From Royal Victoria Infirmary (MG), Newcastle; Princess Alexandra Eye Pavilion (AOM, GL, BWF), Edinburgh; and Ninewells University Hospital (NDG), Dundee, United Kingdom.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Alan O. Mulvihill, FRCSI, FRSCEd, Princess Alexandra Eye Pavilion, Chalmers Street, Edinburgh, EH3 9HA, United Kingdom. E-mail: email@example.com
The use of drugs during pregnancy is a significant social and medical problem that has been associated with congenital abnormalities in the developing embryo and fetus. A relationship between brain and ocular abnormalities in infants born to mothers who misused cocaine in pregnancy has been reported previously.1–3 Our group has also described nystagmus and reduced visual acuity in 14 children following exposure to opiates and benzodiazepines in utero.4 Since our original publication, other researchers have also reported visual system pathology in children exposed to opiates in pregnancy.5,6 The purpose of this article is to describe an enlarged cohort of 25 children, including changes in visual acuity and nystagmus among 13 who were observed for 6 months or longer.
Patients and Methods
This study was a retrospective case series comprising clinical examination and case note review of 25 children with ocular problems who were exposed to controlled drugs during pregnancy. We included all children with nystagmus and a history of maternal opiate and or benzodiazepine use in pregnancy. We excluded children who were born significantly premature (less than 32 weeks’ gestation). We also excluded children with birth asphyxia, fetal alcohol syndrome, family history of nystagmus, or other recognized causes of infantile nystagmus. The children all attended the pediatric eye service of two university teaching hospitals or their affiliated local clinics.
Most of the subjects were identified from the information provided by the referring pediatrician or general practitioner. We had recently begun to specifically ask the parents or caregivers of infants with unexplained nystagmus whether the child had been exposed to drugs in utero and, interestingly, we frequently found the answer to be yes.
The history of drug exposure was recorded in as much detail as realistically possible by interviewing the parents, other relatives, or foster parents. Unfortunately, a significant number of these children are in social care or have been adopted and little additional information was available. Indeed, the drug history was sometimes uncertain even when the mother was available. Nevertheless, our case series represents a “real-life” scenario and, to the best of our knowledge, is the largest to date to focus on ocular disorders secondary to drug exposure in utero. Moreover, every effort was made to identify from the case notes and eliminate other known risk factors in the mother’s lifestyle that might be responsible for the nystagmus, such as the use of tobacco and alcohol. It is important to note that it is possible and indeed probable that other substances were abused in many cases. For example, significant alcohol abuse was identified in only two cases and this may well be a significant underestimate.
All of the identified children were examined by a consultant pediatric ophthalmologist and information on associated systemic or neurological problems was obtained. All of the children had a complete eye examination, including an age-appropriate assessment of visual acuity recorded in logarithm of the minimum angle of resolution (LogMAR) equivalents. We recorded monocular acuities when possible, but these were often so poor as a result of latent nystagmus that our primary measure of vision remained binocular acuity. The characteristics of the nystagmus were recorded, along with any compensatory head posture. The ophthalmic examination included ocular motility, cover testing, cycloplegic refraction, and funduscopy.
A total of 25 children with visual system problems secondary to drug exposure in utero have been identified to date. The mean age at the initial ocular examination was 18.5 months. The most accurate history possible of in utero drug exposure was ascertained in all cases, but there are inevitably gaps in our knowledge. In many children, the examination was difficult and could not be completed. Although ophthalmic examination can be challenging in many young children, it was particularly difficult in this group of children because many were unusually irritable and uncooperative. Hence, there are some gaps in our data, most notably monocular visual acuities.
Twenty-four children were exposed to opiates and one child was exposed to diazepam alone (Table 1). Of the 24 children exposed to opiates, 22 were exposed to methadone, 6 to heroin, and 1 each to diamorphine and dihydrocodeine. As far as can be ascertained, opiate exposure continued throughout pregnancy in all cases. Of the 6 expectant women using heroin, at least 3 changed to a methadone treatment program once they realized they were pregnant. The 3 other children may have been exposed to both heroin and methadone. Thirteen children exposed to opiates were also exposed to diazepam in utero.
Table 1: History of Drug Exposure, Visual Acuity at Presentation, and Principal Clinical Features
Reason for Referral
Ten children (40%) were referred because of concerns regarding visual development. Eight children (32%) were referred due to suspected strabismus, whereas only 5 (20%) were referred because of nystagmus. In the remaining 2 children, the reason for referral was not clear.
All of the children had horizontal nystagmus (Table 1). The nystagmus was fine and pendular in 10 children and jerk type in 9. In 6 children, the nystagmus type was either not recorded or not clinically discernable. Eight children adopted a compensatory head posture, which dampened their nystagmus to varying degrees (face turn = 5; head tilt = 2; chin up = 1). Where the time of onset of nystagmus was known, it was always prior to 6 months of age. In at least 14 children, the nystagmus increased significantly on side gaze, although the true figure may be higher because many children were reluctant to be examined. The nystagmus clinically improved in only 5 of 13 children for whom we have follow-up data (Table 2). Complete resolution of the nystagmus was not noted in any of the children.
Table 2: Changes to Visual Acuity and Nystagmus Among Children With Significant Follow-up
Many children had a significant latent element to their nystagmus and their vision was significantly worsened when one eye was occluded. Additionally, many children objected strongly to any monocular occlusion or blurring. We therefore used binocular visual acuity as our primary measure of visual acuity. At least 9 children (36%) had delayed visual maturation (DVM) where vision was less than expected for their age but which improved by 6 months of age (Table 1). The true number of children with DVM may be considerably higher because we had incomplete histories for many children. The mean LogMAR binocular acuity at presentation was 0.54 (approximately 6/20) at an average of 22 months of age (for all children studied). Follow-up data of 6 months or more were available for 13 children (Table 2). The mean LogMAR binocular best-corrected visual acuity (BCVA) at presentation in this subgroup was 0.54 at an average of 22 months of age. Children in this group were followed up for an average of 26 months. Among these children, the most recent binocular BCVA improved to 0.4 (approximately 6/15) at an average age of 48 months. In 3 children, visual acuity was actually worse at their latest examination compared to the initial assessment. This is most likely an artifact of overestimation of vision by the testing method, Cardiff acuity cards in all three cases.
Electroretinogram (ERG) testing was normal in the 4 children tested (patients 5, 10, 11, and 21). Several other children had been sent for ERG testing, but had either failed to keep their appointments or were unable to cooperate sufficiently to permit reliable testing.
Two children (patients 2 and 17) had bilateral optic nerve hypoplasia and both had been exposed to methadone and diazepam but did not apparently have significant alcohol exposure. No other retinal or macular abnormalities were identified.
Sixteen children (64%) had strabismus, of whom 15 were esotropic and 1 was exotropic. Fourteen children (56%) had bilateral hyperopia of +2.5 diopters or greater and 1 child was mildly myopic.
At least 12 children (48%) demonstrated signs of drug withdrawal (neonatal abstinence syndrome) after birth, although the true figure may be higher because the only information available to us was the referral letter and the history provided by the caregiver. Eight children (32%) had a diagnosis of developmental delay made by a pediatrician. Furthermore, 5 children (20%) had microcephaly, although none had a specific neurologic diagnosis or seizure disorder. Three children had magnetic resonance imaging of the brain as part of their neurologic work-up; in all 3 cases, the scans showed no evidence of structural brain abnormalities. Visual evoked potentials (VEPs), thought to represent a measure of the response of the occipital cortex to visual stimuli, were normal in one case (patient 5) and showed low amplitude in another (patient 10).
There are now several reports in the medical literature of visual system disorders in children exposed to illicit or controlled drugs during pregnancy. McGlone et al. demonstrated marked differences between flash VEPs recorded in the first 4 days of life from term infants born to mothers misusing drugs and from control infants.5 They reported the VEPs of infants exposed to drugs as being of relatively immature waveform and considerably lower amplitude. They also demonstrated that VEPs were not detectable in 24% of neonates exposed to drugs. Hamilton et al. described a range of visual problems among children born to mothers prescribed methadone during pregnancy.6 Children with neonatal abstinence syndrome significant enough to require pharmacological treatment were particularly prone to problems, especially nystagmus. Additionally, evidence is also emerging of developmental delay and behavioral problems among children exposed to opiates in utero.7 Indeed, Hamilton et al. reported that 25% of children had cerebral visual impairment.6 This figure could even be a significant underestimate because diagnoses of cerebral visual impairment may increase as these children approach school age.
A relationship between brain and ocular abnormalities in infants born to mothers who abused cocaine during pregnancy has been widely reported.8–10 The ocular abnormalities included nystagmus along with strabismus and/or hypoplastic discs.10 The pharmacology of cocaine, with its easy access to fetal circulation and its neurotropic characteristics, has been used to explain these visual abnormalities.11
Nystagmus secondary to opiate exposure in utero appears to be a permanent phenomenon, unlike the transient nystagmus seen as part of the neonatal abstinence (withdrawal) syndrome12 or in clinical studies on normal adult volunteers.13 The paucity of retinal and optic nerve pathology and the normal results of ERG examinations suggests that the visual problems seen in these children are primarily due to deficits in the central nervous system rather than the retina. Two studies demonstrating abnormal VEPs in infants and children exposed to methadone during pregnancy further support a central rather than ocular cause for the nystagmus.5,6 Furthermore, the VEP abnormalities suggest a prenatal etiology.6 Many of the children in our study were also exposed to benzodiazepines, leading us to theorize that benzodiazepines may be contributory to the visual system problems described. However, Hamilton et al. concluded that benzodiazepines were not significantly associated with the development of nystagmus in these children.6 We nonetheless had one child who was exposed to benzodiazepines alone (patient 12) and even on re-questioning the mother was adamant that the only drug used during the pregnancy was diazepam.
The current study demonstrates that nystagmus secondary to opiate exposure in utero does not resolve, but may improve in some children. This is not surprising considering that some forms of nystagmus tend to improve as children get older. Similarly, visual acuity remains considerably reduced, although it may improve a little as children get older. However, the mean level of visual acuity (0.4 LogMAR) at an average of 4 years of age is of significant concern. If no further improvement were to occur, these individuals would be at significant disadvantage as they grew older. This level of vision would preclude most from driving and would significantly reduce their employability.
One of the main limitations of our study is its retrospective design. Although a potential association is described between the use of drugs in utero and the development of nystagmus and reduced vision, it is not possible to determine the number of children exposed to such substances who did not develop nystagmus. Moreover, although we actively sought a history of, and eliminated, other known risk factors that can cause nystagmus, it is still possible that other risk factors in the mother’s lifestyle could be contributory, such as poor nutrition, smoking, and unreported alcohol abuse. Finally, although the history of drug exposure in utero may not be complete in certain cases, our cohort represents a “real-life” scenario and the lack of information would be likely to underestimate the strength of the proposed association between drug exposure and nystagmus.
According to the most recent Drug Misuse Statistics Scotland 2008, 566 maternities with drug misuse were recorded in 2006–2007, giving a rate of 10.4 per 1,000 maternities.14 Opiates were involved in 65% of the maternities for which drug misuse was recorded. Other drugs documented were cannabinoids in 29% and sedatives in 11%. Methadone prescribing rates have risen by 26%, from 76 prescriptions per 1,000 population in 2003 to 2004 to 96 prescriptions per 1,000 population in 2007 to 2008.14 The number of children being born to mothers who misuse drugs is now so great that it has started to have a significant impact on healthcare services and substantial healthcare resources are required for the care of these infants.15 One neonatal unit in Scotland has estimated that infants born to mothers who misuse drugs used 18.2% of the neonatal unit cot days over a 3-year period.16 A study from Switzerland analyzed the neonatal impact of a methadone maintenance program in pregnancy and the social resources of the families involved.17 They demonstrated that infants born to women taking methadone had a fourfold higher incidence of microcephaly compared with the normal population, 62% required pharmacological treatment for neonatal abstinence syndrome, and 42% required placement. We anticipate that we are likely to continue seeing more new cases of infantile nystagmus secondary to drug exposure in utero.
To the best of our knowledge, this is the largest cohort of visual system anomalies secondary to drug exposure in utero to be presented in the medical literature and the first to record significant follow-up. This study provides further confirmation of the potential teratogenic effect of medications prescribed as part of drug treatment programs and emphasizes the need for female drug users to be informed of the associated risks to the fetus.
Exposure to opiates and possibly also benzodiazepines during pregnancy may result in permanently reduced vision and nystagmus. There is a growing body of evidence of the effects of opiate exposure in utero on the development of the brain and visual system. Continued surveillance is essential to look for later onset problems that may reveal themselves, such as cerebral visual impairment and developmental delay. These children are likely to require significant healthcare resources from birth onward.
- Hajnal BL, Ferriero DM, Partridge JC, Dempsey DA, Good WV. Is exposure to cocaine or cigarette smoke during pregnancy associated with infant visual abnormalities?Dev Med Child Neurol. 2004;46:520–525.
- Tsay CH, Partridge JC, Villarreal SF, Good WV, Ferriero DM. Neurologic and ophthalmologic findings in children exposed to cocaine in utero. J Child Neurol. 1996;11:25–30. doi:10.1177/088307389601100106 [CrossRef]
- Good WV, Ferriero D. Ocular effects of prenatal cocaine exposure. Ophthalmology. 1994;101:1321.
- Mulvihill A, Cackett P, George N, Fleck B. Nystagmus secondary to drug exposure in utero. Br J Ophthalmol. 2007;91:613–615. doi:10.1136/bjo.2006.105569 [CrossRef]
- McGlone L, Mactier H, Hamilton R, et al. Visual evoked potentials in infants exposed to methadone in utero. Arch Dis Child. 2008;93:784–786. doi:10.1136/adc.2007.132985 [CrossRef]
- Hamilton R, McGlone L, MacKinnon JR, Russell HC, Bradnam MS, Mactier H. Ophthalmic, clinical and visual electrophysiological findings in children born to mothers prescribed substitute methadone in pregnancy. Br J Ophthalmol. 2010;94:696–700. doi:10.1136/bjo.2009.169284 [CrossRef]
- Hunt RW, Tzioumi D, Collins E, Jeffrey H. Adverse neuro developmental outcome of infants exposed to opiate in utero. Early Hum Dev. 2008;84:29–35. doi:10.1016/j.earlhumdev.2007.01.013 [CrossRef]
- Silva-Araújo A, Tavares MA. Development of the eye after gestational exposure to cocaine: vascular disruption in the retina of rats and humans. Ann N Y Acad Sci. 1996;801:274–288. doi:10.1111/j.1749-6632.1996.tb17448.x [CrossRef]
- Church MW, Crossland WJ, Holmes PA, Overbeck GW, Tilak JP. Effects of prenatal cocaine on hearing, vision, growth, and behavior. Ann N Y Acad Sci. 1998;846:12–28. doi:10.1111/j.1749-6632.1998.tb09723.x [CrossRef]
- Dominguez R, Aguirre Vila-Coro A, Slopis J, Bohan T. Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs. Am J Dis Child. 1991;145:688–695.
- Good WV, Ferriero DM, Golabi M, Kobori JA. Abnormalities of the visual system in infants exposed to cocaine. Ophthalmology. 1992;99:341–346.
- Gaillard M, Borruat F. New finding: transitory horizontal pendular nystagmus secondary to neonatal abstinence syndrome [article in French]. Klin Monatsbl Augenheilkd. 2002;219:317–319. doi:10.1055/s-2002-30650 [CrossRef]
- Rottach K, Wohlgemuth W, Dzaja A, Eggert T, Straube A. Effects of intravenous opioids on eye movements in humans: possible mechanisms. J Neurol. 2002;249:1200–1205. doi:10.1007/s00415-002-0806-1 [CrossRef]
- Drug Misuse Statistics Scotland 2008. Edinburgh: Information Services Division (ISD) Publications, Common Services Agency, National Statistics Releases, Crown Copyright; 2008.
- McGlone L, Mactier H, MacKinnon JR. Outcome in infants exposed to methadone in utero. Br Med J. 2008;337:a1774. doi:10.1136/bmj.a1774 [CrossRef]
- Dryden C, Young D, Hepburn M, Mactier H. Maternal methadone use in pregnancy: factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. BJOG. 2009;116:665–671. doi:10.1111/j.1471-0528.2008.02073.x [CrossRef]
- Arlettaz R, Kashiwagi M, Das-Kundu S, Fauchere JC, Lang A, Bucher HU. Methadone maintenance program in pregnancy in a Swiss perinatal center (II): neonatal outcome and social resources. Acta Obstet Gynecol Scand. 2005;84:145–150.
History of Drug Exposure, Visual Acuity at Presentation, and Principal Clinical Features
|Patient No.||Drug Exposure||Age (Mo)||Initial VA||Presenting Features|
|5||Methadone, heroin||No||6||NF||Esotropia||DVM, normal ERG|
|11||Methadone, heroin||No||15||0.6||Esotropia||Normal ERG|
|21||Methadone||Yes||48||0.7||Pendular||Esotropia||DVM, normal ERG|
Changes to Visual Acuity and Nystagmus Among Children With Significant Follow-up
|Patient No.||Age at Last Exam (Mo)||Follow-up (Mo)||Binocular VA (LogMAR)||Nystagmus Improved|