technologies (ART) and fertility treatments;
• transfer of more than one embryo can lead to dizygotic twins.
• campaigns such as ‘one at a time’ have helped raise awareness about multiple births and helped protect health of women and their babies

Question 21

Does having ART increase your chances of having monozygotic twinning? What are the resons for it?

Answer 21

• 2x-5x amount of MZ twins born following IVF
• The reason is thought to be zona pellucida
• Maybe there is something in the media of IVF used that causes zona hardening. So that when the blastocyst is about to implant and it hatches, that there are problems with hatching that lead to twinning of embryo
• It is also speculated that handling the embryo during IVF creates breaks/holes in the zona pellucida that might alter the embryo and increase its chances of twinning

Question 22

What is the cause of higher incidence of having dizygotic twins?

Answer 22

Women aged 35+ twice as likely to have DZ twins than women under 25; percentage of cycles that show spontaneous multiple follicle growth:
- older women –> 25%
- younger women –> 5%

Question 23

What is the reason for older women having dizygotic twins more often?

Answer 23

• DZ twinning associated with DZ twinning
• It is related to HPO axis, as the woman is young there is lots of follicles, thus lots of inhibin produced, which causes negative feedback on pituitary
• As the woman gets older, there will be fewer follicles, fewer granulosa cells, less inhibin, therefore less negative feedback and therefore more FSH produced, more follicles stimulated, increases rate of follicle growth and chance of double ovulation

Question 24

Is there a genetic predisposition to dizygotic twins?

Answer 24

Dizygotic twins:
- there are some factors that make having fraternal twins more likely: they are more common in some ethnic groups; DZ twins can run on the mother’s side of the family
- follicular growth, maturation and ovulation are tightly regulated via various pathways
- ovarian folliculogenesis and determination of ovulation quota are controlled both by circulating concentrations of FSH and by intra-ovarian factors including the two oocyte growth factors, GDF9 and BMP15, as well as their cognate receptors
- mutations in BMP15 and GDF9 have been associated with increased DZ twinning in sheep and humans
- sequence variation at the FSH and SMAD3 loci increases the odds of DZ twinning in women

Question 25

Is there a **genetic predisposition to monozygotic twins**?

Answer 25

monozygotic twins: - not known what causes MZ twins - tend to not run in families - all pregnant women have same chance of having MZ twins - but very rarely, familial monozygotic twinning is seen

Question 26

What are the **possible reasons** for a very rare familial **monozygotic twinning**?

Answer 26

- BUT, very rarely, familial monozygotic twinning is seen i) Can be transmitted by both the father and the mother ii) Suggests that in familial monozygotic twinning, there may be an inherited effect iii) Possibly a defect in one of the zona pellucida proteins iv) A fragile zona pellucida might allow early separation of clumps of blastocyte v) Mutation in a gene that leads to failure/delay of cell-to-cell recognition and adhesion

Question 27

What are **sesquizygotic twins**?

Answer 27

- Semi-identical twins, after SNP analysis compared genotypes between twins, - revealed that twins share and identical maternal allele, but chimeric for two separately identical paternal alleles; - both twins had the same maternal copy but different paternal alleles; - only two cases in the world; maybe one egg fertilized by two sperms

Question 28

What is the **possible mechanism for sesquizygotic twinning**?

Answer 28

- Case of dispermic fertilization – shouldn’t be normally possible (one carrying X, one carrying Y) - Results in three pronuclei: maternal and two paternal nuclei - Then heterogoneic cleavage division takes place, which is a tripolar spindle apparatus instead of bipolar - Three cells will form, two will be biparental lineage and one will be only paternal lineage - Biparental cell lines would outcompete uniparental lines, where twinning then occurs - They are chimeras: one twin was made up proportionally from one type of cells, while the other was made from other types of cells

Question 29

Are **monozygotic twins really identical**?

Answer 29

Recent study sequenced whole genome twin pairs, their parents, partners and offspring; - identified post-zygotic mutations and timed their occurrence by relating them to the specification of primordial germ cells (PGCs) - identified mutations present in offspring but absent in partner/twin sibling - estimated that on avergae 5.2 pre-PGCs mutations exist between twin genomes (but very variable) - 15% of probands had pre-PGCs mutations that were then passed onto their offspring (but absent in their twin sibiling) - **found that no two genomes are identical, not even the genomes of 'identical' twins**