Impaired vision in children prenatally exposed to methadone: an observational cohort study.

BACKGROUND/OBJECTIVES: To examine prevalence of failed visual assessment at 8-10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. SUBJECTS/METHODS: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a 'fail'. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. RESULTS: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual 'fail' outcome, adjusted odds ratio 2.6, 95% CI 1.1-6.2; adjusted relative risk 1.8 (95% CI 1.1-3.4). Visual 'fail' outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference-11-27%). CONCLUSIONS: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301 .

5†Tear proteins in premature babies at risk of retinopathy of prematurity.

This feasibility study aimed to investigate the feasibility of collecting and analysing tear proteins from preterm infants at risk of retinopathy of prematurity (ROP). Additionally, we sought to identify any tear proteins which might be implicated in the pathophysiology of ROP.Eligible infants were those undergoing ROP screening without other ocular pathology. Tear samples were obtained by Schirmer's test strips coincident with routine ROP screening. Mass spectrometry was used for proteomic analysis. All participants' parents gave written, informed consent.Samples were collected from 12 infants, including two sets of twins. Gestation ranged from 25+6 to 31+1 weeks. Median postnatal age at sampling was 30.5 days (range 19 to 66). One infant developed self-limiting ROP. An adequate sample for protein analysis was obtained from each infant. 701 proteins were identified; 261 proteins identified in the majority of tear samples, including several common tear proteins, were used for analyses.Increased risk of ROP as determined by G-ROP prediction criteria was associated with an increase in lactate dehydrogenase B (LDH-B) chain protein in tears. Older, more mature infants demonstrated increased concentration of immunoglobulin complexes within their tear samples and two sets of twins in the cohort showed exceptionally similar proteomes, supporting validity of the analysis.Tear sampling by Schirmer test strips and subsequent proteomic analysis in preterm infants is feasible. A larger study is required to investigate the potential use of tear proteomics in early identification of ROP.

Vitamin A provision for preterm infants: are we meeting current guidelines?

BACKGROUND: Preterm infants have reduced liver stores of vitamin A at birth compared to term born infants. Current guidelines recommend an intake of 700-1500 IU/kg/day vitamin A, and there is evidence to support higher doses for infants with significant lung disease. The importance of appropriate early nutrition for preterm infants is increasingly becoming apparent. OBJECTIVES: To examine whether preterm infants admitted to a UK neonatal unit received the currently recommended amounts of vitamin A during the first 4 weeks of life, and to identify the feeding patterns associated with optimal vitamin A intake. DESIGN: Retrospective case note review. SETTING: UK tertiary neonatal unit. POPULATION: 36 preterm infants with a median gestation of 30 weeks (range 26-33 weeks) and median birth weight of 1305 g (range 880-1800 g). MAIN OUTCOME MEASURE: Mean daily total intake of vitamin A in each of the first 4 weeks of life. RESULTS: Despite a policy of introducing intravenous lipid supplemented with fat soluble vitamins on day 2, only four infants (11%) consistently met the recommended daily intake of vitamin A during the first 2 weeks of life. Adequacy of vitamin A intake in the first 2 weeks of life was not predicted by gestation or pattern of feeding. CONCLUSION: Recommendations for intravenous vitamin A supplementation in parenterally fed preterm infants require revision. Intravenous lipid with added fat soluble vitamins should be started as soon as possible after birth, and consideration given to early oral vitamin A supplementation in those infants tolerant of enteral feeds.

Ophthalmic, clinical and visual electrophysiological findings in children born to mothers prescribed substitute methadone in pregnancy.

BACKGROUND AND AIMS: There are growing concerns regarding visual outcome of infants exposed to opiates (including substitute methadone) and/or benzodiazepines in utero. We describe the combined ophthalmology and visual electrophysiology findings in 20 infants and children who had been exposed to substitute methadone and other drugs of misuse in utero. METHODS: This was a descriptive case series of 20 patients, all of whom had been referred to a paediatric visual electrophysiology service because of concerns regarding visual function, and all of whom had been exposed to methadone in utero. All children underwent a full ophthalmic and orthoptic examination as well as visual electrophysiology testing deemed appropriate on an individual basis. A review was undertaken of paediatric case notes and of maternal antenatal urine toxicology. RESULTS: Ophthalmic abnormalities included reduced acuity (95%), nystagmus (70%), delayed visual maturation (50%), strabismus (30%), refractive errors (30%), and cerebral visual impairment (25%). Visual electrophysiology was abnormal in 60%. A quarter of the children had associated neurodevelopmental abnormalities. The majority of children with nystagmus (79%) had been treated for neonatal abstinence syndrome (NAS). CONCLUSION: Infants born to drug-misusing mothers prescribed methadone in pregnancy are at risk of a range of visual problems, the underlying causes of which are not clear. Those infants with NAS severe enough to receive pharmaceutical treatment may be at particular risk of developing nystagmus. The inclusion of visual electrophysiology in comprehensive visual assessment of children exposed to substance misuse in utero may help clarify the underlying causes by differentiating abnormalities of retinal and cortical origin.

Visual electrophysiological findings in CHARGE syndrome with bilateral colobomas: a case report.

Colobomas are the major ophthalmic manifestation of CHARGE syndrome. Ophthalmological advice may be sought for an infant diagnosed with CHARGE syndrome presenting with coloboma, and electrophysiology can be particularly useful in assessing retinal and cortical function at an early age. Here we describe electrophysiology findings in a four-week-old infant born with bilateral coloboma, more extensive in the right eye, as part of CHARGE syndrome. The left eye showed robust ERGs indicating near-normal rod and cone function. The right eye ERG amplitudes were relatively reduced being around one half to two-thirds that of the left eye ERGs. Flash VEPs were present from both left and right eyes, but the right eye VEP was smaller and delayed relative to that of the left eye. By 5 years of age, right eye acuity was approximately 6/1000 and left eye acuity was 6/12 (Cardiff cards). In cases such as this, it is helpful to give parents a reasonable prediction of visual outcome as soon as possible, allowing instigation of appropriate management and permitting parents to begin to come to terms with the diagnosis. Electrophysiology can provide valuable information on visual function when behavioural testing is limited by the child's ability to co-operate, such as during the early weeks of life.

Drug misuse in pregnancy: losing sight of the baby?

Maternal drug misuse can seriously affect the health of the fetus and newborn infant. The association of maternal drug misuse with prematurity, intrauterine growth restriction (IUGR) and neonatal abstinence syndrome (NAS) is well recognised, and there is growing concern about infant visual development and longer-term neurodevelopmental outcome. Drug misuse is associated with changes in the visual system as measured by the visual evoked potential (VEP) in adults and animal models. A recent study has shown abnormal VEPs in newborn infants exposed to methadone in utero, consistent with reports of delayed visual development in this population. Since visual abnormalities and neurodevelopmental abnormalities can be predicted by abnormal VEPs in infancy, it is postulated that the VEP may be a valuable tool in the detection of the adverse effects of maternal drug misuse upon the infant. This review summarises the impact of maternal drug misuse upon the health of the fetus and newborn infant, addresses the specific effects of maternal drug misuse upon the developing visual system and discusses the potential role of the VEP in the assessment of these infants.

Maternal methadone use in pregnancy: factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources.

OBJECTIVES: The objectives of this study were to investigate factors associated with the development of neonatal abstinence syndrome (NAS) and to assess the implications for healthcare resources of infants born to drug-misusing women. DESIGN: Retrospective cohort study from 1 January 2004 to 31 December 2006. SETTING: Inner-city maternity hospital providing dedicated multidisciplinary care to drug-misusing women. POPULATION: Four hundred and fifty singleton pregnancies of drug-misusing women prescribed substitute methadone in pregnancy. METHODS: Case note review. MAIN OUTCOME MEASURES: Development of NAS and duration of infant hospital stay. RESULTS: 45.5% of infants developed NAS requiring pharmacological treatment. The odds ratio of the infant developing NAS was independently related to prescribed maternal methadone dose rather than associated polydrug misuse. Breastfeeding was associated with reduced odds of requiring treatment for NAS (OR 0.55, 95% CI 0.34-0.88). Preterm birth did not influence the odds of the infant receiving treatment for NAS. 48.4% infants were admitted to the neonatal unit (NNU) 40% of these primarily for treatment of NAS. The median total hospital stay for all infants was 10 days (interquartile range 7-17 days). Infants born to methadone-prescribed drug-misusing mothers represented 2.9% of hospital births, but used 18.2% of NNU cot days. CONCLUSIONS: Higher maternal methadone dose is associated with a higher incidence of NAS. Pregnant drug-misusing women should be encouraged and supported to breastfeed. Their infants are extremely vulnerable and draw heavily on healthcare resources.

Maturation of steady-state flicker VEPs in infants: fundamental and harmonic temporal response frequencies.

Transient flash VEPs allow objective assessment of visual function and are easily recorded in young infants. However, due to their high variability, they are an insensitive surrogate marker of visual development. The aim of our study was to investigate the early maturation of temporal characteristics of steady-state flicker VEPs. Data from 53 VEP sessions were analyzed in term-born infants between birth and 20 months of age. The stimulus was a square-wave modulated luminance flicker with 80% modulation depth at temporal frequencies of 4.7, 7.5, 12.5, and 19 Hz. A total of 18 healthy adults aged between 21 and 54 years served as controls. Contingent on the stimulus frequency, we found pronounced changes of the flicker VEP with age. Regression lines fit to the first harmonic VEP magnitude as a function of age between 3 and 88 weeks of age indicated increases at 7.5 (P = 0.004), 12.5 (P < 0.001), and 19 Hz (P = 0.07) and a non-significant decrease at 4.7 Hz (P = 0.3). The magnitude of the second harmonic increased for all frequencies (4.7 (P = 0.05), 7.5 (P = 0.01), 12.5 (P = 0.13), and 19 Hz (P = 0.18)). Over the whole infant age range, the flicker VEP was dominated by the first harmonic, in contrast to adults, where the response was typically shifted to a higher harmonic at low stimulus frequencies. The optimal stimulus frequency, defined as the frequency eliciting the highest magnitude for F1, shifted to higher rates with age. Due to the difference from adult responses, further developmental changes of the temporal properties must be assumed to occur after the age of 20 months. Changes in temporal characteristics of the flicker VEP with age may be useful as an indicator of visual system maturation and a useful tool to detect visual delay.

Visual evoked potentials in infants exposed to methadone in utero.

We investigated the effects of maternal drug misuse on neonatal visual evoked potentials (VEPs). Flash VEPs were recorded within 4 days of birth from 21 term infants of mothers misusing drugs and prescribed substitute methadone and 20 controls. Waveforms were classified as typical, atypical, immature or non-detectable, and amplitude and latencies were measured. VEPs from drug-exposed infants were less likely to be of typical waveform and more likely to be immature or non-detectable (p<0.01) than those of control infants. They were also smaller in amplitude (median 10.8 vs 24.4 microV, p<0.001). VEPs of drug-exposed infants had matured after 1 week but remained of lower amplitude than VEPs of newborn controls (p<0.01) and were non-detectable in 15%. Flash VEPs differ between maternal drug-exposed and non-drug-exposed newborns. Future research should address the specific effects of maternal methadone and/or other illicit drug misuse on infant VEPs, and associations between neonatal VEPs and subsequent visual development.

Vitamin A and preterm infants: what we know, what we don't know, and what we need to know.

Vitamin A is essential for optimal growth and development. In the developing world, vitamin A supplementation of the newborn infant reduces mortality. In the developed world, extremely preterm infants are born with low body stores of vitamin A and are at high risk of vitamin A deficiency. Optimal vitamin A supplementation for this population is not clearly defined, however, and, despite evidence of benefit, early vitamin A supplementation of extremely preterm infants is not uniformly practised in the United Kingdom. There is an urgent need for studies in preterm infants that include quantification of hepatic stores and functional assessment of vitamin A status as well as long term outcome.

Contact lens electroretinography in preterm infants from 32 weeks after conception: a development in current methodology.

AIM: To assess the feasibility of using a contact lens electrode to record the electroretinogram (ERG) in preterm infants less than 35 weeks after conception. METHODS: The ERG was recorded from seven very low birthweight preterm infants on a total of 14 occasions using an infant monkey contact lens electrode. Age at recording the first ERG ranged from 23 to 51 days (gestational age 32-34 weeks), and weight ranged upwards from 1100 g. RESULTS: No complications were observed. With advancing age and maturity the dark adapted rod threshold decreased, indicating increased retinal sensitivity. CONCLUSIONS: Contact lens recording of the ERG from extremely small immature preterm infants is a practicable and well tolerated procedure. This method of recording the ERG will enable further evaluation of retinal development in this vulnerable population.

Normal linear growth in hypophosphataemic bone disease.

A case of hypophosphataemic bone diseases is described. Despite prescribed phosphate (PO4) supplement and 1.25 dihydroxycholecalciferol therapy, serum PO4 levels have remained low with associated diminished theoretical renal threshold for phosphate (TmPO/GFR) over a seven and a half year follow up period. Linear growth, however, has been normal.

The electroretinogram in preterm infants.

With the hope that the electroretinogram (ERG) in preterm infants could help clarify their vitamin A requirements, a technique for recording the full-field ERG in the neonate is described. One hundred seventy-seven ERGs were performed in 59 preterm and 52 term infants. An ERG was recorded as soon as 7 hours after birth and as early as 30 weeks after conception. In preterm infants the a-wave latency was longer and the amplitude less than in term infants of the same age. The amplitude of the ERG in preterm infants increased with the duration of light exposure. Longitudinal data on 15 preterm infants showed a reduction in a-wave latency. None of the ERG findings correlated with postconceptional age, which suggests that the duration of light exposure is a major determinant of the ERG pattern in preterm infants. Despite low circulating levels of retinol, no correlations with any of the ERG values were found.

Vitamin A status of preterm infants: correlation between plasma retinol concentration and retinol dose response.

Retinol dose response tests were performed on 83 preterm infants shortly before discharge by giving orally 5000 IU of an aqueous dispersion of retinol. Predose plasma retinol concentrations were 2.5-20.5 micrograms/dL (0.087-0.72 mumol/L) and the retinol dose responses were 0-59.8%. The regression of retinol dose response on predose retinol was -0.58. There was a parallel increase in both retinol and retinol-binding protein and an increase in the molar ratio of retinol-binding protein to prealbumin. Prealbumin did not increase. These findings suggest that preterm infants have reduced liver stores of vitamin A.

Central venous catheterisation in very low birthweight infants.

Forty two premature babies (mean birth weight 980 g, mean gestation 27.6 weeks) had central venous lines inserted at a mean age of 10 days through the internal jugular vein because of poor peripheral venous access and for purposes of parenteral feeding and minimal handling. Eight babies died from complications of prematurity and four from septicaemia with a central line in situ, but the other 30 babies had lines in place for a mean of 20 days. A mean weight gain of 17.5 g/kg/day was recorded. Eight babies showed signs of infection at a mean of 22 days after insertion of the line. The other complications were thrombosis related to the catheter (three cases), embolisation (two), and hydrocephalus related to superior vena caval thrombosis (one). The policy of management is outlined, and the risks and benefits of the technique are analysed.