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Monozygotic Twinning

By: Michael L. Reed, Center for Reproductive Medicine of New Mexico
02 June 2004
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Question:
I'd like to present some questions and observations to the group, to gain a greater understanding of the mechanisms driving monozygotic twinning (MZT) in IVF. Most papers suggest a relationship between MZT and time in culture (day 3 vs. day 5/6), and/or use of sequential media, and/or use of zona breaching techniques (ICSI, AH, other?). A recent paper (Jain et al., 2004 JARG 21:103-107) also suggests the possibility of a mechanism involving signaling by closely implanted embryos.

When do the MZT actually form? Pre-hatching, at hatching, or post-hatching/implantation?

I've observed one pre-hatching, expanded blastocyst with two distinct inner cell masses (ICM), and several that appear to have cell masses closely opposed but 'bridged' by a cell or cells - and there are a few papers where others have observed these phenomenon as well - demonstrating that at least some of these MZT are formed pre-implantation, pre-hatching. In discussions with a former professor, he observed blastocysts retreived from superovulated cattle with two ICM's present - is this then a function, in part, of the ovarian stimulation? If so, what is the incidence of MZT in COH intrauterine insemination cycles?

I've also observed embryos hatching directly across the inner cell mass, shaping the ICM into a classic dumbell configuration, suggesting also that hatching (breach from ICSI, AH, or hardened zona) may influence ICM integrity. What is the incidence of MZT from programs that remove the zona entirely before replacement? What is the incidence of MZT in programs that perform ICSI on all patients, or assisted hatching on all patients, or PGD for that matter? And as cryopreservation appears to have an effect on the zona, are there more or less MZT in FET cycles, compared to fresh embryo replacement cycles?

As to the concept proposed by Jain et al., it appears that in my data sets at least - not statistically analyzed - there are more MZT present with multiple embryos implanted - that is, two sacs with three FHT total, as compared to single sac with two FHT.

What about group culture vs. single embryo culture - are there any data that suggest an embryo/volume ratio effect? I group up to six embryos in approximately 50ul (overall MZT of about 1.5%) however I recall that in the very early use of extended embryo culture in his program, Barry Behr mentioned culturing entire cohorts of embyros in a single microdrop (not sure if this is the case now), but Behr et al. reported a MZT rate of approximately 5% in a later paper (2000 JARG 17:349-351) with authors from several programs, however there were no details regarding how the embryos were cultured, respective to groups or single embryos.

Last, what about the details of the culture conditions themselves - oxygen tension, pHi, microdrops vs. tubes (oil overlay), co-culture, sequential (two or more stage-specific media) vs. single non-stage-specific media, and so on?

Thanks!

Mike
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Rod Bycroft, IVF Canada



Rod Bycroft, IVF Canada said on 10 October 2004

"There are many papers implicating IVF, ICSI and embryo culture with an increase in the MZ twinning rate. Extended culture, breaching the zona, assisted hatching are among other manipulations associated with an increased rate in MZ twinning.

However, there is considerable evidence that ovarian stimulation alone will increase the MZ twinning rate beyond the 0.42 - 0.47% reported in the fertile population.

Increased MZ rates were observed by Macourt et al (Aust NZ J Obst & Gynaecol 1982,Feb;22(1):25-8) within the first 6 months of discontinuation of the oral contraceptive. A significant effect was seen in the first three months after discontinuation of the pill. However, it is unclear if any of those studied received clomiphene citrate for post pill amenorrhoea. The use of clomiphene citrate alone is reported to increase the MZ twinning rate.

Derom reported in the Lancet (Lancet 1987 May 30;1(8544):1236-8) that,"AIO (Artificial induction of ovulation)seems to be the first identified biological mechanism influencing the monozygotic twinning rate".

A paper by Schachter, M et al (Hum Reprod 2001 June;16(6):1264-9) supports this hypothesis by stating,"The rate of MZT was consistently increased, irrespective of treatment modality or micromanipulation. This may signify that the aetology of increased MZT after assisted reproduction is the gonadotrophin treatment rather than in-vitro conditions and micromanipulations or multiple embryo transfer".

There is a paradoxical increase in the MZ twinning rate reported by Twin registries in a number of countries over the last fifty years.

Our group, along with the START Clinic in Toronto, Canada, recently reported a 'Cluster' of 14 pregnancies (Poster, CFAS conference 2003).

We can confirm that there are "..more MZT present with multiple embryos implanted". Our data is as follows:

2 sets of quads (1 set of double monozygotic twins, and the other a singleton with a trizygotic triplet)

10 sets of triplets (All MZ twins with a singleton)

2 sets of MZ twins on their own.

One would normally expect to see more single implants of MZ twins rather than a skew towards multiple implantation.

We have also hypothesised that asynchronous development of transferred embryos may augment the implantation process.

All our embryos were grown on their own. Since reporting this study we have 6 more MZT pregnancies to include in our data.

Simpson & Golbus report in their book, 'Genetics in Obstetrics & Gynaecology, 2nd edition, 1992, chapter 13, Twinning. pp 173), "If monozygotic twinning occurs early in development, it is believed that two amnions will be present (diamniotic, dichorionic)(Benirschke and Driscoll,1967; Reid et al., 1972). After approximately day 3, only one chorion can form. Consequently, monozygotic twins that originate after this time will always be monochorionic and usually but not necessarily always diamniotic; 67% of MZ twins are monochorionic (Bulmer, 1970). The amnion becomes established about day 8; therefore, the rare monozygotic twins that arise between days 8 and 14 will be monoamniotic. Monozygotic twinning after day 14 results in conjoined twins".

Our data on the 14 MZ twins is as follows:

Diamniotic, dichorionic; 2 implantations

Diamniotic, monochorionic; 8 implantations

Monoamniotic, monochorionic; 3 implantations

Triamniotic, monochorionic; 2 implantation

Diamniotic, ? Chorionic; 1 implantation

You can see that there is a considerable variation in the observed membranes at gestational scan in our cohort.

I would be interested in seeing your data relating to gestational scans."

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