Abstract
Background
Adults born preterm are at risk of developing cardiovascular morbidities.
Objective
The aim of this study was to evaluate the relationship between retinopathy of prematurity (ROP) and blood pressure (BP) and salivary cortisol levels during adulthood.
Methods
Sixty-nine subjects (mean age 22.6 years) were included. Subjects were adults who were: (a) ex-preterm infants with severe ROP (n = 22), born at gestational age (GA) <30 weeks with a birth weight (BW) <1,000 g, (b) ex-preterm infants with no/mild ROP (n = 21), born at GA <28 weeks with a BW <1,000 g, or (c) full-term controls (n = 26). Anthropometric data, office BP, ambulatory BP, and morning and evening salivary cortisol were analyzed.
Results
As adults, ex-preterm infants with severe ROP had on average 7.4 mm Hg higher systolic office BP than those with no/mild ROP (p = 0.019) and controls (p = 0.007). A high cortisol level, tall height, and severe ROP were independent predictors of higher ambulatory systolic BP during adulthood in forward stepwise regression analysis, independent of GA.
Conclusion
Our results indicate that preterm infants with severe abnormal retinal vascular development during the neonatal period may be at an increased risk for increased BP during adulthood. We found no differences between those with no/mild ROP as infants and controls with regard to BP data.
Keywords: Preterm, Retinopathy of prematurity, Blood pressure, Salivary cortisol
Introduction
Preterm birth is associated with an increased risk of high blood pressure (BP) in young adulthood [1]. Immaturity and being born small for gestational age (GA) [1] are proposed to explain this association. Neonatal complications such as retinopathy of prematurity (ROP) [2] have also been associated with hypertension in children who were born preterm.
The present study evaluated the relationship between severe ROP during infancy and adult BP, physical activity, and salivary cortisol levels. Results were compared with individuals born very preterm without severe ROP and full-term controls. All study participants were part of a cohort born between 1988 and 1993 in Stockholm, Sweden.
Materials and Methods
Subjects
Follow-up BP measurements at age 20–25 years were performed in 69 individuals. Study participants included ex-preterms (n = 43) with a postmenstrual age of ≤30 weeks and full-term normal-weight controls (n = 26) born in Stockholm between 1988 and 1993. In the initial cohort, infants with birth weights (BW) <1,500 g were included. During the neonatal period, 51 of 291 infants died.
All 28 subjects treated for severe ROP in the primary cohort were invited to participate in the present study and 22 accepted. In total, 125 controls were included in the primary cohort, 55 were randomly selected and invited, and 26 participated.
Infants with no/mild ROP and GA <28 weeks at birth were included as preterm controls (n = 42). Twenty-one agreed to participate in the study. Participants and nonparticipants showed no differences in GA and BW within the groups.
The study protocol was approved by the ethics committee at Karolinska Solna, Stockholm. All subjects provided written informed consent.
Definitions
GA was determined by ultrasound during early pregnancy. Standard deviation scores (SDS) were based on the Swedish reference curve at birth [3] and adulthood (Tables 1, 2).
Table 1.
Peri- and neonatal characteristics and current characteristics in adults born preterm with different grades of ROP during their early neonatal weeks (preterms), or born at full term with a normal BW (controls)
| No/mild ROP | Severe ROP | Controls | p | 1 vs. 2 | 1 vs. 3 | 2 vs. 3 | |
|---|---|---|---|---|---|---|---|
| (n = 21) | (n = 22) | (n = 26) | |||||
| Male/female, n | 11/10 | 10/12 | 9/17 | ||||
| Neonatal anthropometrics | |||||||
| BW, g | 850 (719, 986) | 830 (699, 960) | 3,440 (3,323, 3,563) | <0.001 | |||
| BW SDS | −0.83 (−1.31, −0.35) | −0.34 (−0.86, 0.09) | −0.18 (−0.61, 0.26) | 0.13 | |||
| GA, weeks | 26.0 (25.5, 26.5) | 25.5 (25.0, 26.0) | 39.6 (39.1, 40.1) | <0.001 | |||
| Perinatal characteristics | |||||||
| Maternal age, years | 34 (32, 36) | 31 (28, 33) | 31 (28, 33) | 0.07 | |||
| Paternal age, years | 34 (29, 39) | 36 (33, 40) | 34 (30, 38) | 0.76 | |||
| Maternal height, cm | 165 (162, 168) | 169 (166, 172) | 165 (162, 168) | 0.06 | |||
| Paternal height, cm | 181 (179, 184) | 179 (176, 181) | 178 (175, 181) | 0.21 | |||
| Target height cm | 175 (171, 179) | 173 (169, 177) | 174 (170, 187) | 0.77 | |||
| Maternal education level, mean 2–7 | 4.0 (3.4, 4.6) | 4.2 (3.6, 4.8) | 4.0 (3.5, 4.6) | 0.85 | |||
| Paternal education level, mean 2–7 | 4.6 (3.9, 5.2) | 4.2 (3.5, 4.8) | 4.1 (3.5, 4.7) | 0.51 | |||
| Maternal pregnancies, n | 2.8 (2.2, 3.4) | 2.5 (1.9, 3.1) | 1.9 (1.3, 2.4) | 0.09 | |||
| Siblings, n | 0.65 (0.3, 1.0) | 0.91 (0.5, 1.3) | 0.73 (0.4, 1.1) | 0.60 | |||
| Maternal smoking during pregnancy (no/yes), % | 88/13 | 88/13 | 95/5 | 0.67a | |||
| Fertility problems (no/yes), % | 89/11 | 88/13 | 95/5 | 0.70a | |||
| Maternal diabetes(no/yes), % | 100/0 | 95/5 | 100/0 | 0.35a | |||
| Maternal preeclampsia (no/yes), % | 84/16 | 74/26 | 100/0 | 0.06a | |||
| Mode of delivery (vaginal/ section), % | 32/68 | 80/20 | 100/0 | <0.001a | |||
| Prenatal cortisol (no/yes), % | 84/16 | 79/21 | 100/0 | 0.07a | |||
| BPD (no/yes), % | 67/33 | 27/73 | 100/0 | <0.001a | |||
| IVH (no/yes), % | 62/38 | 55/45 | – | 0.62a | |||
| PVL (no/yes), % | 71/29 | 77/23 | – | 0.66a | |||
| Current anthropometrics | |||||||
| Age at follow-up, years | 22 (21.86, 22.7) | 23 (22.3, 23.3) | 23 (22.0, 23.0) | 0.21 | |||
| Height, cm | 170 (166, 175) | 170 (166, 175) | 175 (172, 180) | 0.12 | |||
| Difference from target height, cm | −3.7 (−6.0, −1.5) | −3.4 (−5.6, −1.2) | 2.2 (0.2, 4.1) | <0.001 | 0.84 <0.001 | <0.001 | |
| Weight, kg | 63 (57, 69) | 67 (62, 73) | 73 (67, 78) | 0.07 | |||
| BMI, kg/m2 | 22 (20.2, 23.2) | 23 (21.6, 24.5) | 24 (21.2, 24.9) | 0.17 | |||
| Head circumference, cm | 55 (54, 56) | 56 (55, 57) | 57 (56, 58) | 0.007 | |||
| Waist circumference, cm | 83 (79, 88) | 89 (85, 93) | 86 (82, 90) | 0.21 | |||
| Waist-to-height ratio | 0.49 (0.47, 0.52) | 0.52 (0.50, 0.55) | 0.49 (0.47, 0.51) | 0.09 | |||
| Hip circumference, cm | 91 (86, 95) | 95 (91, 100) | 97 (93, 101) | 0.09 | |||
| Current characteristics | |||||||
| Current smoking or snuff use (no/yes/missing), % | 83/17/3 | 82/18/0 | 72/28/0 | 0.45a | |||
| Physical activity, h/week | 5.3 (3.3, 7.3) | 2.2 (0.3, 4.0) | 4.8 (3.2, 6.5) | 0.07 | |||
| Self-reported wakening period, h | 16.3 (15.5, 17.1) | 15.7 (14.9, 16.5) | 15.5 (14.9, 16.5) | 0.35 | |||
| Self-reported sleeping period, h | 7.7 (6.9, 8.5) | 8.3 (7.5, 9.1) | 8.5 (7.8, 9.3) | 0.30 | |||
Values are presented as the mean (95% CI). Statistical analysis: analysis of variances (ANOVA), followed by post hoc Fischer test unless stated otherwise. BMI, body mass index; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; SDS, standard deviation score.
Pearson χ2 test.
Table 2.
BP data
| No/mild ROP (n = 21) | Severe ROP (n = 22) | Controls (n = 26) | P | 1 vs. 3 | 2 vs. 3 | 1 vs. 2 | |
|---|---|---|---|---|---|---|---|
| Office BP | |||||||
| Mean systolic BP right arm | 124 (119, 129) | 131 (127, 136) | 124 (120, 127) | 0.015 | 0.82 | 0.007 | 0.019 |
| Mean systolic BP left arm | 125 (120, 129) | 131 (126, 136) | 123 (119, 127) | 0.042 | 0.63 | 0.017 | 0.06 |
| Mean diastolic BP right arm | 75 (72, 78) | 77 (74, 81) | 75 (72, 78) | 0.38 | |||
| Mean diastolic BP left arm | 75 (72, 79) | 77 (73, 80) | 74 (71, 77) | 0.45 | |||
| Ambulatory BP | |||||||
| 24-h systolic BP | 123 (120, 127) | 127 (122, 131) | 124 (120, 127) | 0.40 | |||
| 24-h diastolic BP | 72 (70, 74) | 73 (69, 76) | 70 (68, 72) | 0.33 | |||
| 24-h pulse pressure | 51 (49, 54) | 54 (51, 58) | 52 (50, 55) | 0.33 | |||
| 24-h heart rate, beats/min | 74 (69, 78) | 71 (67, 76) | 73 (69, 77) | 0.72 | |||
| 24-h systolic recordings above 140 mm Hg, % | 19 (9, 28) | 28 (16, 40) | 15 (9, 21) | 0.10a | |||
| Day systolic BP | 127 (123, 131) | 130 (126, 135) | 126 (123, 128) | 0.22 | |||
| Day systolic hypertension, % | 19 (7, 37) | 38 (15, 61) | 4 (0, 12) | 0.012a | |||
| Day diastolic BP | 76 (73, 79) | 76 (73, 79) | 74 (71, 76) | 0.35 | |||
| Day diastolic hypertension, % | 5 (1, 15) | 14 (0, 31) | 0 | 0.11a | |||
| Day pulse pressure | 51 (48, 54) | 54 (51, 57) | 52 (50, 55) | 0.37 | |||
| Night systolic BP | 114 (110, 119) | 118 (113, 124) | 113 (109, 117) | 0.18 | |||
| Night systolic hypertension, % | 19 (7, 37) | 43 (20, 66) | 15 (0, 30) | 0.07a | |||
| Night diastolic BP | 62 (59, 65) | 63 (59, 67) | 60 (57, 63) | 0.50 | |||
| Night pulse pressure | 53 (50, 56) | 56 (52, 59) | 53 (50, 55) | 0.31 | |||
| Night systolic recordings above 120 mm Hg, % | 25 (13, 37) | 42 (26, 58) | 25 (15, 34) | 0.09a | |||
| Nocturnal dipping, % | 48 (24, 71) | 45 (21, 69) | 58 (37, 78) | 0.65a | |||
| WCH, % | 19 (1, 37) | 33 (11, 55) | 27 (9, 45) | 0.57a | |||
| Morning cortisol, μg/L | 21 (16, 26) | 22 (16, 27) | 22 (15, 28) | 0.84 | |||
| Evening cortisol, μg/L | 6.8 (5.3, 8.2) | 9.6 (7.6, 11.7) | 7.9 (6.8, 9.0) | 0.035 | 0.30 | 0.11 | 0.012 |
Data are presented as mm Hg (95% CI) unless otherwise stated. The 2 ROP groups were born before gestational week 28, except for 3 individuals in the severe ROP group, born before week 30 (birth weight <1,250 g), between 1988 and 1993. Statistical analysis: analysis of variances (ANOVA), followed by post hoc Fischer test unless stated otherwise. BP, blood pressure; WCH, white coat hypertension.
Pearson χ2 test.
Morbidity Examination: ROP Evaluation
ROP was classified according to an international classification [4]. Each child was classified according to the most advanced ROP stage observed.
Subjects were divided into 2 groups according to ROP staging; no/mild ROP (stage ≤2; n = 21) or severe ROP (stage ≥3; n = 22; Table 1). All individuals with severe ROP were treated with retinal ablation (cryotherapy) according to guidelines current at the time of the study [5].
Maternal and Heredity Factors, Neonatal Information, Self-Reported Physical Activity, and Smoking Habits
The maternal medical history and neonatal information was obtained at the time of the initial study (Table 1). Current subject characteristic information was obtained at the time of the study (Table 1). Two subjects in the severe ROP group took antihypertensive medication.
Data Collection: BP Measurements
An experienced nurse recorded each subject's office BP in both arms and was unaware which group the participant represented. An oscillometric automatic BP monitor (Omron HEM-7201; Omron Healthcare, Kyoto, Japan) was used, with the subject in a supine position after 10 min of rest. Office BP was calculated as the mean of 2 recordings.
Each subject's ambulatory BP was obtained using a noninvasive oscillometric system (Spacelabs 90207, Spacelabs Inc., Redmond, WA, USA) applied on the nondominant arm. The measurement period was at least 24 h, with readings every 20 min. Means were calculated over the entire 24-h period, and for day (6 a.m. to 11 p.m.) and night (11 p.m. to 6 a.m.).
Morning and evening salivary cortisol (immunochemistry, radioimmunoassay, and reference morning [10–46 nmol/L] and evening [3.2–15 nmol/L] levels) were obtained 1 day prior to the BP measurements.
Definitions
The target height (in centimeters) was defined as the maternal height + paternal height (adding 13 [male]/subtracting 13 [female]) divided by 2. Hypertension was defined as the mean systolic daily ambulatory BP >135 mm Hg and/or under BP medication or a mean systolic nighttime BP >120 mm Hg [6]. Diastolic hypertension was defined as daily ambulatory BP >85 mm Hg [6]. Nocturnal dipping was defined as a mean nighttime systolic BP 10% or more below that of the mean daytime systolic BP. White coat hypertension was considered present when the office systolic BP level was at the 95th percentile or higher, with a systolic ambulatory average BP at the 90th percentile or lower and compared with Swedish reference values [7].
Statistics
Individuals' anthropometric data, BP, and salivary cortisol levels are presented as the mean and 95% confidence intervals (CI). The comparison between groups was made by analysis of variance and post hoc Fischer test. The Pearson χ2 test was used. Forward stepwise multiple regression analysis was performed with systolic BP as a dependent variable. p < 0.05 was considered statistically significant. Statistical analyses were performed using Statistica StatSoft, version 10 (Statistica, Tulsa, OK, USA).
Results
Table 1 shows data for the 69 subjects at birth and adulthood. The 2 ex-preterm groups did not reach their target height compared with the controls.
Subjects with no/mild ROP had lower evening cortisol levels compared with those with severe ROP. The adult severe ROP group had approximately 7.4 mm Hg higher systolic office BP than the no/mild ROP (p = 0.019) and control (p = 0.007) groups (Table 2). Additionally, the severe ROP group had a higher incidence of daily systolic hypertension and trended towards a difference in nighttime systolic hypertension (Table 2).
In forward stepwise regression analysis with systolic daily ambulatory BP as the dependent variable, morning cortisol levels (β = 0.268, p = 0.024), height (β = 0.239, p = 0.043), and severe ROP (β = 0.235, p = 0.047) were included as independent predictors (adjusted r2 = 0.15, p < 0.005, n = 65). GA, BW SDS, neonatal bronchopulmonary dysplasia (BPD), and graded physical activity had no impact when included in the analysis. With left arm office systolic BP as a dependent variable, severe ROP (β = 0.331, p = 0.004), height (β = 0.400, p < 0.001), and morning cortisol levels (β = 0.236, p = 0.029) were significant predictors (adjusted r2 = 0.29, p < 0.0001, n = 65) independent of GA, BW SDS, or BPD. Less physical activity was a nonsignificant predictor (β = −0.169, p = 0.14).
Discussion
Subjects with severe ROP as infants, indicating severe early abnormal retinal vessel development, had increased office systolic BP and higher incidences of hypertension in daily systolic ambulatory BP as adults. However, adults born preterm with no/mild ROP did not differ from controls in office or ambulatory BP recordings. Higher morning salivary cortisol, taller height, and severe ROP were related to higher ambulatory daily systolic BP independent of GA, BW SDS, and neonatal BPD.
Morning salivary cortisol was weakly related to office and daytime ambulatory systolic BP. Nearly all of the subjects had salivary cortisol within the normal range. In older men born at term, high salivary cortisol has been associated with hypertension [8].
In the Express study, approximately 70% of extremely preterm infants born at GA <27 weeks developed ROP and one-fifth needed laser therapy [4]. Low weight or poor weight gain, hyperglycemia, and other neonatal morbidities correlate with more severe ROP [9]. Infants with severe ROP experience an early catabolic period with metabolic derangement that may affect cardiovascular development.
We found differences in systolic but not in diastolic BP. This is in accordance with BP findings in another group of preterm children with severe ROP. At the age of 4 years, these infants presented with higher mean office arterial pressure [2]. In a large retrospective meta-analysis, however, ROP was not associated with increased BP in ex-preterm subjects [10].
In our study, about 40% of severe ROP subjects had systolic daytime and nighttime hypertension. In a retrospective study, at a mean age of 52 years, nighttime mean systolic BP was the most significant predictor of cardiac events [6]. Although the sample was small, our results indicate that subjects with severe ROP need early follow-up for BP control and, if required, treatment.
One limitation of this study was the relatively low participation rate, although no simple signs of selection bias were detected between the participating and non-participating subjects. The causal relationship of these findings, as well as the effect on future morbidity, should be investigated in greater depth.
Disclosure Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was supported by the Allmänna BB Foundation, Martina Lundgren, Herman Svensson, the Swedish Medical Society, and by grants from Soderhospital, the Karolinska Insitutet, the Sigvard and Marianne Bernadotte Research Foundation for Children's Eye Care. We also received grants from the Swedish Medical Research Council (No. 2011–2432) and the Swedish government (No. ALFGB2770).
Acknowledgements
We express our gratitude to Lena Swartling for technical assistance, Linda Nilson for BP arrangements, and Birgitta Böhm for providing neonatal information.
References
- 1.Evensen KA, Steinshamn S, Tjonna AE, Stolen T, Hoydal MA, Wisloff U, Brubakk AM, Vik T. Effects of preterm birth and fetal growth retardation on cardiovascular risk factors in young adulthood. Early Hum Dev. 2009;85:239–245. doi: 10.1016/j.earlhumdev.2008.10.008. [DOI] [PubMed] [Google Scholar]
- 2.Kistner A, Sigurdsson J, Niklasson A, Lofqvist C, Hall K, Hellstrom A. Neonatal IGF-1/IGFBP-1 axis and retinopathy of prematurity are associated with increased blood pressure in preterm children. Acta Paediatr. 2014;103:149–156. doi: 10.1111/apa.12478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Niklasson A, Albertsson-Wikland K. Continuous growth reference from 24th week of gestation to 24 months by gender. BMC Pediatr. 2008;8:8. doi: 10.1186/1471-2431-8-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Stahl A, Hellstrom A, Smith LE. Insulin-like growth factor-1 and anti-vascular endothelial growth factor in retinopathy of prematurity: has the time come? Neonatology. 2014;106:254–260. doi: 10.1159/000365132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Cryotherapy for Retinopathy of Prematurity Cooperative Group Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol. 1988;106:471–479. doi: 10.1001/archopht.1988.01060130517027. [DOI] [PubMed] [Google Scholar]
- 6.Hermida RC, Smolensky MH, Ayala DE, Portaluppi F, Crespo JJ, Fabbian F, Haus E, Manfredini R, Mojon A, Moya A, Pineiro L, Rios MT, Otero A, Balan H, Fernandez JR. 2013 ambulatory blood pressure monitoring recommendations for the diagnosis of adult hypertension, assessment of cardiovascular and other hypertension-associated risk, and attainment of therapeutic goals (summary). Joint recommendations from the International Society for Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Spanish Society of Applied Chronobiology, Chronotherapy, and Vascular Risk (SECAC), Spanish Society of Atherosclerosis (SEA), and Romanian Society of Internal Medicine (RSIM) (in Spanish) Clin Investig Arterioscler. 2013;25:74–82. doi: 10.1016/j.arteri.2013.03.002. [DOI] [PubMed] [Google Scholar]
- 7.Nystrom F, Malmstrom O, Karlberg BE, Ohman KP. Twenty-four hour ambulatory blood pressure in the population. J Intern Med. 1996;240:279–284. doi: 10.1046/j.1365-2796.1996.322856000.x. [DOI] [PubMed] [Google Scholar]
- 8.Schoorlemmer RM, Peeters GM, van Schoor NM, Lips P. Relationships between cortisol level, mortality and chronic diseases in older persons. Clin Endocrinol. 2009;71:779–786. doi: 10.1111/j.1365-2265.2009.03552.x. [DOI] [PubMed] [Google Scholar]
- 9.Quinn GE, Dobson V, Saigal S, Phelps DL, Hardy RJ, Tung B, Summers CG, Palmer EA. Health-related quality of life at age 10 years in very low-birth-weight children with and without threshold retinopathy of prematurity. Arch Ophthalmol. 2004;122:1659–1666. doi: 10.1001/archopht.122.11.1659. [DOI] [PubMed] [Google Scholar]
- 10.Hovi P, Vohr B, Ment LR, Doyle LW, McGarvey L, Morrison KM, et al. Blood pressure in young adults born at very low birth weight. Hypertens. 2016;68:880–887. doi: 10.1161/HYPERTENSIONAHA.116.08167. [DOI] [PubMed] [Google Scholar]