Table 1 summarises the participants and study characteristics of all the included studies in this meta-analysis. Eighteen trials [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47] (from 2712 records: database searching [n = 2686] and other sources [n = 26]) met the inclusion criteria. These reported data from 5837 participants (mean age 10.5 years, range 3.5–18 years; 80.7% males). Six studies reported effects for MPH alone [30,31,32,33,34,35], four for AMP alone [36,37,38,39] and three for ATX alone [40,41,42]. Four reported data on both MPH and ATX [43,44,45,46] and one on both AMP and ATX .
Fourteen studies employed an open-label design [30, 33,34,35,36,37, 39,40,41,42,43,44, 46, 48], while the remainder had a double-blind, randomised control design [31, 38, 45, 47]. In total, five studies included a control group in their design [31, 35, 38, 45, 47]. Despite including a control group, two studies [31, 45] did not report cardiovascular parameters for the control group. Another study  reported only data for a safety population including medication and control group data.
Fourteen out of 18 trials [30, 33, 36,37,38,39,40,41,42,43,44,45,46,47] specified the distribution of ADHD subtypes and included participants of the different subtypes: inattentive (n = 14), hyperactive–impulsive (n = 13) and combined type (n = 14). Comorbidity was reported in 12 studies [30, 31, 35, 37, 41,42,43,44,45,46,47,48], with the most commonly reported conditions being oppositional defiant disorder (n = 9 studies), conduct disorder (n = 9), anxiety disorder (n = 7), depression (n = 5) or other disorders (n = 5).
Fourteen studies [30, 31, 33,34,35, 37,38,39, 42, 45,46,47,48] had performed cardiovascular measurements during screening and excluded children with cardiovascular disorders/illnesses/complaints beforehand. Four studies reported no information about the screening process [36, 40, 41, 44].
Trial duration ranged from 4 to 96 weeks (mean 28.7 weeks): 4–12 weeks (n = 8), 13–51 weeks (n = 6) and > 52 weeks (n = 4). The average duration for MPH studies was 28.1 weeks (range 4–96), for AMP studies 29.2 weeks (range 9–52) and for ATX studies 24 weeks (range 4–96). Seven studies [34, 37,38,39,40, 43, 48] reported multiple follow-up outcome measurements. The outcome of the latest follow-up was recorded. The average drop-out rate was 1149/5836 (19.9%; 18 studies). Two studies were published before 2000, nine between 2000 and 2010, and seven after 2010.
Diastolic Blood Pressure
AMP (SMD 0.16, 95% confidence interval [CI] 0.03–0.29, p = 0.02; four studies) and ATX (SMD 0.22, 95% CI 0.10–0.34, p < 0.01; seven studies) were associated with small but statistically significant pre–post differences. The effect for MPH was not significant (SMD 0.16, 95% CI −0.04 to 0.36, p = 0.11; ten studies). When effects were pooled for all medications together, there was a small but statistically significant increase in DBP associated with ADHD medication (SMD 0.18, 95% CI 0.09–0.26, p < 0.01; 17 studies) and no significant difference between the three medications when comparing two drugs per comparison.
Systolic Blood Pressure
MPH (SMD 0.25, 95% CI 0.08–0.42, p < 0.01; ten trials), AMP (SMD 0.09, 95% CI 0.03–0.15, p < 0.01; four studies) and ATX (SMD 0.16, 95% CI 0.04–0.27, p = 0.01; seven studies) each had small but statistically significant pre–post effects on SBP. Across all medications together there was a small and significant pre–post effect (SMD 0.18, 95% CI 0.10–0.27, p < 0.01; 17 studies) with no differences between the three medications when comparing two drugs per comparison.
For HR there were small but significant effects for AMP (SMD 0.37, 95% CI 0.13–0.60, p < 0.01; five studies) and ATX (SMD 0.43, 95% CI 0.26–0.60, p < 0.01; seven studies) but the effects for MPH were not statistically significant (SMD 0.20, 95% CI −0.02 to 0.41, p = 0.07; 10 studies). Pooled pre–post effects across all three medications were small but statistically significant (SMD 0.32, 95% CI 0.20–0.43, p < 0.01; 17 studies) on HR. Figure 2 shows the forest plots for all three medications and the cardiovascular parameters.
Multiple Measurements Over Time
For MPH, three studies [34, 43, 48] reported data of multiple measurements (number of measurements 3–5; duration range 24–96 weeks). A peak in DBP (mean +1.7 mmHg) and HR (mean +3.7 bpm) was reported at the first measurement (average 3.2 months after baseline) compared with baseline and follow-up measurements. Similar results were reported on SBP (mean +1.6 mmHg).
Two AMP studies reported a trend of increased DBP/SBP/HR until 14 weeks  and 52 weeks of treatment . Once again, the highest peak was at the first measurement after baseline (average 6 weeks; mean changes: DBP +1 mmHg; SBP +0.75 mmHg; HR +3.35 bpm).
Arcieri et al.  and Fuentes et al.  studied ATX and reported the highest effect in DBP, SBP and HR at the first measurement (at 6 months after baseline); effects on DBP (+0.2 mmHg) and HR (+2.9 bpm) were statistically significant, while effect on SBP (+0.8 mmHg) was not significant in Arcieri et al. . Despite the increased levels at the first measurement, Arcieri et al.  reported no statistically significant effects on DBP (+0.13 mmHg) and SBP (+0.36 mmHg) at 12 months in comparison with baseline, only HR (+3.26 bpm) was statistically significant. There were no statistically significant effects at 24 months in comparison with the baseline (DBP +1.11 mmHg; SBP +2.13 mmHg; HR +0.21 bpm). Fuentes et al.  observed small changes at 6 months for all cardiovascular parameters (DBP +1.3 mmHg; SBP +0.8 mmHg; HR +7.9 bpm) and at 12 months (DBP +1.6 mmHg; SBP +1.6 mmHg; HR +5.6 bpm) compared with baseline. Only the mean changes for HR were reported as significant.
In summary, the largest change in studies with multiple measurement points was overall reported at the first measurement time point after baseline (average 13.3 weeks; 7 studies).
Moderators of the Treatment Effect
Sensitivity analyses revealed a significant effect of study duration on DBP following AMP treatment (F(1) = 19.55, p = 0.05). Studies <18 weeks reported higher ESs (SMD 0.28) compared with longer duration studies (SMD 0.05). There was a significant effect of publication year on SBP for MPH treatment (F(1) = 5.346, p = 0.05). Studies published before 2007 reported higher ESs (SMD 0.37) than studies after 2007 (SMD −0.02). There was no effect of the following moderators: type of medication (e.g. MPH, AMP, ATX), doses, sample size, age, gender (male percentage), type of ADHD, comorbidity and dropout rate. Due to the homogeneity among studies on age, distribution of gender, ADHD type (yes/no), comorbidity (yes/no) and doses, it was not possible to explore their status as moderating influences. It was also not possible to explore the possible influences of comorbidity because of the small samples for each medication.
Cardiovascular Adverse Effects on Individual Level
A majority of studies (15/18, 83.3%) reported individual-level data about other cardiovascular effects (see Table 2). Cardiovascular effects reported were hypertension and HR above 90th percentile, tachycardia, brachycardia, arrhythmia, palpitations and ECG abnormalities. Overall, 737 cardiovascular adverse effects were reported in these studies for all 5837 participants (12.6%). Studies about MPH reported 149/1171 (12.7%) cardiovascular effects, AMP 462/3705 (12.5%) and ATX 126/961 (13.1%). There were no significant differences between the medication treatments, (F(2) = 3.006, p = 0.007). Notably, the vast majority of patients continued their medication treatment following the report of a cardiovascular adverse event; these resolved spontaneously or medication doses were changed or the events were not considered to be clinically relevant. In case of other cardiovascular effects, 15/737 (2.0%) discontinued the treatment of MPH (5/149, 3.4%), AMP (9/462, 2.0%) or ATX (1/126, 0.8%). Two participants discontinued their treatment at 6 months and one at 6 weeks; the moment of discontinuation was not reported for the remaining 12 participants (see Table 2, last column, for the reasons why these 15 participants discontinued their medication).