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Developmental biology - IVF

Why IVF can result in twins or triplets

In the world's largest study of its kind, scientists determine the frequency and cause for multiple births from single IVF egg transfers...

For some time physicians have known it's better to transfer a single embryo during Assisted Reproduction Treatment (ART) rather than several. Their objective being to avoid the dangers of multiple pregnancies as those risks include not only low birthweight to each baby through premature delivery, but fetal deaths through miscarriages. However, even when Single Embryo Transfer (SET) is performed, some eggs will still twin or even triplet.

In the study published in the journal Human Reproduction, researchers investigated reasons why this happens and for the first time, calculate the proportion of multiple pregnancies after SET to be 1.6% with 1.36% to be the result of a process called zygotic splitting.

In this the largest study to investigate zygotic splitting after SET 937,848 SET cycles were analysed to highlight factors that might increase that risk. These factors include using frozen then thawed embryos for SET, maturing a fertilised egg (blastocyst) in the laboratory for five or six days before SET, and assisting the hatching of an egg by drilling a small hole in the layer of proteins surrounding the embryo - the zona pellucida - to assist its attachment to the wall of a woman's womb.

"As a result of our findings, clinicians may want to consider counseling couples about the small increase in risk for multiple pregnancies as a result of zygotic splitting." explains Dr Keiji Kuroda of the Sugiyama Clinic and Juntendo University Faculty of Medicine in Japan, and one of the authors of the study.
A zygote is the fertilised egg cell that results after combining with a sperm. It contains all the genetic information from both parents to form a new individual when it begins to divide, then subdivide into blastomere cells forming the embryo. Zygotic splitting occurs between days two and six following fertilization. If the zygote divides into two identical twins, they are called "monozygotic" twins. Triplets can also form at this time from a single fertilized egg dividing into three zygotes, and these zygotes will become "monozygotic" triplets.

A multiple pregnancy can result from SET where another egg is fertilized at the same time by a different sperm. The only way to be sure which situation has occurred is to use ultrasound to see if there are one or more gestational sacs and heartbeats. For this study, researchers identified true zygotic pregnancies as different from splitting pregnancies when the number of fetuses exceeded the number of gestational sacs.

Dr Kuroda and his colleagues looked at nearly a million cycles of SET carried out in Japan between 2007 and 2014, reporting to the Japanese ART national registry. More than 99% of all ART treatment cycles were entered in this registry since 2007. After SET using fresh or frozen, then thawed embryos, there were nearly 277,000 clinical pregnancies (an increase of 29.5%), including 4,310 twins (1.56% of pregnancies) and 109 triplets - or 0.04% of pregnancies.

The prevalence of true zygotic splitting was 1.36% compared to singleton pregnancies. Using frozen-thawed embryos increased the risk of zygotic splitting embryos by 34%; maturing blastocysts in the lab for a few days before embryo transfer increased the risk by 79%; assisted hatching by 21%.
"Blastocyst culture was associated with the highest risk for zygotic splitting of the three risk factors identified. Embryo selection using a computer-automated time-lapse image analysis may decrease that risk. Although the use of single embryo transfer has increased worldwide, the prevalence of zygotic splitting pregnancies has not. ART and culture techniques, have improved in recent years leading to a decrease in the risk of zygotic splitting.

Keiji Kuroda MD, Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine; and Center for Reproductive Medicine and Implantation Research, Sugiyama Clinic Shinjuku, Tokyo, Japan.

Japan performs the most IVF cycles worldwide. To aim at a safe live birth for every baby, the SET rate reached 80% of all ET cycles in 2015 (Saito et al., 2018). Therefore, to our knowledge, this is the largest study to analyse zygotic splitting after SET and the first to investigate in detail the number of GSs and foetuses in multiple pregnancies after SET. Furthermore, this is the first report we know of to analyse potential risk factors of zygotic splitting using the data of ‘true’ singleton and ‘true’ zygotic splitting pregnancies after SET.

Y Ikemoto, K Kuroda, A Ochiai, S Yamashita, S Ikuma, S Nojiri, A Itakura and S Takeda.

The authors wish to thank all Japanese reproductive doctors that registered their data in Japanese ART registry and contributed to decrease multiple pregnancies using SET procedure. They also thank the JSOG for providing the ART data in 2007–2014.

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Oct 16, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Ultrasound image showing zygotic splitting in process in the womb. Credit Copyright: Keiji Kuroda

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