Risk factors associated with monozygotic twinning in offspring conceived by assisted reproductive technology

Na Chen; Jingyu Li; Yexing Li; Yiyuan Zhang; Jiarong Li; Jie Gao; Jingmei Hu; Linlin Cui; Zi-Jiang Chen

doi:10.1093/hropen/hoad035

Risk factors associated with monozygotic twinning in offspring conceived by assisted reproductive technology

Hum Reprod Open. 2023 Sep 14;2023(4):hoad035. doi: 10.1093/hropen/hoad035. eCollection 2023.

Authors

Na Chen^{1

2

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7}, Jingyu Li^{1

2

3

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7}, Yexing Li^{1

2

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7}, Yiyuan Zhang^{1

2

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5

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7}, Jiarong Li^{1

2

3

4

5

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7}, Jie Gao^{1

2

3

4

5

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7}, Jingmei Hu^{1

2

3

4

5

6

7}, Linlin Cui^{1

2

3

4

5

6

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8}, Zi-Jiang Chen^{1

2

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4

5

6

7

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10}

Affiliations

¹ Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
² Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, China.
³ Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China.
⁴ Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China.
⁵ Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China.
⁶ Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China.
⁷ National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China.
⁸ Center for Reproductive Medicine, The Second Hospital, Shandong University, Jinan, Shandong, China.
⁹ Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.
¹⁰ Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Study question: What are the factors influencing the occurrence of monozygotic (MZ) twins in offspring conceived by assisted reproductive technology (ART)?

Summary answer: Parental ages, the transfer of fresh versus frozen embryos, and the grade of blastocysts are all related to MZ twinning in ART offspring.

What is known already: Offspring conceived by ART have significantly increased risk of MZ twins, which may be due to the characteristics of the infertile population. The objective of this study was to explore the incidence of monozygotic (MZ) twins after ART and to clarify the risk factors for MZ twinning.

Study design size duration: A total of 255 monozygotic twins were enrolled in this cohort study, and then matched with singletons at a ratio of 1:4 randomly (with 1020 in the control group). All offspring were conceived by single embryo transfer.

Participants/materials setting methods: The collected data were divided into the following three aspects for analysis: characteristics of the infertile population, gamete or embryo manipulations, and factors related to embryo development.

Main results and the role of chance: The incidence of MZ twins was 1.638% (255 out of 15 567 pregnancies after single embryo transfers). Compared to singleton births, a significantly lower rate of frozen embryo transfers (FET; 78.0% vs 86.1% P = 0.002) was seen amongst the MZ twins. Amongst fresh ETs, the rate of blastocyst transfers in the MZ twins group was higher compared to that in the control group (92.9% vs 75.4%, P = 0.005). We also found that certain grades of blastocysts in terms of trophectoderm (TE) development, inner cell mass + TE development and the classification of 'top-quality' embryos were associated with the incidence of MZ twinning (P = 0.025, P = 0.012, P = 0.020, respectively). Logistic regression analysis revealed that higher paternal age (odds ratio (OR) = 0.94, 95% CI = 0.89-1.00, P = 0.029) and FET (OR = 0.48, 95% CI = 0.33-0.68, P = 0.001) may be protective factors against MZ twinning. However, higher maternal age (OR = 1.07, 95% CI = 1.01-1.13, P = 0.027) and the transfer of blastocysts (OR = 4.31, 95% CI = 1.46-12.73, P = 0.008) appeared to be associated with an increased risk of MZ twinning. Amongst blastocyst transfers, a C grade TE may be protective factor against MZ twinning (B: OR = 1.90, 95% CI = 1.18-3.07, P = 0.009; A: OR = 1.58, 95% CI = 0.93-2.67, P = 0.089).

Limitations reasons for caution: First, our definition of MZ twins was based on twins' birth after single embryo transfers (SET), rather than ultrasound examination during early pregnancy. Second, the parental characteristics of the two groups were homogenous, so it was difficult to find any associations between infertility factors and the incidence of MZ twins.

Wider implications of the findings: This multifaceted analysis of the risk factors for MZ twinning provides some information for clinical interventions in high-risk populations.

Study funding/competing interests: This study was supported by the National Key Technology Research and Developmental Program of China (2022YFC2704404), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), Taishan Scholars Program for Young Experts of Shandong Province (tsqn201909195), the Basic Science Center Program (31988101), and the Shandong Provincial Key Research and Development Program (2020ZLYS02). All authors have no conflicts of interest to declare.

Trial registration number: N/A.

Keywords: ART; ICSI; IVF; blastocyst; characteristics of infertile populations; classification of blastocyst; frozen embryo transfer (FET); gamete or embryo manipulations; monozygotic (MZ) twins; single embryo transfer (SET).