Department of Paediatrics, Division of Developmental Neurology - CA 85, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Hum Reprod. 2014 Mar;29(3):502-9. doi: 10.1093/humrep/det396. Epub 2013 Dec 22.
Does ovarian hyperstimulation, the in vitro procedure, or a combination of these two negatively influence blood pressure (BP) and anthropometrics of 4-year-old children born following IVF?
Higher systolic blood pressure (SBP) percentiles were found in 4-year-old children born following conventional IVF with ovarian hyperstimulation compared with children born following IVF without ovarian hyperstimulation.
Increasing evidence suggests that IVF, which has an increased incidence of preterm birth and low birthweight, is associated with higher BP and altered body fat distribution in offspring but the underlying mechanisms are largely unknown.
STUDY DESIGN, SIZE, DURATION: We performed a prospective, assessor-blinded follow-up study in which 194 children were assessed. The attrition rate up until the 4-year-old assessment was 10%.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured BP and anthropometrics of 4-year-old singletons born following conventional IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), or born following modified natural cycle IV (MNC-IVF, n = 52), or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Both IVF and ICSI were performed. Primary outcome measures were the SBP percentiles and diastolic BP (DBP) percentiles. Anthropometric measures included triceps and subscapular skinfold thickness. Several multivariable regression analyses were applied in order to correct for subsets of confounders. The value 'B' is the unstandardized regression coefficient.
SBP percentiles were significantly lower in the MNC-IVF group (mean 59, SD 24) than in the COH-IVF (mean 68, SD 22) and Sub-NC groups (mean 70, SD 16). The difference in SBP between COH-IVF and MNC-IVF remained significant after correction for current, early life and parental characteristics (B: 14.09; 95% confidence interval (CI): 5.39-22.79), whereas the difference between MNC-IVF and Sub-NC did not. DBP percentiles did not differ between groups. After correction for early life factors, subscapular skinfold thickness was thicker in the COH-IVF group than in the Sub-NC group (B: 0.28; 95% CI: 0.03-0.53).
LIMITATIONS, REASONS FOR CAUTION: Larger study groups are necessary to draw firm conclusions. An effect of gender or ICSI could not be properly investigated as stratifying would further reduce the sample size. We corrected for the known differences between MNC-IVF and COH-IVF but it is possible that the groups differ in additional, more subtle parental characteristics. In addition, we measured BP on 1 day only, had no control group of children born to fertile couples (precluding investigating effects of the underlying subfertility) and included singletons only. As COH-IVF is associated with multiple births we may have underestimated cardiometabolic problems after COH-IVF. Finally, multivariable regression analysis does not provide clear insight in the causal mechanisms and we have performed further explorative analyses.
Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome but this is the first study suggesting that ovarian hyperstimulation, as used in IVF treatments, could be a causative mechanism. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo that result in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to assess further the role of ovarian hyperstimulation in poorer cardiometabolic outcome and investigate the underlying mechanisms. The findings emphasize the importance of cardiometabolic monitoring of the growing number of children born following IVF.
STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.
卵巢过度刺激、体外程序，还是两者的结合，会对 IVF 后 4 岁儿童的血压 (BP) 和人体测量学产生负面影响？
与未经卵巢过度刺激的 IVF 相比，接受常规 IVF 加卵巢过度刺激的儿童收缩压 (SBP) 百分位较高。
越来越多的证据表明，体外受精（IVF）的早产和低出生体重发生率增加，与后代的血压升高和体脂分布改变有关，但潜在机制在很大程度上尚不清楚。
研究设计、规模、持续时间：我们进行了一项前瞻性、评估员盲法随访研究，其中评估了 194 名儿童。直到 4 岁评估时，失访率为 10%。
参与者/材料、设置、方法：我们测量了 63 名接受控制性卵巢过度刺激（COH-IVF）的常规 IVF 后单胎儿童（COH-IVF 组）、52 名接受改良自然周期 IVF（MNC-IVF）的儿童（MNC-IVF 组）和 79 名接受辅助受孕的自然受孕的夫妇的单胎儿童（Sub-NC 组）的 4 岁儿童的血压和人体测量学。IVF 和 ICSI 都进行了。主要观察指标是 SBP 百分位数和舒张压 (DBP) 百分位数。人体测量学测量包括三头肌和肩胛下皮褶厚度。应用了几种多变量回归分析来校正亚组混杂因素。值“B”是未标准化的回归系数。
MNC-IVF 组（平均 59，SD 24）的 SBP 百分位数明显低于 COH-IVF 组（平均 68，SD 22）和 Sub-NC 组（平均 70，SD 16）。在纠正当前、早期生活和父母特征后，COH-IVF 和 MNC-IVF 之间的 SBP 差异仍然显著（B：14.09；95%置信区间 (CI)：5.39-22.79），而 MNC-IVF 和 Sub-NC 之间的差异则不显著。两组间 DBP 百分位数无差异。在纠正早期生活因素后，COH-IVF 组的肩胛下皮褶厚度比 Sub-NC 组厚（B：0.28；95%CI：0.03-0.53）。
局限性、谨慎的原因：需要更大的研究群体才能得出明确的结论。由于分层会进一步减少样本量，因此无法正确研究性别或 ICSI 的影响。我们纠正了 MNC-IVF 和 COH-IVF 之间已知的差异，但两组可能在其他更微妙的父母特征上存在差异。此外，我们仅在一天测量血压，没有对照组为生育能力正常的夫妇所生的儿童（排除了对潜在不孕的影响），且仅包括单胎。由于 COH-IVF 与多胎妊娠相关，我们可能低估了 COH-IVF 后的心脏代谢问题。最后，多变量回归分析不能清楚地洞察因果机制，我们进行了进一步的探索性分析。
研究结果对其他描述 IVF 对心脏代谢结果不良影响的研究结果一致，但这是第一项表明卵巢过度刺激（用于 IVF 治疗）可能是一种致病机制的研究。也许卵巢过度刺激通过改变卵母细胞和/或胚胎的早期环境，导致参与血压调节的关键代谢系统发生表观遗传修饰，从而对心脏代谢结果产生负面影响。未来的研究需要进一步评估卵巢过度刺激在较差的心脏代谢结果中的作用，并研究潜在的机制。这些发现强调了对越来越多的 IVF 后儿童进行心脏代谢监测的重要性。
研究资金/利益冲突：作者没有利益冲突要声明。该研究得到了格罗宁根大学医学中心、科妮莉亚基金会和行为与认知神经科学学院的支持。该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。
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