Association of assisted reproductive technology with long-term offspring cardiometabolic health: a multi-cohort study

ObjectivesTo examine association of conception by assisted reproductive technology (ART) with offspring cardio-metabolic health outcomes, and whether these differ by offspring age. DesignMulti-cohort study. SettingFourteen population-based cohort studies with offspring from the UK, Ireland, France, the Netherlands, Portugal, Greece, Italy, Norway, Singapore, and Australia for meta-analysis of various ages. Four cohorts (three European and one Singaporean) with repeated measures for pooled age-change (from 3 to 26 years) trajectory analysis. ParticipantsYoung people sampled from the general population with complete data on mode of conception, confounders, and [&ge;]1 cardio-metabolic outcome measured after birth. ExposuresConception by ART versus natural conception (NC). Main outcome measuresSystolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), glucose, insulin, and glycated haemoglobin (HbA1c). ResultsBetween 35,780 (605 ART) and 4,502 (67 ART) offspring were included in meta-analysis of various ages for each outcome. Mean age at outcome assessment ranged from 13 months to 27.4 years, with most cohorts ((11/14) having mean age <10 years. Compared with NC, ART-conceived offspring had similar SBP (mean difference (ART minus NC): -0.89mmHg; 95%CI: -1.91 to 0.14), DBP (-0.50mmHg; -1.65 to 0.66), and HR (0.02beats/min; -1.00 to 1.03). Cholesterol measures were higher in ART-conceived than NC offspring, for TC (mean % difference: 2.54%; 0.46 to 4.61), HDLc (4.17%; 1.79 to 6.56), and LDLc (4.95%; 0.99 to 8.92), whereas triglycerides were similar (-1.53%; -6.19 to 3.13). No clear differences were seen for glucose (0.25%; -1.38 to 1.88), insulin (-5.04%; -13.20 to 3.12), or HbA1c (-0.07%; -0.14 to 0.00). Trajectory models in up to 17,244 (244 ART) offspring showed that early life trajectory differences were consistent with the above pooled results and showed higher SBP emerging from mid-adolescence to adulthood with ART (e.g., predicted mean difference in SBP at age 26 years for ART versus NC was 5.06mmHg; 1.76 to 8.35). ConclusionsChildren conceived through ART had higher cholesterol and similar blood pressure and hyperglycaemic/insulin resistance measures compared with NC children. Whilst overall this is reassuring, our trajectory analysis in a sub-group of cohorts suggested that those conceived by ART may go on to develop higher blood pressure in early adulthood. Our study shows the importance of follow-up into adulthood and requires validation by independent studies with different study designs including within-sibship and mechanistic studies.