University of Groningen, University Medical Center Groningen, Department of Paediatrics, Division of Developmental Neurology, Hanzeplein 1, Groningen GZ 9713, The Netherlands.
University of Groningen, University Medical Center Groningen, Department of Epidemiology, Hanzeplein 1, Groningen GZ 9713, The Netherlands.
Hum Reprod. 2018 Jan 1;33(1):147-155. doi: 10.1093/humrep/dex337.
Does Day-3 cleavage-stage PGS affect neurodevelopment of 9-year-old IVF offspring?
We did not find evidence of adverse consequences of Day-3 cleavage-stage PGS on neurodevelopment of 9-year-old IVF offspring, although children born after IVF with or without PGS often had a non-optimal neurological condition.
Knowledge on long-term sequelae for development and health of children born following PGS is lacking. This is striking as evidence accumulates that IVF itself is associated with increased risk for impaired health and development in the offspring.
STUDY DESIGN SIZE, DURATION: This prospective, assessor-blinded, multicentre, follow-up study evaluated development and health of 9-year-old IVF children born to women who were randomly assigned to IVF with PGS (PGS group) or without PGS (control group). The follow-up examination at 9 years took place between March 2014 and May 2016.
PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 408 women were included and randomly assigned to IVF with or without Day-3 cleavage-stage PGS. This resulted in 52 ongoing pregnancies in the PGS group and 74 in the control group. In the PGS group, 59 children were born alive; in the control group, 85 children were born alive. At the age of 9 years, 43 children born after PGS and 56 control children participated in the study. Our primary outcome was the neurological optimality score, a sensitive measure of neurological condition assessed with a standardized, age-specific test (Touwen test). Secondary outcomes were adverse neurological condition (neurologically abnormal and the complex form of minor neurological dysfunction), cognitive development (intelligence quotient and specific domains), behaviour (parental and teacher's questionnaires), blood pressure and anthropometrics.
Neurodevelopmental outcome of PGS children did not differ from that of controls; the neurological optimality scores (mean values [(95% CI]: PGS children 51.5 [49.3; 53.7], control children 53.1 [50.5; 55.7]) were not significantly different. The prevalences of adverse neurological outcome (in all but one child implying the presence of the complex form of minor neurological dysfunction) did not differ between the groups (PGS group 17/43 [40%], control group 19/56 [34%]), although the prevalence of complex minor neurological dysfunction in both groups was rather high. Also intelligence quotient scores of the two groups were not significantly different (PGS group 114 [108; 120]); control group 117 [109; 125]), and the behaviour, blood pressure and anthropometrics of both groups did not differ. Mean blood pressures of both groups were above the 60th percentile.
The power analysis of the study was not based on the number of children needed for the follow-up study, but on the number of women who were needed to detect an increase in ongoing pregnancy rates after PGS. In addition, our study evaluated embryo biopsy in the form of PGS at cleavage stage (Day-3 embryo biopsy), while currently PGS at blastocyst stage (Day-5 embryo biopsy) is recommended and increasingly being used.
Our findings indicate that PGS in cleavage stage embryos is not associated with adverse effects on neurological, cognitive and behavioural development, blood pressure and anthropometrics of offspring at 9 years. This is a reassuring finding as embryo biopsy in the forms of PGS and PGD is increasingly applied. However, both groups of IVF offspring showed high prevalences of the clinically relevant form of minor neurological dysfunction, which is a point of concern for the IVF community. In addition, our study confirms findings of others that IVF offspring may be at risk of an unfavourable cardiovascular outcome. These findings are alarming and highlight the importance of research on the underlying mechanisms of unfavourable neurodevelopmental and cardiovascular outcomes in IVF offspring.
STUDY FUNDING/COMPETING INTEREST(S): The randomized controlled trial was financially supported by the Organization for Health Research and Development (ZonMw), The Netherlands (Grant number 945-03-013). The follow-up was financially supported by the University Medical Center Groningen (Grant number: 754510), the Cornelia Foundation, and the graduate schools BCN and Share, Groningen, The Netherlands. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. There are no conflicts of interest.
ISRCTN76355836.
第 3 天卵裂期胚胎 PGS 是否会影响试管婴儿 9 岁后代的神经发育？
我们没有发现第 3 天卵裂期 PGS 对试管婴儿 9 岁后代神经发育有不良影响的证据，尽管体外受精后出生的儿童，无论是否进行了 PGS，往往存在非最佳的神经状况。
缺乏关于 PGS 后儿童发育和健康的长期后果的知识。这令人震惊，因为越来越多的证据表明，体外受精本身会增加后代健康和发育受损的风险。
研究设计、规模、持续时间：这项前瞻性、评估者盲法、多中心、随访研究评估了随机分配到 PGS（PGS 组）或无 PGS（对照组）的体外受精的女性所生的 9 岁试管婴儿的发育和健康情况。9 岁时的随访检查于 2014 年 3 月至 2016 年 5 月进行。
参与者/材料、地点、方法：共有 408 名女性被纳入并随机分配到第 3 天卵裂期胚胎 PGS 或无 PGS 的体外受精。PGS 组中有 52 例持续妊娠，对照组中有 74 例。在 PGS 组中，59 名儿童出生存活；在对照组中，85 名儿童出生存活。9 岁时，43 名接受 PGS 后出生的儿童和 56 名对照儿童参加了研究。我们的主要结局是神经优化评分，这是一种敏感的神经状况衡量标准，使用标准化的、特定年龄的测试（图温测试）进行评估。次要结局是不良神经状况（神经异常和复杂形式的轻度神经功能障碍）、认知发展（智商和特定领域）、行为（家长和教师的问卷）、血压和人体测量学。
PGS 儿童的神经发育结果与对照组没有差异；神经优化评分（平均值[95%CI]：PGS 儿童 51.5[49.3；53.7]，对照组儿童 53.1[50.5；55.7]）无显著差异。两组不良神经结局的发生率（除了一个儿童存在复杂形式的轻度神经功能障碍外）无差异（PGS 组 17/43[40%]，对照组 19/56[34%]），尽管两组的复杂轻度神经功能障碍发生率都相当高。两组的智商评分也无显著差异（PGS 组 114[108；120]；对照组 117[109；125]），两组的行为、血压和人体测量学也无差异。两组的平均血压均高于第 60 百分位数。
局限性/谨慎的原因：该研究的功率分析不是基于需要进行随访研究的儿童数量，而是基于需要检测 PGS 后持续妊娠率增加的女性数量。此外，我们的研究评估了胚胎活检在卵裂期（第 3 天胚胎活检）的形式，而目前推荐并越来越多地使用胚胎活检在囊胚期（第 5 天胚胎活检）。
我们的研究结果表明，第 3 天卵裂期胚胎 PGS 不会对 9 岁后代的神经、认知和行为发育、血压和人体测量学产生不良影响。这是一个令人欣慰的发现，因为胚胎活检的形式 PGS 和 PGD 正在被越来越多地应用。然而，两组体外受精的后代都表现出高度的临床相关形式的轻度神经功能障碍，这是体外受精社区关注的一个问题。此外，我们的研究证实了其他研究的结果，即体外受精的后代可能存在不利的心血管结局的风险。这些发现令人震惊，强调了研究体外受精后代神经发育和心血管不良结局的潜在机制的重要性。
研究资助/利益冲突：随机对照试验由荷兰卫生研究与发展组织（ZonMw）资助（资助编号 945-03-013）。随访由格罗宁根大学医学中心（资助号：754510）、科妮莉亚基金会以及荷兰格罗宁根的研究生学院 BCN 和 Share 资助。研究的赞助商在研究设计、数据收集、数据分析、数据解释或报告撰写方面没有任何作用。没有利益冲突。
ISRCTN76355836。
