Continuing Education Activity

Preeclampsia is a disorder that affects pregnant women, most commonly in their third trimester. Characterized by hypertension and proteinuria, it can involve nearly every organ system and often results in significant end-organ dysfunction. Preeclampsia is relatively common in pregnancy, affecting between 3% and 8% of pregnancies worldwide. Visual symptoms occur in up to 40% of affected patients, and the condition can affect multiple parts of the visual pathway. Although the numerous changes that occur in a woman's body during pregnancy usually revert to their pre-pregnant state during the puerperium, many ocular and cortical alterations caused by preeclampsia can persist after parturition. This article highlights the specific etiologies of visual dysfunction in preeclampsia and its management by an interprofessional team.

Objectives:

• Describe the signs and symptoms of visual pathology in preeclampsia.
• Summarize what is known about visual changes in preeclampsia.
• Review specific etiologies of visual impairment in preeclampsia.
• Identify investigations that are required by the interprofessional team for further understanding of visual changes in preeclampsia.

Introduction

Preeclampsia, formerly called toxemia of pregnancy, is a disorder that affects pregnant women, most commonly in their third trimester. Characterized by hypertension and proteinuria, it can involve nearly every organ system and often results in significant end-organ dysfunction. Preeclampsia is relatively common in pregnancy, affecting up to 3% to 8% of pregnancies worldwide.[1][2] Eclampsia is defined by the occurrence of convulsions in a previously preeclamptic woman in the absence of a pre-existing neurologic condition that could account for the seizures. With an incidence of 0.3% of pregnancies, it is less common than preeclampsia but nearly always includes visual symptoms.[3][4] Hemolysis, elevated liver enzymes, and low platelets (HELLP) is a specific syndrome that can occur during the last trimester of pregnancy or shortly after birth; also a complication of pregnancy, it may represent a severe form of preeclampsia where hypertension and renal and central nervous system abnormalities are present, but not the predominant pathology.[1][5]

Visual symptoms occur in 25% to 40% of patients with preeclampsia and can involve nearly every part of the visual pathway. Symptoms can include decreased vision, diplopia, scotoma, or photopsia.[3][6][7] While there are reports on visual dysfunction in preeclampsia in the medical literature dating back to at least the 1930s, the exact mechanisms have remained elusive until the 21st century.[8][9] Although the numerous changes that occur in a woman's body during pregnancy usually revert to their pre-pregnant state during the puerperium, many ocular and cortical alterations caused by preeclampsia can persist after parturition. Identification of the specific etiologies of visual dysfunction in preeclampsia may meaningfully alter their management and prognosis.

Etiology

The etiologies of visual changes in preeclampsia are numerous, as are their resulting manifestations. Preeclampsia is defined as the first instance after 20 weeks of gestation of systolic blood pressure above 140 mm Hg or diastolic blood pressure above 90 mm Hg and proteinuria of greater than 300 mg/day.[1][3][4][3] Visual pathology from preeclampsia can arise de novo or result from exacerbation of pre-existing ocular or intracranial disease by hypertension, which is a hallmark of preeclampsia, and blood-glucose dysregulation that can also be associated.[10] Furthermore, the side effects of pharmacologic agents used in the treatment of toxemia during pregnancy (ie, magnesium sulfate, benzodiazepines, and phenytoin) may result in visual disturbances.[11][12][13]

Epidemiology

Visual changes are physiologic in pregnancy and can be caused by ocular surface, corneal stromal, and lenticular thickness changes, which respond to the expected hormonal variations during the gestational period. These can lead to refractive changes in the structure of the eye but usually result in a myopic shift of less than 1 diopter magnitude.[3] Blurry vision from these structural shifts can be challenging to differentiate from the pathology found in preeclampsia without a comprehensive eye examination, including funduscopy. Optic nerve and retinal changes are not expected in normal pregnancy. Retinal arterial and structural abnormalities are identified in 30 to 100% of patients with preeclampsia and eclampsia. Retinal vascular anomalies have been found in 70% of fundus examinations of patients with preeclampsia; they include arteriole narrowing, tortuosity, and segmental retinal artery vasospasm.[14] Serous retinal detachment (SRD) is found in 1% to 2% of patients with severe preeclampsia and 10% of patients with eclampsia, but the incidence of SRD in HELLP syndrome has not yet been identified. However, numerous case reports have described SRD as the sole presenting symptom of HELLP.[15][16][17][18][19][20] 

Blindness, both reversible and irreversible, has been shown to have a rate of 0.1% to 3%.[3][14][3][21][22] One study of 84,628 deliveries performed at a tertiary referral center had a relatively high incidence of preeclampsia (11.7%) and exhibited an incidence of blindness of 0.17%, with a predominance of cortical blindness as the cause.[21] Cortical blindness has been identified as a cause of visual pathology in 1% to 15% of pregnancies complicated by preeclampsia.[14][23] Nearly one-third of those with preeclampsia and eclampsia have posterior reversible encephalopathy syndrome (PRES)—the most common etiology of cortical visual pathology. The strongest independent risk factors identified for cortical blindness are the presence of seizures and a history of multiple pregnancies.[24] Few studies have been performed to analyze the incidence and prevalence of intraocular and visual pathway pathology in specific populations with preeclampsia. To the author’s knowledge, there are no studies that identify specific risk factors for acute ischemic stroke causing visual symptoms nor ocular/visual pathway toxicity of commonly administered medications in patients with preeclampsia.

Pathophysiology

The pathophysiology of preeclampsia is complex and discussed elsewhere. In brief, abnormal placentation leads to placental ischemia. The ischemia results in the release of hypoxia-induced factors into circulation that are both angiogenic and anti-angiogenic and decreases circulating nitric oxide and hydrogen sulfide. This leads to subsequent endothelial dysfunction, hypertension, vasodilation, proteinuria, and platelet/red blood cell hemolysis.[2] Classic definitions of preeclampsia include only hypertension after 20 weeks of gestation with associated proteinuria. Still, more recently, the American College of Obstetricians and Gynecologists has sought to broaden the definition to include hypertension and end-organ dysfunction after 20 weeks of gestation.[2][25]

Very little is known about cortical visual pathology in pregnancy and preeclampsia. Gilbert, Prassad, and Mallory have published an excellent review of the effect of pregnancy on neuro-ophthalmologic diagnoses, which include pathophysiologic changes in the brain, the eye, and the visual pathway. Still, there are scarce data regarding many of these conditions for preeclampsia.[26] Visual evoked potentials (VEP) have been used to determine the effect of preeclampsia on cortical vision even without visual symptoms. One study by Brusse et al (2018) evaluated VEP by comparing pregnant patients with chronic hypertension, preeclampsia, or normal blood pressure, most of which did not have visual symptoms. They found that VEP latency and amplitude decreased in normotensive mothers and did not change throughout pregnancy. At the same time, patients with preeclampsia, especially severe preeclampsia, had higher VEP latency and were affected by blood pressure alterations. This change was not appreciated in chronically hypertensive mothers. This small study may indicate cerebral changes that are prominent in patients with preeclampsia even without visual symptoms.[27]

One of the most common causes of cortical visual pathology in preeclampsia is progressive reversible encephalopathy syndrome (PRES). PRES is a radiographic and clinical diagnosis of a constellation of central nervous system findings, including visual disturbances. Vasogenic edema in the posterior cerebral lobes can lead to numerous neurologic syndromes involving visual pathways. Although the posterior circulation and associated cerebral lobes (occipital and parietal) are involved, the involvement of the frontal lobes, temporal lobes, basal ganglia, brain stem, and cerebellum has also been demonstrated. The predominant theory that explains why hypertensive changes preferentially affect the posterior cerebral pathways is that the anterior cerebral circulation contains significantly more sympathetic innervation than the posterior cerebral circulation. Thus, when there are sudden changes to intraarterial fluid pressure, the posterior circulation is slower in its physiologic response. Preeclampsia can lead to sudden changes in blood pressure. This likely is why up to a third of patients with preeclampsia who have neurological symptoms are shown to have PRES.[24][28]

Additionally, cortical visual loss can be caused by ischemic cortical disease. Patients with uncomplicated pregnancies experience a hypercoagulable state related to dehydration, hemoconcentration, and markedly upregulated clotting factor levels and experience stroke at three times the rate of age-matched non-pregnant women. Although the incidence of stroke is much lower in reproductive-age women, 7.7% of pregnancy-related deaths in the United States are caused by strokes, and worldwide this number ranges from 2.7% to 20% of pregnancies. Preeclampsia and eclampsia subsequently increase the risk of both hemorrhagic and ischemic stroke, increasing the risk between 2- and 5-fold.[29][30][31][32][33]  Strokes associated with preeclampsia and eclampsia have been shown to occur most frequently after delivery.[34] Numerous case studies have shown visual disability in these patients stemming from parietal, occipital, and temporal lobe strokes.[35][36][37]

Diplopia is an uncommon neuro-ophthalmologic presentation in pregnancy, but one of its principal causes is abducens nerve palsy. The sixth cranial nerve, the abducens nerve, runs a long intracranial course and is the most exposed cranial nerve that runs through the cavernous sinus.[38] This long intracranial course makes it vulnerable to various intracranial pathologies, including increased intracranial pressure, inflammation, and ischemia, all of which can be induced by preeclampsia.[39][40] Multiple case reports have documented diplopia peripartum from abducens nerve palsies and have all resolved relatively quickly after parturition.[41][42][43] Recent studies have shown intraocular pathology in preeclampsia with and without visual symptoms in addition to specific presenting diseases. Significant data identify chorioretinal changes that can be recognized on imaging and ophthalmoscopy. The retina has a dual circulation and is supplied anteriorly by the intraretinal vasculature, while the posterior retina is fed by choroidal circulation.

Studies of the retina are mostly comparative, and the pathophysiology of disease in patients with preeclampsia is limited to correlation with other diseases and observational studies utilizing clinical imaging equipment. Because of this, there are no studies of histopathological specimens from the retinas of patients with preeclampsia. Fundus photography and optical coherence tomography (OCT) imaging of patients with hypertensive retinopathy and those of patients with preeclampsia have shown that both sets of patients develop serious retinal detachments (SRD), subretinal drusenoid deposits (SDDs), and choroidal vascular abnormalities at similar rates and that are clinically indistinguishable.[44][45][46]

Histopathologic specimens of patients with malignant hypertension show significant choroidal arteriole fibrinoid necrosis and subsequent bullous SRD.[44][47] The choroid has different regulatory mechanisms to compensate for changes in blood pressure and is more affected by sudden hypertensive episodes than the retinal vasculature. Choroidal thickening develops in these episodes of sudden hypertension and has been shown in both patients with malignant hypertension and patients with preeclampsia to lead to choroidal ischemia.[45][47][48][47] Further, choroidal ischemia in hypertensive choroidopathy leads to SDDs, such as those seen in preeclampsia.[49] Choroidal ischemia is one of the proposed mechanisms for geographic chorioretinal atrophy, leading to significant permanent central visual acuity loss.[50] Choroidal ischemia has been demonstrated in 30 to 100% of patients with preeclampsia. The choroid supplies the highest blood flow per area in the body. Choroidal blood flow abnormalities lead to retinal pigment epithelium (RPE) pathology and subsequent retinal pathology due to loss of RPE function. Choroidal thickness- and implied subsequent dysfunction- is increased as measured by OCT in patients within one week after delivery. This thickness resolves postpartum. These changes are specific to preeclampsia and are not seen in an uncomplicated pregnancy.[51][52][53][54] 

This change has been postulated to be related to the increased vascular endothelial growth factor (VEGF) production in preeclampsia, and that choroidal vasculature is VEGF-responsive.[55][56] Further, OCT-angiography has shown changes in the choriocapillaris, the smallest capillary channels of the choroid located closest to the posterior retina. Choriocapillaris blood flow is reduced in preeclampsia and may be the cause of these structural changes.[57] More data are required in this field to determine pathophysiologic changes to the retina and choroid in preeclampsia. In contrast to choroidal measurements, retinal structural and functional pathology have been less well-documented. Peripapillary retinal nerve fiber layer (RNFL) measurements are no different during pregnancy when compared with and without preeclampsia. Still, two months post-delivery, RNFL measurements are significantly lower in patients with preeclampsia. RNFL measurements during pregnancy are likely thickened secondary to fluid retention in pregnancy. The difference in RNFL thickness may only be appreciated after resolving the fluid shifts expected during pregnancy.[58][59][60]

Specific pathophysiologic mechanisms are dependent on the cause of pathology. Retinal vasculature changes are not routine in uncomplicated pregnancies, but between 40-100% of pregnancies complicated by preeclampsia show retinal vascular abnormalities, including arterial tortuosity, vessel narrowing, vasospasms, or occlusion. Measurements of retinal artery caliber show that for every 10 mm Hg increase in systolic blood pressure, the luminal volume of retinal arteries decreases by 1.9 µm.[61][62] Despite earlier evidence of exudates, retinal hemorrhages, vitreous hemorrhages, and cotton wool spots, recent prospective OCT analysis of patients with preeclampsia shows that these retinal findings are not associated with blood pressure measurements in these patients. Data in these studies find that fundus changes are related to changes in vascular structure as opposed to those induced by hypertension.[9]

Therapy for preeclampsia may also cause visual disturbances. Magnesium sulfate can cause visual changes due to impaired accommodation, impaired convergence, and ptosis.[12] Benzodiazepines, although less commonly used, decrease contrast sensitivity, impair visual perception, and cause cortical visual cognitive difficulties, especially regarding higher-level visual integration pathways.[13][63] Phenytoin, used as a second-line agent for seizure treatment and prophylaxis in preeclampsia and eclampsia, can cause cone and rod dysfunction and color vision deficits.[64] Although blood pressure needs to be managed in preeclampsia, rapid decreases in blood pressure may prolong visual symptoms.[21][65]

History and Physical

A thorough history can narrow the broad differential diagnosis for vision changes in preeclampsia. Prior pregnancy history, ocular history, medical history, therapeutic interventions, specific descriptions of the visual deficit, and the time-course of visual symptoms are all crucial in determining the etiology of the visual disturbance. Patients' complaints of blurry vision may be specified to include diplopia, visual field defects, metamorphopsia, or other distortions. Physical examination of patients with intracerebral causes of visual impairment can reveal concomitant neurological deficits associated with the location of pathology. Dilated fundus examination findings are common in patients with preeclampsia and most commonly include arterial narrowing, indicative of the hypertensive state. Additional findings may include peripapillary thickening, choroidal thickening, cotton wool spots, retinal hemorrhages, retinal edema, serous retinal detachments, optic nerve edema, or vitreous hemorrhage.[21]

Evaluation

Blood pressure measurements, both systolic and diastolic, and serum creatinine levels are staples of monitoring patients with preeclampsia and may be predictive of changes in dilated fundus examinations.[3] Ophthalmic evaluation, like most interventions in pregnancy, balances the unknown fetal risks of diagnostic maneuvers with the risks of maternal visual and systemic disease. Retinal angiography most commonly involves the intravenous administration of fluorescein dye and is indispensable in diagnosing retinal vascular disease. Although fluorescein can cross the placenta and can be found in breast milk after administration, the authors have found no studies identifying a known risk for its use during pregnancy, and it is currently categorized as a US Food and Drug Administration pregnancy category C drug (risk unknown but cannot be ruled out).[7][66]

However, other valuable diagnostic tools in ophthalmology offer no risk to fetal development, including fundus autofluorescence, B-scan ultrasonography, and optical coherence tomography. These non-invasive tools are essential in the evaluation of retinal, optic nerve, and choroidal pathology.[46][67] Visual field testing, another non-invasive diagnostic modality, can identify scotomata and help localize pathology. Defects can include blind spot enlargement or specific patterns of deficits such as hemi- and quadrantanopsias.[68][69][70] Magnetic resonance imaging of the brain also poses no known risk to the mother or fetus and can demonstrate posterior cerebral edema as seen in PRES; it can also reveal the presence of ischemic or hemorrhagic strokes.[24][29][30][31][32][33]

Treatment / Management

Identifying the etiology of visual impairment affects overall visual prognosis but is most important in systemic disease management and identifying risks to maternal and fetal life. In addition to prompt delivery of the baby, treatment of patients with HELLP syndrome often requires acute blood transfusions and possible liver transplantation; patients with this serious pregnancy complication can be identified by dilated fundus examination. Management of visual impairment in preeclampsia is achieved by controlling the pathophysiologic mechanisms responsible for the condition – specifically, pharmacologic stabilization of abnormal vital signs and metabolic imbalances, magnesium sulfate administration for seizure prophylaxis, and labor induction or delivery as soon as feasible.[1][71][72] Treatment of blood pressure abnormalities in patients with cortical vision loss due to PRES from preeclampsia has been shown to result in the resolution of visual impairment and radiologic findings.[73]

Differential Diagnosis

Vogt Koyanagi Harada Syndrome 

• Patients with this syndrome may present with serous retinal detachments but differ in that their presentation includes bilateral uveitis, vitiligo, poliosis, orbital pain, and auditory symptoms.

Postural and Volume-dependent Vision Changes

• Patients can develop transient episodes of vision loss related to decreased intraarterial volume in states of dehydration.

Posterior Ischemic Optic Neuropathy

• Patients with severe volume losses, such as in cases of significant postpartum hemorrhage, can have vision loss due to decreased perfusion of the optic nerve posterior to the lamina cribrosa.

Amniotic Fluid Embolus

• In case reports, amniotic fluid emboli have been shown to lead to intraocular fundus changes consistent with Purtscher-like retinopathy after delivery.

Increased Intracranial Pressure

• Increased intracranial pressure often presents with papilledema, headaches, and visual changes. This can be primary (idiopathic intracranial hypertension, [IIH]) or secondary (mass lesion, cerebral venous sinus thrombosis, eclampsia, meningitis). In patients who are pregnant, it can be challenging to discern if pregnancy and its associated weight gain and related hormonal changes cause IIH or are exacerbating a patient’s pre-existing disease. Furthermore, cerebral venous sinus thrombosis, which occurs more commonly in pregnant than nonpregnant women, is an important diagnosis not to miss as it is thought to cause approximately 2% of pregnancy-related strokes.

Pertinent Studies and Ongoing Trials

Current studies are evaluating normal and abnormal fundus findings in patients with preeclampsia.[74] Results from a recent study showed a significant relationship between proteinuria and retinal thickness changes similar to hypertensive retinopathy.[9]

Prognosis

Visual impairment and blindness are reversible, with the majority of ocular pathology seen in preeclampsia. In postpartum studies, the majority of patients who experienced visual symptoms of preeclampsia recovered completely. However, longitudinal studies of patients with preeclampsia have shown permanent changes to retinal microvasculature and cerebral white matter. Long-term studies have also demonstrated an increased risk for retinal structural and vascular disease. Patients with preeclampsia have 5.3 times the risk of tractional retinal detachments, an 8.5-fold increase in non-diabetic and diabetic retinopathy, and 3.7 times the risk of retinal breaks later in life.[75] Changes in retinal vasculature have been shown to persist for at least 6 years postpartum.[74]

Patients with preeclampsia have exhibited an increased incidence of white matter lesions and cerebral pathology postpartum. The distribution of lesions in one small study showed statistically significant differences in the location of white matter lesions when comparing patients with and without preeclampsia and eclampsia. Patients with preeclampsia who had white matter lesions had a 100% incidence of frontal lesions and the highest rate of temporal white matter lesions. Patients with eclampsia most represented the presence of parietal white matter lesions.[76][77][78]  Patients with a history of eclampsia have reported significant visual morbidity due to these white matter lesions. Visual field testing in patients after preeclampsia and eclampsia has shown intact visual fields.[79][80]

Complications

Retinal vascular changes and their progression are an indicator of fetal and maternal mortality.[81] Further, improperly managed preeclampsia and eclampsia can lead to permanent visual impairment. Up to 8.5% of patients with preeclampsia can develop subsequent geographic atrophy that significantly affects central vision.[50] Cortical changes have been noted to persist long after delivery and recovery. A long-term study of patients with a history of preeclampsia found increased temporal lobe white matter lesions independent of cardiovascular status and increased in frequency with time after delivery.[82] The visual corroboration with these radiographic findings has yet to be studied.

Preeclampsia is an independent risk factor for future stroke in patients later in life. Estimates of the increased risk include a roughly 80% increased risk for stroke, with the relative risk/odds ratio between 1.87 and 2.02. Childbearing alone can be a risk for atherosclerosis and carotid disease, which can further cause visual symptoms.[83] Stroke and cardiovascular disease during or after pregnancy can lead to numerous causes of visual impairment and is an important sex-specific differential in causes of cerebrovascular accidents.[84][85][86][33] Systemic health concerns exist in patients with preeclampsia, including a 2- to 7-fold increased risk for cardiovascular disease and an increased risk for renal disease.[87][88]

Deterrence and Patient Education

Vision changes in pregnancies complicated by preeclampsia are most commonly due to ocular and/or brain pathology but can occasionally be caused by medical therapy. Patients should be evaluated by obstetric and ophthalmologic professionals to determine the cause. The development of preeclampsia during pregnancy can increase the risk for other eye and brain diseases post-partum.

Pearls and Other Issues

Vision changes in pregnancies complicated by preeclampsia can be caused by intraocular pathology, cortical changes, and medical therapy. Although vision often returns to baseline, retinal abnormalities and white matter lesions can develop during preeclampsia and persist, sometimes even many years after giving birth.

Enhancing Healthcare Team Outcomes

The evaluation and management of preeclampsia in a pregnant patient require collaboration and coordinated care between multiple medical specialties. Technological advancements in intraocular imaging have allowed for a greater appreciation of retinal vascular changes in this condition. Although our understanding of these processes has improved considerably, there is a need for continued study of these patients to improve visual outcomes both during and after pregnancy. Health care providers should be alert to complaints of acute visual changes in pregnant patients as they can be a presenting sign of significant impending morbidity.

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Disclosure: Ethan Stern declares no relevant financial relationships with ineligible companies.

Disclosure: Nancy Blace declares no relevant financial relationships with ineligible companies.