体外受精与精神发育迟滞轻微增加相关

《美国医学会杂志》(JAMA)7月3日发表的一项瑞典全国性研究显示，在25年内出生的250万人中，体外受精(IVF)后出生的儿童的精神发育迟滞发生率出现了轻微但显著的增加(JAMA 2013;310:75-84)。

相比之下，与自然受孕后出生的儿童相比，IVF后出生的儿童的自闭症发生率未增加。然而，根据IVF类型对数据进行分析后发现，对不育男性使用胞质内精子注射(ICSI)技术与自闭症发生率轻微增加相关。这一研究结果对于美国等发达国家尤其重要，在美国，ICSI的应用较为频繁，甚至在精子样本正常的情况下也是如此。

这项前瞻性队列研究由伦敦国王学院精神病学研究所的Sven Sandin博士及其同事进行，研究人群包括1982~2007年间出生且接受了平均10年随访的2,541,125例儿童。在这些儿童中，30,959例是在IVF后出生。

共有15,830例儿童发生精神发育迟滞，其中180例(1.1%)为IVF后出生的儿童。与自然受孕后出生的儿童相比，IVF后出生的儿童的精神发育迟滞风险出现了具有统计学显著性的增加[相对风险(RR)，1.18]。然而，精神发育迟滞发生率的绝对差异轻微，＜7例/100,000人-年。

共有6,959例儿童发生自闭症，其中103例(1.5%)为IVF后出生的儿童。与自然受孕后出生的儿童相比，IVF后出生的儿童的自闭症风险未显著增加。然而，在采用手术提取的精子和新鲜胚胎实施ICSI技术后出生的儿童中观察到这一风险显著增加(RR，4.60)。ICSI后出生的儿童的精神发育迟滞风险也增加(RR，2.35)。

在早产儿和多胎妊娠后出生的儿童中观察到精神发育迟滞和自闭症风险均进一步增加。

随刊述评：限制多胚胎移植非常重要


Marcelle Cedars博士

加州大学旧金山分校生殖内分泌与不孕科的Marcelle Cedars博士表示，减少多胎数量是目前辅助生殖技术的主要目标。自闭症和精神发育迟滞风险增加主要归因于多胎妊娠和早产，生殖科医生应帮助患者和其他医生了解限制胚胎移植数量的重要性。虽然上述研究显示IVF不增加自闭症风险且与其相关的精神发育迟滞绝对风险较小，但仍需继续对卵巢刺激、胚胎培养和多胚胎移植的意义进行研究(JAMA 2013;310:42-3)。

Cedars博士声明无相关经济利益冲突。

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By: MARY ANN MOON, Clinical Neurology News Digital Network

Children born after in vitro fertilization had a small but significant increase in the incidence of mental retardation in a nationwide Swedish study of 2.5 million births during a 25-year period, according to a report published in the July 3 issue of JAMA.

In contrast, the rate of autistic disorder was not increased among children born after IVF treatment, compared with those born after spontaneous conception.

However, when the data were broken down by type of IVF procedure, the use of one technique – intracytoplasmic sperm injection (ICSI) for paternal infertility – was associated with a small increase in the incidence of autistic disorder, said Dr. Sven Sandin of the Institute of Psychiatry, King’s College London, and his associates.

The latter findings may be particularly important in countries such as the United States where ICSI is often used even when the sperm sample is normal, "because of a presumed (but unproven) higher efficiency," they noted.

Dr. Sandin and his colleagues performed a prospective cohort study to test the hypothesis that IVF in general and ICSI in particular would be associated with an increased risk of mental retardation and autistic disorder. Both IVF and ICSI are known to raise the risk of perinatal complications and preterm birth, which in turn raise the risk of neurodevelopmental abnormalities.

IVF also has been linked with several specific neurological disorders including cerebral palsy, and Russell-Silver, Beckwith-Wiedemann, and Angelman syndromes. There also is concern that ICSI may allow fertilization with suboptimal sperm because it bypasses the natural selection of sperm; that it may physically damage the egg; and that it may contaminate the cytoplasm of the egg cell with culture media when the sperm is inserted, they said.

The study population comprised 2,541,125 children born in 1982-2007 and followed for a mean of 10 years. Among these children, 30,959 were born following an IVF procedure.

A total of 15,830 children had mental retardation, including 180 (1.1%) who were born after IVF. "Compared with offspring born following spontaneous conception, those born after an IVF procedure had a statistically significantly increased risk of mental retardation (relative risk, 1.18)," said Dr. Sandin, who is also in the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates.

However, the absolute difference in rates of mental retardation was small, at fewer than 7 cases per 100,000 person-years.

A total of 6,959 children had autistic disorder, including 103 (1.5%) who were born after IVF. Compared with children born after spontaneous conception, those born after any IVF procedure did not have a significantly increased risk of autism disorder.

However, this risk was significantly greater after one specific procedure, ICSI using surgically extracted sperm with fresh embryos, with an RR of 4.60, the investigators said (JAMA 2013;310:75-84).

The risk for mental retardation also increased in children born after ICSI using surgically extracted sperm with fresh embryos, with an RR of 2.35.

The risks for both mental retardation and autism disorder increased further in preterm births and in cases of multiple gestation.

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Now even more vital to limit multiple embryo transfers

The link between multiple births and preterm births on one hand and the risk of neurodevelopmental disorders on the other is a particularly important finding, because decreasing the number of multiple births is now a primary goal of assisted reproductive technologies, said Dr. Marcelle I. Cedars.

"The increased risk of autistic disorder and mental retardation, largely accounted for by multiple pregnancies and preterm delivery, should provide another opportunity for reproductive health physicians to educate patients and other physicians about the importance of limiting embryo transfer number," she said.

"Even though the data are reassuring regarding the absence of risk of autistic disorder and small absolute risk of mental retardation with IVF, continued study of the implications of ovarian stimulation, embryo culture, and multiple embryo transfer is required."

Dr. Cedars is in the division of reproductive endocrinology and infertility at the University of California–San Francisco and directs the UCSF Women’s Health Clinical Research Center. She reported no relevant financial conflicts of interest. These remarks were taken from her comments in an editorial accompanying Dr. Sandin’s report (JAMA 2013;310:42-3).