Advertisement

Association of umbilical cord insulin-like growth factor 1 levels with severe retinopathy in extremely preterm infants

Open AccessPublished:September 16, 2022DOI:https://doi.org/10.1016/j.pedneo.2022.05.015

      Background

      The association between umbilical cord blood insulin-like growth factor 1 (IGF-1) levels and retinopathy of prematurity (ROP) remains unclear. This study aimed to investigate whether umbilical cord blood IGF-1 levels can predict the development of severe ROP in extremely preterm infants.

      Methods

      This hospital-based retrospective cohort study included infants born at <37 weeks gestational age (GA) between 2019 and 2021 and then classified them into the two GA groups: extremely preterm, <28 weeks and preterm infants, 28–36 weeks. Extremely preterm infants were further subclassified into two groups according to the laser treatment as follows: the severe ROP (ROP-Tx) and ROP (No ROP-Tx) groups. Median umbilical cord blood IGF-1 values were compared between the groups. Perinatal risk factors were identified by univariate and multivariate analyses. Finally, umbilical cord IGF-1 cut-off values requiring ROP treatment with laser were determined by receiver operating characteristic (ROC) curve analyses.

      Results

      A total of 205 infants were enrolled, with 32 being extremely preterm (ROP-Tx: n = 11; No ROP-Tx: n = 21) and 173 being preterm. IGF-1 levels were significantly lower in extremely preterm (13.5 ng/mL) than preterm infants (36 ng/mL, p < 0.001). In extremely preterm infants, IGF-1 levels were significantly lower in the ROP-Tx group than the No ROP-Tx group (10 vs. 19 ng/mL, respectively, p = 0.024). Only GA, umbilical cord blood IGF-1 levels, birth head circumference, and birth chest circumference were identified as risk factors by univariate analysis (p < 0.05). Multivariate analysis showed that only umbilical cord blood IGF-1 was an independent risk factor (odds ratio: 1.26, p = 0.021). ROC curves revealed an IGF-1 cut-off value of 14 ng/mL.

      Conclusion

      The need of laser treatment for ROP was found to be associated with low umbilical cord blood IGF-1 levels in extremely preterm infants. Umbilical cord blood IGF-1 can be used as a biomarker for the risk of developing severe ROP.

      Key Words

      1. Introduction

      Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide.
      • Gilbert C.
      • Foster A.
      Blindness in children: control priorities and research opportunities.
      Therefore, it is important to extract infants at high risk of ROP. Prematurity, high oxygen concentration, sepsis, blood transfusion, intraventricular hemorrhage, and the use of erythropoietin have been identified as risk factors for the development of ROP.
      • Smith L.E.
      Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture.
      Early treatment for retinopathy of prematurity cooperative group
      Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial.
      • Bashinsky A.L.
      Retinopathy of prematurity.
      • Romagnoli C.
      • Tesfagabir M.G.
      • Giannantonio C.
      • Papacci P.
      Erythropoietin and retinopathy of prematurity.
      In recent years, vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), which are involved in the development of retinal blood vessels, have played an important role as biomarkers.
      • Hellstrom A.
      • Perruzzi C.
      • Ju M.
      • Engstrom E.
      • Hard A.L.
      • Liu J.L.
      • et al.
      Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity.
      ,
      • Reddy M.A.
      • Patel H.I.
      • Karim S.M.
      • Lock H.
      • Perry L.
      • Bunce C.
      • et al.
      Reduced utility of serum IGF-1 1evels in predicting retinopathy of prematurity reflects maternal ethnicity.
      Regarding the pathogenesis of ROP, Hallström et al. suggested that IGF-1 is involved in the delay of early retinal vascular development, while VEGF is involved in the pathogenesis of the vasoproliferative phase.
      • Hellstrom A.
      • Perruzzi C.
      • Ju M.
      • Engstrom E.
      • Hard A.L.
      • Liu J.L.
      • et al.
      Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity.
      Thus, in recent years, anti-VEGF therapy, in which antibodies against VEGF are administered intraocularly to delay the development of ROP, has been used in clinical practice. Meanwhile, no therapeutic method using IGF-1 has been established to date. However, a method of selectively administering synthetic IGF-1 to patients with low serum IGF-1 levels to prevent the onset of ROP has been studied and is expected to be a future treatment method.
      • Hellstrom A.
      • Ley D.
      • Hallberg B.
      • Lofqvist C.
      • Hansen-Pupp I.
      • Ramenghi L.A.
      • et al.
      IGF-1 as a drug for preterm infants: a step-wise clinical development.
      IGF-1 plays an important role in fetal and neonatal growth and development of the cardiovascular system, central nervous system, and lungs.
      • Murray P.G.
      • Clayton P.E.
      Endocrine control of growth.
      • Ng P.C.
      • Lam C.W.
      • Lee C.H.
      • Wong G.W.
      • Fok T.F.
      • Chan I.H.
      • et al.
      Leptin and metabolic hormones in preterm newborns.
      • Hellström A.
      • Ley D.
      • Hansen-Pupp I.
      • Hallberg B.
      • Löfqvist C.
      • van Marter L.
      • et al.
      Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development.
      Therefore, low IGF-1 levels at birth, especially in extremely preterm infants, may have a significant impact not only on growth retardation in the early postnatal period but also on delayed retinal vascular development. Long-term low serum IGF-1 levels from birth have been reported to be associated with postnatal growth retardation, impaired brain development, ROP, and chronic lung disease.
      • Kajantie E.
      • Dunkel L.
      • Rutanen E.M.
      • Seppälä M
      • Koistinen R
      • Sarnesto A
      • et al.
      IGF-1, IGF binding protein (IGFBP)-3, phosphoisoforms of IGFBP-1, and postnatal growth in very low birth weight infants.
      • Löfqvist C.
      • Engström E.
      • Sigurdsson J.
      • Hård A.L.
      • Niklasson A.
      • Ewald U.
      • et al.
      Postnatal head growth deficit among premature infants parallels retinopathy of prematurity and insulin-like growth factor-1 deficit.
      • Hansen-Pupp I.
      • Hövel H.
      • Hellström A.
      • Hellström-Westas L.
      • Löfqvist C.
      • Larsson E.M.
      • et al.
      Postnatal decrease in circulating insulin-like growth factor-I and low brain volumes in very preterm infants.
      • Pérez-Muñuzuri A.
      • Fernández-Lorenzo J.R.
      • Couce-Pico M.L.
      • Blanco-Teijeiro M.J.
      • Fraga-Bermúdez J.M.
      Serum levels of IGF1 are a useful predictor of retinopathy of prematurity.
      • Löfqvist C.
      • Hellgren G.
      • Niklasson A.
      • Engström E.
      • Ley D.
      • Hansen-Pupp I.
      • et al.
      Low postnatal serum IGF-I levels are associated with bronchopulmonary dysplasia (BPD).
      However, there have been no reports examining the relationship between umbilical cord blood IGF-1 levels and severe ROP requiring laser treatment. Therefore, this study aimed to clarify the relationship between umbilical cord IGF-1 and severe ROP in extremely preterm infants.

      2. Methods

      2.1 Study design

      A hospital-based retrospective cohort study was conducted at Nihon University Itabashi Hospital, Tokyo, Japan. Written informed consent was obtained from the parents of all infants. This study was approved by the Ethics Committee of Nihon University School of Medicine (no. RK-190910-3) and it was carried out in accordance with the relevant guidelines and regulations. Infants born at <37 weeks gestational age (GA) between 2019 and 2021 were enrolled and then classified into the two GA groups: extremely preterm, <28 weeks and preterm infants, 28–36 weeks. Extremely preterm infants were further subclassified into two groups according to the ROP with laser treatment as follows: the severe ROP (ROP-Tx) and the ROP (No ROP-Tx) groups. The same ophthalmologist performed fundus examinations periodically after birth to diagnose the presence or absence of ROP and determine the indication for laser treatment according to the U.S. ROP guidelines.
      Early treatment for retinopathy of prematurity cooperative group
      Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial.

      2.2 Umbilical cord blood IGF-1 level

      At birth, the umbilicus was double-clamped, and cord blood was sampled from the umbilical vein. Median umbilical cord blood IGF-1 levels were compared between all groups. Umbilical cord blood IGF-1 levels were measured using the radioimmunoassay solid phase method.
      • Chanson P.
      • Arnoux A.
      • Mavromati M.
      • Brailly-Tabard S.
      • Massart C.
      • Young J.
      • et al.
      Reference values for IGF-I serum concentrations: comparison of six immunoassays.
      ,
      • Frystyk J.
      • Freda P.
      • Clemmons D.R.
      The current status of IGF-I assays-A 2009 update.

      2.3 Study methods

      First, umbilical cord blood IGF-1 levels and other factors at birth were compared between extremely preterm and preterm infants and between ROP and non-ROP infants. Second, perinatal and neonatal risk factors were identified by univariate and multivariate analyses, including the following: GA, body weight (BW), BW standard deviation score (SDS), body length (BL), BL SDS, birth head circumference, birth head circumference SDS, birth chest circumference, gender, small-for-gestational age (BW < 10th percentile for GA), Apgar score (at 1 and 5 min), the use of mechanical artificial ventilation, use of oxygen therapy, duration of mechanical artificial ventilation, duration of oxygen therapy, blood transfusion, the use of erythropoietin therapy, respiratory distress syndrome, ligation of patent ductus arteriosus, necrotizing enterocolitis (required surgical intervention and confirmed pathological finding), intraventricular hemorrhage and periventricular leukomalacia (diagnosed by brain ultrasonography and magnetic resonance imaging), histological chorioamnionitis and funisitis (Blanc stage ≥1),
      • Blanc W.A.
      Pathology of the placenta, membranes and umbilical cord in bacterial, fungal and viral infections in man.
      premature rupture of the membrane (diagnosed as rupture before the start of labor), hypertension disorders of pregnancy, and placenta abruption. Finally, umbilical cord IGF-1 cut-off values for ROP treatment were determined by constructing receiver operating characteristic (ROC) curves.

      2.4 Statistical analyses

      To compare umbilical cord blood IGF-1 levels and other factors at birth between extremely preterm and preterm infants and between ROP and non-ROP infants, the Wilcoxon signed-rank test or Chi-squared test was used. The aforementioned perinatal and neonatal factors associated with ROP requiring laser treatment were analyzed by univariate analysis using the Wilcoxon signed-rank test or Fisher's exact test and multiple logistic regression analysis. The umbilical cord blood IGF-1 cut-off value associated with laser treatment was determined using the maximum Youden index of the ROC curve. The Youden index is the point farthest from the boundary delineating the area under the curve and represents the [sensitivity + specificity – 1] value.
      • Fluss R.
      • Faraggi D.
      • Reiser B.
      Estimation of the Youden Index and its associated cutoff point.
      Statistical analyses were performed using JMP version 14 (SAS Institute Inc., Tokyo, Japan). A p-value <0.05 was considered statistically significant.

      3. Results

      3.1 Umbilical cord blood IGF-1 levels

      A total of 205 infants were enrolled, of whom 32 were extremely preterm (ROP-Tx: n = 11; No ROP-Tx: n = 21) and 173 preterm. ROP was developed in 94% of 32 extremely preterm infants and 9% of 173 preterm infants (Table 1). No preterm infants required treatment for ROP. No infants received anti-VEGF therapy.
      Table 1Comparisons of factors at birth and insulin-like growth factor 1 in umbilical cord blood between extremely preterm and preterm infants.
      Extremely preterm n = 32Preterm n = 173p-value
      GA, weeks25 (22–27)34 (28–36)<0.001
      BW, g678 (278–1224)1809 (424–3126)<0.001
      BW SDS−0.47 (−3.95-+1.76)−0.56 (−5.0–+2.41)0.815
      BL, cm30.5 (24.0–37.5)42.5 (27.0–51.5)<0.001
      BL SDS−0.865 (−3.12–+2.7)−0.58 (−4.2–+2.3)0.475
      Birth head circumference, cm22.5 (17.0–27.0)30.2 (20.0–35.5)<0.001
      Birth head circumference SDS−0.175 (−2.32–+2.37)−0.1 (−2.72–+2.51)0.670
      Birth chest circumference, cm18.55 (15.5–22.6)27.0 (15.5–35.0)<0.001
      Male13 (41)77 (45)0.684
      SGA8 (25)49 (28)0.700
      ROP30 (94)16 (9)<0.001
      ROP with leaser treatment11 (34)0 (0)<0.001
      IGF-1, ng/mL (10%ile)510.4
      IGF-1, ng/mL (25%ile)919.5
      IGF-1, ng/mL (50%ile)13.5 (4–48)36 (4–121)<0.001
      IGF-1, ng/mL (75%ile)2052
      IGF-1, ng/mL (90%ile)30.770.6
      Data are shown as median (range) or number (percentage).
      BL, birth length; BW, birth weight; GA, gestational age; IGF-1, insulin-like growth factor 1; SDS, standard deviation score; SGA, small-for-gestational age.
      The median umbilical cord blood IGF-1 level was 30 ng/mL in the 205 infants. Umbilical cord blood IGF-1 levels of extremely preterm infants were significantly lower than those of preterm infants (median value: 13.5 vs. 36 ng/mL, respectively, p < 0.001, Table 1 and Supplementary Figure 1A). Umbilical cord blood IGF-1 levels of ROP infants were significantly lower than non-ROP infants (13 vs. 38 ng/mL, respectively, p < 0.001, Table 2). Furthermore, umbilical cord blood IGF-1 levels were lower in the ROP-Tx group than the No ROP-Tx group (median value: 10 vs. 19 ng/mL, respectively, p = 0.024, Table 3 and Supplementary Fig. 1B).
      Table 2Comparisons of factors at birth and insulin-like growth factor 1 in umbilical cord blood between infants with and without retinopathy of prematurity.
      ROP n = 46non-ROP n = 159p-value
      GA, weeks26 (22–33)34 (26–36)<0.001
      BW, g778 (278–1446)1895 (686–3126)<0.001
      BW SDS−0.90 (−5.0–+1.76)−0.39 (−4.23–+2.41)0.005
      BL, cm33.0 (24.0–42.0)43.0 (30.0–51.5)<0.001
      BL SDS−1.04 (−4.2–+2.7)−0.48 (−3.8–+2.3)0.004
      Birth head circumference, cm24.0 (17.0–28.8)30.5 (20.0–35.5)<0.001
      Birth head circumference SDS−0.30 (−2.32–+2.37)0.02 (−2.72–+2.51)0.023
      Birth chest circumference, cm19.5 (15.5–25.7)27.3 (18.5–35.0)<0.001
      Male19 (41)71 (45)0.687
      SGA19 (41)38 (24)0.020
      IGF-1, ng/mL (10%ile)512
      IGF-1, ng/mL (25%ile)8.823
      IGF-1, ng/mL (50%ile)13 (4–77)38 (4–121)<0.001
      IGF-1, ng/mL (75%ile)23.352
      IGF-1, ng/mL (90%ile)35.371
      Data are shown as median (range) or number (percentage).
      BL, birth length; BW, birth weight; GA, gestational age; IGF-1, insulin-like growth factor 1; SDS, standard deviation score; SGA, small-for-gestational age.
      Table 3Factors associated with treated retinopathy of prematurity in extremely preterm infants.
      Laser treatment
      Yes, n = 11No, n = 21p-value
      GA, weeks25 (22–27)25 (24–27)0.035
      BW, g602 (278–1224)740 (464–1087)0.096
      BW SDS−0.11 (−3.95–+1.76)−0.53 (−3.82–+0.8)0.258
      BL, cm29.0 (24.0–34.2)31.5 (26.5–37.5)0.091
      BL SDS−0.37 (−3.12–+0.8)−0.9 (−3.1–+2.7)0.968
      Birth head circumference, cm20.7 (17.0–26.0)23.5 (20.0–27.0)0.009
      Birth head circumference SDS−0.4 (−2.32–+2.37)−0.1 (−1.8–+1.61)0.226
      Birth chest circumference, cm17.0 (15.5–22.0)19.0 (16.4–22.6)0.035
      Male3 (27)10 (48)0.450
      SGA3 (27)5 (24)1.000
      Apgar score, 1 min2 (0–5)3 (1–7)0.234
      Apgar score, 5 min4 (1–8)7 (1–9)0.190
      Use of mechanical artificial ventilation11 (100)21 (100)
      Use of oxygen therapy11 (100)21 (100)
      Duration of mechanical artificial ventilation, days37 (16–85)36 (9–81)0.361
      Duration of oxygen therapy, days90 (71–142)94 (32–172)0.579
      Blood transfusion7 (64)15 (71)0.703
      Use of erythropoietin therapy11 (100)21 (100)
      RDS11 (100)21 (100)
      PDA with ligation1 (9)2 (10)1.000
      NEC0 (0)0 (0)
      IVH3 (27)1 (5)0.106
      PVL1 (9)2 (10)1.000
      Chorioamnionitis9 (82)12 (57)0.248
      Funisitis6 (55)4 (19)0.056
      PROM1 (9)6 (29)0.374
      HDP1 (9)5 (24)0.637
      Placenta abruption1 (9)1 (5)1.000
      IGF-1, ng/mL (10%ile)4.25.6
      IGF-1, ng/mL (25%ile)710
      IGF-1, ng/mL (50%ile)10 (4–19)19 (4–48)0.024
      IGF-1, ng/mL (75%ile)1425.5
      IGF-1, ng/mL (90%ile)18.431
      The values represent those for children with or without short stature. Values are shown as median (range) or number (percentage).
      BL, birth length; BW, birth weight; GA, gestational age; HDP, hypertension disorders of pregnancy; IGF-1, insulin-like growth factor 1; IVH, intraventricular haemorrhage; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PROM, premature rupture of the membrane; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; SDS, standard deviation score; SGA, small-for-gestational age.

      3.2 Associated factors for severe ROP with laser treatment

      In extremely preterm infants, only GA, umbilical cord blood IGF-1 levels, birth head circumference and birth chest circumference were identified as risk factors by univariate analysis (p < 0.05, Table 3).

      3.3 Multivariate analyses

      Multiple logistic regression analyses using GA, BW SDS, and umbilical cord blood IGF-1 were performed. Only umbilical cord blood IGF-1 was an independent risk factor for severe ROP requiring laser treatment (odds ratio: 1.26, p = 0.021, Table 4).
      Table 4Results of multivariate analysis.
      FactorsOR (95% CI)p-value
      GA, weeks2.06 (0.95–4.49)0.068
      BW SDS0.66 (0.30–1.48)0.318
      IGF-1 in umbilical cord blood, ng/mL1.26 (1.04–1.54)0.021
      BW, birth weight; CI, confidence interval; GA, gestational age; IGF-1, insulin-like growth factor 1; OR, odds ratio; SDS, standard deviation score.

      3.4 Umbilical cord blood IGF-1 cut-off value for ROP with laser treatment

      An umbilical cord blood IGF-1 cut-off value of 14 ng/mL was associated with laser treatment according to the Youden index based on the ROC curve analysis (Table 5).
      Table 5Cut-off values of umbilical cord blood insulin-like growth factor 1 levels for severe retinopathy of prematurity with laser treatment.
      IGF-1, ng/mLSensitivitySpecificityAccuracyYouden index
      40.0910.9520.6560.043
      50.1820.9050.6560.087
      70.2730.9050.6880.178
      80.3640.8570.6880.221
      90.4550.7620.6560.217
      100.5460.7620.6880.307
      110.5460.7140.6560.260
      120.6360.6190.6250.255
      130.7270.6190.6560.346
      140.8180.6190.6860.437
      160.9090.5240.6560.433
      191.0000.4290.6250.429
      201.0000.3330.5630.333
      231.0000.2860.5310.286
      241.0000.2380.5000.238
      271.0000.1910.4690.191
      301.0000.1430.4380.143
      311.0000.0480.3750.048
      481.00000.3440
      The Youden index is the point farthest from the boundary delineating the area under the curve and represents the [sensitivity + specificity – 1] value.
      IGF-1, Insulin-like growth factor-1.

      4. Discussion

      In this Japanese retrospective study, we found that a low umbilical cord blood IGF-1 was an independent risk factor for developing severe ROP requiring laser treatment in extremely preterm infants. Furthermore, an umbilical cord blood IGF-1 cut-off value of 14 ng/mL was associated with laser treatment. These findings clearly indicated that low umbilical cord blood IGF-1 level might be associated with need of ROP treatment in extremely preterm infants.

      4.1 IGF-1 levels

      In fetus, IGF-1 level is influenced by nutrients delivered through placenta rather than by fetal pituitary growth hormone.
      • Fowden A.L.
      The insulin-like growth factors and feto-placental growth.
      Thus, low IGF-1 levels in cord blood indicate a decrease in nutrients from the placenta, which may affect the development of fetal blood vessels and ROP after birth.
      A study regarding cord blood IGF-1 level in only term infants has been reported; mean cord blood IGF-1 level were 58.4 ng/mL.
      • Kadakia R.
      • Ma M.
      • Josefson J.L.
      Neonatal adiposity increases with rising cord blood IGF-1 levels.
      In a report of IGF-1 levels in preterm infants at 33 weeks' corrected GA, the mean IGF-1 level was 23.1 (range: 15.44–39.75) ng/mL, and there was no difference in IGF-1 levels between males (23.1 ng/mL) and females (23.1 ng/mL).
      • Banjac L.
      • Kotur-Stevuljević J.
      • Gojković T.
      • Bokan-Mirković V.
      • Banjac G.
      • Banjac G.
      Relationship between insulin-like growth factor type 1 and intrauterine growth.
      In our study, median cord blood IGF-1 level of 205 preterm infants was 30 ng/mL. There was no difference by sex between males [n = 90, median: 31.5 (range: 4.0–121.0) ng/mL] and females [n = 115, 30.0 (4.0–92.0) ng/mL] (p = 0.969, data not shown).
      In a study evaluating the relationship between IGF-1 levels and nutrition in 87 infants born at 24–32 weeks of gestation, an inverse relationship between parenteral nutrition and IGF-1 levels was reported in the second week of life, and total energy intake was positively associated with IGF-1 levels, especially at 30–33 weeks' corrected GA.
      • Yumani D.F.J.
      • Calor A.K.
      • van Weissenbruch M.M.
      The course of IGF-1 levels and nutrient intake in extremely and very preterm infants during hospitalisation.
      In another report, IGF-1 levels in cord blood strongly correlated with birth weight, leptin, fat mass, and body fat percentage measurements, indicating that IGF-1 may be an important factor in neonatal fat accumulation in utero,
      • Kadakia R.
      • Ma M.
      • Josefson J.L.
      Neonatal adiposity increases with rising cord blood IGF-1 levels.
      but its relationship with ROP remains unclear. Our study showed that cord blood IGF-1 levels in extremely preterm infants were low, especially those with the ROP treatment with laser, and they were an independent risk factor regardless of GA. IGF-1 levels may be associated with nutritional status in utero in extremely preterm infants.
      In another study of preterm infants with birth weight <1251 g in the U.S., the mean IGF-1 level at 28–33 weeks' corrected GA was 20.0 ng/mL (standard error: 0.52) without ROP, 18.0 (0.49) in stage 1 or 2, and 17.0 (0.70) in stage 3; and an association with ROP was reported.
      • Jensen A.K.
      • Ying G.S.
      • Huang J.
      • Quinn G.E.
      • Binenbaum G.
      Postnatal serum insulin-like growth factor I and retinopathy of prematurity.
      This indicates that infants with persistently low serum IGF-1 levels after birth may frequently require treatment for ROP.

      4.2 Factors related to exacerbation of ROP

      Prematurity, high oxygen concentration, sepsis, blood transfusion, intraventricular hemorrhage, and the use of erythropoietin have been reported as risk factors for the development of ROP.
      • Smith L.E.
      Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture.
      Early treatment for retinopathy of prematurity cooperative group
      Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial.
      • Bashinsky A.L.
      Retinopathy of prematurity.
      • Romagnoli C.
      • Tesfagabir M.G.
      • Giannantonio C.
      • Papacci P.
      Erythropoietin and retinopathy of prematurity.
      In our study, only extremely preterm infants required treatment for ROP. Because low GA at birth is the highest risk factor for the development of ROP,
      • Bashinsky A.L.
      Retinopathy of prematurity.
      only extremely preterm infants were used for further analyses. In a comparison between the two groups of extremely preterm infants with and without laser treatment, the group that required laser treatment had significantly shorter GA and smaller birth length, head circumference, and chest circumference (Table 3). In the analysis of perinatal factors, there were no significant differences in the duration of ventilator and oxygen use, blood transfusion, or use of erythropoietin.

      4.3 Potential for treatment with IGF-1 products

      Supplementation with recombinant human (rh) IGF-1 and its binding protein-3 (rhIGFBP-3) is being developed as a treatment to promote growth and maturation and reduces morbidity in extremely preterm infants.
      • Hellstrom A.
      • Ley D.
      • Hallberg B.
      • Lofqvist C.
      • Hansen-Pupp I.
      • Ramenghi L.A.
      • et al.
      IGF-1 as a drug for preterm infants: a step-wise clinical development.
      Another study stated that a deletion of IGF-1 gene is associated with central nervous system disorders, such as learning disabilities and brain growth restriction. Treatment of preterm infants with recombinant IGF-1 has been reported to potentially prevent ROP and central nervous system disorders.
      • Liegl R.
      • Löfqvist C.
      • Hellström A.
      • Smith L.E.
      IGF-1 in retinopathy of prematurity, a CNS neurovascular disease.
      A basic study using a rat model of periventricular leukomalacia reported that IGF-1 was effective in reducing the number of early neurons in the subventricular zone and in increasing the survival of mature neurons in the cerebral cortex.
      • Kim D.J.
      • Cho S.Y.
      • Kim S.U.
      • Jo D.W.
      • Hwang H.I.
      • Shin H.K.
      • et al.
      IGF-1 protects neurons in the cortex and subventricular zone in a periventricular leucomalacia model.
      In a rat model of cerebral hypoxia-ischemia, rhIGF-1 inhibited apoptotic cell death by activating the Akt signaling pathway and also promoted proliferation of neurons and oligodendroglial progenitor cells, suggesting that rhIGF-1 may be useful for clinical therapy.
      • Lin S.
      • Fan L.W.
      • Rhodes P.G.
      • Cai Z.
      Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats.
      In primary IGF-1 deficient mice without tissue IGF-1 gene expression, recombinant IGF-1 can be used to maintain a long-term elevation of serum IGF-1 to establish normal body size, body composition, and maintenance of skeletal structure and function.
      • Elis S.
      • Courtland H.W.
      • Wu Y.
      • Rosen C.J.
      • Sun H.
      • Jepsen K.J.
      • et al.
      Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1.
      Clinical trials conducted to determine whether intravenous supplementation of human recombinant IGF-1 to normal serum concentrations can improve growth and development and reduce morbidity associated with extremely preterm infants are currently in progress.
      • Hellström A.
      • Ley D.
      • Hansen-Pupp I.
      • Hallberg B.
      • Ramenghi L.A.
      • Löfqvist C.
      • et al.
      Role of insulin like growth factor 1 in fetal development and in the early postnatal life of premature infants.
      The reports of extremely preterm infants receiving continuous infusions of rhIGF-1/rhIGFBP-3 have shown that high interleukin-6 and IGFBP-1 levels preceded low IGF-1 levels, and it is necessary to evaluate whether inflammation or infection suppresses serum IGF-1 levels.
      • Klevebro S.
      • Hellgren G.
      • Hansen-Pupp I.
      • Wackernagel D.
      • Hallberg B.
      • Borg J.
      • et al.
      Elevated levels of IL-6 and IGFBP-1 predict low serum IGF-1 levels during continuous infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants.

      4.4 Limitations

      Limitations of this study are as follows: 1) This study was conducted with a small cohort in a single Japanese center. 2) We were not able to assess whether the low IGF-1 levels persisted after birth in extremely preterm infants who required treatment for ROP. Further prospective clinical studies with a large global cohort are needed. Nevertheless, our result indicates that cord blood IGF-1 level is clearly associated with the development of ROP requiring laser treatment in extremely preterm infants.

      5. Conclusion

      In conclusion, the need of laser treatment for ROP was found to be associated with low umbilical cord blood IGF-1 levels in extremely preterm infants. Umbilical cord blood IGF-1 can be used as a biomarker for risk of developing severe ROP requiring laser treatment.

      Declarations of interest

      None.

      Acknowledgements

      This research was supported by the Nihon University School of Medicine Alumni Association's 60th anniversary fund research grant ( 20N601 ), and Grants-in-Aid for Scientific Research (C) ( 21K11582 ) of JSPS KAKENHI .

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

      References

        • Gilbert C.
        • Foster A.
        Blindness in children: control priorities and research opportunities.
        Br J Ophthalmol. 2001; 85: 1025-1027
        • Smith L.E.
        Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture.
        Invest Ophthalmol Vis Sci. 2008; 49: 5177-5182
        • Early treatment for retinopathy of prematurity cooperative group
        Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial.
        Arch Ophthalmol. 2003; 121: 1684-1694
        • Bashinsky A.L.
        Retinopathy of prematurity.
        N C Med J. 2017; 78: 124-128
        • Romagnoli C.
        • Tesfagabir M.G.
        • Giannantonio C.
        • Papacci P.
        Erythropoietin and retinopathy of prematurity.
        Early Hum Dev. 2011; 87: S39-S42
        • Hellstrom A.
        • Perruzzi C.
        • Ju M.
        • Engstrom E.
        • Hard A.L.
        • Liu J.L.
        • et al.
        Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity.
        Proc Natl Acad Sci U S A. 2001; 98: 5804-5808
        • Reddy M.A.
        • Patel H.I.
        • Karim S.M.
        • Lock H.
        • Perry L.
        • Bunce C.
        • et al.
        Reduced utility of serum IGF-1 1evels in predicting retinopathy of prematurity reflects maternal ethnicity.
        Br J Ophthalmol. 2016; 100: 501-504
        • Hellstrom A.
        • Ley D.
        • Hallberg B.
        • Lofqvist C.
        • Hansen-Pupp I.
        • Ramenghi L.A.
        • et al.
        IGF-1 as a drug for preterm infants: a step-wise clinical development.
        Curr Pharm Des. 2017; 23: 5964-5970
        • Murray P.G.
        • Clayton P.E.
        Endocrine control of growth.
        Am J Med Genet C Semin Med Genet. 2013; 163C: 76-85
        • Ng P.C.
        • Lam C.W.
        • Lee C.H.
        • Wong G.W.
        • Fok T.F.
        • Chan I.H.
        • et al.
        Leptin and metabolic hormones in preterm newborns.
        Arch Dis Child Fetal Neonatal Ed. 2000; 83: F198-F202
        • Hellström A.
        • Ley D.
        • Hansen-Pupp I.
        • Hallberg B.
        • Löfqvist C.
        • van Marter L.
        • et al.
        Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development.
        Acta Paediatr. 2016; 105: 576-586
        • Kajantie E.
        • Dunkel L.
        • Rutanen E.M.
        • Seppälä M
        • Koistinen R
        • Sarnesto A
        • et al.
        IGF-1, IGF binding protein (IGFBP)-3, phosphoisoforms of IGFBP-1, and postnatal growth in very low birth weight infants.
        J CIin Endocrinol Metab. 2002; 87: 2171-2179
        • Löfqvist C.
        • Engström E.
        • Sigurdsson J.
        • Hård A.L.
        • Niklasson A.
        • Ewald U.
        • et al.
        Postnatal head growth deficit among premature infants parallels retinopathy of prematurity and insulin-like growth factor-1 deficit.
        Pediatrics. 2006; 117: 1930-1938
        • Hansen-Pupp I.
        • Hövel H.
        • Hellström A.
        • Hellström-Westas L.
        • Löfqvist C.
        • Larsson E.M.
        • et al.
        Postnatal decrease in circulating insulin-like growth factor-I and low brain volumes in very preterm infants.
        J CIin Endorinol Metab. 2011; 96: 1129-1135
        • Pérez-Muñuzuri A.
        • Fernández-Lorenzo J.R.
        • Couce-Pico M.L.
        • Blanco-Teijeiro M.J.
        • Fraga-Bermúdez J.M.
        Serum levels of IGF1 are a useful predictor of retinopathy of prematurity.
        Acta Paediatr. 2010; 99: 519-525
        • Löfqvist C.
        • Hellgren G.
        • Niklasson A.
        • Engström E.
        • Ley D.
        • Hansen-Pupp I.
        • et al.
        Low postnatal serum IGF-I levels are associated with bronchopulmonary dysplasia (BPD).
        Acta Paediatr. 2012; 101: 1211-1216
        • Chanson P.
        • Arnoux A.
        • Mavromati M.
        • Brailly-Tabard S.
        • Massart C.
        • Young J.
        • et al.
        Reference values for IGF-I serum concentrations: comparison of six immunoassays.
        J Clin Endocrinol Metab. 2016; 101: 3450-3458
        • Frystyk J.
        • Freda P.
        • Clemmons D.R.
        The current status of IGF-I assays-A 2009 update.
        Growth Horm IGF Res. 2010; 20: 8-18
        • Blanc W.A.
        Pathology of the placenta, membranes and umbilical cord in bacterial, fungal and viral infections in man.
        Monogr Pathol. 1981; : 67-132
        • Fluss R.
        • Faraggi D.
        • Reiser B.
        Estimation of the Youden Index and its associated cutoff point.
        Biom J. 2005; 47: 458-472
        • Fowden A.L.
        The insulin-like growth factors and feto-placental growth.
        Placenta. 2003; 24: 803-812
        • Kadakia R.
        • Ma M.
        • Josefson J.L.
        Neonatal adiposity increases with rising cord blood IGF-1 levels.
        Clin Endocrinol (Oxf). 2016; 85: 70-75
        • Banjac L.
        • Kotur-Stevuljević J.
        • Gojković T.
        • Bokan-Mirković V.
        • Banjac G.
        • Banjac G.
        Relationship between insulin-like growth factor type 1 and intrauterine growth.
        Acta Clin Croat. 2020; 59: 91-96
        • Yumani D.F.J.
        • Calor A.K.
        • van Weissenbruch M.M.
        The course of IGF-1 levels and nutrient intake in extremely and very preterm infants during hospitalisation.
        Nutrients. 2020; 12: 675
        • Jensen A.K.
        • Ying G.S.
        • Huang J.
        • Quinn G.E.
        • Binenbaum G.
        Postnatal serum insulin-like growth factor I and retinopathy of prematurity.
        Retina. 2017; 37: 867-872
        • Liegl R.
        • Löfqvist C.
        • Hellström A.
        • Smith L.E.
        IGF-1 in retinopathy of prematurity, a CNS neurovascular disease.
        Early Hum Dev. 2016; 102: 13-19
        • Kim D.J.
        • Cho S.Y.
        • Kim S.U.
        • Jo D.W.
        • Hwang H.I.
        • Shin H.K.
        • et al.
        IGF-1 protects neurons in the cortex and subventricular zone in a periventricular leucomalacia model.
        In Vivo. 2012; 35: 307-312
        • Lin S.
        • Fan L.W.
        • Rhodes P.G.
        • Cai Z.
        Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats.
        Exp Neurol. 2009; 217: 361-370
        • Elis S.
        • Courtland H.W.
        • Wu Y.
        • Rosen C.J.
        • Sun H.
        • Jepsen K.J.
        • et al.
        Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1.
        J Bone Miner Res. 2010; 25: 1257-1266
        • Hellström A.
        • Ley D.
        • Hansen-Pupp I.
        • Hallberg B.
        • Ramenghi L.A.
        • Löfqvist C.
        • et al.
        Role of insulin like growth factor 1 in fetal development and in the early postnatal life of premature infants.
        Am J Perinatol. 2016; 33: 1067-1071
        • Klevebro S.
        • Hellgren G.
        • Hansen-Pupp I.
        • Wackernagel D.
        • Hallberg B.
        • Borg J.
        • et al.
        Elevated levels of IL-6 and IGFBP-1 predict low serum IGF-1 levels during continuous infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants.
        Growth Horm IGF Res. 2020; 50: 1-8