Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial.

OBJECTIVE: This study evaluates the 24-month follow-up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial. STUDY DESIGN: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score <85, moderate or severe cerebral palsy, blindness, or hearing loss that prevents communication despite amplification were assessed. RESULTS: Primary outcome was determined for 605/638 (95%). The mean gestational age was 25.8 ± 1.3 weeks and mean birthweight was 805 ± 192 g. Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40). CONCLUSIONS: Treatment group did not affect the risk of death or survival with moderate/severe NDI. Despite early termination, this study represents the largest RCT of extremely preterm infants treated with myo-inositol with neurodevelopmental outcome data.

Secondary 12-Month Ocular Outcomes of a Phase 1 Dosing Study of Bevacizumab for Retinopathy of Prematurity.

Importance: Lower bevacizumab dosages are being used for type 1 retinopathy of prematurity, but there are limited data on long-term ocular outcomes with lower doses. Objective: To evaluate ocular outcomes at 12 months' corrected age for eyes that received a dose of 0.625 mg, 0.25 mg, 0.125 mg, 0.063 mg, or 0.031 mg of bevacizumab for type 1 retinopathy of prematurity. Design, Setting, and Participants: This prospective cohort study used a masked, multicenter, phase 1 dose de-escalation study design and was conducted from April 2016 to October 2017. Study eyes were treated with a dose of 0.25, 0.125, 0.063, or 0.031 mg of bevacizumab; fellow eyes were treated with a dosage 1 level higher than the study eye. Additional treatment after 4 weeks was at investigator discretion. Data analysis occurred from November 2018 to March 2019. Interventions: Intravitreous bevacizumab injections of 0.625 mg to 0.031 mg. Main Outcomes and Measures: Visual fixation, amblyopia, alignment, nystagmus, cycloplegic refraction, and ocular examinations were assessed at 12 months' corrected age as preplanned secondary outcomes. The primary outcome 4 weeks after treatment and secondary outcomes after 6 months' corrected age have been previously reported. Results: Forty-six of 61 infants (75%) had a 12-month follow-up examination (46 study eyes and 43 fellow eyes; median [interquartile range] birth weight, 650 [590-760] g). Of 87 eyes with a cycloplegic refraction, 12 (14% [95% CI, 7%-27%]) had myopia of more than -5.00 D spherical equivalent; 2 (2%; [95% CI, 0%-8%]) had hyperopia greater than 5.00 D spherical equivalent; and 5 infants (11% [95% CI, 4%-24%]) had anisometropia greater than 1.50 D spherical equivalent. Abnormalities of the cornea, lens, or anterior segment were reported in 1 eye (1% [95% CI, 0%-6%]), 3 eyes (3% [95% CI, 1%-10%]), and 3 eyes (3% [95% CI, 1%-10%]), respectively. Optic nerve atrophy was identified in 11 eyes (13% [95% CI, 6%-26%]), and 1 eye (1% [95% CI, 0%-6%]) had total retinal detachment. Strabismus was reported in 13 infants (30% [95% CI, 17%-45%]), manifest nystagmus in 7 infants (15% [95% CI, 6%-29%]), and amblyopia in 3 infants (7% [95% CI, 1%-18%]). Overall, 98% of infants had central fixation in each eye (44 of 45 eyes). Conclusions and Relevance: In this study of low-dose bevacizumab, the secondary outcomes of high myopia, strabismus, retinal detachment, nystagmus, and other ocular abnormalities at 1 year were consistent with rates reported in other studies with higher dosages. Trial Registration: ClinicalTrials.gov identifier: NCT02390531.

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks' Gestational Age: A Randomized Clinical Trial.

Importance: Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. Objective: To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age. Design, Setting, and Participants: Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. Interventions: A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks. Main Outcomes and Measures: Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP. Results: Among 638 infants (mean, 26 weeks' gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks' postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%). Conclusions and Relevance: Among premature infants younger than 28 weeks' gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

Comparison of strategies for grading retinal images of premature infants for referral warranted retinopathy of prematurity.

PURPOSE: To determine the accuracy of identifying referral-warranted retinopathy of prematurity (RW-ROP, defined as any zone I ROP, stage 3 or worse, or plus disease) from retinal image sets using three grading protocols: a single optic disk-centered image, a set of 3 horizontal images, and a 5-image set. METHODS: In this secondary analysis of images from the e-ROP study, a weighted sample of 250 image sets from 250 infants (125 with RW-ROP and 125 without RW-ROP) was randomly selected. The sensitivities and specificities for detecting RW-ROP and its components from a single disk center image, along with nasal and temporal retinal images, were calculated and compared with the e-ROP grading of RW-ROP of all 5 retinal images (disk center and nasal, temporal, superior, and inferior retinal images). RESULTS: RW-ROP was identified with a sensitivity of 11.2% (95% CI, 6.79%-17.9%) using a single disk center image, with a sensitivity of 70.4% (95% CI, 61.9%-77.9%) using 3 horizontal images, and a statistically higher sensitivity of 82.4% (95% CI, 75.0%-89.0%) using all 5 images (P = 0.002). The specificities were 100%, 86.4%, and 90.4%, respectively. For grading using 3 horizontal images, sensitivity was 14.3% for plus disease, 25% for zone I ROP, and 71.2% for stage 3 or worse compared to 40.8%, 50%, and 79.8% for grading using 5-image sets, respectively. CONCLUSIONS: Both a single, disk-centered, posterior pole image and 3 horizontal images were less effective than a 5-image set in determining the presence of RW-ROP on qualitative grading by trained readers.

Correlation of recognition visual acuity with posterior retinal structure in advanced retinopathy of prematurity.

OBJECTIVE: To compare Early Treatment Diabetic Retinopathy Study visual acuity outcome with retinal structural outcome at the 6-year follow-up examination of infants randomized in the Early Treatment for Retinopathy of Prematurity study. METHODS: We compared the results in 606 eyes of subjects in whom both functional (visual acuity) and retinal structural assessments were obtained at age 6 years. Visual acuity assessments were performed by masked testers,and retinal examinations were performed by certified ophthalmologists. MAIN OUTCOME MEASURES: Visual acuity and retinal structure at age 6 years. RESULTS: Concordant outcomes occurred in 462 eyes(76.2%): 402 eyes had favorable functional and structural outcomes and 60 eyes had unfavorable functional and structural outcomes. Discordant outcomes occurred in 92 eyes (15.2%): 86 eyes had unfavorable functional and favorable structural outcomes and 6 eyes had favorable functional and unfavorable structural outcomes.Of the 86 eyes with unfavorable functional and favorable structural outcomes, 43 had optic atrophy (23 eyes) and/or retinal abnormalities that were less severe than those considered to be unfavorable (32 eyes). In 52 eyes (8.6%), retinal structure could not be assessed or the visual acuity was untestable. CONCLUSION: Posterior pole appearance correlates well with visual acuity in 6-year-old infants with a history of advanced retinopathy of prematurity.

Glaucoma in the Early Treatment for Retinopathy of Prematurity (ETROP) study.

PURPOSE: To report the clinical characteristics of infants with severe retinopathy of prematurity (ROP) and glaucoma-based on review of the Early Treatment for Retinopathy of Prematurity (ETROP) study. METHODS: All infants randomized in the ETROP trial were included. Each infant developed high-risk prethreshold ROP in at least one eye. Infants were examined until 6 years postnatal age. The following data were collected: corneal clarity, depth of the anterior chamber, status of the optic nerve and cup/disk ratio, retinal structure, and visual acuity. The diagnosis of glaucoma was based on the investigators best clinical judgment. All infants diagnosed with glaucoma were included in the study. RESULTS: A total of 12 of 718 eyes (1.67%) were diagnosed with glaucoma. Of these, 5 were first reported as having glaucoma at 9 months, 2 at 2 years, 1 each at 3 and 4 years, and 3 at 5 years. The anterior segment was shallow in 7 eyes. Three eyes had normal retinal structure, 1 had macular dragging, and 8 had retinal detachments involving the fovea (stage 4B or worse). At the 6-year follow-up examination only one eye with glaucoma had measurable vision. CONCLUSIONS: Although earlier treatment of significant ROP has resulted in better retinal structure and visual acuity outcomes, nearly 2% of the eyes with high-risk prethreshold ROP developed glaucoma at some point during the first 6 years of life.

Correlation of recognition visual acuity with posterior retinal structure in advanced retinopathy of prematurity.

OBJECTIVE To compare Early Treatment Diabetic Retinopathy Study visual acuity outcome with retinal structural outcome at the 6-year follow-up examination of infants randomized in the Early Treatment for Retinopathy of Prematurity study. METHODS We compared the results in 606 eyes of subjects in whom both functional (visual acuity) and retinal structural assessments were obtained at age 6 years. Visual acuity assessments were performed by masked testers, and retinal examinations were performed by certified ophthalmologists. MAIN OUTCOME MEASURES Visual acuity and retinal structure at age 6 years. RESULTS Concordant outcomes occurred in 462 eyes (76.2%): 402 eyes had favorable functional and structural outcomes and 60 eyes had unfavorable functional and structural outcomes. Discordant outcomes occurred in 92 eyes (15.2%): 86 eyes had unfavorable functional and favorable structural outcomes and 6 eyes had favorable functional and unfavorable structural outcomes. Of the 86 eyes with unfavorable functional and favorable structural outcomes, 43 had optic atrophy (23 eyes) and/or retinal abnormalities that were less severe than those considered to be unfavorable (32 eyes). In 52 eyes (8.6%), retinal structure could not be assessed or the visual acuity was untestable. CONCLUSION Posterior pole appearance correlates well with visual acuity in 6-year-old infants with a history of advanced retinopathy of prematurity. APPLICATION TO CLINICAL PRACTICE When the retinal structure is normal but visual acuity is poor in infants with a history of severe retinopathy of prematurity, other diagnoses such as optic atrophy and cortical visual impairment could at least partially account for the discrepancy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00027222.

Prevalence and course of strabismus through age 6 years in participants of the Early Treatment for Retinopathy of Prematurity randomized trial.

PURPOSE: To present strabismus data for children who participated in the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. METHODS: The prevalence of strabismus, categorized as present or absent, was tabulated for all children with history of high-risk prethreshold retinopathy of prematurity (ROP) who participated in the ETROP randomized trial and were examined at 9 months to 6 years of age. Relationships among strabismus and demographic measures, eye characteristics, and neurodevelopmental factors were analyzed. RESULTS: Among the 342 children evaluated at 6 years, the prevalence of strabismus was 42.2%. Even with favorable acuity scores in both eyes, the prevalence of strabismus was 25.4%, and with favorable structural outcomes in both eyes the prevalence of strabismus was 34.2%. Of children categorized as visually impaired as the result of either ocular or cerebral causes, 80% were strabismic at the 6-year examination. Of 103 study participants who were strabismic at 9 months, 77 (74.8%) remained so at 6 years. Most strabismus was constant at both the 9-month (62.7%) and the 6-year examination (72.3%). After multiple logistic regression analysis, risk factors for strabismus were abnormal fixation behavior in one or both eyes (P < 0.001), history of amblyopia (P < 0.003), unfavorable structural outcome in one or both eyes (P = 0.025), and history of anisometropia (P = 0.04). Strabismus surgery was performed for 53 children. By 6 years, the cumulative prevalence of strabismus was 59.4%. CONCLUSIONS: Most children with a history of high-risk prethreshold ROP develop strabismus at some time during the first 6 years of life.

The effect of surgical preparation technique on the bacterial load of surgical needles and suture material used during strabismus surgery.

PURPOSE: To investigate the effectiveness of 3 surgical preparation techniques in decreasing bacterial contamination of needles and suture material during strabismus surgery. METHODS: Consecutive patients requiring 2-muscle strabismus surgery were randomized into 1 of 3 groups. In Group A, patients' periocular skin and bulbar conjunctivae underwent preparation with 5% povidone-iodine; the drape was placed without regard to eyebrows; and an open wire-loop lid speculum was used. Group B patients underwent the same preparation as Group A patients; however, the eyelashes and eyebrows were scrubbed with 5% povidone-iodine on cotton tip applicators, and the drape was placed to exclude the eyebrows from the surgical field. Group C patients underwent the same preparation as Group B patients; however, a bladed lid speculum was used during surgery to exclude some of the eyelashes from the surgical field. After the procedure, all needles and suture materials were sent separately for aerobic culture. The data were analyzed for differences in contamination rates between the groups. RESULTS: Of 77 patients, 24 (31.4%) had either a needle and/or suture contaminant. Groups A, B, and C had mean contamination rates of 29.6%, 34.6%, and 29.2%, respectively. There was no significant statistical variation in contamination among the 3 groups. The most common organism identified was a coagulase-negative staphylococcus strain. CONCLUSIONS: More meticulous sterile preparation of the surgical field did not result in a meaningful reduction in suture or needle contamination rates during strabismus surgery.

Treatment of symptomatic convergence insufficiency with a home-based computer orthoptic exercise program.

PURPOSE: To determine the efficacy of a home-based computer orthoptic program to treat symptomatic convergence insufficiency. METHODS: A retrospective review of consecutive patients with symptomatic convergence insufficiency treated with a home-based computer orthoptic program was performed. Symptomatic convergence insufficiency was defined as: near point of convergence (NPC) >6 cm, decreased positive fusional vergence, exophoria at near at least 4(Δ) greater than at far, and documented complaints of asthenopia, diplopia, or headaches with reading or near work. The Computer Orthoptics CVS program was used for this study. Before beginning the computer orthoptic program, patients with an NPC >50 cm were given 4 base-in prisms and push-up exercises (NPC exercises with an accommodative target) for 2 weeks. RESULTS: A total of 42 patients were included. Mean treatment duration was 12.6 weeks; mean follow-up, 8.5 months. Of the 42 patients, 35 were treated with the home-based computer orthoptic program and push-up exercises; the remaining 7 only used the computer orthoptic program. Because of a remote NPC, 5 patients were given base-in Fresnel prism before starting treatment. Baseline mean NPC was 24.2 cm; posttreatment mean NPC improved to 5.6 cm: 39 patients (92.8%) achieved an NPC of ≤6 cm (p < 0.001). Positive fusional vergence improved in 39 patients (92.8%). Fourteen patients reduced their near exophoria by ≥5(Δ). A total of 27 patients (64.2%) reported resolution of symptoms after treatment. CONCLUSIONS: In our study, home-based computer orthoptic exercises reduced symptoms and improved NPC and fusional amplitudes. The computer orthoptic program is an effective option for treating symptomatic convergence insufficiency.

Retinopathy of prematurity in infants weighing less than 500 grams at birth enrolled in the early treatment for retinopathy of prematurity study.

PURPOSE: To describe patient characteristics, classification, and onset of prethreshold retinopathy of prematurity (ROP), and ocular findings at 6 months corrected age in infants with birth weights <500 g who were enrolled in the Early Treatment for Retinopathy of Prematurity (ETROP) Study. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Sixty-three infants with birth weights <500 g who developed ROP and were enrolled in the ETROP Study. METHODS: Infants <1251 g at birth were logged at 26 study centers from October 1, 2000, to September 30, 2002, and underwent examinations for ROP. Infants who developed ROP and whose parents/legal guardians consented were enrolled in the ETROP Study. Infants who developed high-risk prethreshold ROP were randomized; 1 eye was treated early with peripheral retinal ablation and the other eye was managed conventionally, or, in asymmetric cases, the high-risk eye was randomized to early peripheral retinal ablation or conventional management. All eyes reaching prethreshold ROP were examined when infants reached 6 months corrected age. MAIN OUTCOME MEASURES: Retinopathy of prematurity incidence, characteristics, and ocular findings among participants. RESULTS: Thirty-four infants reached prethreshold or worse severity in 1 or both eyes. Retinopathy of prematurity was located in zone I in 43.3% of all prethreshold eyes, and plus disease was present in 46.7%. Median postmenstrual age for diagnosis of all prethreshold ROP was 36.1 weeks, but earlier (35.1 weeks) for eyes that developed high-risk prethreshold ROP. In the 27 surviving infants with prethreshold ROP, ophthalmic examination at 6 months corrected age showed a normal posterior pole in 22 (81.5%), a favorable structural outcome with posterior pole abnormalities in 4 (14.8%), and an unfavorable structural outcome (stage 4B) in 1 (3.7%). One infant developed amblyopia, 4 infants developed nystagmus, 4 infants developed strabismus, and 8 infants developed myopia >-5.00 diopters. CONCLUSIONS: This is the first report on characteristics of prethreshold ROP in infants with birth weights <500 g. These infants are at high risk for developing prethreshold ROP, although many initially achieve a favorable structural outcome. They are at risk of developing strabismus, nystagmus, high myopia, and abnormal retinal structure and should therefore receive continued long-term follow-up. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Corneal power measurements in fixating versus anesthetized nonfixating children using a handheld keratometer.

PURPOSE: To compare keratometry measurements on a fixating patient with readings from the same nonfixating patient intraoperatively using the Nidek KM-500 handheld keratometer. METHODS: Consecutive patients who were scheduled for strabismus or nasolacrimal surgery between 5 and 11 years of age were included in the study. Handheld keratometry was performed preoperatively on both eyes with the child fixating and intraoperatively with the child anesthetized. Three readings were taken on each eye. The steepest and flattest corneal meridians were recorded. Intraclass correlation coefficients were calculated to assess reliability, and interchangeability was assessed by the use of the Bland-Altman method. RESULTS: Included in the study were 55 eyes of 28 patients. The average fixating keratometry reading was 44.10 +/- 1.45 D for right eyes and 44.12 +/- 1.42 D for left eyes. The average nonfixating keratometry reading was 44.06 +/- 1.62 D for right eyes and 44.02 +/- 1.54 D for left eyes. The intraclass correlation coefficient for the average keratometry obtained fixating versus nonfixating was 0.96 for right eyes and 0.95 for left eyes. The Bland-Altman analysis showed fairly large limits of agreement between readings, but most readings fall within the limits of variability. The mean time to obtain the intraoperative measurements was 4.26 minutes. CONCLUSIONS: In our study the Nidek KM-500 handheld keratometer provided reliable readings when used intraoperatively on anesthetized nonfixating children and required minimal time to perform.

Repeat probing for treatment of persistent nasolacrimal duct obstruction.

Repeat probing of the nasolacrimal duct is one treatment option for children with persistent symptoms of nasolacrimal duct obstruction (NLDO) following an initial probing. The authors conducted a prospective, multicenter study in which 20 subjects age 6 to <48 months underwent a repeat probing for symptomatic NLDO and had follow-up visits 1 month and 6 months after surgery. Treatment success was defined as the absence of all three clinical signs of nasolacrimal duct obstruction-epiphora, increased tear lake, and mucous discharge. Repeat probing was successful in 56%(95% CI, 33%-76%) of cases.

Retinopathy of prematurity outcome in infants with prethreshold retinopathy of prematurity and oxygen saturation >94% in room air: the high oxygen percentage in retinopathy of prematurity study.

OBJECTIVES: To determine the rate of progression from prethreshold to threshold retinopathy of prematurity (ROP) in infants excluded from Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) because their median arterial oxygen saturation by pulse oximetry (SpO2) values were >94% in room air at the time of prethreshold diagnosis and to compare them with infants who were enrolled in STOP-ROP and had median SpO2 < or =94% in room air. METHODS: Fifteen of the 30 centers that participated in STOP-ROP elected to participate in the High Oxygen Percentage in Retinopathy of Prematurity study (HOPE-ROP) from January 1996 to March 1999. Infants were followed prospectively from the time prethreshold ROP was diagnosed until ROP either progressed to threshold in at least 1 study eye (adverse outcome) or resolved (favorable outcome). RESULTS: A total of 136 HOPE-ROP infants were compared with 229 STOP-ROP infants enrolled during the same time period from the same 15 hospitals. HOPE-ROP infants were of greater gestational age at birth (26.2 +/- 1.8 vs 25.2 +/- 1.4 weeks) and greater postmenstrual age at the time of prethreshold ROP diagnosis (36.7 +/- 2.5 vs 35.4 +/- 2.5 weeks). HOPE-ROP infants progressed to threshold ROP 25% of the time compared with 46% of STOP-ROP infants. After gestational age, race, postmenstrual age at prethreshold diagnosis, zone 1 disease, and plus disease at prethreshold diagnosis were controlled for, logistic regression analysis showed that HOPE-ROP infants progressed from prethreshold to threshold ROP less often than STOP-ROP infants (odds ratio: 0.607; 95% confidence interval: 0.359-1.026). CONCLUSIONS: The mechanisms that result in better ROP outcome for HOPE-ROP versus STOP-ROP are not fully understood. It seems that an infant's SpO2 value at the time of prethreshold diagnosis is a prognostic indicator for which infants may progress to severe ROP. When other known prognostic indicators are factored in, the SpO2 is of borderline significance.