This chapter presents information concerning the effects of pregnancy on the mother's eye. The chapter is organized into four sections. The first presents the “normal” or “physiologic” alterations seen in pregnancy in healthy eyes. This is followed by information related to ocular disease processes arising in pregnancy such as pre-eclampsia. The third section deal with the effects of pregnancy on pre-existing eye disease. These categories may overlap somewhat. For example, a pituitary microadenoma that was asymptomatic prior to pregnancy may worsen and only become symptomatic during pregnancy. Finally, information concerning the use of ophthalmic pharmacologic agents during pregnancy is discussed.

Corneal thickness has been reported to increase during pregnancy with resolution a short time after delivery in three studies.^8,11,12 The amount of increase found varied from 1 micron¹¹ to 16 microns.¹² The change appears to be present throughout pregnancy.¹² Two studies found no change in corneal thickness.^10,23 Possible causes of increased corneal thickness include fluid retention that is often associated with pregnancy.¹²

The corneal curvature has been found to increase (steepen) by one diopter on average in the second half of pregnancy, with resolution postpartum or after cessation of breastfeeding.¹⁰ However, the manifest refraction did not change in this study. A second study showed no change in corneal curvature during pregnancy.²³

The changes in corneal thickness and curvature may be factors in pregnant women developing difficulty with previously comfortable contact lenses.^8,10,13–15 Estimates in the literature are that 25% to 30% of contact lens wearers develop problems during pregnancy.^10,15 A woman may develop contact lens intolerance during one pregnancy but not during another.¹⁰ It is not reported whether the symptoms correlate with the degree of corneal curvature and corneal thickness change. A decrease in tear production was found during the third trimester of pregnancy in about 80% of pregnant women studied.¹⁵ Other changes such as conjunctival modification and lid edema also may be factors leading to discomfort with contact lens wear.¹⁵ It is preferable to avoid prescribing a new correction for patients until several weeks postpartum if this is possible.

There is some weak evidence suggesting that pregnancy may alter corneal immune function. One case report describes bilateral herpes simplex virus (HSV) keratitis in a pregnant contact lens wearer. The authors suggest that pregnancy-associated immunosuppression and contact lens wear may have an additive effect and increase the possibility of HSV recurrence.¹⁶ A retrospective study of 3,608 corneal grafts found that pregnancy was a statistically significant univariate risk factor for graft failure.¹⁷ This suggests that pregnancy might be a risk factor for graft rejection in some patients.

One report suggests that photorefractive keratectomy (PRK) near or during the time of pregnancy may lead to suboptimal outcomes.¹⁸ Another study showed myopic regression in 12/18 (66%) and corneal haze in 10/12 (83%) of PRK eyes during pregnancy. The corneal haze and myopic regression improved in 50% of eyes after delivery.¹⁹ A third study failed to demonstrate impaired PRK outcomes after pregnancy.²⁰

Krukenberg spindles are found more commonly in pregnant women, unassociated with other evidence of pigmentary dispersion. The spindles become smaller late in pregnancy and postpartum. It has been hypothesized that the development of Krukenberg spindles may be related to hormonal changes, and that resolution late in pregnancy relates to increased facility of outflow.²¹

There is one case report of a woman with bilateral keratoconus who developed corneal perforation late in pregnancy.²² The authors suggest a possible role of pregnancy in the development of perforation although this finding may be incidental.

One cross-sectional study compared 38 nonpregnant to 93 pregnant women and found no differences in refractive error, corneal curvature, corneal thickness, accommodative amplitude, AC/A ratio, and fusion break ranges between the two groups.²³

Two studies have demonstrated that intraocular pressure is higher in the peripartum period for women with third trimester hypertension or pre-eclampsia than in normotensive pregnant women.^29,32 A third study failed to corroborate this association.²⁴

Several etiologies for pregnancy-related reduction in intraocular pressure have been proposed. There is an increased facility of outflow^33–36 and increased uveoscleral outflow,²⁴ possibly related to hormonal effects. Changes in progesterone levels during pregnancy may correlate with changes in intraocular pressure.³⁷ There may be decreased episcleral venous pressure,^38,39 consistent with a general decrease of venous pressure in the upper extremities during pregnancy. Finally, there is also a small change in ocular rigidity during pregnancy.⁴⁰ Aqueous production appears to remain constant during pregnancy.^36,37

One case of acute angle closure glaucoma during labor has been reported. However, the patient was later believed to have had unrecognized subacute attacks prior to pregnancy.⁴¹

An increase in lens autofluorescence has been reported in pregnant patients with diabetes compared with nonpregnant diabetic patients.⁴⁴ This observation suggests the possibility of lenticular metabolic alterations during pregnancy.

A recent case-control study from central India⁴⁵ showed that having more than three babies doubled the risk of developing bilateral cataracts in the 35- to 45-year age range. The extent to which this is related to nutritional status is not clear.

Patients with hyperemesis gravidarum (pernicious vomiting in pregnancy) can develop thiamine deficiency, leading to Wernicke's encephalopathy with nystagmus and extraocular muscle palsies.^47–53

VISUAL FIELD

A number of different studies of visual fields during pregnancy were performed in the first half of this century, motivated by findings of pituitary enlargement during pregnancy.⁵⁴ Some studies found no change in most pregnant women,⁵⁵ some found concentric constriction,⁵⁶ and some found bitemporal constriction.^57–59 These early studies found changes most prominently late in the pregnancy that generally resolved by 2 weeks postpartum. Patient fatigue and nonuniform equipment and illumination may have been factors in these findings.⁵⁵ It is important to know that none of these healthy women was symptomatic in terms of visual field change.

No recent studies of visual fields in normal pregnant women have been performed. It is felt that the increase in size of the pituitary gland during pregnancy is not sufficient to cause visual field change except when there is an unusual position of the pituitary relative to the optic chiasm.⁵⁴

A complaint of visual field change in a pregnant woman should not be dismissed. Rather, it should be considered an indication for evaluation for a possible disease process such as an enlarging pituitary adenoma, meningioma, or lymphocytic hypophysitis (discussed in the following).

NORMAL PITUITARY

It was reported as early as 1909 that the normal pituitary gland undergoes enlargement during pregnancy. This was confirmed by later work⁶⁴ and by recent studies using magnetic resonance imaging (MRI).^65,66 Beyond the first week postpartum, the pituitary rapidly returns to normal size regardless of the status of breastfeeding.⁶⁶ Pregnancy-related pituitary enlargement is associated with an increased number of prolactin-secreting cells present during pregnancy.⁶⁷ MRI also demonstrates increased intensity of the anterior lobe of the pituitary that is thought to be related to this increase in prolactin-secreting cells and to possible increases in endoplasmic reticulum.⁶⁸ This enlargement does not lead to visual field defects. Therefore, a visual field defect in a pregnant woman should be evaluated for a possible pathologic cause.

INTRACRANIAL DISORDERS

Pituitary adenomas and meningiomas do appear to become more symptomatic and grow more rapidly during pregnancy, although intracranial tumors overall do not appear to be more frequent than in nonpregnant women.^60,61 Because some of the symptoms of intracranial processes, such as nausea and vomiting, may be related to pregnancy alone, there may be a delay in diagnosing intracranial disorders. Intracranial disorders should be included in the differential diagnosis of pregnant women with visual acuity or visual field loss, persistent headaches, or oculomotor palsies,^62,63 while realizing that other processes may be responsible as well.

Pituitary Adenoma

Asymptomatic pituitary adenomas are common. A recent meta-analysis estimated the prevalence of pituitary adenomas at 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies).⁶⁹ Historically, these tumors have been characterized based on size with microadenomas measuring less that 1 cm and macroadenomas measuring greater than or equal to 1 cm. Although pituitary adenomas are now further classified according to immunohistochemistry and functional status, the risk of visual changes in pregnant women with pituitary adenomas is related primarily to tumor size.

The availability of drugs such as bromocriptine and cabergoline to induce ovulation in women with amenorrhea and amenorrhea allow many women with pituitary adenomas to conceive.⁸⁸ Pituitary adenomas can enlarge during pregnancy, probably as a result of a combination of the physiologic enlargement seen in normal pregnant women and growth of tumor. An MRI study of 17 pregnancies in women with prolactinomas reported no change in size in 45%, increased size in 27%, and decreased size in 27%.⁷² Another investigation estimated the risk of adenoma growth during pregnancy at 1% for microadenomas and 23% for macroadenomas.⁷³ The critical clinical issue for the ophthalmologist is whether this enlargement is associated with visual symptoms and signs, which then warrant treatment during pregnancy.

The most common visual findings are bitemporal visual field defects and visual acuity decrease (Fig. 1),⁷⁸ but other visual disturbance, headaches, and rare diplopia also may be seen.^74,75 The risk of a woman developing visual loss during pregnancy primarily is related to tumor size. A cohort study of 111 pregnancies in 65 women found that six of eight (75%) with macroadenomas, whereas none of 57 (0%) with microadenomas developed vision loss during pregnancy.⁷⁰ A smaller study of four women with macroprolactinomas similarly showed irreversible visual field loss in three of four (75%).⁷¹ A third study found a rate of visual involvement in five of 91 (5.5%) with microadenomas and 36% of macroadenomas.⁷⁶ In contrast, one study reported that only one of 14 pregnant women with large prolactinomas developed visual field defects during pregnancy.⁷⁷ A final study reported that four of 18 (22%) with adenomas developed visual loss but tumors were not differentiated according to size.⁷⁸

There is often spontaneous regression of the adenoma postpartum (see Fig. 1), so that the decision to treat depends on the severity of visual findings during pregnancy, and how early in pregnancy the findings developed.⁷⁴ Fortunately, the dopamine agonists bromocriptine and cabergoline can cause tumor regression both within and outside of the context of pregnancy. Many studies have demonstrated the efficacy of bromocriptine for pregnancy-associated adenoma progression^79–85 and there have not been any reports of adverse pregnancy outcomes related to the drug.^83–85 Cabergoline also appears to be effective^86,87 and safe⁸⁷ during pregnancy. One case report describes the successful treatment of a thyrotropin secreting macroadenoma during pregnancy with octreotide resulting in improved visual fields, reduced tumor size, and good pregnancy outcome. Surgical therapy of symptomatic adenomas also has been successfully employed during pregnancy.⁸⁰

Because the risk of symptomatic progression of a microadenoma during pregnancy is small, discontinuation of dopamine agonist therapy should be considered once pregnancy is confirmed. Treatment options for patients with macroadenomas include discontinuation of dopamine agonist therapy when pregnancy is confirmed and reinstituting therapy if the patient develops vision loss, continuous dopamine agonist therapy throughout pregnancy, and surgical debulking of the tumor prior to pregnancy.⁸⁹ Decisions regarding management should be guided by an ophthalmologist, endocrinologist, obstetrician, radiologist, and possibly a neurosurgeon.

Intracranial Meningioma

Sixty-five percent of all intracranial meningiomas occur in women.¹⁹² Growth of these tumors is typically slow, producing insidious visual disturbances. In contrast, during pregnancy some meningiomas rapidly enlarge producing dramatic and relatively acute vision loss^193,194 The diagnosis can be delayed because nausea, vomiting, and other symptoms caused by the tumor may be attributed to pregnancy.¹⁹³ The tumors present more commonly during the second half of pregnancy.⁶¹ The predominance of meningiomas in women, their accelerated growth during pregnancy and the luteal phase of menstruation, and an association with breast cancer led to studies examining the potential role of hormones on meningioma growth.²⁰⁰ Subsequent studies have supported this association by demonstrating that about 70% of meningiomas express progesterone receptors and approximately 30% express estrogen receptors.²⁰¹

Ocular findings can include decreased visual acuity, visual field defects that depend on the location of the tumor, oculomotor palsies, papilledema, and late optic atrophy.^195–199 Symptoms may abate spontaneously after delivery and can recur during subsequent pregnancies.^193,202 Hormone-responsive intracranial meningiomas should be considered in the differential diagnosis of visual disturbances during pregnancy.¹⁹³ Close cooperation among ophthalmologist, neurosurgeon, obstetrician, and neonatologist are essential for an optimal outcome.

The treatment of choice during pregnancy is usually surgical excision,¹⁹³ but brachytherapy has been decribed²⁰³ and external beam radiation may be considered. Antiprogesterone therapy may be effective in receptor positive cases but is unlikely to have a role during pregnancy.

Lymphocytic Hypophysitis

Lymphocytic hypophysitis (LH) or adenohypophysitis is a rare autoimmune condition that occurs most frequently in women in the last trimester of pregnancy or the early postpartum period. The most common presenting symptoms are visual field defects and headache. Most patients show signs of isolated or multiple pituitary hormone deficiencies. Adrenocorticotropin hormone (ACTH) secretion is most frequently impaired, followed by thyroid stimulating hormone (TSH) gonadotropins, growth hormone (GH), and prolactin (PRL). One-third of the cases involve hyperprolactinemia.⁹⁰

One study of 16 patients found that 63% had anterior pituitary hypofunction, 56% had symptoms consistent with an expanding pituitary mass, 38% had hyperprolactinemia, 25% had associated autoimmune thyroiditis, and 19% had diabetes insipidus. Computed tomography (CT) and MRI scanning demonstrated a pituitary mass mimicking an adenoma in 83% of cases.⁹¹

Because LH can present with headache, visual field defects, hyperprolactinemia, and a pituitary mass by imaging, this disorder can be difficult to distinguish clinically from a prolactinoma. However, this differentiation is critical because a failure to recognize LH can lead to untreated pituitary insufficiency and death⁹² and an incorrect diagnosis of pituitary adenoma may lead to unnecessary transsphenoidal surgery. A study of 45 patients with lymphocytic hypophysitis and 806 with pituitary adenoma during pregnancy found that history and endocrinologic evaluation will usually differentiate these disorders. The spontaneous pregnancy rate was 100% in LH, whereas only 2.4% in patients with pituitary adenoma. Prolactin levels averaged 34.6 in LH compared with 393 for pituitary adenomas. Hypothyroidism and hypocortisolism were present in 57.5% of LH cases but only 2.5% of patients with pituitary adenomas. There were no distinguishing features on radiographic studies.⁹³

The authors recommend that patients presenting to an ophthalmologist during pregnancy with signs and symptoms consistent with a pituitary disorder be co-managed with an endocrinologist, obstetrician, radiologist, and possibly a neurosurgeon.

There is strong anecdotal evidence in the form of case reports that treatment with steroids can lead to marked improvement in vision loss from LH and possibly avoid permanent pituitary insufficiency in some cases.^94–98 Most cases lead to varying degrees of irreversible visual field loss or pituitary insufficiency. However, there are five reported cases of complete recovery^98–102 and only one of those cases was treated with steroids.⁹⁸

Little was known about the etiology of LH until recently. Serum autoantibodies directed against a 49-kDa cytosolic protein had been detected by immunoblotting in 70% of patients with biopsy proven LH. In 2002, the target pituitary autoantigen was identified as alpha-enolase¹⁰³ and similar autoantigen targeting of the gamma-enolase isoform found in placental tissue was soon found.¹⁰⁴ This established a direct link between pituitary and placental autoantigens and provides a theoretical basis for the strong predilection for LH to occur during or shortly after pregnancy. The authors are not aware of any evidence suggesting increased perinatal morbidity or mortality associated with LH.

Idiopathic Intracranial Hypertension (Benign Intracranial Hypertension or Pseudotumor Cerebri)

Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure characterized by normal brain imaging, normal cerebrospinal fluid (CSF) composition, and elevated CSF pressure. IIH occurs at the same rate in pregnant and nonpregnant women,^{105,108,113,114} but one study showed worsening of symptoms among nine of 11 patients with pre-existing IIH who became pregnant.¹⁰⁶

The most common symptoms of IIH in pregnancy are headaches and visual changes. One study found that among 240 normal pregnant women, 12 developed IIH during one or more pregnancies. Ten had headaches, five had transient visual obscuration, four had reduced visual acuity, four had visual field loss, and three developed diplopia. All 12 women developed bilateral papilledema of varying severity.¹⁰⁷

Visual outcome does not appear to differ between pregnant and nonpregnant women with IIH.^105,107,108 A study of 13 pregnant IIH patients found that vision loss occurred at the same rate as age- and parity-matched controls.¹⁰⁸ In addition, pregnancy outcomes are not adversely affected by IIH.^105,109,110

The management of IIH during pregnancy includes weight control, nonketotic diet, steroids, and certain analgesics. Diuretics have been used in some cases. When medical management fails, serial lumbar punctures, optic nerve sheath fenestration, or lumboperitoneal shunt¹¹¹ can be considered.¹⁰⁵ Treatment decisions should be made in coordination with an obstetrician and possibly a neurosurgeon. Therapeutic abortion to limit progression of the disease generally is not indicated.^105,111 The risk of recurrent IIH in subsequent pregnancies does not appear to be increased.¹⁰⁹ Women who have developed IIH during pregnancy should not be advised against future pregnancies.¹¹²

Intracranial Aneurysms and Arteriovenous Malformations

Hemorrhagic cerebrovascular accidents (CVAs) are the most common neurosurgical diagnosis made in pregnancy.¹¹⁵ Intracranial hemorrhages are responsible for 4% to 12% of all maternal deaths^133,134 and can be caused by arterial aneurysms, arteriovenous malformations (AVMs), metastatic choriocarcinoma, and disseminated intravascular coagulation (DIC).^123,131 One retrospective study of 50,700 pregnancy-related admissions identified 13 hemorrhagic CVAs. Seven hemorrhages were subarachnoid and six were intracerebral. Five were caused by AVMs, three by arterial aneurysms, two by DIC, and three were idiopathic.¹³¹ Another retrospective meta-analysis study found that among 152 intracranial hemorrhages, 77% were caused by aneurysms and 23% by AVMs.¹³⁴

Fifty percent of ruptured arterial aneurysms in women under the age of 40 are pregnancy-related.¹¹⁶ The hemodynamic and endocrinologic changes of pregnancy appear to be the cause of arterial alterations that can lead to new aneurysm formation or enlargement or rupture of a pre-existing aneurysm.^115–118 Aneurysm rupture occurs more often in primiparous women¹¹⁵ and in the third trimester of pregnancy.^115,129,131 In one study, 92% of intracranial hemorrhages occurred antepartum and 8% postpartum.¹³⁴ In contrast, women with AVMs do not appear to be at a significantly increased risk of hemorrhage during pregnancy. Seven studies have reported no elevated risk of hemorrhage from AVMs during pregnancy.^{129,137–142}

The most common presentation of a ruptured aneurysm or AVM is severe headache, seizure, or other neurologic signs from subarachnoid hemorrhage (SAH). However, enlarging aneurysms or AVMs can cause mass effects leading to cranial nerve palsies, optic nerve compression,¹¹⁹ or papilledema. One study reported that the possibility of focal neurologic deficit was higher among patients with intracranial AVMs than aneurysms.¹⁴⁰ Patients with SAH can also develop subhyaloid or vitreous hemorrhage (Terson's syndrome).¹²⁰ Secondary intraocular hemorrhage usually is managed conservatively,¹²⁰ but vitrectomy may be indicated in bilateral or non-clearing cases.

The early diagnosis and management of a ruptured arterial aneurysm or AVM are critical in order to optimize the chances of maternal and fetal survival.¹¹⁶ The clinical challenge is that differentiating eclampsia from SAH can be difficult and may lead to a delay in diagnosis.^{116,118,121–123,134,135} The diagnosis is further complicated by the fact that pre-eclampsia and eclampsia are independent risk factors for aneurysm rupture¹²⁴ so that these entities may coexist. Clinicians should maintain a high level of suspicion for intracranial aneurysm when pregnant women present with headache, seizure, altered consciousness, focal neurologic signs, visual changes, or diplopia. Urgent MRI and magnetic resonance angiography scanning is the current diagnostic modality of choice because there is no radiation risk or side effects of contrast media.¹³²

The management of intracranial aneurysms generally is the same for pregnant as nonpregnant patients^117,118 and neurosurgical considerations take precedence over obstetric considerations.^{117,137,144,145} When SAH occurs, endovascular obliteration,^125,126,143 neurosurgical clipping,¹²⁷ or stereotactic radiosurgery¹⁴³ of the aneurysm or AVM may be carried out in order to avoid recurrent hemorrhage and secondary ischemia.¹¹⁵ One study of AVMs recommended that patients at high operative risk be managed conservatively until after delivery.¹⁴³ Another study from 1990 reported that surgical management of aneurysms, but not AVMs, was associated with improved maternal and fetal survival. Taken together, these studies suggest that the threshold for neurosurgical intervention might be lower for aneurysms than AVMs, although this decision should be made by the neurosurgeon. The risk of rebleeding in the same pregnancy was 27% among AVMs in one study.¹³⁶ Visual field and optic nerve changes can resolve over time following surgery.^119,130

Once an aneurysm or AVM has been treated successfully, pregnancy can be allowed to progress to term. Most obstetricians prefer vaginal delivery in these cases,^118,125 although one study reported a bias toward caesarian section among patients with AVM.¹⁴³ Fetal mortality is not increased among mothers with intracranial aneurysms provided that the mother survives.¹²⁸ Women with arterial aneurysms or AVMs are not advised against future pregnancy in most cases.¹²⁹

Cerebral Venous and Sinus Thrombosis

Cerebral venous and sinus thrombosis (CVST) in the pregnant and puerperal state occurs with an incidence of 10 to 20 per 100,000 deliveries and accounts for 5% to 20% of all cerebral venous thrombosis.¹⁶² The signs and symptoms are nonspecific, which can lead to a potentially fatal delay in diagnosis.^169,171 A retrospective study of 138 cases found that 74 (54%) presented in the first 7 days of the postpartum period.¹⁷⁰ The most common signs and symptoms were fever (62%), headache (48%), seizure (46%), hemiplegia (43%), altered consciousness (41%), and papilledema (35%).¹⁷⁰ Another retrospective study of 25 cases reported similar presenting clinical signs, which included headache (96%), focal neurologic deficits (60%), papilledema (43%), and seizure (40%).¹⁶⁹ Magnetic resonance venography (MRV) is the preferred diagnostic modality, and treatment is with heparin anticoagulation.

The increased incidence of intracranial venous thrombosis is attributed to the hypercoagulable state of pregnancy,^172,173 inherited protein C^172,174,175 and S deficiencies,^172,176,177 and eclampsia.¹⁷⁸ A prospective study found that 78% of patients with venous thrombosis during pregnancy and the puerperium demonstrated activated protein C resistance (factor 5 Leiden).¹⁷⁴ Three case reports have found associated protein S deficiency.^172,176,177 There is one case report of transverse sinus thrombosis associated with eclampsia.¹⁷⁸ The authors suggest a causative mechanism but this association may be incidental. It is recommended that causes of inherited hypercoagulability be investigated in all women who develop CVST during pregnancy or puerperium.

Mortality from CVST is less than 20%.^171,179 The visual prognosis generally is good with blindness occurring because of late optic atrophy in two of 77 (3%) patients in one retrospective study.¹⁸⁰ Women with pregnancy-related CVST should not be discouraged from future pregnancies.^171,181 In one retrospective study, among 39 women with a history of CVST during pregnancy, 14 had 22 subsequent pregnancies resulting in 19 births and one elective and two spontaneous abortions. Five patients were prophylactically treated with low-dose heparin.¹⁸¹ In another study, among 77 women with pregnancy-related CVST there was no recurrence of CVST during subsequent pregnancies and only one postpartum deep venous thrombosis occurred.¹⁸⁰

Metastatic Choriocarcinoma

Gestational choriocarcinoma is a malignant tumor that frequently undergoes hematogenous metastasis to highly vascularized organs such as the lung, brain, and liver. The incidence of choriocarcinoma is one in 50,000 live births and one in 30 molar pregnancies.¹⁴⁶ Intracranial choriocarcinoma metastases can present as intracerebral,^148–153 subarachnoid,^153–155 or subdural hemorrhages.^156,157 These tumors can bleed primarily or cause arterial aneurysms^{148,154,156,168} or arteriovenous fistulae¹⁵⁵ with secondary bleeding. In a retrospective analysis of 10 cases, the most common presenting symptoms were features consistent with elevated intracranial pressure and hemiparesis.¹⁴⁷ Ophthalmic signs and symptoms may be present and can include visual acuity or visual field loss, transient visual obscuration, papilledema, and retinal hemorrhages.^147,154 It is important to consider this rare tumor in cases of young women presenting with stroke symptoms because it is potentially curable.¹⁴⁹

Amniotic Fluid or Air Embolism

Amniotic fluid embolism is a rare but serious complication of pregnancy resulting in death in the majority of patients.^160,161 Particulate matter of amniotic origin has been identified at autopsy in the brain, lungs, and kidneys.¹⁶⁰ Focal neurologic deficits are rare^162,164 but can affect the optic nerve, visual pathways, or occipital cortex. One case report describes isolated cortical blindness from air embolism that occurred following induced abortion and improved following treatment with hyperbaric oxygen.¹⁶³

Carotid-Cavernous Fistulae

There are reports of five carotid-cavernous fistulas developing or worsening during pregnancy.^165–168 One spontaneous fistula improved without intervention after the mother aborted the pregnancy in the twelfth week.¹⁶⁵ A second spontaneous fistula worsened 3 weeks after a normal delivery before improving without intervention.¹⁶⁵ One carotid-cavernous fistula was caused by metastatic choriocarcinoma.¹⁶⁸ A traumatic fistula that had resolved 4 years prior to pregnancy recurred causing two antepartum and one postpartum hemorrhages. The authors propose that pregnancy-related hormonal and hemodynamic changes caused the recurrence and hemorrhage.¹⁶⁷ However, the paucity of reports about carotid-cavernous fistulae during pregnancy suggest that this association may be incidental

OPTIC NERVE

Multiple Sclerosis and Optic Neuritis

Multiple sclerosis (MS) is a common cause of optic neuritis and is the most common chronic disabling neurologic disease affecting women of childbearing age.²¹¹ Pregnancy has a protective effect on MS with fewer and less severe relapses, especially during the third trimester.^211–215 However, the relapse rate increases in the first 3 months following delivery before returning to pre-pregnancy rates.^211–215 Breastfeeding and epidural analgesia have no deleterious effect on relapse rates.^211,213,214 The Pregnancy and Multiple Sclerosis study prospectively followed 254 women with MS through 269 pregnancies. Compared with year prior to pregnancy, there was a reduction in the relapse rate during pregnancy, which was most marked in the third trimester. There was striking increase in the relapse rate in the first 3 months after delivery, although 72% of the women did not experience a relapse during these 3 months. After this, the rates returned to pre-pregnancy levels.^213–214 Relapse rates remained at pre-pregnancy rates at the 2 year follow-up.²¹⁴ A recent retrospective review of 351 women with MS confirmed the finding that the MS relapse rate decreases throughout pregnancy and increases during the puerperium.²¹⁵

Overall, pregnancy has no long-term effect on MS related disability or disease course.^211–214,²¹⁶ Apart from methotrexate and cyclophosphamide, most drugs used routinely in the treatment of MS, including steroids, can be used safely by pregnant women.²¹⁶ A study of 14 pregnant women with relapsing-remitting MS, who were treated with postpartum IVIg in an attempt to avoid postdelivery recurrences, found that none of the patients who received postpartum IVIg relapsed²¹⁷ compared with the expected relapse rate of about 28%.²¹⁴ Further study is needed to confirm this apparent protective effect.

Women with MS who desire children can be reassured that their infants are not at increased risk of malformations, preterm delivery, low birth weight, or infant death.^{211,213,214,216} Because a woman's past history of relapses may be the best indicator of future clinical course and long-term disability,^212–214 women with more severe disease may wish to complete their families as soon as possible.²¹⁶

A condition called “lactation optic neuritis” has been described in the first 12 months following delivery unassociated with known MS.^204,205 The clinical course is similar to classic optic neuritis that occurs without lactation. It is possible that decreased immunosuppressive activity during the postpartum period induces the initial clinical manifestation of a previously unrecognized demyelinating disorder such as MS.²⁰⁴ The paucity of cases reported in the literature also suggests that this also could be an incidental association

ADDITIONAL PREGNANCY-RELATED OPTIC NEUROPATHIES

Devic's syndrome (neuromyelitis optica) is characterized by optic neuritis with transverse myelitis and may present during pregnancy.^206,207 Severe vomiting in pregnancy (hyperemesis gravidarum) can lead to optic neuritis.²⁰⁸ One case of ischemic optic neuropathy has been reported in association with severe pre-eclampsia.²⁰⁹ A case of bilateral idiopathic optic neuritis with permanent visual loss recently was reported in association with pregnancy.²¹⁰ One case of pregnancy-related papillophlebitis in a woman with no identifiable coagulation defect has been reported.³⁴⁹

OTHER NEURO-OPHTHALMOLOGIC DISORDERS

Cortical Vision Loss in Pre-Eclampsia and Eclampsia

Pre-eclampsia and eclampsia are the most common causes of pregnancy-related focal neurologic deficits. These deficits are characteristically of sudden onset and resolve over time. The precise pathogenesis of these strokelike focal deficits remains poorly understood.^162,164 Transient visual changes occur in up to 25% of patients¹⁸² and cortical blindness is a rare but dramatic finding. A prospective study of 15 women who developed pre-eclampsia/eclampsia-related cortical blindness found complete resolution over 4 hours to 8 days.¹⁸³ Another retrospective analysis of 19 cases of eclampsia reported transient cortical blindness in two patients with complete recovery in both.¹⁸⁴

The etiology of cortical vision loss remains controversial. Many authors have proposed a mechanism of cerebral vasospasm with ischemic injury,^183,185,186 whereas others suggest that increased capillary permeability leads to hydrostatic edema.^187–189 Except for rare cases with persistent neurologic deficits and neuroradiologic abnormalities, the reversibility of vision loss argues against true ischemic necrosis.¹⁶² Recent studies have demonstrated cerebral vasospasm by angiography,¹⁸⁵ transcranial color-coded sonography,¹⁸⁵ and MRA¹⁸⁸ with concurrent MRI,^185,188 and single photon emission computed tomography¹⁸⁷ findings consistent with cerebral edema. This suggests that cerebral vasospasm leads to relative ischemia and changes in regional blood flow that cause reversible edema. Hypercalcemia¹⁹⁰ and inflammatory cytokines of placental origin¹⁹¹ recently have been proposed as putative inciting factors.

Horner's Syndrome

Horner's syndrome has been reported as a complication of epidural anesthesia for labor. Although not uncommon in women in labor, this complication is virtually unknown in patients outside of the context of labor.²¹⁸ The incidence of Horner's syndrome was estimated in a prospective study of 200 women who received epidural analgesia during labor. The incidence was 1.3% among 150 who delivered vaginally and 4% among 50 patients who underwent caesarian section.²²¹ There are two case reports of trigeminal nerve palsy following epidural anesthesia for labor.^219,223

The etiology seems to be cephalad spread of local anesthesia, sometimes via unexplained routes and with surprising selective targeting effect.²¹⁹ The propensity in pregnant women is believed to be caused by pregnancy-related anatomic and physiologic changes of the epidural space.²¹⁹ In one case report, an epidurogram after Horner's syndrome developed from epidural anesthesia demonstrated unilateral left spread ascending to upper thoracic levels with delayed spread toward the right lumbar epidural space.²²⁰ This complication generally is transient in nature but must be accompanied by close maternal and fetal monitoring because it can be associated with maternal hypotension caused by autonomic effects.²²²

Myasthenia Gravis

Myasthenia gravis (MG) frequently affects young women in their childbearing years. Several retrospective studies suggest that approximately 40% of women with pre-existing MG clinically worsen during pregnancy.^224–229 This deterioration usually occurs during the first trimester^226,229 or shortly after delivery.^224,225 The authors are not aware of any studies that specifically evaluate the ophthalmic signs and symptoms of MG during pregnancy but suspect that they would approximate overall disease activity.

The rate of neonatal myasthenia gravis (NMG) after delivery varies widely in the literature from 6% to 50%.^{225,228–231} The incidence of NMG seems to be more common among infants born to mothers with puerperal infections or shorter antenatal disease duration.²²⁴ The newborns of thymectomized mothers are relatively protected.²²⁴ Two studies demonstrate good correlation between maternal antiacetylcholine receptor antibody titers and the development of NMG, so this testing may be helpful.^228,231 The largest study of neonatal outcomes retrospectively evaluated 127 births of mothers with MG compared with population-wide controls. Women with MG had 8% more complications during delivery, premature rupture of membranes was three times more common, and caesarian sections were twice as common. Five children (3.9%) had severe anomalies and three of them died.²³² Another study showed that perinatal mortality also was increased among mothers who remained asymptomatic during pregnancy.²³³ This suggests that neonatal outcomes are not only related to MG disease severity but also to effects of the underlying immunologic dysfunction on the fetus. To the authors' knowledge, perinatal mortality has not been evaluated for cases of isolated ocular myasthenia.

Treatment of MG during pregnancy requires close coordination among the obstetrician, neurologist, pediatrician, and ophthalmologist when ocular symptoms are present. Treatment during pregnancy may include immunosuppressive therapy, plasmapheresis, intravenous human immunoglobulins,²²⁵ and thymectomy.²³⁴

Ocular Migraine

The lifetime prevalence of migraine with aura (MA) is 5%, with a female to male ratio of 2 to 1.²³⁵ Visual disturbances are the most common aura phenomenon, occurring in 90% of patients with MA.²³⁵ Several retrospective and two prospective studies have demonstrated improvement of migraine during pregnancy.^236–240 The largest prospective study included 49 migraineurs who became pregnant. Migraine symptoms improved in 47% during the first trimester, 85% during the second trimester, and 87% in the third trimester. Complete remission was achieved in 79% of women by the end of pregnancy. Migraine recurred in 55% during the first month after delivery but breastfeeding seemed to afford some protection.²³⁷ Retrospective studies have demonstrated that women with migraine onset at menarche and those with perimenstrual migraine are more likely to go into remission during pregnancy.²³⁸ However, this association has not been observed in prospective studies.^236,237 Retrospective studies also have shown that migraine with aura appears to be overrepresented among the small number of women (4%–8%) whose migraines worsen during pregnancy.²³⁸ Migraine can begin during pregnancy in 1% to 17% of cases, often during the first trimester, and involves a higher proportion with aura.²³⁸ The positive effects of pregnancy on migraine probably are related to uniformly high and stable estrogen levels.^240,241

The symptoms of headache and visual changes during pregnancy are nonspecific. The development or worsening of migrainelike symptoms during pregnancy can indicate an underlying structural lesion or disease process such as an arterial aneurysm, arteriovenous malformation, progressive meningioma, venous sinus thrombosis, or pre-eclampsia, all of which are more common during pregnancy. Therefore, appropriate diagnostic testing should be performed to rule out other organic causes of headache and visual changes.^242,243

Migraine during pregnancy does not increase the risk of pregnancy-related complications such as pre-eclampsia/eclampsia, abnormal labor, fetal loss, or congenital anomalies.²³⁸ Safe and effective acute care treatments include paracetamol, opioids, and antiemetics.²⁴⁴ The use of triptans appears to be safe, but data are limited and they are not broadly recommended.^244,245 Preventative treatments include relaxation, biofeedback, beta-blockers such as labetalol, some antidepressants, and gabapentin.^244,246

THYROID ORBITOPATHY

Graves' disease occurs in approximately 1/1,000 pregnancies and the diagnosis is made following conception in approximately 50%.²⁴⁷ Hyperthyroidism may worsen during the first trimester^248–251 but tends to improve during the second and third trimesters.^252–254

The etiology of early worsening of hyperthyroidism is related to the thyroid stimulating activity of human chorionic gonadotropin (hCG).^250,251 This can cause the aggravation of pre-existing Graves' disease²⁵⁰ or de novo hyperthyroidism called gestational transient thyrotoxicosis that is frequently associated with hyperemesis.^249,251 The authors are not aware of any studies that evaluate the effect of pregnancy-related early worsening of Graves' disease on its ophthalmic manifestations, and suspect that because this early aggravation is caused by elevated hCG rather than an increase in autoantibodies against shared thyroid-orbital antigen, ophthalmologic signs and symptoms are likely unaffected.

The improvement in Graves' disease during the second and third trimesters was previously attributed to a reduction of thyroid-stimulating antibody activity.²⁵² More recent studies have demonstrated a change in the specificity of TSH receptor antibody from stimulatory to blocking activity during pregnancy.^252–254 Whether this alteration in antibody activity also improves the ophthalmic manifestations of Graves' disease has not been explored in the literature.

Graves' disease in pregnancy carries a risk of fetal thyrotoxicosis from transplacental transfer of thyroid-stimulating antibodies, or fetal hypothyroidism from antithyroid drugs or thyroid-blocking antibodies.²⁵⁵ The treatment options for Graves' disease include antithyroid drugs, radioablation, and surgery.^256,257 Propylthiouracil (PTU) is the drug of choice for treating pregnant and breastfeeding women because of limited transfer into placenta and breast milk.^256,258 Radioiodine therapy is contraindicated in pregnancy and must be completed at least 4 months prior to conception.²⁵⁷ Surgery has a limited role in Graves' disease but could be considered in the context of pregnancy.²⁵⁷

Studies evaluating the treatment of Graves' ophthalmopathy during pregnancy have not been performed. The authors recommend conservative therapy whenever possible during pregnancy. Strabismus can be managed with prisms or patching. Ocular surface symptoms and exposure keratopathy can be treated with lubricants, punctual plugs, topical steroids or cyclosporine, or tarsorrhaphy in severe cases. Compressive optic neuropathy can be managed via orbital decompression or oral steroids but external beam radiation should be avoided. The authors do not recommend eyelid or muscle surgery during pregnancy because lid position and strabismus may not remain stable postpartum.

ORBITAL TUMORS

The growth of orbital hemangiomas during pregnancy has been reported.^259–261 One case report describes the accelerated growth of a primary orbital schwannoma during pregnancy.²⁶² The etiology of pregnancy-related tumor growth has not been investigated in these cases but may be related to hormone receptor expression, analogous to meningioma growth during pregnancy.

Two cases of orbital rhabdomyosarcoma have been reported during pregnancy.^263,264 One case was associated with placental metastasis.²⁶³ A case of primary orbital melanoma that presented during the first trimester of pregnancy has been reported.²⁶⁵

ORBITAL HEMATOMAS

Orbital hematomas can develop during labor or in the early postpartum period.²⁶⁶ Pain and diplopia are the most common presenting symptoms.

PRE-ECLAMPSIA AND ECLAMPSIA

Pre-eclampsia typically develops in the second half of pregnancy and is characterized by hypertension, edema, and proteinuria. Eclampsia is pre-eclampsia with convulsions and usually occurs late in pregnancy. In healthy women, pre-eclampsia generally is seen in first pregnancies with an incidence estimated at 5%. Risk factors for pre-eclampsia include very young or advanced maternal age, multifetal pregnancy, hemolytic disease of the newborn, diabetes mellitus, chronic systemic hypertension, and renal disease. Pre-eclampsia and eclampsia place the fetus at risk because of placental vascular insufficiency. In the first half of the 20th century, severe changes in retinal arteriolar caliber were believed to reflect placental vascular insufficiency and constitute an indication for pregnancy termination. Therefore, a great deal of attention was paid to retinal findings in pre-eclampsia. With improved medical and obstetric management of hypertension and other aspects of pre-eclampsia, retinal findings are no longer used to assess this disease. In addition, retinal changes in pre-eclampsia now may be significantly less frequent than they were in the past.

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.²⁶⁷ Recent studies, discussed in the following, 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.²⁶⁸

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 also can occur and may contribute to visual loss. Early studies of retinal disorders in pre-eclampsia have been discussed in previous reviews.²⁶⁹

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% to 100% of pre-eclamptic patients.²⁷⁰ Recently, a retrospective study of fluorescein angiograms in pre-eclamptic patients identified normal retinal vessel caliber in 16 of 16 patients. In contrast, four of 14 patients with pre-existing chronic systemic hypertension had retinal vascular changes.²⁷¹ Another study 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.²⁷² 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 probably is 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.²⁷³ When present, the retinal arteriolar attenuation associated with pre-eclampsia generally resolves after delivery, presumably because of 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 generally are not seen in pre-eclampsia²⁷² and should raise suspicion about additional concurrent systemic disease.

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 (Fig. 2) but occasionally are cystic.^268,274 In the early 20th century, serous retinal detachments were seen in 1% of severely pre-eclamptic patients and about 10% of eclamptic patients.^275,276 A more recent retrospective study 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 usually were 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.²⁷⁷ The apparent historical increase in the incidence of serous detachments and RPE lesions is likely owing to improved diagnostic instrumentation and ancillary testing.

The etiology of choroidal dysfunction is thought to be ischemia, based on fluorescein angiography, limited histopathologic study, the presence of Elschnig's spots on resolution,²⁷⁸ and indocyanine green angiography.²⁷⁹ This is further supported by the observation that posterior ciliary artery blood flow velocity is increased in pre-eclampsia, suggesting vasospasm.²⁷³ The primary choriocapillaris ischemia presumably leads to RPE ischemia manifest as yellow opacification 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 macular dystrophy or tapetoretinal degeneration.²⁸⁰ Rare patients may develop optic atrophy if chorioretinal atrophy is extensive.²⁸¹

One study 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.²⁸² Retinopathy is more closely associated with higher levels of blood pressure than is serous detachment.²⁸³ 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.²⁸⁴

Postpartum serous detachments have been reported in pre-eclamptic patients,^285,286 and there are rare reports of exudative detachments in patients without pre-eclampsia.^287,288 Although 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 noted in two patients with this disorder.^289,290

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 typically are affected, and there is an 8:1 male predominance.²⁹¹ A recent retrospective case-control study involving 624 patients showed that systemic steroid use and pregnancy are the most important risk factors for CSC with odds ratios of 37 and 7, respectively.³⁰² The hormonal or hemodynamic changes of pregnancy may predispose some women to CSC.

Many cases of CSC associated with pregnancy are reported in the medical literature.^292–302 Unlike the serous retinal detachments observed in pre-eclampsia and eclampsia, CSC generally is 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 two women, always in the same eye, in subsequent pregnancies. One patient had four successive pregnancies with CSC,²⁹⁸ and one had two successive pregnancies complicated by CSC.²⁹⁹ There is also one case report of a woman developing CSC 1 month postpartum in two successive pregnancies.³⁰⁰ 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.²⁹⁵ Therefore, the occurrence of CSC during one pregnancy does not necessarily mean that it will recur in future pregnancies. There is a report of one patient who experienced a recurrence of CSC outside the context of pregnancy.²⁹⁵

There is an increased incidence of subretinal white exudates (presumed to be fibrin) in pregnancy-associated CSC (approximately 90%) compared with CSC in males and nonpregnant women (approximately 10%). One case series reported that three of four patients with pregnancy-related CSC had subretinal exudates.²⁹⁵ Another study found that 6/6 cases of pregnancy-related CSC had subretinal exudates compared with only 6/50 (12%) of non–pregnancy-related cases.²⁹⁶ A recent case report showed highly reflective subretinal material on OCT that corresponded clinically to subretinal exudates.³⁰¹ The etiology of the higher prevalence of subretinal exudates in pregnancy-associated CSCR is unknown.

OCCLUSIVE VASCULAR DISORDERS

An increase in the level of clotting factors and clotting activity occurs during pregnancy.³⁰³ Several pathologic sources of thrombosis and embolic events also can occur. One review of ischemic cerebrovascular disease suggested that pregnancy is associated with a 13-fold increase in the risk of cerebral infarctions compared with nonpregnant women.³⁰³ This increased risk of vaso-occlusive disease also may manifest as retinal or choroidal vascular occlusions.

Retinal Artery Occlusion

Two cases of unilateral central retinal artery occlusion (CRAO),^304,305 one case of bilateral CRAO,³⁰⁶ two cases of unilateral branch retinal artery occlusion (BRAO),^307,308 and three cases of bilateral multiple BRAO³⁰⁹ have been reported in association with pregnancy and in the absence of additional risk factors. Three cases of arteriolar occlusion were associated with pre-eclampsia^306,309 and one was associated with disc edema.³⁰⁸ Five of the eight (63%) cases occurred within 24 hours of delivery, suggesting that this is a particularly susceptible period.

One study 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.³⁰⁹

Nine additional cases of pregnancy-associated BRAO have been reported in the literature.^310–315 However, all of these cases had significant additional risk factors for vascular occlusion. Because 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.³¹⁰ Three cases that occurred postpartum were associated with hypercoagulability from protein C³¹¹ or protein S^309,312 deficiency. Three cases were associated with thromboembolic occlusions attributed to mitral valve prolapse³¹³ and amniotic fluid embolism.^160,161 The final two cases developed BRAO in the first trimester in association with migraine headaches.³¹⁴

Retinal Vein Occlusion

Retinal vein occlusion associated with pregnancy is exceedingly rare. The authors are aware of only four pregnancy-related central retinal vein occlusions (CRVO) have been reported to date^315–317 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.³¹⁵ Another study reported the case of a 27-year-old woman who was 6 months pregnant when she developed a unilateral CRVO. The authors suggested impaired fibrinolysis after venous stasis as a possible mechanism.³¹⁶ 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.³¹⁷ The final case is that of a patient with 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 Coagulation

Disseminated intravascular coagulation (DIC) is an acute pathologic process with widespread thrombus formation in small vessels. It can occur in obstetric complications such as abruptio placentae and intrauterine fetal death that release placental thromboplastin into 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.^318–321 The development of serous retinal detachments in pregnancy, especially late pregnancy, may be an early ocular sign of DIC.³²¹ The authors are aware of case reports of two patients with DIC causing serous retinal detachments.^318,321 These detachments tend to be bilateral and symptomatic. With recovery from the systemic disorder, vision generally returns to normal with only residual pigmentary change.^320,321

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. Women who are pregnant or in the postpartum period are overrepresented, making up approximately 20% of TTP patients.^325,326

Visual changes occur in approximately 8% of cases³²² because of thrombus formation in the choriocapillaris and secondary RPE and outer retinal ischemia. Clinical findings usually are bilateral and include serous retinal detachments, yellow spots at the level of the RPE, and localized arteriolar narrowing. Sequelae include RPE pigmentary changes and Elschnig spots with a return to baseline vision over several weeks in most cases.^322–324

Aggressive treatment with plasma transfusions and plasmapheresis have improved maternal and fetal survival.³²⁵ In published reports, 10 of 11 (91%) with idiopathic TTP, 11 of 18 (61%) women who were pregnant or postpartum at their initial presentation, and 11 of 11 (100%) with congenital TTP developed active TTP during a subsequent pregnancy.^326,327 A retrospective study of nine patients reported fetal mortality from preterm delivery and intrauterine death in 33%.³²⁸ Therefore, pregnant patients with a history of TTP must be closely followed in a tertiary obstetric unit with plasmapheresis available.³²⁷

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 DIC³²⁹ with the potential ocular complications described in the preceding. Two patients developed multiple branch retinal arteriolar occlusions presumably related to particulate material from the amniotic fluid.^160,161 Another patient had massive blood loss from an amniotic fluid embolism leading to severe retinal and choroidal ischemia and blindness in one eye.³³⁰

UVEAL MELANOMA

Pregnancy is heralded by a hormone-dependent tendency to hyperpigmentation and well-known cutaneous changes such as chloasma and an increase in pigmentation of pre-existing nevi owing to increased levels of melanocyte-stimulating hormone in pregnancy.³³¹ Although estrogen and progesterone may stimulate melanogenesis, there is no evidence that this can cause malignant transformation of melanocytic cells.

A case-control study 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.³³² However, others have reported a trend toward a larger than expected number of ocular melanomas presenting during pregnancy.³³³ There are also a number of anecdotal reports of uveal melanomas presenting or growing rapidly during pregnancy.^334–338 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.^337,339 It is possible that other hormones may be involved,³³⁷ 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. One study 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 with a matched group of tumors in nonpregnant women.³⁴⁰

The treatment of pregnancy-associated uveal melanoma has been described in two studies. Among 16 cases in one study, 10 eyes were enucleated, four received plaque radiotherapy during or after pregnancy, and two 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.³⁴⁰ Another report of eight cases demonstrated no treatment-related pregnancy complications. The authors suggest that brachytherapy is safer toward the end of pregnancy or after delivery.³⁴¹

Childbearing may be associated with improved survival in choroidal melanoma. One large prospective cohort study reported that 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.³⁴² 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.³⁴³ A much smaller third study also showed similar 5-year survival between pregnant and non-pregnant women with posterior uveal melanoma.³⁴⁰

The authors are aware of three cases of choriocarcinoma that metastasized to the choroid.^158,159 Two of the cases presented with vision loss and pain. One case required enucleation¹⁵⁸ and a second resolved with systemic chemotherapy alone.¹⁵⁹

DIABETIC RETINOPATHY

The modern medical, ophthalmologic, and obstetric management of pregnant diabetic patients has greatly improved outcomes 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,^350,351 congenital anomalies, and fetal morbidity.³⁵² 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.³⁵³ However, another study suggested that blood glucose control may counteract adverse fetal effects associated with maternal retinopathy and nephropathy.³⁵⁴

Diabetic woman who may become pregnant should establish excellent glucose control before conception, because 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.³⁵⁵ Laser treatment of diabetic macular edema before pregnancy also may be important, although the effects of pregnancy on macula edema have not been adequately studied.

The Diabetes in Early Pregnancy (DIEP) study, a study of 155 insulin-dependent diabetic pregnant women,³⁵⁶ as well as the data from the Diabetic Control and Complications Trial³⁵⁷ and the previous data summarized by Sunness,³⁵³ 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.³⁵⁶ 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.³⁵⁸ 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.^357,359,360

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.^353,361

Progression of Diabetic Retinopathy during Pregnancy

The interpretation of changes in diabetic retinopathy as being caused by pregnancy is confounded by changes related to blood glucose levels. As medical advances continue to improve glycemic control, changes in blood glucose control that occur at the onset of pregnancy will be minimized and it may be easier to obtain a more direct understanding of the role of pregnancy in the progression of diabetic retinopathy. In the meantime, several mechanisms have been proposed as possible etiologic factors contributing to diabetic retinopathy during pregnancy. Retinal hemodynamics may play an important role. The increase in cardiac output, combined with decreased peripheral vascular resistance during pregnancy,³⁶² 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.^363–365 In contrast, two studies report a reduction in retinal capillary blood flow that may exacerbate ischemia and lead to retinopathy progression.^366,267 Other studies have suggested a possible role for various growth factors found at increased concentrations during pregnancy such as IGF-1,³⁶⁸ phosphorylated IGF binding protein,³⁶⁹ placenta growth factor,^370,371 endothelin-1,³⁷² and fibroblast growth factor-2.³⁷³ These factors may exert additive or synergistic effects.³⁷⁴

Short- and Long-Term Effects of Pregnancy on Diabetic Retinopathy

Because there is a high rate of regression of retinopathy during the postpartum period, one must consider short- 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.³⁷⁵ One study of short-term effects included 16 women with no retinopathy or nonproliferative retinopathy. Progression during pregnancy was compared with 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.³⁷⁶

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 and 98 nonpregnant women. Progression was observed in 16% of the pregnant group compared with only 6% in the nonpregnant group. Furthermore, 32% of the nonpregnant group had retinopathy at baseline, compared with only 22% of the pregnant cohort. Therefore, one might have expected more progression in the nonpregnant group because of worse baseline disease, making these findings more significant.³⁷⁷ 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.³⁷⁸ 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.³⁷⁹

There are four studies concerning the long-term effects of pregnancy on diabetic retinopathy. The first included 40 women followed for 12 months postpartum. Among 19 study participants with no retinopathy at baseline, 30% developed mild nonproliferative retinopathy during the second and third trimester. By 1 year postpartum, none had clinically detectable retinopathy. Among the 21 women with retinopathy at baseline, 11 worsened during pregnancy and two developed proliferative disease. None of these 11 women had regressed to her initial retinopathy status by 1 year postpartum.³⁸⁰ The second study reported changes at 12 months postpartum. Among 10 patients with no initial retinopathy who developed mild retinopathy during pregnancy, half experienced total postpartum regression, 30% had partial regression, and 20% had no change. Among five patients with initial mild retinopathy who progressed to moderate nonproliferative retinopathy, 40% experienced complete regression, 40% partial regression, and 20% no regression. However, among 12 who progressed from mild initial retinopathy to severe nonproliferative retinopathy, only 17% had total regression, 58% had partial regression, and 25% had no regression. The third study compared 28 diabetic women to 17 nulliparous matched controls over a 7-year period. Only five of 26 (19.2%) of women who had been pregnant experienced progression of retinopathy compared with eight of 16 (50%) nulliparous women, suggesting that pregnancy does not affect long-term progression and may even afford a protective effect.³⁸¹ A final study of 80 women who had completed at least one successful pregnancy found no increase in the risk of proliferative retinopathy later in life compared with matched controls.³⁸²

Two studies suggest that the number of prior pregnancies does not appear to be a long-term factor in the severity of retinopathy present when duration of diabetes is taken into account.^383,384 In fact, a cross-sectional European study reported lower levels of retinopathy in diabetics with multiple past pregnancies compared with women matched for age and duration of diabetes.³⁸⁵ It is not clear if this improved status was caused by a prolonged period of tight metabolic control and better patient education, or if pregnancy confers a long-term protective effect. Another possibility involves the bias that only women with better metabolic control may have undergone the stress of multiple pregnancies.

The Role of Baseline Retinopathy Status, Duration of Diabetes, and Metabolic Control

The major determinants of the progression of diabetic retinopathy in a pregnant woman are the duration of diabetes and the degree of retinopathy at the onset of pregnancy.^{355,356,378,386–388} Therefore, women with diabetes are strongly encouraged to complete childbearing early in their adult life.³⁸⁹

The baseline level of retinopathy at conception is the major risk factor for progression of retinopathy, according to the DIEP. When a logistic regression model was used to separate the influence of diabetes duration (shorter duration is less than 15 years; longer duration is more than 15 years) from the effect of a worse baseline level of nonproliferative diabetic retinopathy, the baseline retinopathy was highly significant but the duration of retinopathy was not. Analysis of patients with moderate or more severe retinopathy in the DIEP showed deterioration (defined as a two-step or more worsening determined on the final scale of the modified Airlie House Diabetic Retinopathy Classification) in 55% of patients with shorter duration and 50% of patients with longer duration of diabetes. However, the rates of development of proliferative retinopathy were 39% of patients with longer duration of diabetes and only 18% of patients with shorter duration of diabetes. The HbA1c level at the beginning of pregnancy was used in the DIEP as a measure of metabolic control. Women with a HbA1c level of 6 standard deviations (SD) or more from the control mean had a statistically significant higher risk of progression of retinopathy compared with patients with a HbA1c baseline level within 2 SD of the control mean.³⁵⁶

A longitudinal analysis of the effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial (DCCT) was published recently. Pregnant women in the intensive treatment group had a 1.63-fold greater risk of retinopathy progression during pregnancy than nonpregnant women, compared with a 2.48-fold greater risk in the conventional treatment group.³⁷⁵

A prospective study of 179 pregnancies in 139 women with type-1 diabetes reported a 10% progression rate of retinopathy in women with duration of diabetes 10 to 19 years compared with 0% in women with duration less than 10 years. Furthermore, women with moderate to severe retinopathy experienced progression in 30% of cases compared with only 3.7% with less severe retinopathy.³⁹⁰

One study prospectively that followed 112 pregnant women with insulin-dependent diabetes and found an association between the severity of retinopathy and poor glycemic control before and after pregnancy. However, no such correlation was found with intensive glycemic control during pregnancy. Women who had progression of retinopathy during or after pregnancy had an average diabetes onset at age 14 years compared with 19 years in women whose retinopathy remained stable.

Baseline Retinopathy Level

The following discussion of the progression of retinopathy during pregnancy is subdivided according to the baseline level of retinopathy present. Many of the studies did not use the more recent classification recommended by the Early Treatment Diabetic Retinopathy Study (ETDRS). Whenever possible, the results have been organized according to this classification.¹³⁵

No Initial Retinopathy

In an earlier meta-analysis that included 484 diabetic pregnancies with no initial retinopathy, 12% of these patients developed some background change during pregnancy, and one patient (0.2%) developed proliferative retinopathy. In 23 cases, for which postpartum follow-up was available, there was regression of the nonproliferative changes in 57%.³⁵⁵ The DIEP reported a 10.3% progression to mild nonproliferative diabetic retinopathy for this group of patients.³⁵⁶ Four other studies of eyes with no initial retinopathy reported progression rates of 0%, 7%, 26%, and 28% respectively.^{388,392–394}

A 12-year prospective study of patients with gestational diabetes did not demonstrate an increased risk of diabetic retinopathy.³⁹⁵ However, retinal vascular tortuosity in gestational diabetics has been reported, and some degree of tortuosity persisted at 5 months postpartum.³⁹⁶ There is one case report of a previously healthy nulliparous woman with gestational diabetes diagnosed at 8 weeks gestation. Glycemic control was instituted and the patient developed bilateral proliferative retinopathy by 31 weeks gestation. The patient had a markedly elevated HbA1c at initial diagnosis, suggesting that she may have been diabetic before becoming pregnant.³⁹⁷ A retrospective review of 100 gestational diabetics concluded that routine examinations have little utility in these patients.³⁹⁸

Mild Nonproliferative Diabetic Retinopathy

In two studies that included 24 pregnant women with fewer than 10 microaneurysms and dot hemorrhages in both eyes, 8% developed additional microaneurysms and 0% developed proliferative retinopathy.³⁵⁵ A more recent study showed that microaneurysm counts increase during pregnancy, peak at 3 months postpartum, and then decline to baseline levels.³⁹⁹ The DIEP study found that 18.8% of patients with mild nonproliferative retinopathy showed a two-step progression on the modified Airlie House classification through the end of pregnancy. Only 6% progressed from mild nonproliferative to proliferative retinopathy.³⁵⁶ A study that included seven patients with minimal retinopathy reported progression in only one during pregnancy that improved after delivery.³⁹⁴

Moderate to Severe Nonproliferative Diabetic Retinopathy

The DIEP found that 54.8% of patients with moderate retinopathy showed a two-step progression on the modified Airlie House diabetic retinopathy classification and 29% developed proliferative retinopathy by the end of pregnancy.³⁵⁶ In addition, 25% of those who developed proliferative retinopathy had high-risk characteristics as defined by the Diabetic Retinopathy Study.⁴⁰⁰

Ten studies published before 1988 that included 259 pregnant women with nonproliferative diabetic retinopathy were summarized by Sunness. The analysis of this information showed that 47% of patients had an increase in the severity of nonproliferative changes during pregnancy. Differences in the scale of measurements of diabetic retinopathy among the studies caused wide variations in progression rates. Most of the studies included mild and moderate retinopathy in the wider group of nonproliferative retinopathy. Only 5% of patients in this analysis developed proliferative retinopathy during pregnancy.³⁵⁵

Four studies after 1988 reported progression rates of nonproliferative retinopathy ranging from 12% to 55%.^{388,392,393,401} Two of these studies reported rates of proliferative retinopathy development at 8% and 22% during pregnancy.^393,401

Proliferative Retinopathy

In a meta-analysis including 122 women with proliferative retinopathy at baseline, 46% had some increase in neovascularization that developed during pregnancy.³⁵⁵ A more recent study reported a 63% rate of progression in eyes with proliferative retinopathy at baseline.³⁸⁸

Optimal treatment of proliferative disease before pregnancy reduces the risk of progression during pregnancy. In the 1988 Sunness review, those patients who had scatter laser photocoagulation before pregnancy showed a 26% rate of progression of their proliferative disease and visual loss compared with 58% of patients without prior treatment. Those patients with complete regression of proliferative disease before pregnancy did not demonstrate progression of proliferative disease during pregnancy.³⁵⁵ In a more recent analysis, half of the patients with proliferative disease who underwent scatter laser photocoagulation prior to pregnancy required additional scatter treatment during pregnancy. In addition, 65% of patients who had proliferative disease during pregnancy required photocoagulation postpartum. No patient had proliferative disease that did not respond to laser photocoagulation.⁴⁰²

Proliferative retinopathy may regress near the end of pregnancy or in the postpartum period. One study found that four out of five women who developed proliferative retinopathy during pregnancy had spontaneous regression to nonproliferative status within 2 months postpartum.³⁸⁰ In contrast, another study of eight women with proliferative disease reported no spontaneous regression by 3 months postpartum.³⁸⁸ The possibility of spontaneous regression is a factor to consider when determining if laser photocoagulation is indicated. Most retina specialists aggressively treat patients who have high-risk proliferative retinopathy;³⁹¹ some retinal specialists treat one eye or both in cases that are not high risk, given the problem of rapid progression during pregnancy. After consideration of high-risk factors such as high initial HbA1c and duration of diabetes, these decisions must be made on a case-by-case basis.

Vitreous hemorrhage during labor and delivery has been reported in a few cases,⁴⁰³ but there is no evidence justifying performing a cesarean section on the basis of proliferative retinopathy alone, given the relative safety of vitrectomy for the treatment of nonclearing vitreous hemorrhage if necessary.³⁵⁵

Diabetic Macular Edema in Pregnancy

Diabetic macular edema that involves or threatens the fovea currently is treated with focal laser photocoagulation outside the context of pregnancy in order to reduce the risk of moderate vision loss. Patients who develop macular edema during pregnancy frequently have different prognoses than nonpregnant patients. Spontaneous resolution after pregnancy is a common occurrence and is associated with improvement of visual acuity more frequently than in nonpregnant patients.⁴⁰¹

One study reported that 16 (29%) of 56 eyes of diabetic pregnant women with initial proliferative or nonproliferative retinopathy developed diabetic macular edema during pregnancy. Of these 16 eyes, 14 (88%) had improvement in visual acuity and resolution of macular edema postpartum without laser treatment.⁴⁰⁴

In general, pregnant women with diabetic macular edema should not be treated during pregnancy because of the high rate of spontaneous improvement postpartum. Possible exceptions include cases in which lipid is threatening the fovea or severe progressive macular edema develops early in pregnancy. However, more detailed and systematic study of diabetic macular edema is required to allow evidence based management recommendations.

Other Risk Factors for Diabetic Retinopathy Progression during Pregnancy

Nephropathy and systemic hypertension are additional risk factors for the progression of diabetic retinopathy during pregnancy. A well-known association exists between nephropathy and retinopathy in nonpregnant patients. One study in pregnant diabetics showed that eight of nine patients in whom macular edema developed during pregnancy had proteinuria of more than 1 g per day.⁴⁰⁵ Two studies report that elevated systolic blood pressure is a risk factor for the progression of diabetic retinopathy.^388,406 Systolic blood pressure within the normal range but over 115 mm Hg has been associated with an increased risk of retinopathy progression among pregnant patients.³⁹² The DIEP found a 1.3 odds ratio for two-step progression of retinopathy for every 10-mm Hg increase in systolic blood pressure.³⁵⁶

Diabetic Retinopathy and Maternal and Fetal Well-Being

Advanced diabetic retinopathy has been considered a risk factor for adverse fetal outcomes because it may reflect more widespread systemic disease. Pregnancies associated with nonproliferative diabetic retinopathy may not be at higher risk for adverse fetal outcomes.⁴⁰⁷ However, one study reported an adverse fetal outcome in 43% of 28 women with proliferative retinopathy compared with only 13% of 131 women with nonproliferative retinopathy.³⁵³ Another study of 20 pregnancies of 17 women with proliferative retinopathy reported spontaneous abortion in two cases (10%), stillbirth in one case (5%), and three had major congenital anomalies.⁴⁰² A third study reported that among 60 pregnant patients with diabetes, the seven with proliferative retinopathy had a significantly higher incidence of fetal distress.⁴⁰⁸ A final study of 26 women with proliferative retinopathy reported serious neonatal morbidity in 19% and mortality in 12%.⁴⁰⁹

One prospective study of 205 women with type-1 diabetes found that low birth weight was associated with retinopathy progression. However, retinopathy progression was not associated with earlier delivery, macrosomia, respiratory distress syndrome, neonatal hypoglycemia, or neonatal death.⁴¹⁰

Improved medical and obstetric management has improved the outcome of diabetic pregnancies. In a study of 22 pregnancies complicated by retinopathy and nephropathy in which good glycemic control was present antepartum and throughout pregnancy, there were no infant deaths and only one case of mild respiratory distress syndrome.³⁵⁴ A retrospective study of 482 diabetic pregnancies reported only three perinatal deaths which was statistically equivalent to that of nonpregnant deliveries over the same period.⁴¹¹

Two studies suggest an association between diabetic retinopathy and the development of pre-eclampsia. The first followed 683 consecutive pregnancies with type-1 diabetes and found that retinopathy was a statistically significant independent predictor of pre-eclampsia.⁴¹² The second study looked retrospectively at 65 pregnant type-1 diabetic patients and reported that deterioration of retinopathy occurred more frequently in those with pre-eclampsia (4/8) than those without pre-eclampsia (5/65).⁴¹³ Perhaps central retinal artery vasospasm associated with pre-eclampsia exacerbates retinal ischemia

TOXOPLASMIC RETINOCHOROIDITIS

The likelihood of congenital toxoplasmosis occurring in the offspring of a mother with active retinochoroiditis or chorioretinal scars is often a concern. However, usually this is unfounded because congenital toxoplasmosis in the fetus results only from infection of the mother that occurs during the pregnancy itself. The presence of focal toxoplasmic retinochoroiditis or scars in a patient reflects congenital infection in essentially all cases and not new infection of the mother.⁴¹⁴

The fetus of a woman with active retinochoroiditis or inactive scars does not seem to be at risk for contracting congenital toxoplasmosis. A study of 18 pregnant patients with active toxoplasmosis or scars, some with a high stable toxoplasmosis titer found that no infants developed congenital toxoplasmosis.⁴¹⁵ There is one recent case report of a pregnant woman who developed a branch retinal artery occlusions adjacent to an area of active toxoplasmic retinochoroiditis.⁴¹⁶

NONINFECTIOUS UVEITIS

Uveitis disease activity may be altered during pregnancy and the postpartum period. However, data are limited and somewhat contradictory. A retrospective evaluation of 76 pregnancies of 50 women with noninfectious uveitis has been reported. The pregnancies were associated with Vogt-Koyanagi-Harada (VKH) syndrome in 33 women, Behçet disease in 19, and idiopathic uveitis in 24. Worsening of uveitis occurred within the first 4 months of pregnancy in 49/76 (64%) pregnancies and later in pregnancy in 17 (22%). No flare-up occurred in 21 cases (28%). An early pregnancy worsening was typical of VKH and idiopathic uveitis. Postpartum worsening occurred in 38/59 cases (64%) and was characteristic of Behçet disease.⁴¹⁷

Six patients with pre-existing VKH syndrome who improved during pregnancy have been reported.^418–420 All patients had flare-ups of their disease postpartum. Sarcoid uveitis also may improve during pregnancy⁴²¹ or develop de novo during the postpartum period.⁴²² A recent prospective observational case series of four pregnant women with idiopathic uveitis reported improvement in all patients and complete regression in three.⁴²⁴ However, two cases of VKH syndrome arising de novo in the second half of otherwise normal pregnancies also have been reported, with full remission occurring postpartum.⁴²³

Some authors speculate that elevated endogenous free cortisol levels associated with pregnancy may suppress uveitis.^421,422 A recent prospective study of four women with chronic noninfectious uveitis measured hormone and cytokine levels during pregnancy and for 6 months postpartum. In all cases, uveitis improved after the first trimester and flared postpartum. Serum estrogen and progesterone were highly elevated during pregnancy but decreased dramatically postpartum. TGF-beta levels were depressed during pregnancy. The authors conclude that pregnancy-related augmentation of hormone levels and TGF-beta may suppress uveitis during pregnancy but lead to postpartum flare-ups.⁴²⁵

Rapid growth of choroidal hemangiomas has been reported during pregnancy.⁴²⁹ Another case report described the development of exudative retinal detachments associated with choroidal hemangiomas during pregnancy.⁴³⁰ The hemangioma may regress postpartum.⁴³¹ These changes have been attributed to pregnancy-related hormonal perturbations.

Two previously healthy women developed unilateral endogenous candida endophthalmitis after undergoing surgically induced abortions. One eye underwent vitrectomy and intravitreal amphotericin B injection with a final visual acuity of 20/200. The other eye had a retinal detachment with delayed diagnosis, resulting in count fingers visual acuity.⁴³²

Retinitis pigmentosa is sometimes characterized by a sudden pregnancy-associated deterioration in visual fields after a period of relative stability. It is difficult to determine whether changes are related to pregnancy or are just coincidental. Five to ten percent of women with retinitis pigmentosa who have been pregnant reported worsening during pregnancy^13,433 and did not return to baseline after delivery.¹³ We are aware of one report in the literature of visual field deterioration during pregnancy, which resolved postpartum.⁴³⁴ One case of pericentral retinal degeneration that worsened during pregnancy has been reported.⁴³⁵

FLUORESCEIN ANGIOGRAPHY

Fluorescein crosses the placenta and enters the fetal circulation in humans.⁴³⁶ No teratogenic effects in humans have been reported to the National Registry of Drug-Induced Ocular Side Effects.¹³ European investigators have performed research studies involving the administration of fluorescein to 22 pregnant diabetic women and noticed no adverse effects on the fetus.⁴³⁷ Another study of neonatal outcomes among 105 patients who underwent fluorescein angiography (IVFA) during pregnancy showed no increased rate of adverse neonatal outcomes.⁴³⁸ However, this study included only 41 cases of fluorescein angiography during the first trimester, the time when teratogenic effects are more likely to take place and are more severe. Nevertheless, one survey reported that 77% of retinal specialists never perform IVFA on a patient they know is pregnant.⁴³⁹ In another survey, 89% of retina specialists who had seen a pregnant woman who required fluorescein angiography withheld testing out of fear of teratogenicity or lawsuit.⁴⁴⁰ Therefore, fluorescein angiography in pregnant women can be considered if the results would change the management of a vision-threatening problem and appropriate informed consent is obtained.

INDOCYANINE GREEN ANGIOGRAPHY

Indocyanine green does not cross the placenta, is highly bonded to plasma proteins, and is metabolized by the liver. Reports of only 6 cases of the use of indocyanine green angiography (ICGA) during pregnancy have been published.^441,442 In a survey of 520 retina specialists, 105 had withheld ICGA out of fear of teratogenicity or lawsuit during pregnancy and only 24% thought it was safe to use ICGA in a pregnant patient. The authors suggest that current practice patterns concerning the use of ICGA in pregnancy may be unnecessarily restrictive.⁴⁴⁰ Like IVFA, we recommend that ICGA in pregnant women can be considered if the results would change the management of a vision-threatening problem and appropriate informed consent is obtained.

PHOTODYNAMIC THERAPY

The authors are aware of only one case report of adverse fetal or neonatal effects after accidental exposure to Verteporfin photodynamic therapy during the third week of pregnancy.⁴⁴³ Caution is recommended.

TOPICAL ANESTHETIC AND DILATING DROPS

No teratogenic effects related to the use of topical anesthetics or dilating drops have been reported. However, systemic administration of phenylephrine, atropine, and homatropine early in pregnancy has been associated with minor fetal malformations. For this reason, a review of ophthalmic medications during pregnancy considered dilating drops as relatively contraindicated.⁴⁴⁴ Fetal hypoxia has been reported late in pregnancy or during labor in women receiving parenteral phenylephrine. The underlying conditions for which these drugs were used systemically may have been the causative factors in the adverse events, not the drugs themselves. These drops may be used when there is a clear indication to do so, using pressure on the nasolacrimal sac to minimize systemic absorption.

TOPICAL STEROIDS

Topical steroids have not been noted to cause teratogenic effects, although there may be effects of systemic steroids.⁴⁴⁴ There should be a clear indication for the use of topical steroids during pregnancy.

TOPICAL ANTIBIOTICS AND ANTIVIRALS

No adverse fetal effects have been related to topical antibiotic use, but consideration should be given to the noted systemic effects of antibiotic administration. One review suggested that erythromycin and polymyxin B may be the safest antibiotics during pregnancy.⁴⁴⁴ Topical (or systemic) administration of antivirals to animals has been found to have teratogenic effects.⁴⁴⁴

GLAUCOMA MEDICATIONS

There is only limited information regarding human administration of topical glaucoma medication. There are case reports of patients treated with pilocarpine⁴⁴⁵ and with timolol⁴⁴⁶ during pregnancy without an adverse fetal outcome. A study of 10 patients exposed to latanoprost during the first trimester reported one miscarriage and nine normal neonatal outcomes. The study is too small to draw definitive safety conclusions.⁴⁵² The neonate of a patient who used echothiophate iodide (phospholine iodide) was thought to have suppressed pseudocholinesterase levels for a time following delivery.⁴⁴⁷ Systemic administration of large amounts of these agents have caused teratogenic effects in animals. However, timolol is secreted and concentrated in breast milk, and therefore should not be used for nursing mothers.⁴⁴⁵

There are reports that carbonic anhydrase inhibitors are teratogenic in animals in doses similar to those of patients. There are reports of cataracts, congenital glaucoma, microphthalmia, and teratoma in infants born to women on acetazolamide.⁴⁴⁴ There also have been reports of no effect of carbonic anhydrase to the fetus;⁴⁴⁸ therefore, carbonic anhydrase inhibitors are relatively contraindicated during pregnancy.

Further discussion of the issues in glaucoma treatment of pregnant women are available in a number of articles.^{444,448–451,453}

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