Prenatal determinants of optic nerve hypoplasia: Review of suggested correlates and future focus

Abstract

Optic nerve hypoplasia (ONH), a congenital malformation characterized by an underdeveloped optic nerve, is a seemingly epidemic cause of childhood blindness and visual impairment with associated lifelong morbidity. Although the prenatal determinants of ONH are unknown, early case reports have led to a longstanding speculation that risky health behaviors (e.g., prenatal use of recreational drugs, alcohol) are a likely culprit. There has yet to be a systematic review of the epidemiology of ONH to assess the common prenatal features that may help focus research efforts in the identification of likely prenatal correlates. A review of the past 50 years of epidemiologic research was conducted to examine the prenatal features linked with ONH and provide direction for future research. There are select prominent prenatal features associated with ONH: young maternal age and primiparity. Commonly implicated prenatal exposures (recreational or pharmaceutical drugs, viral infection, etc.) were rare or uncommon in large cohort studies of ONH and therefore unlikely to be major contributors to ONH. Familial cases and gene mutations are rare. The preponderance of young mothers and primiparity among cases of ONH is striking, although the significance is unclear. Recent research suggests a potential role for prenatal nutrition, weight gain, and factors of deprivation. With the rapidly increasing prevalence of ONH, future research should focus on investigating the relevance of young maternal age and primiparity and exploring the recently suggested etiologic correlates in epidemic clusters of ONH.

Introduction

The birth defect known as optic nerve hypoplasia (ONH) has emerged as the leading single ocular cause of childhood blindness and visual impairment in the United States and Europe.7, 22, 27, 53 Underdevelopment of the optic nerve in one or both eyes is the defining feature (Fig. 1); the diagnosis of ONH is rarely limited to visual impairment alone, however.⁸ Hoyt et al described cases of ONH associated with hypopituitarism, some of which also were missing the septum pellucidum. They incorrectly attributed recognition of this association to Georges de Morsier.³⁴ De Morsier described “septo-optic dysplasia” in a postmortem report in an 84-year-old woman with normal vision, but a vertically rotated optic tract, along with an absent septum pellucidum.¹⁶ He, in fact, did not report optic nerve hypoplasia, nor recognize a syndrome that encompassed other midline brain anomalies. Nonetheless, a definition of septo-optic dysplasia (SOD) has evolved that includes optic nerve hypoplasia associated with midline brain malformations (radiographically absent septum pellucidum, hypoplastic corpus callosum, or pituitary abnormalities) and/or hypopituitarism. A detailed history of the evolution of our understanding of the clinical associations of ONH is reported elsewhere. It is now clear that isolated ONH is uncommon, even when neuroimaging is normal.²⁰

Fewer than 30 cases of ONH were reported prior to 1970.¹⁶ In the subsequent 30 years, the prevalence of ONH increased six-fold to 1.1 per 10,000 children.⁵² The rise in prevalence occurred amidst declines in other causes of childhood visual impairment.⁷ Although some degree of increased surveillance for ONH is probable, this is unlikely to account for the rapid rise.

Despite the progress of clinical research in understanding the profound impact of ONH on childhood development, the etiology of ONH remains largely unknown although numerous prenatal determinants have been suggested. Early case reports31, 32, 33, 42, 44, 62, 72 (lowest level of evidence) incited a long-standing speculation that parental risky health behaviors (e.g., recreational drugs, alcohol) may be to blame, yet larger cohort studies (higher level of evidence)²⁴ fail to confirm this. These prenatal exposures are not likely to be major contributors to ONH, and thus we must look beyond these factors in epidemiologic research on ONH.

We review the literature of the past 50 years to examine the evidence for the prenatal factors purported to predispose offspring to ONH.