Division of Obstetrics and Gynaecology, University of Western Australia, Perth, WA, Australia.
Women and Infants Research Foundation, Perth, WA, Australia.
Hum Reprod. 2022 Jul 30;37(8):1880-1895. doi: 10.1093/humrep/deac122.
Is the cardiometabolic health of adolescents conceived through ART worse than that of their counterparts conceived without ART?
The majority of cardiometabolic and vascular health parameters of adolescents conceived through ART are similar or more favourable, than those of their counterparts of similar age and conceived without ART.
It has been proposed that the cardiometabolic health of offspring conceived with ART may be unfavourable compared to that of their counterparts conceived without ART. The literature pertaining to cardiometabolic health of offspring conceived after ART is contradictory, but generally suggests unfavourable cardiometabolic health parameters, such as an increase in blood pressure (BP), vascular dysfunction and adiposity, as well as unfavourable glucose and lipid profiles. With over 8 million children and adults born through ART worldwide, it is important to investigate whether these early signs of adverse cardiometabolic differences persist into adolescence and beyond.
STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective cohort study that recruited 303 adolescents and young adults conceived after ART (aged 13-21 years) and born between 1991 and 2001 in Western Australia. Their health parameters, including cardiometabolic factors, were assessed and compared with counterparts from the Raine Study Generation 2 (Gen2). The 2868 Gen2 participants were born 1989-1992 and are representative of the Western Australian adolescent population. At ∼17 years of age (2013-2017), 163 GUHS participants replicated assessments previously completed by Gen2 at a similar age.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Cardiometabolic parameters were compared between a total of 163 GUHS and 1457 Gen2 adolescents. Separate male (GUHS n = 81, Gen2 n = 735) and female (GUHS n = 82, Gen2 n = 722) analyses were conducted. Assessments consisted of a detailed questionnaire including health, lifestyle and demographic parameters, anthropometric assessments (height, weight, BMI, waist circumference and skinfold thickness), fasting serum biochemistry, arterial stiffness and BP (assessed using applanation tonometry). Abdominal ultrasonography was used to assess the presence and severity of hepatic steatosis, and thickness of abdominal fat compartments. Non-alcoholic fatty liver disease (NAFLD) was diagnosed if there was sonographic fatty liver in the absence of significant alcohol consumption. Chi2, Fisher's exact and Mann-Whitney U tests, performed in SPSS V25, examined cohort differences and generalized estimating equations adjusted for the following covariates: singleton vs non-singleton pregnancy, birthweight (z-score), gestational age, BMI, smoking, alcohol consumption in the past 6 months and parent cardiovascular status. Arterial stiffness measures and waist circumference were additionally adjusted for height, and female analyses were additionally adjusted for use of oral contraceptives in the preceding 6 months.
In adjusted analyses, GUHS females had a lower BMI (22.1 vs 23.3 kg/m2, P = 0.014), and thinner skinfolds (triceps, subscapular, mid-abdominal; 16.9 vs 18.7 mm, P = 0.021, 13.4 vs 15.0 mm, P = 0.027, 19.7 vs 23.2 mm, P < 0.001, respectively), whereas males were not significantly different. Waist circumference was lower in GUHS adolescents (males: 78.1 vs 81.3 cm, P = 0.008, females: 76.7 vs 83.3 cm, P = 0.007). There were no significant differences between the two groups in glucose, insulin, homeostatic model assessment for insulin resistance, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), alanine aminotransferase and high-sensitivity C-reactive protein in both sexes. In females, serum triglycerides were lower in GUHS adolescents (1.0 vs 1.2 mmol/l, P = 0.029). GUHS males had higher serum HDL-C (1.1 vs 1.0 mmol/l, P = 0.004) and a lower TC/HDL-C ratio (3.2 vs 3.6, P = 0.036). There were no significant differences in the prevalence of NAFLD or steatosis severity scores between the cohorts in males and females. GUHS females had less subcutaneous adipose tissue (9.4 vs 17.9 mm, P < 0.001), whereas GUHS males had greater visceral adipose thickness (44.7 vs 36.3 mm, P < 0.001). There was no significant difference in pre-peritoneal adipose thickness. Pulse wave velocity was lower in GUHS males (5.8 vs 6.3 m/s, P < 0.001) and heart rate corrected augmentation index was lower in GUHS females (-8.4 vs -2.7%, P = 0.048). There were no significant differences in BP or heart rate in males or females between the two groups.
LIMITATIONS, REASONS FOR CAUTION: Despite the substantial study size and the unique study design of the ART cohort, we were unable to differentiate between different types of ART, due to the low number of ICSI cycles (e.g. IVF vs ICSI), draw definite conclusions, or relate the outcomes to the cause of infertility. Considering the differences in time points when both cohorts were studied, external factors could have changed, which could not be accounted for. Given the observational nature of this study, causation cannot be proven.
Contrary to our hypothesis and previous findings focussing mainly on childhood, this study reports mostly similar or favourable cardiometabolic markers in adolescents conceived with ART compared to those conceived without ART. The greater visceral adipose thickness, particularly present in males, requires further investigation. While these findings are generally reassuring, future well-designed and appropriately powered studies are required to definitively address the issue of cardiometabolic health in ART adults.
STUDY FUNDING/COMPETING INTEREST(S): This project was supported by NHMRC project grant number 1042269 and R.J.H. received education grant funding support from Ferring Pharmaceuticals. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia.
N/A.
通过 ART 受孕的青少年的心脏代谢健康是否比未经 ART 受孕的同龄人差？
通过 ART 受孕的青少年的大多数心脏代谢和血管健康参数与具有相似年龄和未经 ART 受孕的同龄人相似或更有利。
有人提出，通过 ART 受孕的后代的心脏代谢健康可能不如未经 ART 受孕的同龄人有利。关于 ART 后后代心脏代谢健康的文献存在争议，但普遍表明心脏代谢健康参数不利，例如血压（BP）升高、血管功能障碍和肥胖，以及葡萄糖和血脂谱不利。全球有超过 800 万儿童和成年人通过 ART 出生，因此有必要研究这些早期的不利心脏代谢差异是否会持续到青春期及以后。
研究设计、规模、持续时间：成长健康研究（GUHS）是一项前瞻性队列研究，招募了 303 名通过 ART（年龄 13-21 岁）受孕的青少年和年轻人，他们于 1991 年至 2001 年在澳大利亚西部出生。评估了他们的健康参数，包括心脏代谢因素，并与 Raine 研究第二代（Gen2）的对照组进行了比较。2868 名 Gen2 参与者于 1989-1992 年出生，代表了澳大利亚西部青少年人群。在大约 17 岁（2013-2017 年）时，163 名 GUHS 参与者复制了 Gen2 之前在相似年龄进行的评估。
参与者/材料、设置、方法：总共比较了 163 名 GUHS 和 1457 名 Gen2 青少年的心脏代谢参数。分别对男性（GUHS n=81，Gen2 n=735）和女性（GUHS n=82，Gen2 n=722）进行了分析。评估包括详细的问卷调查，包括健康、生活方式和人口统计学参数、人体测量评估（身高、体重、BMI、腰围和皮褶厚度）、空腹血清生化、动脉僵硬度和 BP（使用平板眼压计测量）。腹部超声用于评估肝脂肪变性的存在和严重程度，以及腹部脂肪隔的厚度。如果在没有显著饮酒的情况下存在超声脂肪肝，则诊断为非酒精性脂肪性肝病（NAFLD）。卡方、Fisher 确切检验和 Mann-Whitney U 检验在 SPSS V25 中进行，检验队列差异，并对以下协变量进行广义估计方程调整：单胎与非单胎妊娠、出生体重（z 分数）、胎龄、BMI、吸烟、过去 6 个月的饮酒情况和父母心血管状况。动脉僵硬度测量值和腰围另外根据身高进行了调整，女性分析另外根据过去 6 个月内使用口服避孕药进行了调整。
在调整分析中，GUHS 女性的 BMI 较低（22.1 与 23.3kg/m2，P=0.014），皮肤褶皱较薄（三头肌、肩胛下、中腹部；16.9 与 18.7mm，P=0.021，13.4 与 15.0mm，P=0.027，19.7 与 23.2mm，P<0.001），而男性则无显著差异。GUHS 青少年的腰围较小（男性：78.1 与 81.3cm，P=0.008，女性：76.7 与 83.3cm，P=0.007）。两组在男女两性的血糖、胰岛素、稳态模型评估的胰岛素抵抗、低密度脂蛋白胆固醇、非高密度脂蛋白胆固醇（非-HDL-C）、总胆固醇（TC）、丙氨酸氨基转移酶和高敏 C 反应蛋白方面均无显著差异。在女性中，GUHS 青少年的血清甘油三酯较低（1.0 与 1.2mmol/l，P=0.029）。GUHS 男性的血清 HDL-C 较高（1.1 与 1.0mmol/l，P=0.004），TC/HDL-C 比值较低（3.2 与 3.6，P=0.036）。在男性和女性中，两组之间 NAFLD 的患病率或脂肪变性严重程度评分均无显著差异。GUHS 女性的皮下脂肪组织较少（9.4 与 17.9mm，P<0.001），而 GUHS 男性的内脏脂肪厚度较大（44.7 与 36.3mm，P<0.001）。腹膜前脂肪厚度无显著差异。GUHS 男性的脉搏波速度较低（5.8 与 6.3m/s，P<0.001），GUHS 女性的心率校正增强指数较低（-8.4 与-2.7%，P=0.048）。两组在男性或女性中均无 BP 或心率的显著差异。
局限性、谨慎的原因：尽管研究规模很大，并且 ART 队列的研究设计独特，但由于 ICSI 周期（例如 IVF 与 ICSI）数量较少，我们无法区分不同类型的 ART，无法得出明确的结论，或将结果与不孕的原因联系起来。考虑到这两个队列研究的时间点不同，可能已经发生了外部因素的变化，无法对此进行解释。由于本研究为观察性研究，因此不能证明因果关系。
与我们的假设和之前主要集中在儿童期的研究结果相反，这项研究报告说，与未经 ART 受孕的同龄人相比，ART 受孕的青少年在心脏代谢标志物方面大多相似或更有利。男性中存在的较大的内脏脂肪厚度需要进一步研究。尽管这些发现总体上令人欣慰，但仍需要进行精心设计和适当加权的未来研究，以明确解决 ART 成年人的心脏代谢健康问题。
研究资金/利益冲突：该项目得到了 NHMRC 项目拨款 1042269 的支持，RJH 从默克雪兰诺、费森尤斯制药公司获得教育资助。RJH 是澳大利亚西部生育专家的医学主任，也是 Western IVF 的股东。他曾获得默克、默克-雪兰诺和费森尤斯制药公司的教育赞助。PB 是 Concept Fertility Centre 的科学主任，位于西澳大利亚的 Subiaco。JLY 是 PIVET 医疗中心的医学主任，位于西澳大利亚的珀斯。
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