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Sensorimotor outcomes in children with prenatal exposure to methadone
Accepted Manuscript Sensorimotor outcomes in children with prenatal exposure to methadone Sylvia H. Yoo, MD, Lauren M. Jansson, MD, Hee-Jung Park, MD PII:
S1091-8531(17)30193-3
DOI:
10.1016/j.jaapos.2017.05.025
Reference:
YMPA 2645
To appear in:
Journal of AAPOS
Received Date: 9 March 2017 Revised Date:
16 April 2017
Accepted Date: 10 May 2017
Please cite this article as: Yoo SH, Jansson LM, Park H-J, Sensorimotor outcomes in children with prenatal exposure to methadone, Journal of AAPOS (2017), doi: 10.1016/j.jaapos.2017.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Sensorimotor outcomes in children with prenatal exposure to methadone Sylvia H Yoo MD,a Lauren M Jansson, MD,b and Hee-Jung Park, MDc
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Author affiliations: aNew England Eye Center, Tufts Medical Center, Boston, Massachusetts; b Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, Maryland; c Virginia Mason Medical Center, Seattle, Washington Submitted March 8, 2017. Revision accepted May 4, 2017.
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Correspondence: Sylvia H. Yoo, 800 Washington St Box 450, Boston, MA 02111 (email: [email protected]).
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Presented as a poster at the 40th Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus, Palm Springs, California, April 2-6, 2014. Study conducted at Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD and Johns Hopkins Bayview Medical Center, Baltimore, MD
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Word count: 3,029 Abstract only: 212
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Abstract Purpose To report the presentation and characteristics of strabismus in children with prenatal methadone
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exposure. Methods
The medical records children with prenatal methadone exposure were retrospectively reviewed.
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Those who were evaluated by pediatric ophthalmology were included. Information on the timing and types of prenatal exposure by trimester of pregnancy was then collected from the patients’
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mothers’ charts. The children’s perinatal histories and ophthalmologic findings were collected from their pediatric clinic charts and ophthalmology clinic charts, respectively. Results
A total of 210 children with prenatal methadone exposure were identified, of whom 32 (15.2%)
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underwent eye examinations and 21 (10%) had strabismus. Five patients had esodeviations, with a mean age of onset of 11.6 months; 16 had exodeviations, with a mean age of onset of 6.8 months. Three patients with strabismus were born prematurely, and 2 had intracranial disease.
Conclusions
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Two patients underwent strabismus surgery.
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The incidence of strabismus in patients with prenatal methadone exposure was higher than the general population (10% vs 3%-4%). Intermittent exotropia was the most common type of strabismus and presented earlier than in the general population, with no association with other systemic disease. Prenatal exposure to methadone was likely confounded by exposure to other substances, environmental factors, and genetics. Poor compliance with follow-up reduced the power of the study.
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Methadone maintenance treatment during pregnancy has been shown to improve maternal and neonatal outcomes for women with opioid use disorder.1,2 However, the long-term effects of prenatal exposure to methadone and of neonatal abstinence syndrome (NAS), which may occur
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in 57%-78% of methadone-exposed infants,3,4 are difficult to assess because of the many
confounding factors, including other illicit drug use or licit drug misuse,5 prematurity, and
psychosocial factors. An increased incidence of strabismus compared to the general population,
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as a possible long-term effect of prenatal methadone exposure, has been reported in studies on ophthalmic and neurobehavioral outcomes in this population.6-9 Our study describes the
underwent eye examinations. Subjects and Methods
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presentation and characteristics of strabismus in children with prenatal methadone exposure who
This study was approved by the Johns Hopkins Institutional Review Board. The medical records
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of children born between January 2007 and December 2012 to mothers who were on methadone, other drugs, and alcohol and who were followed at the Center for Addiction and Pregnancy (CAP), a comprehensive, urban drug treatment center that treats pregnant and post-partum
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women and their children, described elsewhere.10 Patients enroll in treatment at any point during their pregnancies and receive obstetric care and substance abuse treatment. Children born to CAP
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patients and who are followed in the CAP pediatric clinic undergo routine well-child examinations and sick appointments. Of the approximately 100 infants born to mothers followed at CAP per year, only approximately 40% can be admitted to the CAP pediatric clinic due to insurance limitations. Year-to-year, the CAP pediatric clinic follows about 350 active patients. The remaining 60% of CAP deliveries are followed at non-CAP pediatric clinics, which refer to various ophthalmologists in the community. A list of all children admitted to the CAP pediatric
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clinic between January 2007 and December 2012 was collected. Among these children, all who were referred to and evaluated by pediatric ophthalmology were included. None of these
parental, or guardian concern about the patients’ eyes or vision.
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identified patients were excluded. Patients were referred if there was primary care physician,
Information about the mothers’ prenatal substance use was collected from the mothers’ CAP clinical records. Prenatal substance use data included methadone dose range by trimester,
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exposure to prescribed buprenorphine, and concurrent exposure to alcohol and tobacco anytime during the pregnancy. Prenatal exposure to the following substances was collected by trimester
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of use: marijuana; cocaine; other opiates, including morphine and opioid-containing pain relievers; benzodiazepines; barbiturates; and methamphetamine. These data were based on patient report and random weekly urine toxicology screenings, which are the standard of care at CAP. Additionally, use of psychotropic and seizure medications was collected by trimester of
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use.
The children’s neonatal data and eye examination findings were collected from their hospital and pediatric ophthalmology clinic charts. Neonatal data included gestational age at
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birth, birth weight, and presence or not of intraventricular hemorrhage, periventricular leukomalacia, or hydrocephalus. Occurrence of NAS and whether or not it required treatment,
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was also noted. All children referred from the CAP pediatric clinic and evaluated by pediatric ophthalmology underwent complete ophthalmologic examinations. From the pediatric ophthalmology clinic charts, we extracted age at presentation to the eye clinic, reported onset of strabismus, and family history of strabismus and/or amblyopia, if known. In addition, we recorded abnormal anterior or posterior segment findings, cycloplegic refraction, presence of nystagmus and amblyopia. Ocular alignment was assessed using cover-uncover and alternate
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prism cover testing at distance and at near in primary gaze. The type of strabismus, control of ocular alignment, and any surgical intervention were recorded. All available follow-up data were recorded, regardless of age.
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Statistical Analysis
Odds ratios were calculated and the Fisher exact test was used to assess for an association
between strabismus and the following prenatal and neonatal variables: methadone exposure by
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trimester, maximum methadone dose during pregnancy, exposure to buprenorphine, alcohol, tobacco, marijuana, cocaine, other opiates, benzodiazepines, barbiturates, or methamphetamine;
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psychotropic medication exposure; known intracranial disease; history of NAS, premature birth (< 37 weeks’ gestation), and small-for-gestational-age status at birth. A P value of <0.05 was considered significant. Results
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A total of 210 CAP pediatric clinic patients who had prenatal methadone exposure and were born between January 2007 and December 2012 were identified. Of these, 32 (15%) were referred to ophthalmology and underwent comprehensive eye examinations by a pediatric ophthalmologist.
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Of the total cohort of 210 patients, 21 (10%) were found to have strabismus. Prenatal exposure data andperinatal and eye examination data are provided in Table 1.
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Over half of the patients (54.5%) without strabismus were born prematurely, whereas
14.3% of patients with strabismus were premature. The mean gestational age (with standard deviation) at delivery of the patients with strabismus was 38.4 ± 2.7 weeks; of patients without strabismus, 35.6 ± 4.0 weeks. The majority of patients in each group were appropriate for gestational age based on published intrauterine growth curves used by the American Academy of Pediatrics.11
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Less than 10% of patients in each group (2 with strabismus and 1 without strabismus) had developed intracranial disease perinatally, including intraventricular hemorrhage, periventricular leukomalacia and hydrocephalus. Most of the patients in both groups (81.0% of patients with
Two patients with mild NAS were not treated pharmacologically.
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strabismus and 90.9% of those without) had NAS, with the majority requiring pharmacotherapy.
None of the patients without strabismus had nystagmus; 5 with strabismus (23.8%) also
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had nystagmus, including sensory defect nystagmus (1 patient), congenital motor nystagmus (1 patient), and fusion maldevelopment nystagmus syndrome (3 patients).
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Of the 21 patients found to have strabismus, 16 had exodeviations (mean age of onset, 6.8 ± 5.5 months), and 5 had esodeviations (mean age of onset, 11.6 ± 7.0 months). See Table 2. All patients with exodeviations had intermittent exotropia or exophoria (1 patient). Stereoacuity was not reliably measured in any patient due to age. Eighteen of the patients with strabismus returned
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for follow-up eye examinations, with a mean follow-up duration of 16.6 months (range, 1-55 months). Only 2 of the 11 patients without strabismus returned for follow-up, 1 at 3 months and 1 at 2 months. Five patients with an exodeviation (31.3%) had improvement of strabismus
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control, including one patient with a macular scar due to toxoplasmosis, whose exodeviation improved with patching. Of the patients with intermittent exotropia, 7 had worsened control,
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including 1 who was not compliant with myopic correction and 1 who had a large-angle of deviation, developed strabismic amblyopia, and underwent strabismus surgery. One patient with intermittent exotropia remained stable. Of the 5 patients with esodeviations, 3 had a constant esotropia and 2 had an intermittent esotropia. One patient with constant esotropia was born at 28 weeks’ gestation and had improvement of strabismus control at final follow-up. Three of these patients had moderate hyperopia and accommodative esotropia. These 3 patients had worsening
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of control; 2 were not compliant with hyperopic correction, and 1 underwent bilateral medial rectus recession. One patient with an esodeviation remained stable with full-time anisohyperopic correction.
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Refractive error among the patients with strabismus ranged from −1.50 to +3.50 D
(spherical equivalent). One patient had 2.50 D of anisometropia. Eight patients were diagnosed with amblyopia due to strabismus, anisometropia, or macular scar due to toxoplasmosis. Among
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patients without strabismus, refractive error ranged from −1.00 to +3.50 D (spherical equivalent). Detailed prenatal exposure data from the mothers’ CAP charts were not available for 8 of
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the 32 patients (25%) referred to ophthalmology (4 with and 4 without strabismus) due to missing charts or missing data. However, prenatal methadone exposure had been reported by all of the children’s parents or guardians during their visits with ophthalmology, and these children were established CAP pediatric patients. Of the 32 patients, 24 (75%) were under the care of a
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biological parent, 6 were under the care of a relative, and 2 were in foster care. The 24 patients for whom detailed prenatal exposure data was collected were exposed to one or more substances in addition to methadone, including alcohol, tobacco, marijuana, cocaine, other opiates
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(including heroin and opioid pain relievers), benzodiazepines, and psychotropic medications prenatally. One patient without strabismus was exposed to buprenorphine, briefly prescribed to
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the patient’s mother as an alternative to methadone, and a second patient without strabismus was exposed to barbiturates prenatally. None of the patients with detailed prenatal exposure data had known exposure to methamphetamine. Methadone exposure by trimester and by maximum dose during pregnancy is shown in Table 3. Most patients were exposed to methadone by the second and third trimesters. There was no statistically significant association between presence of strabismus, and the following prenatal and neonatal variables: methadone exposure by trimester;
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maximum methadone dose during pregnancy; exposure to buprenorphine, alcohol, tobacco, marijuana, cocaine, other opiates, benzodiazepines, barbiturates, or methamphetamine; psychotropic medication exposure; known intracranial disease; history of NAS; premature birth;
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or being small for gestational age. Discussion
The increased incidence of strabismus in patients with prenatal methadone exposure has
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previously been reported to be 14%-25%,6-9,12 which is approximately 3.5 to 8 times that in the general population. In a cohort of children with prenatal methadone exposure, Gill and
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colleagues6 reported no significant association between strabismus and birth weight, head circumference at birth, gestational age, maternal nonopiate drug use, family history of strabismus, or maternal methadone dose. Others have reported an association between strabismus and low birth weight8 in this population, and others have found that infants with prenatal
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methadone exposure had greater likelihood of having a small head circumference, which persisted, and developmental delay,13 each of which alone are associated with an increased risk of strabismus.6 In our cohort, we did not find a difference between children with and without
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strabismus with regard to any of the variables studied. Although prematurity and low birth weight have been reported as risk factors for
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strabismus,14 some studies have found that both are independent risk factors, whereas others have found that only either prematurity or low birth weight are risk factors.14-16 In our study cohort, prematurity was not associated with a higher rate of strabismus; in fact, the inverse was found (P = 0.03), likely due to the relative degree of prematurity in each group. One of the 3 premature patients in the strabismus group was born before 32 weeks, whereas 4 of the 6 premature patients in the nonstrabismus group were born before 32 weeks. This may also be a
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chance finding due to the small sample size. A positive family history is also a risk factor for strabismus. This information was not
statistically significant association with presence of strabismus.
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consistently available or complete; however, analysis of the available data did not find a
Gill and colleagues6 reported a mean age of strabismus onset of 8.3 months (range, 0-19 months) in their cohort. We report a younger mean age of onset of intermittent exotropia in our
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cohort than in the general population (mean age of onset, 33 months; median, 12 months).17 In the general population, improvement of control occurs in 26% of cases, similar to our cohort.
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The mean age of onset of an esodeviation was also younger in our cohort than in the general population (mean age of onset, 2.5 years).18
Infantile exotropia presenting in the first year of life, more than esotropia, is associated with coexisting ocular or systemic disease, most commonly neurologic disease and
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prematurity.19 None of the patients in our cohort had a constant exotropia. The 2 patients with strabismus and intracranial disease in our cohort had intermittent exotropia and esotropia. Of the 3 premature patients with strabismus, 1 each had intermittent exotropia, intermittent esotropia,
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and constant esotropia. We found less diagnosed systemic disease in our cohort, including neurological disease and prematurity, than expected among the patients with strabismus and
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especially among the patients with an exodeviation with early age of onset. Spiteri Cornish and colleagues9 also reported on the types of strabismus presenting in children with prenatal illicit substance exposure, with the most common being constant esotropia. Although their study was comparatively large and included 46 patients with strabismus, the exposed population included children with prenatal illicit substance exposure both with and without methadone exposure. Nystagmus has also been reported to occur more frequently in children with prenatal
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methadone exposure, occurring in 3.7% of children in a study by Spiteri Cornish and colleagues.9 Of the 5 patients who had nystagmus in our study, 1 had a unilateral macular scar due to toxoplasmosis, 1 had a history of prematurity and intraventricular hemorrhage, and 1 had
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developmental delay and was born full-term. The remaining 2 were born full-term with no
known intracranial disease or developmental delay. Prenatal opiate exposure likely affects the developing visual pathways and increases the risk of nystagmus. Abnormal visual pathways have
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been demonstrated with flash visual evoked potential (VEP) testing, which were markedly
different within the first 3 days of life in full-term infants with prenatal drug exposure compared
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to control infants.20 These VEP abnormalities persisted to 6 months of age, and 11% had nystagmus.12
The incidences of gestational opioid use disorders and medication-assisted treatment for these disorders have been increasing overall,21,22 as has average methadone doses used for
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treatment.22,23 Prior reports have considered >20 to 40 mg/day8 to be high dose; the maximum dose range in our group was 30–140 mg/day. We considered ≥100 mg/day to be high dose. NAS develops in 60%-80% of infants with prenatal methadone or buprenorphine exposure, 65%
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requiring treatment.24 Higher maternal methadone doses during pregnancy, however, have not been associated with increased incidence of NAS.23,25,26 In our cohort, there was no statistically
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significant association between presence of strabismus and either high-dose prenatal methadone exposure or NAS. Single nucleotide polymorphisms, which have been associated with opioid addiction risk in adults, have also been associated with shorter hospital stays and less need for treatment in infants with NAS, affecting the level of postnatal opiate exposure. There may be neurological effects from both prenatal and postnatal drug exposure, which may partly be a result of genetic factors.27 In our population of patients referred to ophthalmology, NAS occurred in the
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majority of patients but there was no significant association between NAS and strabismus. Gill and colleagues6 and Nelson and colleagues8 also did not find an association between NAS and presence of strabismus, suggesting that prenatal rather than postnatal exposure is more likely
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associated with strabismus.
Due to the relatively small number of patients identified, we included all patients who were referred to ophthalmology from the CAP pediatric clinic, including those with other risk
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factors for strabismus such as prematurity, intracranial disease, macular scar, and positive family history of strabismus, which dilutes our finding of a greater incidence of strabismus in children
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exposed to methadone prenatally. Not all children born at CAP are followed in the CAP pediatric clinic due to insurance limitations; thus, patients followed at an outside pediatric clinic may not have been referred to our ophthalmology clinic, resulting in a potential underestimation of the percentage of patients with strabismus. In addition, the study may have been underpowered to
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find statistically significant associations between prenatal methadone and other drug exposure and strabismus. CAP charts were missing detailed exposure data for 25% of patients’ mothers, which limits the results of the analysis done. In addition, other exposure data may be incomplete,
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despite thorough review of the mothers’ charts. For example, cigarette use was obtained by mother’s report. Cigarette use during pregnancy has been reported to increase the risk of
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strabismus in children.28 Urine toxicology may not detect a substance due to timing or exposure during an early trimester, prior to presenting to CAP. Meconium drug levels were not available. These known and unknown exposures to substances other than methadone are likely confounding factors in our results. In addition, parental history of strabismus onset may be inaccurate, though it is notable that Gill and colleagues6 published strabismus data in this population using only a strabismus questionnaire for parents who deferred an ophthalmologic
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evaluation. Poor compliance with recommended treatments and follow-up, common in this difficult-to-study population, are also factors that may confound the characteristics of strabismus that were collected. Follow-up for the patients with strabismus was limited to a mean of 16.6
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months, with longest follow-up of 55 months. None of the patients without strabismus at their initial evaluation were later found to have strabismus; however, many of these patients did not return for follow-up. Thus, it is unknown whether any patients in this group later developed
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strabismus.
Screening and surveillance of patients with prenatal methadone and other substance
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exposures for ophthalmologic disease, especially strabismus, are recommended. Early referrals are warranted if there are any concerns for strabismus or other eye disease, because intermittent exotropia may present earlier than in the general population. Those treating children with in utero exposure to methadone should be aware of the increased risk of strabismus with prenatal
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methadone exposure. Furthermore, the parents and guardians of these children should be informed of this risk both pre- and postnatally in the context of reported improved maternal and
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neonatal outcomes with maintenance treatment during pregnancy.
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Table 1. Perinatal, clinical, and non-methadone exposure data
0.03 NS NS
17 (81.0)
10 (90.9)
NS
5 (23.8) 10 (47.6)
0 4 (36.4)
NS NS
17 (70.8)
7 (29.2)
0 5 (29.4) 13 (76.5) 5 (29.4) 11 (64.7) 11 (64.7) 6 (35.3) 0 0 12 (70.6) 4 (19.0)
1 (14.3) 2 (28.6) 3 (42.9) 4 (57.1) 5 (71.4) 6 (85.7) 3 (42.9) 1 (14.3) 0 6 (85.7) 4 (36.3)
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6 (54.5) 1 (9.1) 1 (9.1)
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3 (14.3) 4 (19.0) 2 (9.5)
NS NS NS NS NS NS NS NS
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Total patients referred for pediatric ophthalmology exam (N = 32) Premature Small for gestational age Perinatal intracranial a disease Neonatal abstinence syndrome Nystagmus Family history strabismus and/or amblyopia Available exposure data (n = 24) Buprenorphine Alcohol Tobacco Marijuana Cocaine Opiatesb Benzodiazepines Barbiturates Methamphetamine c Psychotropic medications Unavailable prenatal exposure data
Patients with Patients without P value strabismus, no. strabismus, no. (%) (%) n = 21 (66%) n = 11 (34%)
NS
NS, not statistically significant. a
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Intraventricular hemorrhage, periventricular leukomalacia, hydrocephalus. Heroin and opioid pain relievers. c Psychotropic medications: bupropion, buspirone, escitalopram, fluoxetine, hydroxyzine, lithium, mirtazapine, nortriptyline, quetiapine, sertraline, trazodone, valproic acid, venlafaxine. b
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Table 2. Strabismus follow-up data (n = 21)
5 7 1 3 1 3 1
SD, standard deviation. a
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Includes 1 patient with a macular toxoplasmosis scar whose deviation improved with patching. b One patient underwent surgery.
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No.
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Deviation type Exodeviations (n = 16 [76.2%]) a Improved b Worsened Stable No follow-up Esodeviations (n = 5 [23.8%]) Improved b Worsened Stable
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Table 3. Methadone exposure data Patients with Patients without strabismus, no. (%) strabismus, no. (%) P value 17 (70.8) 7 (29.2) 10 (58.8) 3 (42.9) NS 5 (29.4) 3 (42.9) NS 2 (11.8) 1 (14.3) NS 10 (58.8) 4 (57.1) NS 6 (35.3) 3 (42.9) NS a 5 (23.8) 4 (36.4) --
Total available (n = 24) All trimesters 2nd and 3rd trimesters 3rd trimester only Maximum dose <100 mg Maximum dose ≥100 mg Unavailable
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Exposure data
NS, not statistically significant. a
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Includes 1 patient whose substance exposure data was available, but specific methadone dosing data unavailable.
S1091-8531(17)30193-3
DOI:
10.1016/j.jaapos.2017.05.025
Reference:
YMPA 2645
To appear in:
Journal of AAPOS
Received Date: 9 March 2017 Revised Date:
16 April 2017
Accepted Date: 10 May 2017
Please cite this article as: Yoo SH, Jansson LM, Park H-J, Sensorimotor outcomes in children with prenatal exposure to methadone, Journal of AAPOS (2017), doi: 10.1016/j.jaapos.2017.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Sensorimotor outcomes in children with prenatal exposure to methadone Sylvia H Yoo MD,a Lauren M Jansson, MD,b and Hee-Jung Park, MDc
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Author affiliations: aNew England Eye Center, Tufts Medical Center, Boston, Massachusetts; b Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, Maryland; c Virginia Mason Medical Center, Seattle, Washington Submitted March 8, 2017. Revision accepted May 4, 2017.
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Correspondence: Sylvia H. Yoo, 800 Washington St Box 450, Boston, MA 02111 (email: [email protected]).
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Presented as a poster at the 40th Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus, Palm Springs, California, April 2-6, 2014. Study conducted at Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD and Johns Hopkins Bayview Medical Center, Baltimore, MD
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Word count: 3,029 Abstract only: 212
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Abstract Purpose To report the presentation and characteristics of strabismus in children with prenatal methadone
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exposure. Methods
The medical records children with prenatal methadone exposure were retrospectively reviewed.
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Those who were evaluated by pediatric ophthalmology were included. Information on the timing and types of prenatal exposure by trimester of pregnancy was then collected from the patients’
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mothers’ charts. The children’s perinatal histories and ophthalmologic findings were collected from their pediatric clinic charts and ophthalmology clinic charts, respectively. Results
A total of 210 children with prenatal methadone exposure were identified, of whom 32 (15.2%)
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underwent eye examinations and 21 (10%) had strabismus. Five patients had esodeviations, with a mean age of onset of 11.6 months; 16 had exodeviations, with a mean age of onset of 6.8 months. Three patients with strabismus were born prematurely, and 2 had intracranial disease.
Conclusions
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Two patients underwent strabismus surgery.
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The incidence of strabismus in patients with prenatal methadone exposure was higher than the general population (10% vs 3%-4%). Intermittent exotropia was the most common type of strabismus and presented earlier than in the general population, with no association with other systemic disease. Prenatal exposure to methadone was likely confounded by exposure to other substances, environmental factors, and genetics. Poor compliance with follow-up reduced the power of the study.
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Methadone maintenance treatment during pregnancy has been shown to improve maternal and neonatal outcomes for women with opioid use disorder.1,2 However, the long-term effects of prenatal exposure to methadone and of neonatal abstinence syndrome (NAS), which may occur
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in 57%-78% of methadone-exposed infants,3,4 are difficult to assess because of the many
confounding factors, including other illicit drug use or licit drug misuse,5 prematurity, and
psychosocial factors. An increased incidence of strabismus compared to the general population,
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as a possible long-term effect of prenatal methadone exposure, has been reported in studies on ophthalmic and neurobehavioral outcomes in this population.6-9 Our study describes the
underwent eye examinations. Subjects and Methods
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presentation and characteristics of strabismus in children with prenatal methadone exposure who
This study was approved by the Johns Hopkins Institutional Review Board. The medical records
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of children born between January 2007 and December 2012 to mothers who were on methadone, other drugs, and alcohol and who were followed at the Center for Addiction and Pregnancy (CAP), a comprehensive, urban drug treatment center that treats pregnant and post-partum
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women and their children, described elsewhere.10 Patients enroll in treatment at any point during their pregnancies and receive obstetric care and substance abuse treatment. Children born to CAP
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patients and who are followed in the CAP pediatric clinic undergo routine well-child examinations and sick appointments. Of the approximately 100 infants born to mothers followed at CAP per year, only approximately 40% can be admitted to the CAP pediatric clinic due to insurance limitations. Year-to-year, the CAP pediatric clinic follows about 350 active patients. The remaining 60% of CAP deliveries are followed at non-CAP pediatric clinics, which refer to various ophthalmologists in the community. A list of all children admitted to the CAP pediatric
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clinic between January 2007 and December 2012 was collected. Among these children, all who were referred to and evaluated by pediatric ophthalmology were included. None of these
parental, or guardian concern about the patients’ eyes or vision.
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identified patients were excluded. Patients were referred if there was primary care physician,
Information about the mothers’ prenatal substance use was collected from the mothers’ CAP clinical records. Prenatal substance use data included methadone dose range by trimester,
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exposure to prescribed buprenorphine, and concurrent exposure to alcohol and tobacco anytime during the pregnancy. Prenatal exposure to the following substances was collected by trimester
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of use: marijuana; cocaine; other opiates, including morphine and opioid-containing pain relievers; benzodiazepines; barbiturates; and methamphetamine. These data were based on patient report and random weekly urine toxicology screenings, which are the standard of care at CAP. Additionally, use of psychotropic and seizure medications was collected by trimester of
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use.
The children’s neonatal data and eye examination findings were collected from their hospital and pediatric ophthalmology clinic charts. Neonatal data included gestational age at
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birth, birth weight, and presence or not of intraventricular hemorrhage, periventricular leukomalacia, or hydrocephalus. Occurrence of NAS and whether or not it required treatment,
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was also noted. All children referred from the CAP pediatric clinic and evaluated by pediatric ophthalmology underwent complete ophthalmologic examinations. From the pediatric ophthalmology clinic charts, we extracted age at presentation to the eye clinic, reported onset of strabismus, and family history of strabismus and/or amblyopia, if known. In addition, we recorded abnormal anterior or posterior segment findings, cycloplegic refraction, presence of nystagmus and amblyopia. Ocular alignment was assessed using cover-uncover and alternate
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prism cover testing at distance and at near in primary gaze. The type of strabismus, control of ocular alignment, and any surgical intervention were recorded. All available follow-up data were recorded, regardless of age.
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Statistical Analysis
Odds ratios were calculated and the Fisher exact test was used to assess for an association
between strabismus and the following prenatal and neonatal variables: methadone exposure by
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trimester, maximum methadone dose during pregnancy, exposure to buprenorphine, alcohol, tobacco, marijuana, cocaine, other opiates, benzodiazepines, barbiturates, or methamphetamine;
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psychotropic medication exposure; known intracranial disease; history of NAS, premature birth (< 37 weeks’ gestation), and small-for-gestational-age status at birth. A P value of <0.05 was considered significant. Results
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A total of 210 CAP pediatric clinic patients who had prenatal methadone exposure and were born between January 2007 and December 2012 were identified. Of these, 32 (15%) were referred to ophthalmology and underwent comprehensive eye examinations by a pediatric ophthalmologist.
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Of the total cohort of 210 patients, 21 (10%) were found to have strabismus. Prenatal exposure data andperinatal and eye examination data are provided in Table 1.
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Over half of the patients (54.5%) without strabismus were born prematurely, whereas
14.3% of patients with strabismus were premature. The mean gestational age (with standard deviation) at delivery of the patients with strabismus was 38.4 ± 2.7 weeks; of patients without strabismus, 35.6 ± 4.0 weeks. The majority of patients in each group were appropriate for gestational age based on published intrauterine growth curves used by the American Academy of Pediatrics.11
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Less than 10% of patients in each group (2 with strabismus and 1 without strabismus) had developed intracranial disease perinatally, including intraventricular hemorrhage, periventricular leukomalacia and hydrocephalus. Most of the patients in both groups (81.0% of patients with
Two patients with mild NAS were not treated pharmacologically.
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strabismus and 90.9% of those without) had NAS, with the majority requiring pharmacotherapy.
None of the patients without strabismus had nystagmus; 5 with strabismus (23.8%) also
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had nystagmus, including sensory defect nystagmus (1 patient), congenital motor nystagmus (1 patient), and fusion maldevelopment nystagmus syndrome (3 patients).
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Of the 21 patients found to have strabismus, 16 had exodeviations (mean age of onset, 6.8 ± 5.5 months), and 5 had esodeviations (mean age of onset, 11.6 ± 7.0 months). See Table 2. All patients with exodeviations had intermittent exotropia or exophoria (1 patient). Stereoacuity was not reliably measured in any patient due to age. Eighteen of the patients with strabismus returned
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for follow-up eye examinations, with a mean follow-up duration of 16.6 months (range, 1-55 months). Only 2 of the 11 patients without strabismus returned for follow-up, 1 at 3 months and 1 at 2 months. Five patients with an exodeviation (31.3%) had improvement of strabismus
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control, including one patient with a macular scar due to toxoplasmosis, whose exodeviation improved with patching. Of the patients with intermittent exotropia, 7 had worsened control,
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including 1 who was not compliant with myopic correction and 1 who had a large-angle of deviation, developed strabismic amblyopia, and underwent strabismus surgery. One patient with intermittent exotropia remained stable. Of the 5 patients with esodeviations, 3 had a constant esotropia and 2 had an intermittent esotropia. One patient with constant esotropia was born at 28 weeks’ gestation and had improvement of strabismus control at final follow-up. Three of these patients had moderate hyperopia and accommodative esotropia. These 3 patients had worsening
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of control; 2 were not compliant with hyperopic correction, and 1 underwent bilateral medial rectus recession. One patient with an esodeviation remained stable with full-time anisohyperopic correction.
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Refractive error among the patients with strabismus ranged from −1.50 to +3.50 D
(spherical equivalent). One patient had 2.50 D of anisometropia. Eight patients were diagnosed with amblyopia due to strabismus, anisometropia, or macular scar due to toxoplasmosis. Among
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patients without strabismus, refractive error ranged from −1.00 to +3.50 D (spherical equivalent). Detailed prenatal exposure data from the mothers’ CAP charts were not available for 8 of
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the 32 patients (25%) referred to ophthalmology (4 with and 4 without strabismus) due to missing charts or missing data. However, prenatal methadone exposure had been reported by all of the children’s parents or guardians during their visits with ophthalmology, and these children were established CAP pediatric patients. Of the 32 patients, 24 (75%) were under the care of a
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biological parent, 6 were under the care of a relative, and 2 were in foster care. The 24 patients for whom detailed prenatal exposure data was collected were exposed to one or more substances in addition to methadone, including alcohol, tobacco, marijuana, cocaine, other opiates
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(including heroin and opioid pain relievers), benzodiazepines, and psychotropic medications prenatally. One patient without strabismus was exposed to buprenorphine, briefly prescribed to
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the patient’s mother as an alternative to methadone, and a second patient without strabismus was exposed to barbiturates prenatally. None of the patients with detailed prenatal exposure data had known exposure to methamphetamine. Methadone exposure by trimester and by maximum dose during pregnancy is shown in Table 3. Most patients were exposed to methadone by the second and third trimesters. There was no statistically significant association between presence of strabismus, and the following prenatal and neonatal variables: methadone exposure by trimester;
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maximum methadone dose during pregnancy; exposure to buprenorphine, alcohol, tobacco, marijuana, cocaine, other opiates, benzodiazepines, barbiturates, or methamphetamine; psychotropic medication exposure; known intracranial disease; history of NAS; premature birth;
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or being small for gestational age. Discussion
The increased incidence of strabismus in patients with prenatal methadone exposure has
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previously been reported to be 14%-25%,6-9,12 which is approximately 3.5 to 8 times that in the general population. In a cohort of children with prenatal methadone exposure, Gill and
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colleagues6 reported no significant association between strabismus and birth weight, head circumference at birth, gestational age, maternal nonopiate drug use, family history of strabismus, or maternal methadone dose. Others have reported an association between strabismus and low birth weight8 in this population, and others have found that infants with prenatal
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methadone exposure had greater likelihood of having a small head circumference, which persisted, and developmental delay,13 each of which alone are associated with an increased risk of strabismus.6 In our cohort, we did not find a difference between children with and without
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strabismus with regard to any of the variables studied. Although prematurity and low birth weight have been reported as risk factors for
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strabismus,14 some studies have found that both are independent risk factors, whereas others have found that only either prematurity or low birth weight are risk factors.14-16 In our study cohort, prematurity was not associated with a higher rate of strabismus; in fact, the inverse was found (P = 0.03), likely due to the relative degree of prematurity in each group. One of the 3 premature patients in the strabismus group was born before 32 weeks, whereas 4 of the 6 premature patients in the nonstrabismus group were born before 32 weeks. This may also be a
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chance finding due to the small sample size. A positive family history is also a risk factor for strabismus. This information was not
statistically significant association with presence of strabismus.
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consistently available or complete; however, analysis of the available data did not find a
Gill and colleagues6 reported a mean age of strabismus onset of 8.3 months (range, 0-19 months) in their cohort. We report a younger mean age of onset of intermittent exotropia in our
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cohort than in the general population (mean age of onset, 33 months; median, 12 months).17 In the general population, improvement of control occurs in 26% of cases, similar to our cohort.
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The mean age of onset of an esodeviation was also younger in our cohort than in the general population (mean age of onset, 2.5 years).18
Infantile exotropia presenting in the first year of life, more than esotropia, is associated with coexisting ocular or systemic disease, most commonly neurologic disease and
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prematurity.19 None of the patients in our cohort had a constant exotropia. The 2 patients with strabismus and intracranial disease in our cohort had intermittent exotropia and esotropia. Of the 3 premature patients with strabismus, 1 each had intermittent exotropia, intermittent esotropia,
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and constant esotropia. We found less diagnosed systemic disease in our cohort, including neurological disease and prematurity, than expected among the patients with strabismus and
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especially among the patients with an exodeviation with early age of onset. Spiteri Cornish and colleagues9 also reported on the types of strabismus presenting in children with prenatal illicit substance exposure, with the most common being constant esotropia. Although their study was comparatively large and included 46 patients with strabismus, the exposed population included children with prenatal illicit substance exposure both with and without methadone exposure. Nystagmus has also been reported to occur more frequently in children with prenatal
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methadone exposure, occurring in 3.7% of children in a study by Spiteri Cornish and colleagues.9 Of the 5 patients who had nystagmus in our study, 1 had a unilateral macular scar due to toxoplasmosis, 1 had a history of prematurity and intraventricular hemorrhage, and 1 had
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developmental delay and was born full-term. The remaining 2 were born full-term with no
known intracranial disease or developmental delay. Prenatal opiate exposure likely affects the developing visual pathways and increases the risk of nystagmus. Abnormal visual pathways have
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been demonstrated with flash visual evoked potential (VEP) testing, which were markedly
different within the first 3 days of life in full-term infants with prenatal drug exposure compared
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to control infants.20 These VEP abnormalities persisted to 6 months of age, and 11% had nystagmus.12
The incidences of gestational opioid use disorders and medication-assisted treatment for these disorders have been increasing overall,21,22 as has average methadone doses used for
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treatment.22,23 Prior reports have considered >20 to 40 mg/day8 to be high dose; the maximum dose range in our group was 30–140 mg/day. We considered ≥100 mg/day to be high dose. NAS develops in 60%-80% of infants with prenatal methadone or buprenorphine exposure, 65%
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requiring treatment.24 Higher maternal methadone doses during pregnancy, however, have not been associated with increased incidence of NAS.23,25,26 In our cohort, there was no statistically
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significant association between presence of strabismus and either high-dose prenatal methadone exposure or NAS. Single nucleotide polymorphisms, which have been associated with opioid addiction risk in adults, have also been associated with shorter hospital stays and less need for treatment in infants with NAS, affecting the level of postnatal opiate exposure. There may be neurological effects from both prenatal and postnatal drug exposure, which may partly be a result of genetic factors.27 In our population of patients referred to ophthalmology, NAS occurred in the
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majority of patients but there was no significant association between NAS and strabismus. Gill and colleagues6 and Nelson and colleagues8 also did not find an association between NAS and presence of strabismus, suggesting that prenatal rather than postnatal exposure is more likely
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associated with strabismus.
Due to the relatively small number of patients identified, we included all patients who were referred to ophthalmology from the CAP pediatric clinic, including those with other risk
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factors for strabismus such as prematurity, intracranial disease, macular scar, and positive family history of strabismus, which dilutes our finding of a greater incidence of strabismus in children
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exposed to methadone prenatally. Not all children born at CAP are followed in the CAP pediatric clinic due to insurance limitations; thus, patients followed at an outside pediatric clinic may not have been referred to our ophthalmology clinic, resulting in a potential underestimation of the percentage of patients with strabismus. In addition, the study may have been underpowered to
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find statistically significant associations between prenatal methadone and other drug exposure and strabismus. CAP charts were missing detailed exposure data for 25% of patients’ mothers, which limits the results of the analysis done. In addition, other exposure data may be incomplete,
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despite thorough review of the mothers’ charts. For example, cigarette use was obtained by mother’s report. Cigarette use during pregnancy has been reported to increase the risk of
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strabismus in children.28 Urine toxicology may not detect a substance due to timing or exposure during an early trimester, prior to presenting to CAP. Meconium drug levels were not available. These known and unknown exposures to substances other than methadone are likely confounding factors in our results. In addition, parental history of strabismus onset may be inaccurate, though it is notable that Gill and colleagues6 published strabismus data in this population using only a strabismus questionnaire for parents who deferred an ophthalmologic
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evaluation. Poor compliance with recommended treatments and follow-up, common in this difficult-to-study population, are also factors that may confound the characteristics of strabismus that were collected. Follow-up for the patients with strabismus was limited to a mean of 16.6
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months, with longest follow-up of 55 months. None of the patients without strabismus at their initial evaluation were later found to have strabismus; however, many of these patients did not return for follow-up. Thus, it is unknown whether any patients in this group later developed
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strabismus.
Screening and surveillance of patients with prenatal methadone and other substance
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exposures for ophthalmologic disease, especially strabismus, are recommended. Early referrals are warranted if there are any concerns for strabismus or other eye disease, because intermittent exotropia may present earlier than in the general population. Those treating children with in utero exposure to methadone should be aware of the increased risk of strabismus with prenatal
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methadone exposure. Furthermore, the parents and guardians of these children should be informed of this risk both pre- and postnatally in the context of reported improved maternal and
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neonatal outcomes with maintenance treatment during pregnancy.
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Table 1. Perinatal, clinical, and non-methadone exposure data
0.03 NS NS
17 (81.0)
10 (90.9)
NS
5 (23.8) 10 (47.6)
0 4 (36.4)
NS NS
17 (70.8)
7 (29.2)
0 5 (29.4) 13 (76.5) 5 (29.4) 11 (64.7) 11 (64.7) 6 (35.3) 0 0 12 (70.6) 4 (19.0)
1 (14.3) 2 (28.6) 3 (42.9) 4 (57.1) 5 (71.4) 6 (85.7) 3 (42.9) 1 (14.3) 0 6 (85.7) 4 (36.3)
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6 (54.5) 1 (9.1) 1 (9.1)
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3 (14.3) 4 (19.0) 2 (9.5)
NS NS NS NS NS NS NS NS
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Total patients referred for pediatric ophthalmology exam (N = 32) Premature Small for gestational age Perinatal intracranial a disease Neonatal abstinence syndrome Nystagmus Family history strabismus and/or amblyopia Available exposure data (n = 24) Buprenorphine Alcohol Tobacco Marijuana Cocaine Opiatesb Benzodiazepines Barbiturates Methamphetamine c Psychotropic medications Unavailable prenatal exposure data
Patients with Patients without P value strabismus, no. strabismus, no. (%) (%) n = 21 (66%) n = 11 (34%)
NS
NS, not statistically significant. a
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Intraventricular hemorrhage, periventricular leukomalacia, hydrocephalus. Heroin and opioid pain relievers. c Psychotropic medications: bupropion, buspirone, escitalopram, fluoxetine, hydroxyzine, lithium, mirtazapine, nortriptyline, quetiapine, sertraline, trazodone, valproic acid, venlafaxine. b
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Table 2. Strabismus follow-up data (n = 21)
5 7 1 3 1 3 1
SD, standard deviation. a
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Includes 1 patient with a macular toxoplasmosis scar whose deviation improved with patching. b One patient underwent surgery.
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No.
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Deviation type Exodeviations (n = 16 [76.2%]) a Improved b Worsened Stable No follow-up Esodeviations (n = 5 [23.8%]) Improved b Worsened Stable
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Table 3. Methadone exposure data Patients with Patients without strabismus, no. (%) strabismus, no. (%) P value 17 (70.8) 7 (29.2) 10 (58.8) 3 (42.9) NS 5 (29.4) 3 (42.9) NS 2 (11.8) 1 (14.3) NS 10 (58.8) 4 (57.1) NS 6 (35.3) 3 (42.9) NS a 5 (23.8) 4 (36.4) --
Total available (n = 24) All trimesters 2nd and 3rd trimesters 3rd trimester only Maximum dose <100 mg Maximum dose ≥100 mg Unavailable
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Exposure data
NS, not statistically significant. a
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Includes 1 patient whose substance exposure data was available, but specific methadone dosing data unavailable.