Glaucoma Management in Pregnancy and Postpartum
1) Summary:
The management of glaucoma during pregnancy and lactation presents unique challenges. Several glaucoma medications have potential adverse effects in the fetus or breastfeeding infant, and should be considered only after carefully balancing the potential dangers to the fetus or infant with the risk of worsening glaucoma in the mother. When medical treatment is employed, systemic absorption should be minimized through nasolacrimal occlusion or punctal plugging. Alternatives to medical treatment should be considered, including laser trabeculoplasty or observation off medical treatment. Glaucoma surgery during pregnancy should be avoided if at all possible, particularly in the first trimester when the risk of abortion and the teratogenicity anesthetics, sedative agents, and anti-metabolites is highest. If glaucoma surgery is considered during pregnancy, special considerations should be taken regarding the use of antimetabolites, patient positioning, and the type of anesthesia administered.
2) Introduction
Glaucoma is most commonly found in adults over the age of 40, but will occasionally occur in females of childbearing age. Often, women will have had preexisting glaucoma which originally began in childhood (i.e. congenital glaucoma or anterior segment dysgenesis), or glaucoma secondary to other conditions such as uveitis or diabetes. The treatment of glaucoma in and around pregnancy offers the unique challenge of balancing the risk of vision loss to the mother with potential harm to the fetus or newborn.
Here, will discuss the management of glaucoma in and around pregnancy. Special consideration will be given to the stage of pregnancy, including women who could or would like to become pregnant, and breastfeeding mothers. Additionally, the unique risks of medical and surgical glaucoma treatment will be discussed, as will therapeutic alternatives to, and modifications of, standard medical treatment.
3) Epidemiology
Glaucoma has been reported to occur in roughly 2-3% of adults over the age of 40, though the prevalence increases substantially with age for all races and ethnicities. Few data exist regarding the prevalence of glaucoma prior to the age of 40, when women are most likely to become pregnant. In one Japanese study, the prevalence of open angle glaucoma, defined by a visual field defect along with corroborating optic nerve findings, was 0.48%, 0.42%, and 0.73% among women aged 15-24,25-34, and 35-44 respectively.1 Additionally, women of childbearing age may have glaucoma acquired early in childhood (congenital glaucoma, anterior segment dysgenesis, or glaucoma after cataract formation), or glaucoma resulting from coexisting conditions presenting early in life, i.e. uveitic or neovascular glaucoma.
4) IOP changes and disease course
In women without glaucoma, intraocular pressure typically decreases during pregnancy. In one study of pregnant women, the mean intraocular pressure of first trimester patients was higher two mmHg than that of third trimester patients.2 Potential mechanisms for this IOP reduction include greater aqueous outflow facility due to hormonal changes, decreased episcleral venous pressure due to reduction of venous pressure in the upper limbs, and metabolic acidosis resulting from gestation. 3, 4 Specifically, increased progesterone and relaxin levels may decrease intraocular pressure and increase the coefficient of facility of aqueous outflow during the menstrual cycle and pregnancy. However, the extent to which these IOP changes should be anticipated in women with pre-existing glaucoma is unclear.
One small study of 15 women examined glaucoma progression during pregnancy. The authors found no increase in IOP or visual field progression in 57% of subjects. However, 18% of the women demonstrated progressive visual field loss, while an additional 18% demonstrated IOP elevation without visual field progression. Amongst the women with IOP increases, the mean increase was 10 mm Hg (range 1.3mmHg to 22.5 mmHg). Many women in this second group required additional medication to control their IOP.5
5) Medical treatment
The safety of glaucoma medications in pregnancy has been classified by the United States Food and Drug Administration (FDA) based on evidence available from human and animal studies. Category A medications have strong evidence of safety based on human studies. Category B medications have varying and /or contradictory human and animal data. For example, a drug may be graded as Class B if animal studies showed some harm but human studies indicated safety, or if animal studies showed safety and no human studies were available. Category C is used to describe medicines which showed side effects in animal models, or where inadequate animal and human studies are available. Category D medications indicate human studies showing risk to the fetus, while Category X drugs show strong evidence of birth defects.
5.1 Beta-blockers
Oral beta-blockers are categorized as class C medications in pregnancy. No specific categorization is available for topical beta blockers. Timolol can cross the placental barrier, thus resulting in fetal bradycardia and cardiac arrhythmia. Furthermore, beta-blockers can be secreted into breast milk and may cause similar effects in newborn infants. Indeed, one study of timolol use in children found plasma timolol levels ranging from 3.5 ng/ml in a five-year-old child to 34 ng/ml in a three-week-old infant.6 The same study also reported that the mean one-hour plasma timolol concentration was reduced by approximately 40% when punctal occlusion was performed. No formal studies have examined the relative effects of different timolol concentrations or dosing recommendations. However, minimal difference in IOP lowering has been noted for 0.25% timolol as compared to 0.5% timolol, and with 0.5% timolol doses once daily, as compared to twice daily.
5.2 Alpha 2 Agonists
Brimonidine is classified as a Category B medication by the FDA. However,no well-controlled human studies have been done to rule out a potential teratogenic effects. Additionally, brimonidine poses substantial risk to the newborn, having been reported to cause central nervous system depression and apnea. The drug penetrates the blood-brain barrier, and can cross the placenta and possibly excrete into breast milk, posing a real risk of apnea or hypotension in infants. Thus, even if brimonidine is used during pregnancy, it should be discontinued before labor and during breastfeeding to prevent potentially fetal apnea in the infant.
5.3 Prostaglandin Analogues
Prostaglandin analogues are classified as Category C drugs, and are associated with a high incidence of miscarriage in animal studies. Additionallly, a systematic review documented that orally or vaginal use of misoprostol in pregnancy is associated with an increased risk of Moebius syndrome and terminal transverse limb defects.7 Prostaglandins can also stimulate uterine contractions producing premature labor, though it is unclear whether the very low drug concentrations used in ophthalmic prostaglandin formulations are sufficient to elicit this side effect. Therefore, these medications should be used with caution. One small series followed 10 women exposed to latanoprost in the first trimester. Normal delivery occurred in 9 women without neonatal malformation, with one spontaneous abortion noted in a 46 year-old woman.8 Nonetheless, given the theoretical risk of premature delivery, prostaglandin analogues are not a choice for first-line medication in pregnancy.
5.4 Topical Carbonic Anhydrase Inhibitors
Brinzolamide is classified as a category C medication in pregnancy. In animal studies, there was a statistically lower fetal body weight with the oral medication (375 times the human ophthalmic dose). However, no organ malformations were not seen even at this high dose.9
Dorzolamide is also classified as Category C medication. There were malformations of the vertebral bodies in rabbits exposed to dorzolamide during pregnancy, suggesting that brinzolamide may be a better alternative.10
No controlled reports of brinzolamide or dorzolamide exist in human pregnancy. As such, it may be used during pregnancy with caution when the possible benefit to the mother outweights the theoretical risk to the fetus. It is uncertain if these medications are excreted in human milk, and thus their safety in breastfeeding is unknown.
5.5 Oral Carbonic Anhydrase Inhibitors
Acetazolamide is classified as a Category C medication. Systemic high dose carbonic anhydrase inhibitors in rat can introduce in forelimb anomalies.11 Also, a case report of neonatal sacrococcygeal teratoma was published regarding a woman who taking acetazolamide in early pregnancy.12 On the other hand, there were no fetal adverse effects in 12 pregnant women who used oral acetazolamide for idiopathic intracranial hypertension management.13
Acetazolamide may also result in potential metabolic complications to the newborn or breast-feeding child. One case report exists of oral acetazolamide used during pregnancy crossing the placenta and causing transient renal tubular acidosis in a newborn.14 However, another case report demonstrated that acetazolamide plasma level of infants exposed to the medication through breast milk were very low.15 Therefore, acetazolamide is approved by the American Academy of pediatrics for using during nursing.16
Methazolamide is also classified as a Category C medication. Skeletal malformations have been reported in rat when giving 40 times the human dose.17 No controlled investigations exist in human pregnant women. Details regarding whether the drug is excreted into human milk is unknown.
5.6 Minimizing systemic absorption of eye drops
All eye drops have potential systemic side effects which could possibly be avoided, or at least minimized, by reducing systemic absorption of the medication. Nasolacrimal occlusion and eyelids closure are easy techniques that can reduce the systemic adverse effects.18 Nasolacrimal occlusion is performed by using the fingertips to apply pressure over the puncta and canaliculi for 5 or more minutes to occlude nasolacrimal drainage. In one study, Systemic absorption of topical timolol was diminished 67% by nasolacrimal occlusion and 65% by eyelids closure.19
Additionally, both nasolacrimal occlusion and eyelids closure can increase eye-drug contact time resulting in higher intraocular drug concentrations, and less systemic absorption.19 Punctual plugging can reduce tear drainage and improve mean tear meniscus levels such that systemic absorption of drugs is lowered.20,21 However, there are no direct studies on systemic absorption of glaucoma medications with punctal plugging. Nonetheless, this option should be discussed with women who choose to continue topical IOP-lowering therapy in and around pregnancy, given the strong likelihood that it would significantly reduce systemic drug absorption.
6. Role of Laser
Laser trabeculoplasty may be considered in pregnant women to eliminate or reduce the number of necessary medications. Unfortunately, ALT appears to be less effect for IOP control in young patients.22 A retrospective study of Argon laser trabeculoplasty reported that 60% of lasered patients had uncontrolled IOP and required glaucoma surgery within two years following ALT.22 However, given the short time-frame of pregnancy, trabeculoplasty may still be considered in these patients. One study demonstrated IOP reduction after cyclophotocoagulation in a pregnant patient with uveitic glaucoma, though retrobulbar or sub-Tenon’s anesthesia would still be required. 23
7. Surgery
7.1 Surgical options
Glaucoma surgery could be considered during pregnancy if the patient has glaucoma progression despite using maximum safe medications. However, there are specific risks of glaucoma surgery in pregnant patients, including the risks of local and general anesthesia, and the need for post-operative medications. Additionally, glaucoma filtration surgery in pregnant patients may be at relatively higher risk of failure because of their young patient age 24 and contraindicated antimetabolite usage.
7.2 Anesthetic Concerns of Surgery
Surgical anesthesia in pregnancy poses risks to both the mother and fetus. Maternal physiology is altered such that plasma volume and cardiac output are greater, and peripheral vascular resistance is reduced, thus lowering blood pressure. Additionally, supine position in the second and third trimester can induce profound hypotension due to aortic and vena caval compression by the uterus. Ideally, the pregnant women should be placed on their left side, though this may complicate positioning of the eye for surgery. The patient should be well hydrated and oxygenated before anesthesia induction to prevent maternal hypotension and hypoxia.25
In pregnancy, minute ventilation and oxygen consumption increase, while functional residual capacity decrease. Thus, the pregnant women can develop hypoxia and hypercapnia more quickly. Furthermore, airway management is hard in pregnant patients who have breast enlargement, weight gain, and laryngeal edema.25 The risk for gastric acid aspiration through anesthesia induction is raised in gravid patients as gastroesophageal sphincter tone and intestinal motility are reduced. Full stomach precaution techniques have to be performed to reduce the risk of gastric acid aspiration.25
For general anesthesia cases, narcotics, paralyzing agents, and inhaled anesthetic agents can influence to the fetus. Thiopental is a narcotic agent that has been shown to not have a teratogenic effect in animal or human studies.25 Succinylcholine is a paralytic agent that is often used before intubation. High dose exposure of this agent may affect neuromuscular paralysis in newborn.25 Halothane and nitrous oxide are inhaled anesthesia agents that have been published growth retardation and congenital anomalies in animal studies. However, there are no well controlled human studies that have been reported teratogenic effects of these agents.25 The side effects of these medications make local anesthesia much more preferable if at all possible.
Regarding local anesthesia, fetal bradycardia was reported when applying bupivacaine in pregnancy but lidocaine has not been related with any adverse effect in the fetus.26 If nursing patients need to do glaucoma surgery, lidocaine should be administrated immediately after nursing for lowering of lidocaine in breast milk.27
7.3 Surgical Positioning
Supine position in second and third trimester gestation can induce profound systemic hypotension due to aortic and vena caval compression by the uterus. Consideration should be given to rotating the patients hips, abdomen, and thighs while maintaining a normal head position for ophthalmic surgery.
For maternal safety, uterine displacement ought to be considered to prevent systemic hypotension. Because of diminishing of gastroesophageal sphincter tone in pregnant patients, full stomach precaution techniques should be performed to reduce the risk of gastric acid aspiration.
Intraoperative noninvasive fetal monitoring should be considered in major surgery, but may not be necessary for the short durations of glaucoma surgery. Additionally, monitoring may not be necessary in the first or early second trimester when the fetus is not viable. Alternately, pre- and post-operative fetal monitoring can be considered to document the well-being of the fetus in the periods immediately before and after surgery. Teratogenic effects in anesthetic or sedative agents remain a possible risk. However, avoiding surgery in first trimester may decrease the risk of teratogenicity and spontaneous abortion.28
The risk of preterm labor or abortion is increased with surgery during pregnancy. Topographic monitoring in the postoperative period may detect preterm labour.29 Fetal heart rate monitoring is a good detector of fetal asphyxia during surgery.29 If fetal heart rate monitoring is not available, fetal ultrasound before and immediately after surgery is reasonable to examine the gross anatomical abnormalities of the fetus.
7.4 Intra- and Peri-Operative Medications
Mitomycin C is an antifibrotic agent which is frequently applied in glaucoma surgery. A decrease of mean litter size and body weight and an increase of exencephaly in second gestation mice were associated with mitomycin use.29 There are no studies which reported teratogenic effect of this drug in the fetus, though the mechanism of action of the drug strongly suggests a possible teratogenic risk.
Fluorouracil is an antimetabolite that has been associated with several congenital anomalies in mothers who had obtained intravenous 5-fluorouracil in first trimester.30 The risk of subconjunctival administration is not known.
The use of antimetabolite agents for glaucoma surgery ought to be avoided in gravid patients because of the potential teratogenic effects.31
Topical antibiotics are common used after glaucoma surgery, and the risks of many antibiotics in pregnancy have described, though primarily as orally-administered medications.
Erythromycin is the oldest of macrolides, which badly passes over the placenta. This medication is classified as category B. There are no studies relating erythromycin and congenital anomalies.25 There are also no reports of adverse effects of the macrolides in breastfeeding.32 Tetracyclines are classified as a category D medications that can cross placenta quickly. They may cause brown discoloration of the deciduous teeth and suppress of bone growth when applying after fifteen weeks of pregnancy. There are no data of teeth discoloration when exposure mother’s milk.32
Aminoglycosides are classified as a category D medications. Gentamicin, neomycin and tobramycin are the aminoglycosides which rapidly crosses the placenta. There is no evidence that the aminoglycosides has the teratogenic effect in the fetus except possible eight cranial nerve damage.25 Tobramycin can be detected only in limited amounts in mother’s milk.32
Chloramphenicol is not advised for using in pregnancy because it has been linked with the gray baby syndrome.25
Fluoroquinolones are classified as a category C medications. Ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin are all fluoroquinolones that cross the placenta. Animal studies have indicated that quinolone can cause cartilage damage of the fetus. Nevertheless, one study of the first trimester pregnant women who were giving fluoroquinolones have shown no significant increase of congenital anomalies.32 Regarding breastfeeding, no reports have shown levofloxacin, gatifloxacin and moxifloxacin passing into the breastmilk. In animal experiments, quinolone can damage the cartilage of the joint.32
In summary, Erythromycin seems to be the less adverse effect in pregnancy and lactation, and should be strongly considered as the antibiotic of choice after glaucoma surgery in the pregnant or breast-feeding woman.
Corticosteroids are classified as a category C medication. Topical corticosteroids are nearly always used after glaucoma surgery. All systemic glucocorticoids cross the placenta. Prednisolone and methylprednisolone cross the placenta less than betamethasone and dexamethasone and may have less of an effect on the fetus.32 Some studies have been published suggesting the absence of fetal teratogenicity with oral steroids.31 Given the strong tendency to use topical steroids after glaucoma surgery, and the absence of clear complications associated with these medicines, their use should be strongly considered if surgery is necessary in the pregnant or breastfeeding woman.
Atropine is classified as a category C medication. Topical atropine is occasionally used postoperatively in glaucoma surgery. Atropine can affect fetal heart rate, though the effect may be less likely with ophthalmic dose.25
For all topical medications used in conjunction with glaucoma surgery, punctual occlusion, eyelid closure, or punctal plugging should be considered to decrease systemic absorption of the medication.
8. Stages of pregnancy
8.1 Pre-Conception
Ideally, a discussion of the treatment plan of a woman’s glaucoma should be initiated before pregnancy begins. In this way, the adverse effects of medications can be prevented during the first trimester, when much organogenesis is occurring. Additionally, alternate effective methods to lower IOP (including surgery if necessary) can be explored or achieved prior to pregnancy beginning. Women of childbearing age should know to alert their doctor immediately should they suspect they are pregnant, or if they are planning to start or add to their family.
8.2 First Trimester
A discussion of the risks of medication and the best strategy for IOP-lowering should occur as soon as pregnancy is noted, as organogenesis has often begun when pregnancy is first identified, and medications taken during organogenesis can result in birth defects. Pregnancy discussions should include a discussion of medication concentration/dosage, methods to minimize systemic drug absorption, and if medication can be withheld for parts of the pregnancy.
Brimonidine, a Category B drug, may be the safest option for the first trimester. Prostaglandins also have evidence of safety during this period.8 Other anti glaucoma medications such as beta-blocker, prostaglandins and carbonic anhydrase inhibitors should be avoided when possible in first trimester to reduce potential teratogenic effects. Discussions with the patient should include observation off treatment in this critical period.
For glaucoma surgery, anesthetic, sedative agents, and metabolites are all possible teratogenic agents. Therefore, avoiding surgery in first trimester may decrease the risk of teratogenicity and spontaneous abortion.
8.3 Second Trimester
In second trimester, brimonidine can be applied and beta-blockers can be used with regular fetal heart rate and fetal growth monitoring. If prostaglandin analogues are used, premature labour symptoms and signs should be described to the patient, and the medication should be stopped in any such symptoms are noted. When topical or oral carbonic anhydrase inhibitors are used, fetal growth retardation monitoring may be considered.
8.4 Third Trimester
Brimonidine, beta-blocker, topical carbonic anhydrase inhibitors, can be used with caution. Avoidance of prostaglandins may decrease the risk of premature labor, which is particularly important early in the third trimester. Late in the third trimester, brimonidine should be discontinued because it can induce central nervous system depression in newborns. Topical carbonic anhydrase inhibitors may to be the optimal choice in this period.
Glaucoma surgery can perform with caution in second and third trimester if the patients have a strong indication for the procedure. However, anesthetic, sedative agents, and metabolites still have potential risk for the fetus. Additionally, uterine displacement ought to be performed to prevention of maternal hypotension that can induce fetal asphyxia.
Argon laser trabeculoplasty is an alternative glaucoma treatment that can be perform in all trimesters. ALT may be less effective in generating IOP lowering in gravid patients, but may result in short-term IOP control until the end of pregnancy.
8.5 Postpartum
Acetazolamide and beta-blocker are certified by the American Academy of pediatrics for use during nursing. However, low doses of these medications should be considered when used in the breast feeding period. Brimonidine is contraindicated for use in lactating mothers due to the risk of central nervous system depression in the newborn.
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