Vascular health of fathers with history of intracytoplasmic sperm injection

Abstract

Objective

Studies suggest that men who undergo assisted reproductive technologies (ART) may have a higher risk of cardiovascular disease; however, limited data on this matter is available. This observational pilot study aimed to investigate the overall vascular health of fathers with history of intracytoplasmic sperm injection (ICSI) compared to fathers whose partners conceived spontaneously.

Methods

Diet quality, physical activity, sedentary behavior as well as overall vascular function including the assessment of pulse wave analysis, intima-media thickness (cIMT), arterial stiffness of the common carotid artery (CCA) and blood lipids, were evaluated.

Results

A total of 34 fathers with history of ICSI and 29 controls (48.49 [46.32 − 57.09] years vs. 47.19 [40.62 − 55.18] years, p = 0.061) were included. After adjusting for age, no significantly increased cardiovascular risk was detected regarding vascular function.

Conclusions

The results suggest an unaltered cardiovascular risk profile in fathers with history of ICSI. In the future, prospective multicenter studies are required to validate these preliminary results.

Keywords:

• Assisted reproductive technologies
• vascular function
• infertility
• fathers
• men

Introduction

Infertility is a disorder of the male or female reproductive system defined as the failure to conceive after at least 12 months or more of regular attempts [1]. According to the World Health Organization (WHO), approximately one in six people globally have experienced infertility at some stage in their lives [2]. It is reported that at least 30 million men worldwide are infertile [3]. Different conditions and diseases can lead to male infertility, such as the obstruction of the reproductive tract, hormonal imbalances, and testicular failure to produce sperm. Lifestyle factors such as smoking, alcohol abuse, or obesity can also negatively affect male fertility. Additionally, exposure to pollutants and toxins can directly harm gametes [4].

Assisted reproductive technologies (ART) opened up new possibilities for couples facing fertility challenges. In 1978, the world’s first child was conceived through in-vitro fertilization (IVF) [5]. Fourteen years later, the first child was conceived through intracytoplasmic sperm injection (ICSI) [5]. Due to its technical features, which allow a single sperm cell to be directly injected into an oocyte to facilitate fertilization, ICSI is mainly used to treat male infertility [6]. According to the European Society of Human Reproduction and Embryology, more than one million ART treatment cycles were performed as of 2018, of which approximately 40% were ICSI treatments [7].

Increasing evidence suggests that infertility might be related to the development of vascular dysfunction [8–10]. Kasman et al. demonstrated in their retrospective review that infertile men had an elevated risk of developing arterial hypertension, diabetes, dyslipidemia, and heart disease compared to control subjects undergoing vasectomy [11].

Prospective data on vascular function of fathers who suffered from infertility is, however, scarce. Hence, our study aimed to investigate overall vascular function of fathers with history of ICSI compared to fathers whose partners conceived naturally.

Methods

Ethical approval

This study was conducted following the Declaration of Helsinki. The Ethics Committee of the Medical Faculty of LMU Munich approved this study on 27 December 2020 (Ethikkommission der Medizinischen Fakultät der Ludwig-Maximilians-Universität München, Pettenkoferstraße 8a, 80336 Munich, Germany; Project number: 20-0844). Prior written informed consent was obtained from all study participants.

Study design

Study participants were recruited in cooperation with the Division of Gynecological Endocrinology and Reproductive Medicine, Division of Obstetrics and Gynecology, University Hospital, LMU Munich (Munich, Germany). Families who successfully conceived a child with help of ICSI treatment were informed in writing about the ongoing study. Families who conceived a child naturally served as controls and were recruited within the greater Munich area (Germany). The study participants were examined at the Division of Pediatric Cardiology and Intensive Care, University Hospital, LMU Munich (Munich, Germany) between May 2021 and March 2022.

Medical history, physical examination, and level of education

Conception types (ICSI vs. spontaneous) were recorded. Paternal age at childbirth (years) was calculated. The medical history of each father was reviewed, focusing on the presence of cardiovascular disease (e.g. arterial hypertension, disorders of glucose, and/or lipid metabolism). Smoking status and regular medication intake were assessed. A physical examination was performed on all study participants. Body weight (kg), height (cm), waist circumference (cm), and hip circumference (cm) were measured in all subjects. The waist-to-hip ratio was then calculated. Furthermore, body mass index (BMI, kg/m²) was calculated. Weight classification was defined as follows: underweight if BMI < 18.5 kg/m², normal weight if BMI ≥ 18.5 kg/m² but < 25 kg/m², overweight if BMI ≥ 25 kg/m² but < 30 kg/m², and obese if BMI ≥ 30 kg/m². The educational level of fathers was determined according to the German education system: no school leaving qualification (0), lower secondary school leaving certificate (1), intermediate secondary school leaving certificate (2), general qualification for university entrance (3), completed apprenticeship (4), and completed university degree (5).

Adherence to the Mediterranean diet

Participants’ adherence to the Mediterranean diet was assessed. High adherence to the Mediterranean diet is considered beneficial for cardiovascular health [12]. The validated 14-item Mediterranean diet assessment tool developed by Martínez-González et al. was translated into German and used to assess participants’ adherence to the Mediterranean diet [13]. A score ≤7 was considered as low adherence to the Mediterranean diet, and a score >7 was considered as high adherence [13].

Level of physical activity and sedentary behavior

Participants’ levels of physical activity and sedentary behavior were evaluated. To determine the level of physical activity of study participants, the German version of the Global Physical Activity Questionnaire (GPAQ) provided by the WHO was applied [14]. Corresponding picture cards were presented for each activity type. Total Metabolic-Equivalent (MET)-minutes and recreational MET-minutes per week were calculated based on GPAQ recommendations [14]. Adults with a total of ≥600 MET-minutes per week met WHO recommendations [14]. In addition, the study participants were asked how many times per week muscle-strengthening activities were performed and how much time per day (hours/day) they spent with sedentary activities.

Vascular function

Pulse wave analysis

An oscillometric blood pressure device (Mobil-O-Graph^®, IEM GmbH, Germany) was used to measure brachial systolic blood pressure (SBP, mmHg), brachial diastolic blood pressure (DBP, mmHg), mean arterial pressure (MAP, mmHg), heart rate (HR, bpm), central SBP (cSBP, mmHg), central DBP (cDBP, mmHg), augmentation index averaged to a heart rate of 75 bpm (AIx@75, %) and pulse wave velocity (PWV, m/s). Cuff sizes were selected based on the participants’ right upper arm circumference. Participants were asked to remain supine and still for ≥5 minutes before and during the study. Three consecutive measurements were performed and averaged. SBP and DBP were considered elevated if SBP ≥130 mmHg and DBP ≥85 mmHg [15].

Sonography of the common carotid artery

Sonography of both common carotid arteries (CCA) was performed by one investigator for all study participants using either a Philips iE33 xMatrix or a Philips Epiq 7G ultrasound device (Philips Healthcare, Amsterdam, The Netherlands). During the examination, study participants were asked to keep in a supine position with the neck extended to a 45° angle and turned toward the opposite of the examination side [16]. Offline analysis was performed by one investigator.

Peak circumferential strain, peak strain rate, and arterial distensibility

The area directly below the carotid bifurcation was scanned in short-axis view using a 3–8 MHz sector array transducer (Philips Healthcare, Amsterdam, The Netherlands). Three consecutive loops were recorded under three-lead ECG tracking and transferred to a separate workstation (QLAB Cardiovascular Ultrasound Quantification Software version 11.1; Philips Healthcare, Amsterdam, The Netherlands) for offline analysis. The SAX-A function of the software was then utilized. To accurately track the vessel’s wall and to avoid the tracking of perivascular tissue, the region of interest (ROI) was manually adjusted. Pixels of the vascular ROI were then tracked in 2D throughout the cardiac cycle. Peak circumferential strain (CS, %) and peak strain rate (SR, 1/s) were determined manually. To improve data validity, an average of three measurements was calculated for each CCA side. Arterial distensibility (mmHg⁻¹×10⁻³) was calculated using the following formula [17]: $$\text{Arterial Distensibility}=\frac{2\times \text{Peak Circumferential Strain}}{\text{Systolic Blood Pressure}-\text{Diastolic Blood Pressure}}$$

Additionally, CS, SR, and arterial distensibility of the right and left CCA were averaged.

Carotid intima-media thickness

Both CCAs were scanned in long-axis view using a 3–12 MHz linear array transducer (Philips Healthcare, Amsterdam, The Netherlands) at the level of carotid bifurcation. Three consecutive loops were recorded with simultaneous three-lead ECG tracking and transferred to a separate workstation (QLAB Cardiovascular Ultrasound Quantification Software version 11.1; Philips Healthcare, Amsterdam, The Netherlands) for offline analysis. Carotid intima-media thickness (cIMT, mm) was assessed semi-automatically at end-diastole (R-wave on ECG) on each side. The ROI was set proximal to the carotid bifurcation and the length of ROI was adjusted to 10 mm. To improve data validity, three measurements were taken, and an average was calculated for each CCA individually. Additionally, cIMT of the right and left CCA were averaged.

Stiffness index β

The sonographic study protocol described above was applied. Both CCAs were scanned in long-axis view using a 3–12 MHz linear array transducer (Philips Healthcare, Amsterdam, The Netherlands). M-Mode was applied proximal to the carotid bifurcation. End-diastolic diameter (dD, mm) and end-systolic diameter (sD, mm) of both CCAs were measured offline by a masked investigator (IntelliSpace Cardiovascular Ultrasound Viewer, Philips Healthcare, Amsterdam, The Netherlands).

Stiffness index β was calculated using the following formula [17]: $$\text{Stiffness Index}\beta =\frac{\mathrm{\text{ln}}\left(\frac{\mathrm{\text{SBP}}}{\mathrm{\text{DBP}}}\right)}{\Delta \mathrm{D}/\mathrm{\text{dD}}}$$

Blood lipid profile

Total cholesterol (TC, mg/dL), low-density lipoprotein cholesterol (LDL-C, mg/dL), high-density lipoprotein cholesterol (HDL-C, mg/dL), non-high-density lipoprotein cholesterol (non-HDL, mg/dL), triglycerides (mg/dL) and lipoprotein a (Lp(a), mg/dL) were measured to assess the blood lipid profile. A fasting period of ≥4 h was required before blood sampling. The presence of elevated conventional blood lipids was defined according to adult recommendations [18,19]. An Lp(a) ≥50 mg/dL was defined as increased [20].

Statistical analysis

Continuous parameters were tested for normality using the Kolmogorov–Smirnov test or the Shapiro–Wilk test. For normally distributed continuous variables, the unpaired t-test was used. For non-normally distributed continuous variables, the Mann–Whitney-U test was applied. The chi-square test was used to compare nominal data. Analysis of covariance (ANCOVA) was used to adjust for confounders, such as age. Normally distributed data were presented as mean ± standard deviation (SD) and non-normally distributed data as median (interquartile range [IQR]). IBM SPSS Statistics for Windows version 29.0 (IBM Corp., Armonk, NY) was used for data analysis. A p < 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 34 fathers with history of ICSI and 29 control subjects were included in this study.

In the group with history of ICSI, seven subjects had arterial hypertension, four had dyslipidemia, two had glucose metabolism disorders, one had prostate cancer, one displayed with history of transient ischemic attack (TIA) and one had thyroid disease. Seven fathers with history of ICSI were taking antihypertensive medication, one subject was taking lipid-lowering medication, two subjects were taking antidiabetic medication, one subject was taking blood thinners, and one subject was taking L-thyroxine.

In the control group, four subjects had arterial hypertension, three had dyslipidemia, one displayed a history of thrombosis, one displayed with history of pheochromocytoma and one had TIA. Two subjects had thyroid disease. Two subjects were taking antihypertensive medication, two subjects were taking lipid-lowering medication, one subject was taking blood thinners, and two subjects were taking L-thyroxine.

Median age was 48.49 (46.32 − 57.09) years in fathers with history of ICSI and 47.19 (40.62 − 55.18) years in controls (p = 0.061). The two groups did not differ significantly in anthropometric variables and smoking status (Table 1). Both groups differed significantly in educational level (p = 0.017). Paternal age at birth in fathers with history of ICSI was significantly higher compared to controls (p < 0.001). Patients’ characteristics are visualized in Table 1.

Table 1. Patients’ characteristics.

Variable	ICSI (n = 34)	Control (n = 29)	p Value
Age (years)	48.49 (46.32 − 57.09)	47.19 (40.62 − 55.18)	0.061
Bodyweight (kg)	93.67 ± 15.79	90.91 ± 10.83	0.415
Height (cm)	181.86 ± 6.01	183.94 ± 5.15	0.150
BMI (kg/m^2)	28.32 ± 4.62	26.90 ± 3.34	0.174
Underweight (n (%))	0 (0)	0 (0)	0.357
Normal weight (n (%))	9 (26.47)	8 (27.59)
Overweight (n (%))	14 (41.18)	16 (55.17)
Obese (n (%))	11 (32.35)	5 (17.24)
Waist/hip-circumference ratio	0.97 ± 0.05	0.96 ± 0.06	0.723
Smoking status (n (%))^a	10 (29.41)	5 (17.86)	0.290
Paternal educational level	4.00 (3.00 − 5.00)	5.00 (5.00 − 5.00)	0.017*
Paternal age at birth (years)	38.52 (34.92 − 45.47)	33.53 (30.09 − 35.24)	<0.001***

ICSI: intracytoplasmic sperm injection; BMI: body mass index

^a28 control subjects were included in the analysis. Paternal educational level was assessed according to the German education system: no school leaving qualification (0), lower secondary school leaving certificate (1), intermediate secondary school leaving certificate (2), general qualification for university entrance (3), completed apprenticeship (4), and completed university degree (5). Data is presented as mean ± SD for normally distributed parameters and as median (IQR) for non-normally distributed parameters. Nominal data is presented as n (%). *p < 0.05; ***p ≤ 0.001.

Diet quality, level of physical activity, and sedentary behavior

Both groups did not differ significantly in diet quality. Compared to controls, fathers with history of ICSI tended to achieve more total MET-minutes per week. Moreover, fathers with history of ICSI were significantly less engaged in sedentary behavior compared to controls (p = 0.046). Data on diet quality, level of physical activity, and sedentary behavior are given in Table 2.

Table 2. Diet quality, level of physical activity, and sedentary behavior.

Variable	ICSI (n = 34)	Control (n = 29)	p Value
MEDAS^a	5.85 ± 2.64	5.86 ± 2.48	0.983
Total MET-minutes per week^b	1950 (930–5005)	1510 (550–2355)	0.050
Recreational MET-minutes per week	480 (150–1290)	720 (270–1500)	0.476
Muscle strengthening activities (times/week)	0 (0 − 0.125)	0 (0–1)	0.711
Sedentary behavior (hours/day)	8.18 ± 3.25	9.74 ± 2.76	0.046*

ICSI: intracytoplasmic sperm injection; MEDAS: Mediterranean diet adherence score; MET: metabolic-equivalent

Data is presented as mean ± SD for normally distributed parameters and as median (IQR) for non-normally distributed parameters. Nominal data is presented as n (%).

^a 33 ICSI subjects were included in the analysis.

^b 32 ICSI subjects and 28 control subjects were included in the analysis.

*p < 0.05.

Vascular function

PWV and stiffness index β were significantly higher in fathers with history of ICSI (p = 0.048, p = 0.019). The remaining vascular variables did not differ significantly between both groups (Table 3). After ANCOVA adjustment for age, vascular function variables showed no significant differences between both groups (Table 4).

Table 3. Vascular function.

Variable	ICSI (n = 34)	Control (n = 29)	p Value
Pulse wave analysis
SBP (mmHg)^a	127.94 ± 11.38	124.91 ± 12.58	0.329
Elevated SBP (n (%))^a	13 (38.24)	9 (33.33)	0.692
DPB (mmHg)^a	86.32 ± 8.12	83.54 ± 8.58	0.201
Elevated DBP (n (%))^a	18 (52.94)	11 (40.74)	0.343
MAP (mmHg)^a	105.40 ± 9.21	102.53 ± 9.87	0.246
cSBP (mmHg)^a	122.38 ± 11.77	119.05 ± 11.99	0.280
cDBP (mmHg)^a	87.54 ± 8.41	84.69 ± 8.58	0.197
Heart rate (bpm)^a	58.38 ± 9.53	60.14 ± 8.90	0.465
AIx@75 (%)^a	10.29 ± 9.47	11.68 ± 13.42	0.652
PWV (m/s)^a	7.48 ± 0.83	7.01 ± 0.99	0.048*
Sonography of the common carotid artery
CCA CS (%)^b	6.61 ± 2.31	7.02 ± 1.99	0.463
CCA SR (1/s)^b	1.60 ± 0.53	1.84 ± 0.48	0.079
CCA Dis (mmHg^−1 × 10^−3)^c	319.67 ± 105.95	347.98 ± 99.05	0.294
Stiffness index β^d	4.97 (3.42 − 7.05)	3.50 (2.86–5.84)	0.019*
cIMT (mm)^e	0.63 ± 0.11	0.58 ± 0.09	0.056

ICSI: intracytoplasmic sperm injection; SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure; cSBP: central systolic blood pressure; cDBP: central diastolic blood pressure; AIx@75: augmentation index averaged to a heart rate of 75 bpm; PWV: pulse wave velocity; CCA: common carotid artery; CS: peak circumferential strain; SR: peak strain rate; Dis: arterial distensibility

^a27 control subjects were included in the analysis. ^b33 ICSI subjects were included in the analysis. ^c33 ICSI subjects and 27 control subjects were included in the analysis. ^d32 ICSI subjects and 26 control subjects were included in the analysis. ^e33 ICSI subjects and 28 control subjects were included in the analysis.

Data is presented as mean ± SD for normally distributed parameters. Nominal data is presented as n (%). *p < 0.05.

Table 4. Age-adjusted vascular function.

Variable	ICSI (n = 34)	Control (n = 29)	p Value
SBP (mmHg)^a	127.66 ± 2.08	125.26 ± 2.34	0.451
DBP (mmHg)^a	85.74 ± 1.38	84.26 ± 1.56	0.486
MAP (mmHg)^a	104.97 ± 1.63	103.08 ± 1.83	0.451
cSBP (mmHg)^a	121.97 ± 2.05	119.57 ± 2.31	0.447
cDBP (mmHg)^a	86.98 ± 1.42	85.40 ± 1.59	0.469
Heart rate (bpm)^a	58.16 ± 1.61	60.41 ± 1.82	0.365
AIx@75 (%)^a	9.45 ± 1.87	12.74 ± 2.11	0.255
PWV (m/s)^a	7.30 ± 0.07	7.23 ± 0.08	0.491
Sonography of the common carotid artery
CCA CS (%)^b	6.76 ± 0.37	6.85 ± 0.39	0.872
CCA SR (1/s)^b	1.66 ± 0.08	1.77 ± 0.09	0.347
CCA Dis (mmHg^−1 × 10^−3)^c	323.91 ± 18.05	342.80 ± 20.02	0.493
Stiffness index β^d	6.31 ± 0.71	4.49 ± 0.79	0.099
cIMT (mm)^e	0.62 ± 0.02	0.60 ± 0.02	0.406

ICSI: intracytoplasmic sperm injection; SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure; cSBP: central systolic blood pressure; cDBP: central diastolic blood pressure; AIx@75: augmentation index averaged to a heart rate of 75 bpm; PWV: pulse wave velocity; CCA: common carotid artery; CS: peak circumferential strain; SR: peak strain rate; Dis: arterial distensibility

The analysis of covariance (ANCOVA) was used to test for significance.

^a27 control subjects were included in the analysis. ^b33 ICSI subjects were included in the analysis. ^c33 ICSI subjects and 27 control subjects were included in the analysis. ^d32 ICSI subjects and 26 control subjects were included in the analysis. ^e33 ICSI subjects and 28 control subjects were included in the analysis. Data is presented as mean ± SD for normally distributed parameters.

Blood lipid profile

No differences were found in blood lipid profile between the two groups (Table 5).

Table 5. Blood lipid profile.

Variable	ICSI (n = 34)	Control (n = 29)	p Value
TC (mg/dL)	205.12 ± 36.52	198.24 ± 40.44	0.481
Increased TC (n (%))	19 (55.88)	14 (48.28)	0.547
LDL-C (mg/dL)	132.38 ± 32.38	124.41 ± 40.36	0.388
Increased LDL-C (n (%))	25 (73.53)	16 (55.17)	0.128
HDL-C (mg/dL)	51.32 ± 13.25	56.24 ± 17.17	0.205
Decreased HDL-C (n (%))	15 (44.12)	10 (34.48)	0.436
Non-HDL-C (mg/dL)	153.74 ± 37.60	142.03 ± 44.04	0.260
Increased Non-HDL-C (n (%))	27 (79.42)	18 (62.07)	0.128
Triglycerides (mg/dL)	121.50 (89.00 − 181.75)	149.00 (82.50 − 189.00)	0.831
Lp(a) (mg/dL)^a	8.00 (5.00 − 26.25)	9.00 (5.00 − 12.00)	0.895
Increased Lp(a) (n (%))^a	6 (20.00)	4 (13.79)	0.731

ICSI: intracytoplasmic sperm injection; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; non-HDL-C: non-HDL cholesterol; Lp(a): lipoprotein (a)

Data is presented as mean ± SD for normally distributed parameters and as median (IQR) for non-normally distributed parameters. Nominal data is presented as n (%).

^a30 ICSI subjects were included in the analysis.

Discussion

This pilot study investigated overall vascular health in fathers with history of ICSI. In total, 34 fathers with history of ICSI and 29 controls were enrolled.

Fathers with history of ICSI tended to be older at time of examination. Moreover, they displayed a significantly higher paternal age at birth. While both groups did not differ significantly in anthropometric variables as well as smoking status, paternal educational level was significantly altered between the two cohorts.

This study design accounted for potential confounders, such as diet quality, physical activity, and sedentary behavior. Both groups did not differ significantly in diet quality. However, fathers with history of ICSI were, in comparison to peers, physically more active and engaged significantly less in sedentary behavior.

Overall vascular function was visualized using different non-invasive methodologies including the measurement of brachial blood pressure, central blood pressure, and PWV through an oscillometric blood pressure device. Further, arterial stiffness and cIMT of the CCA were evaluated sonographically.

Interestingly, fathers with history of ICSI demonstrated a significantly higher pulse wave velocity as well as a significantly higher stiffness index β compared to peers. However, these results did not remain significant when adjusted for age.

The assessment of blood lipids revealed no significant alterations between both groups.

Overall vascular function did not display significant differences between both groups suggesting a clinically unaltered cardiovascular risk profile in fathers with history of ICSI.

Associations between male infertility and cardiovascular health

The literature suggests that male infertility might be associated with increased cardiovascular morbidity and mortality: Kasman et al. demonstrated in their retrospective review of insurance data, that infertile men had an elevated risk of developing arterial hypertension, diabetes, dyslipidemia, and heart disease compared to control subjects undergoing vasectomy [11]. A retrospective longitudinal cohort study by Wei et al. investigated the long-term risk of cardiovascular hospitalization in fathers with history of ART [21]. The authors demonstrated that ART was linked with a 24% elevated risk of paternal cardiovascular hospitalization [21]. In addition, a retrospective cohort study by Eisenberg et al. with 135,903 male subjects revealed that childless men display, compared to fathers, a 17% higher risk of dying from cardiovascular disease [22].

The exact pathophysiological mechanisms explaining the increased cardiovascular morbidity and mortality among infertile men are not yet fully understood. In the following, we want to elaborate on some pathophysiological considerations:

As approximately 15% of the male genome is involved in reproduction [23,24], it looks plausible that other organ systems, such as the cardiovascular one, can be genetically influenced by infertility. Male fertility can be negatively influenced by hormonal imbalances, such as testosterone deficiency [25]. Testosterone deficiency itself has been linked with an increased cardiovascular risk [25,26]. Sexual dysfunctions such as erectile dysfunction are encountered more frequently in male subjects with infertility [27]. The literature suggests that erectile dysfunction is linked with endothelial dysfunction and can be considered as an independent cardiovascular risk factor [25]. A Danish cohort study by Latif et al. investigated the predictive value of semen quality as a biomarker for long-term morbidity in 4712 men [23]. Interestingly, the authors were able to demonstrate that a sperm concentration <15 million/mL was associated with a 40% increased risk for cardiovascular hospitalization [23]. Moreover, poor lifestyle habits (e.g. poor diet quality and low level of physical activity) as well as acquired cardiometabolic risk factors (e.g. excess weight and diabetes) are thought to lower male fertility [28–30]. Further, infertility can have negative effects on male mental health [31]. A systemic review and meta-analysis by Kiani et al. highlighted that depression affects 16.75–18.55% of infertile men [31]. This needs to be taken into consideration as people with depression are more like to develop cardiovascular diseases compared to the general population [32].

To summarize, the pathophysiological mechanisms explaining the increased cardiovascular morbidity and mortality among infertile men are complex and require further research.

Limitations

In contrast to our expectations, this study did not reveal a significantly lower vascular health in fathers with history of ICSI. Primarily, this might be due to the low sample size, the relatively young age of subjects, the suboptimal age matching, the different educational levels, and differences in physical activity as well as sedentary behavior between both groups.

Both groups did not differ significantly in age. However, there was a tendency of an increased age in the group of fathers with history of ICSI. For this matter, vascular parameters were adjusted for age. In addition, median age was relatively low in the examined groups. Further studies need to investigate whether an increased cardiovascular morbidity of fathers with history of ICSI can be detected at advanced age. Unlike reported within the literature, fathers with history of ICSI did not display significant differences in anthropometric variables and acquired cardiometabolic risk factors (e.g. excess weight and dyslipidemia) which could have positively influenced vascular health [11,30]. The differences in paternal educational levels could have posed a bias. In contrast to literature regarding infertile men, our results revealed that fathers with history of ICSI were physically more active and engaged significantly less in sedentary behavior compared to controls. Notably, these factors could have positively influenced vascular function in the cohort of fathers with history of ICSI.

To the best of our knowledge, this was the first study investigating overall vascular health in fathers with history of ICSI compared to peers. As this was a pilot study, a prior power analysis was not feasible. Different non-invasive methodologies were applied to assess vascular function. Limitations on the vascular methodologies used in this study were elaborated on in recent publications of our departments [33,34]. The study design was not longitudinal. Further, the study sample of this pilot study can be considered as relatively low. Participants were recruited by one center and presented with different comorbidities. This study did not address the exact factors leading to male infertility nor baseline markers of male reproductive health (e.g. hormones, sperm morphology, sperm concentration, and genetics) at time of ICSI treatment.

To overcome the above-mentioned limitations, prospective longitudinal multi-centric studies of men with infertility are required in the future.

Conclusion

This pilot study investigated the overall vascular health in fathers with history of ICSI compared to fathers whose partners conceived naturally. Overall vascular function did not display significant differences between both groups suggesting an unaltered cardiovascular risk profile in fathers with history of ICSI. In the future, prospective multicenter studies with a lager study sample are required to validate these preliminary results.

Acknowledgments

We would like to thank Megan Crouse for editorial assistance.

Disclosure statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Outside the submitted work: N.R.: Support for symposium and others from Ferring Arzneimittel GmbH, Theramex Germany GmbH, Merck KGaA, Teva GmbH, and Besins Healthcare.

Additional information

Funding

Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) − 413635475 – and the Munich Clinician Scientist Program (MCSP) of LMU Munich.