ART与部分先天性畸形风险增加相关

波士顿——在国际生育协会联盟和美国生殖医学会联合会议上，北欧国家联盟的研究者报告称，辅助生殖技术(ART)与部分器官系统的先天性畸形风险相关，风险虽小但达到了统计学显著性。

基于来自丹麦、瑞典、挪威和芬兰的大规模医学登记库，研究者对这些参与国引入体外受精(IVF)、卵胞浆内精子注射(ICSI)以及冷冻胚胎移植技术之后出生的58,714例单胎和27,919例双胎的数据进行了分析。关于ART的数据来自全国性ART登记库。ART妊娠后出生的单胎与人数大4倍的由自然妊娠单胎组成的对照组在母亲产次和出生年份上相匹配。分析期内出生的所有自然妊娠双胎也被视为对照组。

研究者采用欧洲先天性异常监测(EUROCAT)系统对畸形进行了分类，并且根据器官系统进行了分组。

作为CoNARTas研究小组的代表，丹麦哥本哈根Rigshospitalet医院生殖专科的Anna-Karina Aaris Henningsen博士报告称，在ART后出生的所有儿童(包括单胎和双胎)中开展的分析显示，先天性心脏畸形(比如共同动脉干，大血管错位，单心室，房室间隔缺损等等)的比值比为1.12，置信区间提示有统计学意义。不过，在总人群中其他器官系统畸形均与ART无关。


Anna-Karina Aaris Henningsen博士

针对母亲产次、出生年份、产妇年龄、儿童性别和所属国家等因素校正之后的多因素分析显示，使用ART后出生的单胎发生先天性心脏畸形的比值比为1.20，消化道畸形的比值比为1.56 (食道闭锁，十二指肠闭锁或狭窄等等)，泌尿生殖系统畸形的比值比为1.49 (比如双肾不发育、肾发育不良或先天性肾积水等等)。

在这项匹配队列研究中，研究者还发现与非辅助妊娠相比，ART还与单胎和双胎妊娠胎盘早剥风险相关，风险虽小但也达到了统计学意义，并且所有北欧国家都得出了一致的结果。

Henningsen博士总结道，与自然妊娠后出生的儿童相比，使用ART后出生的单胎儿童发生心脏、消化道或尿路畸形的几率显著增加；发生心脏畸形的风险增加20%，消化道畸形风险增加56%，尿路畸形风险增加49%。不过，对于神经系统、腹壁、生殖器、口面区域、四肢或染色体的先天性畸形，在ART帮助下出生的儿童与自然妊娠对照组相比无显著差异。

Henningsen博士指出：“但这种风险仍然非常小，现在还有很多问题我们无法解答，我们还需要继续研究。”例如，我们不清楚这些差异是否是由ART本身导致的，还是与使用ART的夫妇潜在的不孕不育问题有关。此外，IVF与ICSI技术之间，或者新鲜与冷冻胚胎移植技术之间可能存在畸形发生率上的差异。

在Henningsen博士发言后的提问环节，有一名与会者问道，测量偏倚是否可能与观察到的差异有关，因为与自然妊娠后出生的儿童相比，使用ART后出生的儿童可能会接受更加密切的先天性畸形监测。对此，Henningsen博士回答道：“只要儿童存在重要畸形，都会被记录在登记库，无论他是使用ART后出生的还是自然妊娠后出生的儿童。”

这项研究由欧洲人类生殖与胚胎学会(ESHRE) 、丹麦哥本哈根大学、丹麦科技创新局以及北欧妇产科联合会(NFOG)共同资助。Henningsen博士声明无相关利益冲突。

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By: NEIL OSTERWEIL, Internal Medicine News Digital Network

BOSTON – Assisted reproductive technologies are associated with a small but significant risk for congenital malformations in some organ systems, reported investigators from a consortium of Nordic countries at the conjoint meeting of the International Federation of Fertility Societies and the American Society for Reproductive Medicine.

Singleton children born to parents who used assisted reproductive technology (ART) were significantly more likely than were children born through spontaneous pregnancies to have malformations of the heart, gastrointestinal tract, or urinary tract, reported Dr. Anna-Karina Aaris Henningsen of the Fertility Clinic at the Rigshospitalet in Copenhagen.
 
Combined data from the extensive medical registries in Denmark, Sweden, Norway, and Finland showed that, compared with controls, singletons born with the help of ART had a 20% increase in risk for any heart malformation, 56% increase in risk for gastrointestinal anomalies, and 49% increase in risk for urinary tract malformations.

In contrast, congenital malformations of the nervous system, abdominal wall, genitals, orofacial region, limbs, or chromosomes were not more common in ART-conceived children than in spontaneously conceived controls, the investigators found.

"It’s still a very small increased risk, and there are many things we can’t answer yet, things we need to look into," Dr. Henningsen said, speaking on behalf of colleagues in the CoNARTas Study Group.

For example, it’s unclear whether the differences might be a causal effect of ART or related to underlying fertility problems of the couples using ART. In addition, there may be differences in rates of malformations between in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) techniques, or between fresh- and frozen-embryo transfer methods, she said.

In the matched cohort study, the authors also found that ART was associated with a small but significant risk for placental abruption in both singleton and twin pregnancies, compared with unassisted pregnancies, findings that were consistent across the Nordic countries.

The authors looked at population-based data on 58,714 singletons and 27,919 twins born after the introduction of IVF, ICSI, and frozen-embryo transfer in each of the participating countries. Data on ART came from national ART registers. Singletons born from ART pregnancies were matched on the mother’s parity and year of birth with a fourfold larger control group of spontaneously conceived singletons. All spontaneously conceived twins born during the study period also were counted as controls.

They used the European surveillance of congenital anomalies (EUROCAT) system to classify malformations and group them according to organ system.

In analyses looking at all children born after ART – both twins and singletons – the odds ratio for congenital heart malformations (such as common arterial truncus, transposition of great vessels, presence of a single ventricle, atrioventricular septal defect, etc.) was 1.12, with a confidence interval indicating significance. No other organ system anomalies, however, were associated with ART in the overall population.

In a multivariate analysis controlling for mother’s parity, year of birth, maternal age, child’s sex and country, the authors found that ART in singletons was associated with an odds ratio of 1.20 for congenital heart malformations, 1.56 for gastrointestinal malformations (esophageal atresia, duodenal atresia or stenosis, etc.), and 1.49 for urogenital malformations (such as bilateral renal agenesis, renal dysplasia, or congenital hydronephrosis).

In the question-and-answer portion following Dr. Henningsen’s presentation, an audience member asked whether ascertainment bias might account for the differences seen, because ART-born children may be scrutinized more closely than are spontaneously-born children for congenital malformations.

"If the child has a major malformation, it will be registered, regardless if it’s an ART child or a spontaneously conceived child," she replied.

The study was supported by the European Society of Human Reproduction and Embryology (ESHRE), the University of Copenhagen, the Danish Agency for Science, Technology and Innovation, and the Nordic Federation of Obstetrics and Gynecology (NFOG). Dr. Henningsen reported having no conflict of interest disclosures.