Abstract
Background
Intravitreal bevacizumab (IVB), an anti-vascular endothelial growth factor (VEGF) antibody, is a widely adopted treatment for retinopathy of prematurity (ROP). Although animal studies have demonstrated that IVB inhibits alveologenesis in neonatal rat lung, the clinical influence of IVB on respiratory outcomes has not been studied.
Research Question
Does IVB affect the respiratory outcome in preterm infants with bronchopulmonary dysplasia?
Study Design and Methods
We retrospectively assessed very low birth weight (VLBW) preterm infants admitted to our neonatal ICU between January 2016 and June 2021. Furthermore, we evaluated the short-term respiratory outcomes after IVB therapy in VLBW preterm infants requiring ventilatory support at 36 weeks’ postmenstrual age (PMA).
Results
One hundred seventy-four VLBW preterm infants with bronchopulmonary dysplasia were recruited. Eighty-eight infants showed ROP onset before being ventilator free, and 78 infants received a diagnosis of the most severe ROP before being ventilator free. Among them, 32 received a diagnosis with type 1 ROP and received IVB treatment. After adjusting for gestational age, birth body weight, and baseline respiratory status, we discovered that IVB is associated significantly with prolonged ventilatory support and a lower likelihood of becoming ventilator free (hazard ratio, 0.53; P = .03).
Interpretation
IVB may have a short-term respiratory adverse effect in patients requiring ventilatory support at 36 weeks’ PMA. Therefore, long-term follow-up for respiratory outcomes may be considered in VLBW infants who receive IVB treatment.
Key Words: bronchopulmonary dysplasia, intravitreal bevacizumab, retinopathy of prematurity, vascular endothelial growth factor
Graphical Abstract
Take-home Points.
Study Question: Does intravitreal bevacizumab (IVB) affect the respiratory outcome in preterm infants with bronchopulmonary dysplasia (BPD)?
Results: In the retrospective cohort study evaluating very low birth weight infants with retinopathy of prematurity and BPD, IVB was associated with prolonged ventilatory requirement and a decreased likelihood of achieving ventilator-free status.
Interpretation: IVB may influence preterm lung development, thereby prolonging ventilatory dependence.
FOR EDITORIAL COMMENT, SEE PAGE 1231
Retinopathy of prematurity (ROP) is a notable complication in premature infants and a leading cause of childhood blindness. An increasing prevalence of treatment-requiring ROP has been observed worldwide.1 Ludwig et al2 reported an increase in ROP incidence from 14.7% in 2000 to 19.9% in 2012 in the United States because of the improved survival of prematurity.
The treatment for ROP has evolved in recent years. Although laser photocoagulation has been the standard treatment for ROP,3 anti-vascular endothelial growth factor (VEGF) intravitreal injection emerged in 2007 as a new treatment method.4 Intravitreal bevacizumab (IVB), the most used intravitreal anti-VEGF agent, not only outperformed laser photocoagulation in patients with type 1 ROP with zone 1 disease, but also reduced refractive error and showed better short-term structural outcome and foveal development.4, 5, 6 Thus, IVB became another primary treatment option for type 1 ROP.7
However, regarding the use of IVB in preterm infants, some concerns about its detrimental effects on developing organs exist. Researchers have discussed its effect on the visual outcome and systemic side effects, such as hypotension and neurodevelopmental impairment.8,9 Additionally, previous pharmacokinetic studies have reported detectable serum bevacizumab levels and suppressed serum VEGF levels 2 months after IVB treatment.10,11 Nevertheless, the potential side effects of IVB on respiratory outcomes have been discussed rarely.
Bronchopulmonary dysplasia (BPD) is characterized by a disruption of alveolar development resulting from complex interactions of perinatal factors.12,13 Among the multifactorial mechanisms, disruption of angiogenesis, which results in impaired pulmonary vascular growth, is one of the main contributing factors.14,15 VEGF signaling is crucial to lung development. Several animal studies have shown that inhibiting VEGF signaling results in abnormal pulmonary vascular growth and impaired alveolarization.16,17 Additionally, recent animal studies claimed that IVB could penetrate the blood-ocular barrier and could affect neonatal lung development.18,19 The clinical implications of these animal studies warrant further investigation.
This study aimed to evaluate the impact of IVB on respiratory outcomes in very low birth weight preterm infants requiring ventilatory support at 36 weeks’ postmenstrual age (PMA). We hypothesized that IVB adversely affects pulmonary maturation, leading to prolonged ventilatory support.
Study Design and Methods
Study Participants
This was a single-center, retrospective cohort study performed on infants younger than 31 weeks’ gestational age (GA), birth body weight (BBW) of ≤ 1,500 g, admitted to the neonatal ICU at the National Taiwan University Hospital between January 2016 and June 2021. The infants enrolled required ventilatory support, either noninvasive respiratory support (including nasal CPAP [NCPAP] and nasal intermittent positive pressure ventilation [NIPPV]) or invasive mechanical ventilation (such as conventional ventilator or high-frequency oscillatory ventilation) at 36 weeks’ PMA. A high-flow nasal cannula was not used during the admission courses because it was not covered by the National Health Insurance in Taiwan. The exclusion criteria included chromosome anomalies, congenital anomalies, infants who received ROP treatment other than IVB, and infants who were weaned off ventilatory support before ROP onset. Furthermore, those who could not be evaluated for respiratory status at 36 weeks’ PMA, such as those with incomplete medical records or those receiving recurrent intubation unrelated to preterm complications, were excluded. The study was approved by the institutional review board of the National Taiwan University Hospital (Identifier: 202112112RINB). This research adhered to the tenets of the Declaration of Helsinki.
Ventilator Weaning Strategy
Infants were extubated from a mechanical ventilator to NIPPV with appropriately sized binasal prongs. Fio2 was set as low as possible to keep oxygen saturation at > 90%. If NIPPV fails and respiratory acidosis or high oxygen demand (Fio2 ≥ 0.6) with dyspnea develop, reintubation is required.
If an infant properly tolerates NIPPV, the ventilator breath rate is reduced gradually until shifting to NCPAP. The positive end-expiratory pressure of NCPAP is set to 5 cm H2O and increases to 7 cm H2O if needed, according to the work of breathing. Concerning the toxicity of oxygen, Fio2 is tapered down to 0.21 before withdrawing positive end-expiratory pressure. If an infant is receiving NCPAP of 5 cm H2O with an Fio2 of 0.21 and has been clinically stable for 2 consecutive days, then an interval training for the withdrawal of NCPAP is initiated.
Ventilator-free status is achieved if an infant tolerates this well without resuming NCPAP. However, if an infant cannot be weaned off ventilatory support at 1 month corrected age, and no need exists for other in-hospital medical care, the doctors discuss with the parents a discharge plan with a home ventilator, including bilevel positive airway pressure or high-flow nasal cannula, owing to the importance of the golden time of an infant's neurodevelopment by social interaction at home.
ROP Examination and Treatment
The ROP screening criteria in our hospital follows the recommendation of the American Academy of Ophthalmology, which include (1) infants with GA younger than 31 weeks, (2) BBW of ≤ 1,500 g, or (3) selected infants with an older GA and a higher BBW, but with an unstable clinical course (as defined by the attending neonatologist).20 We also complied with the recommended ROP screening schedule. The indications for ROP treatment (type 1 ROP) are the criteria established by the Early Treatment for Retinopathy of Prematurity Study.3 The first-line treatment for type 1 ROP in the study cohort was IVB injection; however, written informed consent was obtained from the parents after a thorough discussion of treatment options, including both laser photocoagulation and IVB.
An experienced retina specialist performed the ROP examination and treatment procedure. The IVB treatment included injecting 0.625 mg (0.025 mL) bevacizumab intravitreally via the pars plicata within 72 h of detection. Patients with type 1 ROP who received only IVB treatment were enrolled as the study group. Those with any stage of ROP except type 1 ROP and who did not receive any treatment were registered as the control group.
Outcome Variables
Clinical characteristics, neonatal morbidities, risk factors for poor respiratory outcomes, timing of ROP onset and progression, and respiratory status at different time points were collected via a retrospective chart review. ROP onset was defined as the first time an ophthalmologist detected ROP. The most severe ROP was defined as the first time the most severe ROP was detected, regardless of the staging. Ventilator-free status denoted that an infant no longer required ventilatory support. Time from ROP event to ventilator-free status was defined as the period from the ROP event until ventilator-free status was achieved, death, or discharge from the hospital, whichever occurred first.21, 22, 23
Respiratory distress syndrome was defined by clinical diagnosis and requirement of surfactant therapy. Patent ductus arteriosus was defined as hemodynamically significant patent ductus arteriosus requiring any kind of treatment. Intraventricular hemorrhage was defined as moderate to severe intraventricular hemorrhage (grades 3 or 4 based on Papile’s classification).24 Necrotizing enterocolitis was defined as necrotizing enterocolitis beyond Bell’s stage 2. Sepsis was defined as a clinical symptom after positive blood culture results. We recorded the status of these preterm morbidities before the onset of ROP events.
The classification of respiratory status was based on the bronchopulmonary dysplasia grading in the 2018 National Institute of Child Health and Human Development definition.25 When combined, the respiratory status grades 2 and 3 represented not only higher respiratory severity, but also oxygen dependence at a given time.
Statistical Analysis
Continuous variables were compared using the Mann-Whitney U test and are presented as median (interquartile range), whereas categorical variables were compared using the χ2 test and are presented as number (percentage). The Kaplan-Meier plot, log-rank test, and Cox proportional hazard regression were applied to the survival analysis for the prediction of ventilator-free status in this study. For multivariate regression model building, candidate variables were selected according to the literature or the significant differences between the study and control groups. Then, univariate prescreening with P < .1 identified covariates that could be added to the multivariate regression. Multicollinearity was checked by a variance inflation factor, and variance inflation factor of < 3 indicated the absence of collinearity. Harrell’s C-index represented the goodness-of-fit measure for a regression model. A C-index value of > 0.7 indicates a good model. The proportional hazard assumption was confirmed by Schoenfield’s residuals. Statistical analyses were performed using MedCalc version 18.6 software (MedCalc Software) and STATA version 14.0 software (StataCorp LP). A P value of < .05 was regarded as statistically significant.
Results
During the study period, 187 preterm infants with GA younger than 31 weeks, BBW of ≤ 1,500 g, and dependent on a ventilator at 36 weeks’ PMA were admitted to the neonatal ICU. One hundred seventy-four preterm infants were included in the analysis. Among them, 71 infants (41%) did not have a diagnosis of ROP, 69 infants (40%) had a diagnosis of any stage of ROP except type 1 ROP and did not receive any treatment, and 34 infants (19%) had a diagnosis of type 1 ROP and received IVB treatment. Two infants were excluded from the IVB study group because IVB was performed after the infant achieved ventilator-free status; thus, 32 infants with IVB entered the final analysis. In the ROP control group, 56 infants demonstrated ROP onset before achieving ventilator-free status, and 46 infants received a diagnosis of the most severe ROP before achieving ventilator-free status (Fig 1). The event timeline is illustrated in Figure 2.
Figure 1.
Diagram showing patient enrollment algorithm. IVB = intravitreal bevacizumab; ROP = retinopathy of prematurity.
Figure 2.
Event timeline of the study (ROP with IVB) and control (ROP without IVB) groups. IVB = intravitreal bevacizumab; ROP = retinopathy of prematurity.
Infants With ROP Onset Before Achieving Ventilator-Free Status
Comparing infants with ROP onset before achieving ventilator-free status, no significant differences were found between the IVB study group (n = 32) and the ROP control group (n = 56) regarding the baseline characteristics, except for GA and baseline respiratory status (Table 1). The IVB group had a significantly lower GA (25.4 weeks; P = .003) and a poorer baseline respiratory status (P = .01). Although PMA at ROP onset was not significantly different between the two groups, the IVB group had higher PMA at the time of achieving ventilator-free status (49.5 vs 42.1 weeks; P = .001), higher PMA at discharge (51.4 weeks vs 45.1 weeks; P = .002), and longer hospitalization (180 vs 127.5 days; P < .001).
Table 1.
Comparison of Patients With ROP Onset Before Achieving Ventilator-Free Status With or Without IVB Treatment
| Variable | ROP With IVB Before Achieving Ventilator-Free Status (n = 32) | ROP Onset Before Achieving Ventilator-Free Status (n = 56) | P Value |
|---|---|---|---|
| Characteristics | |||
| GA, wka | 25.4 (24.4-26.5) | 26.3 (25.4-28.1) | .003 |
| BBW, ga | 675 (613-813) | 719.5 (637-839) | .20 |
| CSb | 23 (71.9) | 44 (78.6) | .48 |
| Male sexb | 17 (53.1) | 25 (44.6) | .08 |
| SGAb | 8 (25) | 24 (42.9) | .10 |
| Multibirthb | 12 (37.5) | 15 (26.8) | .11 |
| Prenatal steroidb | 29 (90.6) | 53 (94.6) | .40 |
| Chorioamnionitisb | 8 (25) | 11 (19.6) | .56 |
| RDSb | 16 (50) | 26 (46.4) | .75 |
| PDAb | 24 (75) | 37 (66.1) | .39 |
| IVHb | 7 (21.9) | 5 (8.9) | .09 |
| NECb | 2 (6.3) | 2 (3.6) | .56 |
| Sepsisb | 4 (12.5) | 11 (19.6) | .39 |
| PMA at ROP onset, wka | 34.1 (33.1-35.8) | 35.1 (33.4-37.2) | .11 |
| Respiratory status at ROP onsetb | .01 | ||
| Grade 1 | 5 (15.6) | 26 (46.4) | |
| Grade 2 | 17 (53.1) | 19 (33.9) | |
| Grade 3 | 10 (31.3) | 11 (19.6) | |
| Outcomes | |||
| PMA at ventilator-free status, wka | 49.5 (43.4-54.6) | 42.1 (39.7-48.6) | .001 |
| PMA at discharge, wka | 51.4 (46.5-56.9) | 45.1 (41.4-50.9) | .002 |
| Hospitalization, da | 180 (147-220) | 127.5 (101-163) | < .001 |
Data are presented as No. (%) or median (interquartile range). BBW = birth body weight; CS = caesarean section; GA = gestational age; IVB = intravitreal bevacizumab; IVH = intraventricular hemorrhage; NEC = necrotizing enterocolitis; PDA = patent ductus arteriosus; PMA = postmenstrual age; RDS = respiratory distress syndrome; ROP = retinopathy of prematurity; SGA = small for gestational age.
P value assessed using the Mann-Whitney U test.
P value assessed using the χ2 test.
The Kaplan-Meier plot analysis with a log-rank test revealed a lower probability of achieving ventilator-free status in the IVB group than in the control group (P = .001) (Fig 3). Multivariate Cox’s proportional hazard regression with ventilator-free status as the dependent variable demonstrated that IVB (adjusted hazard ratio [HR], 0.44; P = .004), BBW (adjusted HR, 1.00; P < .001), chorioamnionitis (adjusted HR, 0.33; P = .003), and baseline more than grade 2 respiratory status (adjusted HR, 0.48; P = .01) were independently related (Table 2). Harrell’s C-index of the multivariate model was 0.78 (95% CI, 0.73-0.83).
Figure 3.
Kaplan-Meier plot showing event time distribution from ROP onset to ventilator-free status. The probability of achieving ventilator-free status was significantly lower in patients with ROP with IVB (P = .001, log-rank test). IVB = intravitreal bevacizumab; ROP = retinopathy of prematurity.
Table 2.
Predictors of Achieving Ventilator-Free Status in Patients With ROP Onset Before Achieving Ventilator-Free Status
| Variable | Univariate |
Multivariate |
|||
|---|---|---|---|---|---|
| HR | P Value | HR | 95% CI | P Value | |
| IVB, yes or no | 0.43 | .001 | 0.44 | 0.25-0.78 | .004 |
| GA | 1.33 | < .001 | 1.02 | 0.87-1.18 | .82 |
| BBW | 1.00 | < .001 | 1.00 | 1.00-1.01 | < .001 |
| SGA, yes or no | 1.07 | .79 | . . . | . . . | . . . |
| Prenatal steroid, yes or no | 1.02 | .97 | . . . | . . . | . . . |
| Chorioamnionitis, yes or no | 0.39 | .005 | 0.33 | 0.16-0.68 | .003 |
| RDS, yes or no | 0.82 | .40 | . . . | . . . | . . . |
| PDA, yes or no | 0.71 | .19 | . . . | . . . | . . . |
| NEC, yes or no | 0.63 | .44 | . . . | . . . | . . . |
| Sepsis, yes or no | 0.66 | .21 | . . . | . . . | . . . |
| Respiratory status grade 2 and 3 at ROP onset, 2+3/1 | 0.27 | < .001 | 0.48 | 0.27-0.84 | .01 |
HR and P value assessed by Cox’s proportional hazard analysis. BBW = birth body weight; GA = gestational age; HR = hazard ratio; IVB = intravitreal bevacizumab; NEC = necrotizing enterocolitis; PDA = patent ductus arteriosus; RDS = respiratory distress syndrome; ROP = retinopathy of prematurity; SGA = small for gestational age.
Infants With the Most Severe ROP Diagnosed Before Achieving Ventilator-Free Status
Additionally, to compare infants with the most severe ROP diagnosed before achieving ventilator-free status, the IVB group (n = 32) still had a significantly lower GA than the ROP control group (n = 46), whereas the other baseline characteristics were similar (Table 3). At the time of IVB administration, 18 infants (56%) had respiratory status grade 1, nine infants (28%) had grade 2 respiratory status, and five infants (16%) had respiratory status grade 3. The median PMA of IVB was 38.5 weeks (interquartile range, 36.4-41.0 weeks). Compared with the most severe ROP control group, the IVB group had higher PMA at the time of achieving ventilator-free status (49.5 weeks vs 43.1 weeks; P = .01), higher PMA at discharge (51.4 weeks vs 45.4 weeks; P = .007), and longer hospitalization (180 days vs 132 days; P = .002).
Table 3.
Comparison of Patients With the Most Severe ROP Detected Before Achieving Ventilator-Free Status With or Without IVB Treatment
| Variable | ROP With IVB Before Achieving Ventilator-Free Status (n = 32) | Most Severe ROP Before Achieving Ventilator-Free Status (n = 46) | P Value |
|---|---|---|---|
| Characteristics | |||
| GA, wka | 25.4 (24.4-26.5) | 26.6 (25.3-28.1) | .004 |
| BBW, ga | 675 (613-813) | 709.5 (648-850) | .24 |
| CSb | 23 (71.9) | 35 (62.5) | .68 |
| Male sexb | 17 (53.1) | 19 (33.9) | .31 |
| SGAb | 8 (25.0) | 21 (37.5) | .07 |
| Multibirthb | 12 (37.5) | 12 (21.4) | .29 |
| Prenatal steroidb | 29 (90.6) | 43 (76.8) | .48 |
| Chorioamnionitisb | 8 (25.0) | 9 (16.1) | .57 |
| RDSb | 16 (50.0) | 23 (41.1) | 1.00 |
| PDAb | 24 (75.0) | 29 (51.8) | .27 |
| IVHb | 7 (21.9) | 5 (8.9) | .19 |
| NECb | 2 (6.3) | 1 (1.8) | .36 |
| Sepsisb | 4 (12.5) | 9 (16.1) | .41 |
| PMA at the most severe ROP, wka | 38.5 (36.4-41.0) | 37.6 (34.7-40.6) | .17 |
| Respiratory status at the most severe ROPb | .44 | ||
| Grade 1 | 18 (56.25) | 32 (57.1) | . . . |
| Grade 2 | 9 (28.13) | 10 (21.74) | . . . |
| Grade 3 | 5 (15.63) | 4 (8.70) | . . . |
| Outcomes | |||
| PMA at ventilator-free status, wka | 49.5 (43.4-54.6) | 43.1 (39.8-50.6) | .01 |
| PMA at discharge, wka | 51.4 (46.5-56.9) | 45.4 (41.9-52.7) | .007 |
| Hospitalization, da | 180 (147-220) | 132 (99-178) | .002 |
Data are presented as No. (%) or median (interquartile range). BBW = birth body weight; CS = caesarean section; GA = gestational age; IVB = intravitreal bevacizumab; IVH = intraventricular hemorrhage; NEC = necrotizing enterocolitis; PDA = patent ductus arteriosus; PMA = postmenstrual age; RDS = respiratory distress syndrome; ROP = retinopathy of prematurity; SGA = small for gestational age.
P value assessed using the Mann-Whitney U test.
P value assessed using the χ2 test.
The Kaplan-Meier plot analysis with a log-rank test revealed that the possibility of achieving ventilator-free status in the IVB group also was significantly lower than in the control group (P = .02) (Fig 4). However, after adjusting for GA, BBW, maternal chorioamnionitis, sepsis, and baseline respiratory status grades 2 and 3, IVB remained a significant predictor of achieving ventilator-free status (adjusted HR, 0.53; P = .03) (Table 4) in the multivariate regression model, whose Harrell’s C-index was 0.76 (95% CI, 0.71-0.82).
Figure 4.
Kaplan-Meier plot showing event time distribution from the most severe ROP to ventilator-free status. The probability of achieving ventilator-free status was significantly lower in patients with ROP with IVB (P = .02, log-rank test). IVB = intravitreal bevacizumab; ROP = retinopathy of prematurity.
Table 4.
Predictors of Achieving Ventilator-Free Status in Patients With the Most Severe ROP Diagnosed Before Achieving Ventilator-Free Status
| Variable | Univariate |
Multivariate |
|||
|---|---|---|---|---|---|
| HR | P Value | HR | 95% CI | P Value | |
| IVB, yes or no | 0.54 | .02 | 0.53 | 0.29-0.95 | .03 |
| GA | 1.28 | < .001 | 0.96 | 0.81-1.13 | .62 |
| BBW | 1.00 | < .001 | 1.00 | 1.00-1.01 | < .001 |
| SGA, yes or no | 1.08 | .76 | . . . | . . . | . . . |
| Prenatal steroid, yes or no | 0.85 | .75 | . . . | . . . | . . . |
| Chorioamnionitis, yes or no | 0.35 | .004 | 0.31 | 0.14-0.67 | .003 |
| RDS, yes or no | 0.88 | .61 | . . . | . . . | . . . |
| PDA, yes or no | 0.77 | .35 | . . . | . . . | . . . |
| NEC, yes or no | 0.47 | .30 | . . . | . . . | . . . |
| Sepsis, yes or no | 0.47 | .047 | 0.58 | 0.25-1.32 | .19 |
| Respiratory status grade 2 and 3 at the most severe ROP, 2+3/1 | 0.30 | < .001 | 0.31 | 0.17-0.59 | < .001 |
Hazard ratio and P value were assessed by Cox’s proportional hazard analysis. BBW = birth body weight; GA = gestational age; HR = hazard ratio; IVB = intravitreal bevacizumab; NEC = necrotizing enterocolitis; PDA = patent ductus arteriosus; RDS = respiratory distress syndrome; ROP = retinopathy of prematurity; SGA = small for gestational age.
To evaluate the impact of IVB injection timing further, we divided the infants with IVB based on the median timing of IVB (PMA, 38.5 weeks) into two groups: early and late IVB. The time from IVB to achieving ventilator-free status was not significantly different between the two groups (58.5 days vs 65.5 days; P = .85).
Discussion
Our results suggested that IVB is associated with prolonged ventilatory support and a lower possibility of achieving ventilator-free status after adjusting for GA, BBW, and baseline respiratory status. Consistent with previous reports, chorioamnionitis and sepsis are the other significant risk factors for prolonged ventilator dependence.13,26
Bevacizumab, a monoclonal antibody that inhibits VEGF, frequently is used by oncologists and ophthalmologists to treat vascular-related disorders. Nevertheless, numerous bevacizumab-related adverse effects have been reported, including epistaxis, headache, hypotension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.27 Additionally, rare but life-threatening pulmonary hemorrhage has been reported in patients with cancer after systemic administration of bevacizumab, as well as in ocular conditions after intravitreal injection.28,29 Therefore, an individualized risk to benefit assessment was recommended for patients with lung cancer before receiving bevacizumab by expert consensus.30 In adult patients, IVB is associated with risks of high BP, cerebrovascular accidents, myocardial infarction, cutaneous lupus erythematosus, and acneiform eruption.31,32
Hypotension and abnormal liver function have been reported in preterm infants with ROP after IVB.8,33 Moreover, much attention has been paid to the neurodevelopmental outcomes in IVB-treated preterm infants concerning the systemic effect of VEGF suppression.9 Tsai et al34 conducted a meta-analysis and concluded that, except for minor differences in motor performance, IVB does not significantly increase the risk of severe neurodevelopmental impairment or cerebral palsy. Because of concerns about systemic side effects, the Pediatric Eye Disease Investigator Group conducted a dose de-escalation study of IVB and discovered that 0.004 mg may be the lowest dose effective for ROP.35 Recently, the group demonstrated that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF level 4 weeks after IVB administration.36
In parallel with improved survival of extremely preterm infants, BPD predisposed the survivors to cardiorespiratory morbidity and neurodevelopmental impairment, as well as increasing the cost of health care resources.37, 38, 39, 40, 41 Early detection, either via chest or cardiac echocardiography, had been studied for further individualized respiratory care.42, 43, 44, 45 The phenotype of BPD evolved from a fibrocystic disease secondary to ventilator trauma and oxygen injury to impairment of parenchymal development and pulmonary vascular growth dysregulation.15,46,47
Previous clinical studies have supported the essential role of VEGF in BPD development.10,48,49 The effect of anti-VEGF agents in immature lungs was explored previously in preclinical studies. Le Cras et al17 reported that treating newborn rats with systemic Su-5416, an anti-VEGF agent, impaired pulmonary vascular growth and postnatal alveolarization. Additionally, Valencia et al19 showed that intravitreal anti-VEGF injection alters type IV collagenase and exaggerates arrested alveologenesis in neonatal rats. A recent animal study performed by Duggan et al18 also reported altered lung biomarkers of angiogenesis, thus resulting in pulmonary hemorrhage and sequelae. These studies supported our findings that IVB treatment of ROP may be associated with short-term poor respiratory outcomes in very low birth weight preterm infants with BPD.
Previous analysis of the systemic effects of IVB demonstrated suppressed serum VEGF levels for at least 2 months afterward.10,11 Animal studies investigating the pulmonary effect of IVB in neonatal rats discovered altered lung biomarkers of angiogenesis and damaged tissue structure, similar to the histologic changes observed in bronchopulmonary dysplasia.18,19 IVB treatment may prolong ventilatory support dependence by suppressing serum VEGF, thereby altering lung angiogenesis in preterm infants.
To the best of our knowledge, this is the first clinical evidence showing that intravitreal anti-VEGF agents may influence lung development in preterm infants with BPD. Our study helps to extrapolate the results of controlled animal studies to the complex and multifactorial human experience. More importantly, despite its benefits for ROP, the potential adverse effect of IVB on lung maturation should be considered.
We acknowledge some limitations in this study. First, we were unable to enroll patients with type 1 ROP without any treatment as the control group because all patients with type 1 ROP received treatment in our hospital. As a result, we could not differentiate whether prolonged ventilator requirement was the result of type 1 ROP alone or type 1 ROP with IVB in this cohort study. However, after performing multivariate regression analysis, we discovered that IVB remained a significant independent risk factor. In addition, the adverse respiratory effect occurred after IVB treatment, when type 1 ROP was in resolution, implying that the prolonged ventilatory dependence is more likely attributed to IVB.
Alternatively, patients with ROP who received laser photocoagulation could have been another option for the control group, but most of these patients were born more than 1 decade ago, which was a different epoch in preterm and BPD management. Second, this single-center retrospective cohort study had a relatively small study population. In addition, serum bevacizumab or VEGF levels cannot be determined retrospectively. Further large-scale, multicenter prospective cohort studies with an adequate sample size should be conducted to confirm the current findings. Third, we studied only short-term respiratory outcomes during the initial hospitalization; thus, future long-term follow-up for respiratory outcomes with appropriate clinical scores50 is warranted.
Interpretation
In conclusion, this study suggests that IVB may prolong ventilatory support requirement in preterm infants with BPD. However, as with all medical therapies, the clinician should consider the risk to benefit ratio before using IVB in neonates, especially those with BPD and refractory ROP considering multiple IVB treatments.
Acknowledgments
Author contributions: P.-N. T. takes responsibility for the content of the manuscript. C.-Y. H. conceptualized and designed the study, collected data, conducted the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript. M.-H. C. supervised the statistical analysis and critically reviewed the manuscript. H.-C. H., H.-C. C., C.-Y. C., and T.-A. Y. coordinated and supervised data collection and critically reviewed the manuscript. T.-T. L. contributed to ROP diagnosis and treatment and critically reviewed the manuscript. W. V. C. critically reviewed and revised the manuscript for important intellectual content. P.-N. T. conceptualized and designed the study, conducted the initial analyses, supervised the study, and reviewed and revised the manuscript.
Financial/nonfinancial disclosures: None declared.
Funding/support: This study is funded by the National Taiwan University Hospital [Grant NTUH.110-T15] and the Ministry of Science and Technology [Grant MOST 108-2314-B-002-155-MY3].
Role of sponsors: The funding organization had no role in the design or conduct of this research.
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