Ophthalmology

Introduction

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.

Results

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.

Drug Exposure

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

Nystagmus

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

Discussion

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.