Chapter 92 Pregnancy-Related Diseases
Retinal and choroidal disorders arising in pregnancy
Pre-eclampsia and eclampsia
Early reports gave an impressive rate of visual disturbances. Scotoma, diplopia, dimness of vision, and photopsias were noted in 25% of patients with severe pre-eclampsia and up to 50% of patients with eclampsia.1 Recent studies, discussed below, suggest that the rate of visual disturbance has decreased markedly with improved medical management of pre-eclampsia. Although photic stimuli may predispose to seizures in susceptible patients, the benefits of an ophthalmoscopic examination outweigh the small risk of seizure when an examination is indicated.2
Pre-eclampsia and eclampsia have been associated with a retinopathy similar to hypertensive retinopathy; serous retinal detachments; yellow, opaque retinal pigment epithelium (RPE) lesions; and cortical blindness. Arterial and venous occlusive disease can also occur and may contribute to visual loss. Early studies of retinal disorders in pre-eclampsia have been discussed in previous reviews.3
Retinopathy in pre-eclampsia and eclampsia
Focal or generalized retinal arteriolar narrowing is the most common ocular change seen in pre-eclampsia, but its frequency is declining. Early studies reported arteriolar attenuation in 40–100% of pre-eclamptic patients.4 A retrospective study of fluorescein angiograms in pre-eclamptic patients by Schreyer identified normal retinal vessel caliber in 16 of 16 patients. In contrast, 4 of 14 patients with pre-existing chronic systemic hypertension had retinal vascular changes.5 Jaffe prospectively demonstrated a statistically significant difference in arteriolar caliber between 56 study participants with severe pre-eclampsia and 25 healthy controls, but no difference between 17 patients with mild pre-eclampsia and controls.6 These studies suggest that arteriolar narrowing may be more common in pregnant patients with chronic pre-existing hypertension than those with mild pre-eclampsia. The difference in the reported prevalence of retinopathy between the early and recent literature is probably related to better medical management of pre-eclampsia and its complications.
The cause of retinal arteriolar narrowing seems to be central retinal artery vasospasm suggested by increased central retinal artery blood flow velocity.7 When present, the retinal arteriolar attenuation associated with pre-eclampsia generally resolves after delivery, presumably due to normalization of central retinal artery blood flow. Other typical hypertensive retinopathy changes such as hemorrhages, cotton-wool spots, lipid deposits, diffuse retinal edema, and papilledema are generally not seen in pre-eclampsia6 and should raise suspicion about additional concurrent systemic disease. Recently, Gupta and colleagues found that the severity of retinopathy in pre-eclampsia is directly related to the level of placental insufficiency and intrauterine growth retardation. Serum uric acid levels also had a statistically significant correlation with retinopathy in this group, but the meaning of this finding needs further research to investigate possible causation. Interestingly, the severity of retinopathy did not correlate with degree of systolic or diastolic hypertension, suggesting that retinopathy in pre-eclampsia may be independent of systemic blood pressure.8
Choroidopathy in pre-eclampsia and eclampsia
Choroidal dysfunction is a common ocular complication of pre-eclampsia and eclampsia that manifests clinically as serous retinal detachments or yellow RPE lesions. The serous retinal detachments usually are bilateral and bullous but occasionally are cystic.2,9 In the early twentieth century, serous retinal detachments were seen in 1% of severely pre-eclamptic patients and about 10% of eclamptic patients.10,11 More recently, Saito retrospectively evaluated 31 women with severe pre-eclampsia or eclampsia and found that 40/62 (65%) eyes had serous retinal detachments and 36/62 (58%) had RPE lesions. RPE lesions were usually located in the macular or peripapillary regions, 33/36 (92%) were solitary or grouped, and 3/36 (8%) were large and geographic. After delivery, all serous retinal detachments and RPE lesions resolved. The three eyes with geographic RPE lesions all developed significant chorioretinal atrophy.12 The apparent historical increase in the incidence of serous detachments and RPE lesions is almost certainly due to improved examination instrumentation and diagnostic testing such as fluorescein angiography.
The etiology of choroidal dysfunction is thought to be ischemia based on fluorescein angiography, limited histopathologic study, the presence of Elschnig spots on resolution13 and indocyanine green angiography.14 This is further supported by the observation that posterior ciliary artery blood flow velocity is increased in pre-eclampsia suggesting vasospasm.7 The primary choriocapillaris ischemia presumably leads to RPE ischemia manifest as yellow opacification and/or fluid pump dysfunction allowing subretinal fluid accumulation.
Although serous retinal detachment and RPE dysfunction can cause marked loss of visual acuity, these changes fully resolve postpartum and most patients return to normal vision within a few weeks. Some patients have residual RPE changes in the macula. Years later, these changes can mimic a macular dystrophy or tapetoretinal degeneration.15 Rare patients may develop optic atrophy if chorioretinal atrophy is extensive.16
Saito has suggested that serous detachments are more specific to pre-eclampsia and eclampsia, whereas retinopathy is seen more often in pre-eclampsia superimposed on pre-existing hypertension.17 Retinopathy is associated with higher levels of blood pressure than is serous detachment.18 Although retinopathy was believed to be a reflection of possible placental insufficiency and possible adverse neonatal outcome, serous retinal detachment is not an additional risk factor.19
Postpartum serous detachments have been reported in pre-eclamptic patients,20,21 and there are rare reports of exudative detachments in patients without pre-eclampsia.22,23 While these serous retinal detachments may be mechanistically distinct, they also resolve over several weeks.
The HELLP syndrome consists of hemolysis, elevated liver enzymes, and low platelets, and it is generally associated with severe pre-eclampsia or eclampsia. Bilateral serous retinal detachments and yellow-white subretinal opacities have been seen in rare patients with this disorder.24–28
Other ocular changes seen in pre-eclampsia and eclampsia
Cortical blindness that appears late in pregnancy or shortly after delivery is an uncommon complication of severe pre-eclampsia and eclampsia. The etiology of vision loss may be occipital ischemia in watershed areas from vasospasm,29–32 possibly related to extracellular hypercalcemia,33 ischemia from antiphospholipid antibody-related vascular occlusion,34 vasogenic edema,35–42 petechial41 or larger hemorrhages,42,43 hypertensive encephalopathy,44,45 ischemia from hypotension during delivery,46 or as part of a postictal state.47 Most patients recover normal vision over several weeks. A prospective study by Cunningham showed that 15/15 women with cortical blindness experienced complete recovery over 4 hours to 8 days. CT scanning was obtained in 13/15 and MRI scanning in 5/15 revealing edema and petechial hemorrhages in the occipital cortex.41
The presence of large intracranial hemorrhages may portend a worse prognosis in terms of both mortality and visual recovery. Akan evaluated CT scans from 22 patients with neurologic complications from eclampsia and found that 2 of the 3 patients who died had massive intracranial hemorrhages.42 Drislane found that among 4 patients with severe pre-eclampsia and multifocal cerebral hemorrhages, 1 died and the 3 others developed prolonged cognitive deficits.43
Cortical vision loss has been reported in eight patients with HELLP syndrome. One had postictal cortical dysfunction,47 one had venous sinus thrombosis,48 two had signs of cortical ischemia or edema,49,50 and one was idiopathic.51 Three patients (2.7%) in a prospective evaluation of 107 women diagnosed with HELLP syndrome developed cortical blindness.52 Retinal arterial and venous occlusions have been reported in patients with pre-eclampsia. These may be a cause of irreversible visual loss and will be discussed later. Other ocular disorders reported associated with pre-eclampsia and eclampsia include ischemic optic neuropathy53 and optic neuritis,54,55 ischemic papillophlebitis,56 peripheral retinal neovascularization,57 choroidal neovascularization,58 macular edema,59 macular ischemia,60 and a tear of the retinal pigment epithelium.61 One patient with HELLP syndrome was reported to have developed a vitreous hemorrhage.62
Central serous chorioretinopathy
Central serous chorioretinopathy (CSC) is caused by localized RPE dysfunction resulting in the accumulation of subretinal fluid. People between the ages of 20 and 50 years are typically affected and there is an 8 : 1 male predominance.63 Pregnancy may predispose some women to CSC. The limited amount of information available concerning CSC in pregnancy makes it difficult to determine whether CSC during pregnancy is typical CSC coincident with pregnancy or if it is a separate disorder possibly related to the hormonal hypercoagulability or hemodynamic changes of pregnancy.
Only a few dozen cases of CSC associated with pregnancy are reported in the medical literature.64–72 Unlike the serous retinal detachments observed in pre-eclampsia and eclampsia, CSC is generally unilateral. The women were all previously healthy and no cases were associated with pre-eclampsia or eclampsia. No patients had antecedent eye disease other than refractive error. Primiparas and multiparas were both represented. Most of the cases developed in the third trimester and all resolved spontaneously within a few months after delivery. There were no cases of significant visual sequelae.
Pregnancy associated CSC may recur in the context or outside of subsequent pregnancy. CSC recurred in at least two women, always in the same eye, in subsequent pregnancies. One patient had four successive pregnancies with CSC,70 and one had two successive pregnancies complicated by CSC.71 There is also one case report of a woman developing CSC 1 month postpartum in two successive pregnancies.72 However, there is also a report of a woman with CSC in her third pregnancy who did not experience a recurrence during a subsequent pregnancy.67 So the occurrence of CSC during one pregnancy does not necessarily mean that it will recur with future pregnancies. There is a report of one patient who experienced a recurrence of CSC outside the context of pregnancy.67
There is an increased incidence of subretinal white exudates (presumed to be fibrin) in pregnancy-associated CSC (approximately 90%) compared to CSC in males and nonpregnant women (approximately 10%). Sunness reported that 3 of 4 patients with pregnancy-related CSC had subretinal exudates.67 Gass found that 6/6 cases of pregnancy related CSC had subretinal exudates compared to only 6/50 (12%) of non-pregnancy related cases.68 However, a recent series of 3 pregnant women with CSC without any exudates has been reported.73 The cause of this higher prevalence of subretinal exudates in pregnant women is unknown.
Occlusive vascular disorders
An increase in the level of clotting factors and clotting activity occurs during pregnancy.74 Several pathologic sources of thrombosis and embolic events can also occur. One review of ischemic cerebrovascular disease suggested that pregnancy is associated with a 13-fold increase in the risk of cerebral infarctions compared to nonpregnant women.75 This increased risk of vaso-occlusive disease may also manifest as retinal or choroidal vascular occlusions.
Retinal artery occlusion
Two cases of unilateral central retinal artery occlusion (CRAO),76,77 one case of bilateral CRAO,78 five cases of unilateral branch retinal artery occlusion (BRAO),79,80 and 3 cases of bilateral multiple BRAO75 have been reported in association with pregnancy and in the absence of additional risk factors. One case of cilioretinal artery occlusion has been reported.81 Three cases of arteriolar occlusion were associated with pre-eclampsia78,82 and 1 was associated with disc edema.80 Five of the 12 (42%) cases occurred within 24 hours of delivery, suggesting that this is a particularly susceptible period. Two of the patients with unilateral BRAO also were found to have mild transient protein S deficiency upon further systemic workup.83
Blodi reported that multiple retinal arteriolar occlusions were seen within 24 hours after childbirth in four women. Two patients were pre-eclamptic and required cesarean section. One of the two also had evidence of cerebral infarctions. The third patient had hypertension, pancreatitis, and premature labor. The fourth was a previously healthy 16-year-old who had an oxytocin-induced labor and had a generalized seizure 2 hours after delivery. The patients reported decreased vision and all had fundus findings characterized by retinal patches characteristic of ischemia and intraretinal hemorrhages that were similar to Purtscher’s retinopathy. After resolution, patients were left with focal arteriolar narrowing and optic disc pallor. The visual acuities ranged from 20/20 to 4/200 and visual field defects were compatible with the areas of occlusion. The authors suggest that complement-induced leukoemboli could have caused the retinal arteriolar occlusions.82
At least eight additional cases of pregnancy-associated BRAO have been reported in the literature.84–90 However, all of these cases had significant additional risk factors for vascular occlusion. Since pregnancy is a common condition, it is difficult to know whether these cases represent true pregnancy associations, multifactorial or synergistic etiologies, or just chance occurrences. One case was associated with intramuscular progestogen therapy for a threatened abortion.84 Three cases that occurred postpartum were associated with hypercoagulability from protein C85 or protein S82,86 deficiency. Two cases were associated with thromboembolic occlusions attributed to mitral valve prolapse87 and amniotic fluid embolism.88 The final 2 cases developed BRAO in the first trimester in association with migraine headaches.89
Retinal vein occlusion
Retinal vein occlusion associated with pregnancy is exceedingly rare. Only 5 pregnancy-related central retinal vein occlusions (CRVO) have been reported to date91–93 and we are not aware of any branch retinal vein occlusions. A study of central retinal vein occlusions with diurnal intraocular pressure determination in young adults included a 33-year-old pregnant woman in her third trimester who had unilateral venous dilation and tortuosity with two subretinal hemorrhages and mild foveal edema.91 Gabsi reported the case of a 27-year-old who was 6 months pregnant when she developed a unilateral CRVO. The authors suggested impaired fibrinolysis after venous stasis as a possible mechanism.92 A 30-year-old woman presented in the 28th week of her second pregnancy with HELLP syndrome. She developed a unilateral CRVO 10 days after emergency caesarean section.93 Rahman reported a case of CRVO associated with pre-eclampsia 3 weeks postpartum in a 20-year-old woman.94 The final case is that of a mild bilateral CRVO that developed early in pregnancy and resolved over several months (J. Wroblewski, personal communication). The paucity of reported cases linking pregnancy to retinal vein occlusion makes the strength of this association suspect.
Disseminated intravascular coagulopathy
Disseminated intravascular coagulopathy (DIC) is an acute pathological process with widespread thrombus formation in small vessels. It can occur in obstetrical complications such as abruptio placentae and intrauterine fetal death that release placental thromboplastin into the maternal circulation and activate the extrinsic coagulation system. This process has a tendency to occlude the posterior choroidal vessels leading to RPE ischemia, dysfunction of the retinal pigment epithelial pump mechanism, and subsequent serous retinal detachments in the macular and peripapillary regions.95–98 The development of serous retinal detachments in pregnancy, especially late pregnancy, may be an early ocular sign of DIC.98 We are aware of case reports of only 2 patients in whom DIC caused serous retinal detachments.95,98 These detachments tend to be bilateral and symptomatic. With recovery from the systemic disorder, vision generally returns to normal with only residual pigmentary change.97,98 Patel reported a case of bilateral retinochoroidal infarction associated with pre-eclampsia and DIC with permanent vision loss.99
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TTP) is a rare, idiopathic, acute, systemic coagulopathy characterized by platelet consumption and thrombus formation in small vessels. TTP occurs at any age with a peak incidence in the third decade of life and a female to male preponderance of 3 : 2. Visual changes occur in approximately 8% of cases100 due to thrombus formation in the choriocapillaris and secondary RPE ischemia. Clinical findings are usually bilateral and include serous retinal detachments, yellow spots at the level of the RPE, and localized arteriolar narrowing. We are aware of 32 reported cases of TTP in association with pregnancy. Sequelae include RPE pigmentary changes and Elschnig spots with a return to baseline vision over several weeks in most cases.100–102
Amniotic fluid embolism
Amniotic fluid embolism is a serious complication of pregnancy with high mortality, second only to pulmonary thromboembolism as a cause of death during pregnancy and the postpartum period. Those patients who survive the initial event usually develop DIC103 with the potential ocular complications described above. Two patients developed multiple branch retinal arteriolar occlusions, presumably related to particulate material from the amniotic fluid.104,105 Another patient had massive blood loss from an amniotic fluid embolism leading to severe retinal and choroidal ischemia and blindness in one eye.106
Uveal melanoma
Pregnancy is heralded by a hormone-dependent tendency to hyperpigmentation and well-known cutaneous changes like chloasma and an increase in pigmentation of pre-existing nevi owing to increased levels of melanocyte-stimulating hormone in pregnancy.107 Although estrogen and progesterone may stimulate melanogenesis, there is no evidence that this can cause malignant transformation of melanocytic cells.
A case–control study by Holly et al. found a decreased risk of uveal melanoma for women who had ever been pregnant with an increase in protective effect with more live births. The largest effect was observed between nulliparous and parous women.108 Others, however, have reported a trend toward a larger-than-expected number of ocular melanomas presenting during pregnancy.109 There are also a number of anecdotal reports of uveal melanomas presenting or growing rapidly during pregnancy.110–115 These reports led to speculation that uveal melanoma may be hormone-responsive but two studies have failed to show any estrogen or progesterone receptor expression in ocular melanomas.113,116 A large retrospective study showed no association of uveal melanoma with the use of oral contraceptives or hormone replacement therapy.117 It is possible that other hormones may be involved113 or that tumor growth may be related to pregnancy-associated immune modulation.
Pregnancy-related uveal melanoma does not seem to differ histologically from uveal melanoma not associated with pregnancy. Shields reported that among 10 pregnancy-related choroidal melanomas evaluated after enucleation the tumors did not differ in cell type, mitotic activity, and other features when compared to a matched group of tumors in nonpregnant women.118
The treatment of pregnancy-associated uveal melanoma has been described in two studies. Among 16 cases reported by Shields, 10 eyes were enucleated, 4 received plaque radiotherapy during or after pregnancy, and 2 cases were observed. Among 14 of 16 patients who elected to carry the pregnancy to term, all delivered healthy babies with no infant or placental metastases.118 Romanowska-Dixon reported 8 cases in which there were no treatment-related pregnancy complications. The authors do suggest that brachytherapy is safer towards the end of pregnancy or after delivery.119
Childbearing may be associated with improved survival in choroidal melanoma. Egan et al. performed a large prospective cohort study in which death rates from metastasis were 25% higher in nulliparous women and men than in women who had given birth. The protective influence of parity was greatest in the first 3 years of follow-up and increased with the number of live births.120 These results contradict a small earlier study by the same group that concluded rates of metastasis were not higher among women who reported pregnancies or oral contraceptive use.121 A much smaller study by Shields also showed similar 5-year survival between pregnant and non-pregnant women with posterior uveal melanoma.118
Other changes arising in pregnancy
A choroidal osteoma has been reported that presented in the ninth month of pregnancy with visual loss due to choroidal neovascularization.122 Cases of acute macular neuroretinopathy,123,124 Valsalva maculopathy,125 and cystoid macular edema126 have been observed in the immediate postpartum period. Placental metastases from orbital rhabdomyosarcoma127 and primary ocular melanoma have been reported.128
Pre-existing conditions
Diabetic retinopathy
The modern medical, ophthalmologic, and obstetrical management of pregnant diabetic patients has greatly improved the outcome of pregnancy for both the fetus and the mother. Laser photocoagulation has reduced the risk of vision loss from diabetic retinopathy and improved glucose control has improved the likelihood of good fetal outcomes. Well-controlled blood glucose and adequate glycosylated hemoglobin (HbA1c) before conception and throughout the pregnancy may reduce the risk of spontaneous abortion,129,130 congenital anomalies, and fetal morbidity.131 A recent study suggested that the severity of diabetic retinopathy may be a significant factor in predicting adverse fetal outcomes, even after correcting for blood glucose control.132 Another study suggested, however, that blood glucose control may counteract adverse fetal effects associated with maternal retinopathy and nephropathy.133
Diabetic women who may become pregnant should establish excellent glucose control before conception, since the major period of fetal organogenesis may take place before the mother is even aware that she is pregnant. In addition, a diabetic woman’s retinopathy status should be evaluated and stabilized prior to conception. This is particularly important for patients with severe nonproliferative or proliferative retinopathy because scatter laser photocoagulation may reduce progression during pregnancy.134 Laser treatment of diabetic macular edema before pregnancy may also be important, although the effects of pregnancy on macula edema have not been adequately studied.
The Diabetes in Early Pregnancy Study (DIEP), a study of 155 insulin-dependent diabetic pregnancies,135 as well as the data from the Diabetic Control and Complications Trial136 and the previous data summarized by Sunness,134 all provide evidence that better metabolic control before pregnancy diminishes the progression of diabetic retinopathy. Recent studies have found a strong correlation between the glycosylated hemoglobin level in the first month and the degree of deterioration once tight metabolic control is achieved.135 Nerve fiber layer infarctions commonly are associated with the institution of tight metabolic control of chronic hyperglycemic patients. One study described the retinopathy status of 13 patients managed by insulin pump during pregnancy. Two patients who had rapid decrease in the HbA1c level developed acute ischemic changes and ultimately proliferative retinopathy.136 However, the long-term benefits of adequate blood glucose control outweigh concerns about the transient worsening of retinopathy that has been associated with the sudden imposition of tight metabolic control.137–139
The frequency of ophthalmic follow-up of a diabetic patient during pregnancy is determined by her baseline retinopathy status. Guidelines for eye care in diabetic patients recommend that a diabetic woman planning pregnancy within 12 months should be under the care of an ophthalmologist, undergo repeat evaluation in the first trimester, and after that at intervals dependent on the initial findings.132,140
Progression of diabetic retinopathy during pregnancy
Retinal hemodynamics may play an important role. The increase in cardiac output combined with decreased peripheral vascular resistance during pregnancy141 have been suggested as pathogenic factors for the development or progression of diabetic retinopathy. Three studies suggest that retinal hyperperfusion may exacerbate pre-existing microvascular damage.142–144 In contrast, two studies report a reduction in retinal capillary blood flow that may exacerbate ischemia and lead to retinopathy progression.145,146 Other studies have suggested a possible role for various growth factors found at increased concentrations during pregnancy such as IGF-1,147 phosphorylated IGF-binding protein,148 placenta growth factor,149,150 endothelin-1,151 and fibroblast growth factor-2.152 These factors may exert additive or synergistic effects.153
Short- and long-term effects of pregnancy on diabetic retinopathy
Since there is a high rate of regression of retinopathy during the postpartum period, one must consider short-term and long-term changes separately. The DCCT research group reported that pregnant women in the conventional treatment group were 2.9 times more likely to progress three or more levels from baseline retinopathy status than nonpregnant women. The odds ratio peaked during the second trimester and persisted as long as 12 months after delivery.154 One study of short-term effects included 16 women with no retinopathy or nonproliferative retinopathy. Progression during pregnancy was compared to progression between 6 and 15 months postpartum in the same women. The number of microaneurysms showed a rapid increase between the 28th and 35th weeks of pregnancy. Six months postpartum the number of microaneurysms decreased but in most cases remained higher than the baseline level. The number of microaneurysms remained stable over the subsequent 9-month postpartum period.155
Three other studies compared short-term progression of retinopathy between separate control groups of nonpregnant women and pregnant women over the same time period. The first compared the course of diabetic retinopathy in 93 pregnant women and 98 nonpregnant women. Progression was observed in 16% of the pregnant group compared to only 6% in the nonpregnant patients. Furthermore, 32% of the nonpregnant group had retinopathy at baseline compared to only 22% of the pregnant cohort. Therefore, one might have expected more progression in the nonpregnant group due to worse baseline disease, making these findings more significant.156 A second study compared 39 nonpregnant women, 46% of whom had retinopathy at baseline, with 53 pregnant diabetic women, 57% of whom had retinopathy at baseline. In the nonpregnant group the microaneurysms remained stable, streak or blob hemorrhages appeared in three patients (8%), and no nerve fiber layer infarctions developed over 15 months. In the pregnant group, microaneurysms increased moderately, and streak and blob hemorrhages and nerve fiber layer infarctions increased markedly over the same follow-up period. One patient with nonproliferative diabetic retinopathy from the pregnant group developed proliferative retinopathy.157 In the third study, there were 133 pregnant and 241 nonpregnant women. The groups were statistically equivalent in terms of baseline retinopathy levels. Within each quartile of glycosylated hemoglobin, pregnant women had a greater tendency to have worsening of retinopathy and the nonpregnant women had a greater tendency to have improvement in their level of diabetic retinopathy during the follow-up interval.158
