The Management of Glaucoma in Pregnancy
M. Reza Razeghinejad
L. Jay Katz
INTRODUCTION
Glaucoma and pregnancy fortunately are rarely seen together, since the vast majority of women who develop glaucoma are over 40 years. While glaucoma primarily affects older people, we now see more female glaucoma patients becoming pregnant because some women in some societies are choosing to delay child bearing. Additionally, congenital, juvenile, or secondary (e.g., traumatic angle recession, neovascular) glaucoma patients may become pregnant. Glaucoma is rarely first discovered during pregnancy because intraocular pressure (IOP) is usually noted to decrease during pregnancy.1,2 However, some patients may develop uncontrolled IOP during gestation and need medical or surgical intervention. The treatment of glaucoma in and around pregnancy offers the unique challenge of balancing the risk of vision loss to the mother with potential side effects and teratogenic effects of drugs or surgical intervention to the fetus.
After giving birth to the baby if the mother plans on nursing her infant, it is important to consider the excretion of any glaucoma medication administered to mother in her breast milk that may affect the infant.
THE COURSE OF GLAUCOMA IN PREGNANCY
Intraocular Pressure and Corneal Changes in Pregnancy
Intraocular Pressure
The exact effects of pregnancy on the IOP in glaucoma are not entirely understood. Studies in nonglaucomatous subjects have shown a statistically significant decline in IOP during all trimesters of pregnancy compared with nonpregnant controls.2,3,4,5,6 IOP declines as pregnancy progresses, with a statistically significant decrease in IOP from the first to the third trimester. The fall of IOP is greater in nonhypertensive and multigravida patients compared to hypertensive and nulligravidae women, respectively.7,8 The only study in pregnant patients with ocular hypertension revealed that IOP declined by 24.4%, and about 61% of the total decrease occurred between the 24th and 30th weeks of pregnancy. The IOP decreased by 19.6%, and about 35% of the total decrease occurred between the 12th and 18th weeks of pregnancy in individuals without ocular hypertension.5 In other words, the decline in IOP was greater in patients with ocular hypertension. IOP has been found to be associated with systemic blood pressure levels in population-based studies.9,10 Hypertension is the most common disorder that occurs during pregnancy.11 Qureshi et al.6 measured IOP in normotensive and hypertensive pregnant patients at three trimesters. The results were compared with nonpregnant normotensive individuals as a control group. In all trimesters of pregnancy, IOP was found to be lower in nonpregnant control subjects. A significantly higher mean IOP was detected in third trimester of hypertensive pregnant women (P < .05), as compared to third trimester normotensive pregnant women. The difference was 0.53 ± 1.5 mm Hg. The authors postulated that the physiologic basis for the IOP-blood pressure relationship in this population may be the result of an increased production of aqueous humor induced by increased blood pressure. However, Phillips and Gore7 found that the mean IOP of third trimester hypertensive pregnant women did not differ significantly from that of third trimester nonhypertensives.
The physiological mechanisms responsible for the decrease of IOP during pregnancy are not known. IOP reduction has been proposed to be caused by several factors: (1) an increase in uveoscleral outflow based on changes in the mother’s endogenous hormone levels, (2) a decrease in episcleral venous pressure reflecting an overall reduction of venous pressure in the upper extremities, and (3) decreased aqueous production due to a slight metabolic acidosis induced by the mother’s pregnant state and the effect of human chorionic gonadotropin (hCG) on the ciliary processes.12,13,14,15
hCG reduces IOP by stimulating the production of cyclic adenosine monophosphate that decreases aqueous humor production.16 In one study the rate of aqueous formation in seven pregnant patients showed no change during pregnancy, but IOP showed a consistently significant fall (17.1 mm Hg at 14 weeks to 13.0 mm Hg at 40 weeks), returning after delivery to values seen in early pregnancy. IOP reduction may thus be due to increased outflow, not to decreased aqueous production.13 Paterson and Miller17 found that during pregnancy the outflow facility rose steeply for about 20 weeks. It then underwent a sudden reduction followed by a slow recovery with another sharp decrease at term. Throughout pregnancy the estrogen and progesterone levels gradually rise and reach a peak at 40 weeks. Since these hormone levels rise gradually throughout pregnancy, the fall in IOP may not be attributable to progesterone and estrogen. Ziai et al.18 were also unable to find a statistically significant correlation while comparing the observed changes in outflow facility and the observed changes in the progesterone level. The pattern of change in outflow facility seems to follow closely that of relaxin serum level. Relaxin serum level rises to a peak at 20 weeks and then falls off completely from 20 to 24 weeks, and then reappears, rises to a maximum at parturition, and completely disappears again 48 hours later. This pattern seemed to follow closely that of the facility of outflow observed during pregnancy, when it consistently occurred in all cases at approximately 20 weeks. Wilke noted lower episcleral venous pressure in pregnant women.19 It has been reported that the reduction of episcleral venous pressure was consistent with the generalized reduction of peripheral vascular resistance during pregnancy.20 The increased outflow facility and consequently IOP reduction observed in pregnant patients is attributed to hormonal changes.2,17,18
Some case reports describe women with glaucoma whose IOPs have been difficult to control despite medical and surgical interventions.21,22 In a retrospective study conducted on 28 eyes of 15 pregnant glaucoma patients with varying severity and types of glaucoma, in 16 eyes the level of IOP remained stable during pregnancy with no associated loss of visual field. In five eyes there was progression within the field of vision while the level of IOP remained stable or increased, and in five eyes the level of IOP increased, but there was no progression of the damage to the visual field. In the remaining two eyes the data was inconclusive. Glaucoma medications were used to control the level of IOP in 13 of the 15 remaining patients.23
A 28-year-old woman had a controlled IOP with latanoprost for 5 years, but in pregnancy it increased to 30 mm Hg even after adding timolol and dorzolamide and receiving laser trabeculoplasty (LT). Finally, she underwent trabeculectomy without antimetabolites.24 All reports emphasize the importance of regular follow-up of pregnant patients with glaucoma. Although a population of patients may show decreasing IOP in pregnancy, an individual patient may develop worsening glaucoma and vision loss while pregnant.
Noncontact tonometers were shown to increase intraobserver agreement in IOP measured late in pregnancy and may be superior to both Goldmann and Schiotz tonometers in the management of pregnant patients.25 Although the Goldmann tonometer is regarded as a standard tonometer, in those pregnant patients who are reluctant to receive a topical anesthetic agent for IOP measurement the noncontact tonometry can be employed. However, there have been no teratogenic effects reported with the use of topical anesthetics.12,26
Cornea
The reported corneal changes in pregnancy include a decrease in corneal sensitivity, with the largest changes late in pregnancy,27 and an increase in thickness during pregnancy.28 In a study of corneal curvature in pregnant women there was a statistically significant increase in corneal curvature during the second and third trimester which resolved postpartum or after the cessation of breast-feeding.29 Weinreb et al.28 measured central corneal thickness in 89 pregnant women and compared it with nongravid or postpartum controls and reported increased corneal thickness of 16 microns in pregnant subjects. The authors postulated that this increase may be the result of the generalized physiologic increase in water retention during the pregnant state. This observation of increased corneal thickness was confirmed by other investigators.18 Another study, however, evaluating the corneal thickness and curvature of 100 pregnant patients confirmed no difference between pregnant and nonpregnant women.30 In 27 patients, corneal thickness was recorded during the third trimester, and again 6 weeks postpartum. The corneal thickness was the same during pregnancy as it was after delivery.31 An increase in corneal thickness has not been observed consistently in all studies. If we propose that corneal thickness increases in pregnancy, we should expect higher IOP readings.
The importance of central corneal thickness for the diagnosis, management, and prognosis of glaucoma is well documented. IOP is underestimated in structurally thinner corneas, whereas it is overestimated in structurally thicker corneas. A major exception is corneal edema, which causes an underestimation of IOP despite thickening.32,33 Some studies showed increase in corneal thickness and curvature that can lead to overestimation of IOP measurement. The suggested cause of increase in corneal thickness is corneal edema that logically should lead to lower IOP readings. Additionally, it is well known that a change in the elasticity of ligaments and connective tissue occurs in pregnancy, and this tissue softening may extend to that of the corneoscleral envelope to produce reduced corneoscleral rigidity making applanation tonometry readings falsely low. The only available instrument for checking corneal biomechanical properties is the Ocular Response Analyzer, and we are aware of no study that has been conducted in pregnant women using this device yet. Finally, it is possible that IOP is not actually lower during pregnancy, but rather there is increased measurement error in pregnant women.
Newly developed Krukenberg’s spindles on the cornea have been observed early in pregnancy, and they tend to decrease in size during the third trimester and postpartum.34 The hormonal effects of estrogen, progesterone, and melanocyte stimulating hormone are postulated as the cause of this increased pigmentation and the increased facility of outflow is suggested as a possible cause of the clearing of pigment late in pregnancy.
Optic Nerve Structure and Function
Two principal theories for the pathogenesis of glaucomatous optic neuropathy include a mechanical and a vascular theory. According to the mechanical theory, increased IOP causes stretching of the lamina cribrosa beams and also causes damage to retinal ganglion cell axons. The vascular theory of glaucoma considers glaucomatous optic neuropathy as a consequence of insufficient blood supply due to either increased IOP or other risk factors reducing ocular blood flow. Nevertheless, some patients with normal pressure develop similar glaucomatous disc and visual field changes, which indicate there must be other risk factors involved in the pathogenesis of the disease. Retrobulbar hemodynamic alterations and lower end diastolic blood flow velocity in the central retinal artery correlated with the progression rate of visual field damage in patients with controlled IOP.35,36
Healthy women increase plasma volume by 50% in pregnancy.37 This physiologic hypervolemia facilitates delivery of nutrients to the fetus, protects the mother from hypotension, and reduces the hazard of hemorrhage at delivery. The resistance to blood flow is lower due to a decrease in blood viscosity secondary to a low hematocrit percentage. The peripheral resistance is reduced in gestation, and cardiac output is elevated after the end of the first trimester of pregnancy, remaining elevated throughout pregnancy. Arterial blood pressure remains virtually constant and heart rate rises, but only very slightly.38,39,40 In a study on healthy pregnant patients, retrobulbar blood flow showed a significant decrease in resistive index and pulsatility index values with advancing gestational age.41 Pulsatile ocular blood flow in 27 healthy pregnant subjects was higher compared with the nonpregnant controls. It increased further in the second trimester of gestation over the first, and the authors supposed that the pulsatile ocular blood flow increase during pregnancy may be correlated with estrogen secretion.42 These physiologic changes facilitate organ perfusion, including retrobulbar blood flow in pregnancy.
The mean diurnal IOP variation was 2.3 and 1.1 mm Hg, respectively, in the nonpregnant healthy subjects compared with pregnant individuals at the third trimester, respectively.43 The less fluctuation of IOP and improved retrobulbar blood flow in pregnancy may have a protective effect on the optic nerve. However, all pregnant patients need to have a close follow up to check IOP and optic nerve status during their pregnancies.
Optic nerve evaluations consist of structural and functional tests. The structural tests include funduscopy, Heidelberg Retinal Tomography (which examines the optic nerve head in terms of cupping and neuroretinal rim), and Optic Coherent Tomography and Scanning Laser Polarimetry (which evaluate the retinal nerve fiber layer). We found no study assessing the optic nerve using these structural tests in pregnant women in the literature.
In order to evaluate the optic nerve by funduscopy or imaging, a dilated pupil examination is more informative than undilated pupil. The systemic use of phenylephrine, atropine, homatropine, and scopolamine has been reported to be associated with minor fetal abnormalities, such as inguinal hernia and club foot,44 but no teratogenic effects related to the use of topical anesthetics or dilating drops have been reported.26
Visual field is the available test for checking the function of the optic nerve in glaucomatous patients. There are controversial reports about the visual field changes in pregnancy. In one study, 60% of pregnant healthy subjects had constriction of peripheral visual field.45 Other reported defects include bitemporal contraction, concentric contraction, and enlarged blind spots. These defects were shown to be reversible by 10 days after birth.12
Although the increasing size of the pituitary gland (an average of 120% during a normal pregnancy) may exert pressure on the chiasma or optic nerve,46 based on radiographic measurements the field changes in pregnancy probably depend upon functional modification rather than upon enlargement or vascular changes in the pituitary gland.45 The majority of reported visual field defects in pregnancy were in the temporal hemifield,12 but the usual locations for glaucomatous visual field defects are in the nasal hemifields, and the defects respect the vertical meridian.47 The reversibility of any kind of visual field defect after pregnancy and the location of the defect in visual field are important clues in differentiating glaucomatous from pregnancy-induced visual field defects.
LABOR IN GLAUCOMATOUS PATIENTS
The sympathetic system discharge that induces pupillary dilation and Valsalva maneuver during labor are factors that may affect glaucoma patients. In pregnant women the sympathetic system discharge is high because of the stress and also secondary to the release of oxytocin. Oxytocin is a potent neurotransmitter that causes the sympathetic nervous system to discharge, which in turn produces a temporary pupillary mydriasis and may lead to an acute attack in susceptible patients. One case of acute angle-closure attack during labor has been reported. However, the patient was later believed to have had unrecognized subacute attacks prior to pregnancy.48 A 40-year-old pregnant patient developed acute angle-closure attack in both eyes after receiving intravenous ritodrine. The authors surmised that administration of ritodrine and hospitalization in a dark room for bed rest, together with the emotional stress caused by preterm labor, precipitated the attack.49 It seems logical to make sure all pregnant patients with angle-closure glaucoma or occludable angle have a patent iridotomy before labor.
Valsalva maneuver can increase IOP temporarily.50 Whether this IOP increase can affect the optic nerve and worsen the optic neuropathy has not been studied. There is no definite evidence in the literature to recommend that glaucomatous patients have cesarean section instead of normal vaginal delivery. The theoretical risks of elevated eye pressure and decreased blood flow to the optic nerve during the pushing phase of labor should be discussed with those patients with severe glaucomatous optic nerve damage. These concerns should be addressed with the obstetrician. With respect to the effect of retrobulbar blood flow and perfusion pressure on the progression of glaucoma,36,51 all efforts should be made to prevent significant blood loss and hypotension during labor.
GLAUCOMA MEDICAL THERAPY
Drug treatment of glaucoma at any stage of pregnancy is controversial due to the lack of any clinical studies on the effect of antiglaucoma medications on human fetuses and pregnant women. Most evidence comes from single-case reports or animal studies with the limitations that these impose. In a survey of ophthalmologists in the UK, 26% had previously treated pregnant women with glaucoma. Interestingly, 31% were unsure how to treat a pregnant woman who had uncontrolled IOP; 40% used topical treatment. Of those who prescribed medical treatment, 45% used topical beta-blockers first, 33% used topical prostaglandin analogues first, and 22% used other medications first.52
Every woman in the general population has a 3% to 5% risk of having a child with a birth defect or cognitive impairment. Drug and chemical exposure during pregnancy is believed to account for only about 1% of congenital malformations.53 Two important factors to consider when assessing the teratogenic potential of a medication are the stage of pregnancy at which the exposure occurred and the amount of medication taken. Potential teratogenic drug effects of any medication may be more significant if administered during the first 12 weeks of fetal development (organogenesis). However, a number of pregnancies are unplanned. This may lead to exposure to drugs which are not recommended for pregnant women before the women are aware of their pregnancies and typically during the first 12 weeks.
Once the drug has entered the fetal circulation, it may be excreted into the amniotic fluid from the kidneys, the lungs, or the skin. Thus, the length of fetal exposure to an administered drug may be much longer than in adults because of recirculation through the swallowing and breathing movements of the fetus and re-excretion by the fetal kidneys.54 The topical medications may result in harmful effects on the fetus though the amount of drug administered is very low.
Because 80% of eyedrop volume is absorbed by drainage through the nasopharyngeal mucosa and absorbed systemically, bypassing hepatic metabolism, all ophthalmic topical medication may produce systemic side effects.55 In one study, systemic absorption of topical timolol was diminished 67% by nasolacrimal occlusion and 65% by eyelid closure.56 The minimum amount of medical treatment possible for glaucoma should be prescribed.
Generally, less than 20% of all the drugs classified by the Food and Drug Administration (FDA) fall into categories A or B. Most topical antiglaucoma drugs belong to category C, and none are placed in category A or X (Table 54H.1).57 Brimonidine and dipivefrin have been ascribed class B status, which presumes safety based on animal studies only.57
Preservatives of Drops
Preservatives such as benzalkonium chloride (BAK) are commonly used in eyedrop formulations. BAK also improves penetration of some water-soluble molecules through the corneal epithelium. BAK causes bronchoconstriction through a combination of mast cell activation and stimulation of neural pathways, especially in patients who receive more than one antiglaucoma drug.58 Whether it can affect the lung maturation of the fetus has not been determined. In a study of rats on the embryotoxicity of this preservative, a dose-related increase in fetal resorption, death, and reduction in litter size and weight were observed. BAK was not associated with any discernible visceral malformations, although minor sternal defects occurred in fetuses exposed to a single dose of 100 and 200 mg/kg.59 The concentration of BAK in anti-glaucoma eye drops (Table 54H.2) is miniscule compared to the above study.
TABLE 54H-1 U.S. Food and Drug Administration Classification of Drug Safety in Pregnancy | ||||||||||||
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For patients who require more than one topical agent for adequate IOP control, fixed-combination products offer the advantages of a simplified medical regimen and potential for better compliance and less exposure to preservatives. The preparations of carteolol, levobunolol, and metipranolol have lower concentrations of BAK than do betaxolol and timolol maleate solution. Preservative-free tafluprost, a prostaglandin agent, is also available and can be used in those allergic to BAK.60 In Travatan Z, BAK is replaced with SOFZIA, an ionic buffered preservative system,61 and there are no data whether Travatan Z is preferable to Travatan in pregnant patients with glaucoma. Alphagan P also utilizes a nonBAK preservative, Purite.
Beta-blockers
Beta-blockers are divided into selective and nonselective groups. The nonselective topical beta-blockers are timolol maleate, timolol hemihydrates, carteolol, levobunolol, and metipranolol. Betaxolol is the only beta-1 selective beta-blocker commercially available. Beta-blockers are categorized as class C medications in pregnancies. There are limited examples of the use of timolol in pregnancy, but we found no published study about use of other topical beta-blockers. It is advised not to use beta-blockers in the first trimester because of possible harmful effects on the fetus.62 Only one case with cardiac conduction disorder has been reported in the literature as the teratogenic effect of intrauterine exposure to timolol.55 The fetus of a 37-year-old pregnant woman who was using timolol 0.5% once daily without employing punctal occlusion developed bradycardia and arrhythmia. The irregularity but not bradycardia disappeared after halving the timolol dose (0.25% once daily). After stopping the drug bradycardia disappeared. The authors surmised that the drug interfered with the development of the embryonic heart. However, there is always the possibility that the cardiac conduction disorder had nothing to do with the use of timolol.55 In contrast, some other reports detected no specific problem in the newborns of pregnant women who were on topical timolol.63,64 In a study of 15 pregnant women with glaucoma (13 receiving topical medications), 11 patients were receiving topical beta-blockers and were not associated with any adverse effects.23
Theoretically, beta-blockade in pregnancy results in uterine contraction that could result in a small placenta and fetal growth retardation.65 However, in a study using a population-based data set, 244 pregnant women who had been prescribed topical medications to control glaucoma during pregnancy were compared with 1,952 pregnant women matched for age, year of delivery, maternal hypertension, and gestational diabetes to determine the adjusted odds ratio of having low birth weight (LBW) infants. The majority of pregnant women (77.5%) were prescribed beta-blockers, and only 2.9% were prescribed carbonic anhydrase inhibitors (CAI) to control IOP. The odds ratio of LBW infants for women on antiglaucoma medications was 1.63 times that of women in the comparison cohort. The adjusted odds ratio was 2.15 for women on other than beta-blockers compared with the comparison cohort. However, no significant difference in the risk of LBW infants was observed comparing women who were on beta-blockers and women in the comparison cohort (odds ratio = 1.48). The authors concluded that beta-blockers can be the firstline drug when considering glaucoma medical treatment in pregnant women.
TABLE 54H-2 Preservative of Antiglaucoma Medications | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Although some reports state that beta-blockers should not be used during pregnancy, the obstetricians are most comfortable with their use to control hypertension in pregnant patients.66 Half of a typical dose of timolol 20 to 60 mg/day will reach the systemic circulation because of the hepatic metabolism of the drug. The story is different in the topical form. Typically a drop volume is 30 µL, and each 1 mL of timolol 0.5% ophthalmic solution contains 5 µg timolol. If a patient is given timolol 0.5% twice daily and the entire drop is absorbed, the total daily systemic exposure would be approximately 600 µg. Thus, the systemic burden of timolol 0.5% used in both eyes twice daily is less than 6% of a 20-mg oral dose of timolol.67
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