Ocular Immunology & Inflammation, 20(4), 277287, 2012 2012 Informa Healthcare USA, Inc.

. ISSN: 0927-3948 print/1744-5078 online DOI: 10.3109/09273948.2012.684736

Original article

Treatment of Severe Inflammatory Eye Disease in Patients of Reproductive Age and during Pregnancy
Denis Wakefield1, Ahmed Abu El-Asrar2, and Peter McCluskey3
1 School of Medical Sciences, University of New South Wales, Sydney, Australia, 2Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia, and 3Save Sight Institute, University of Sydney, Sydney, Australia

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AbSTRAcT
Inflammatory eye diseases (IED) such as uveitis affect females and males in the prime of their reproductive life. Despite their propensity to lead to significant visual loss, there have been very few studies of the management of patients with IED who are pregnant or plan a pregnancy during the course of therapy. The first trimester and postpartum period may be associated with an exacerbation of IED and it is important to have available medications that control the disease and do not cause miscarriage or fetal abnormalities. Several immunosuppressive drugs are contraindicated in pregnancy (methotrexate and alkylating agents), while others (corticosteroids, azathioprine, and cyclosporin) may be considered for use in pregnancy. Most drugs are excluded from use in pregnancy not because of proven teratogenicity but because of the lack of available evidence of their safety for the fetus. KEYWORDS: Veitis, pregnancy, therapy, infertility

Pregnancy is associated with remission or clinical improvement in some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis (MS), while other autoimmune diseases, such as systemic lupus erythematosis, are often exacerbated during pregnancy.1,2 Furthermore, the postpartum period may be associated with an exacerbation of a number of autoimmune diseases. This is well illustrated in a recent study of patients with Vogt Koyanaga Harada (VKH) disease, Behet disease, and idiopathic uveitis from Saudi Arabia.3 The study noted a flare in disease activity within the first 4 months of pregnancy and a relative decrease in disease activity during late pregnancy, with an exacerbation of inflammatory eye disease within 6 months of childbirth. These observations are similar to a previous North American study that demonstrated that pregnancy was associated with a lower number of flare-ups of noninfectious uveitis when compared to patients who were not pregnant.4 Flare-ups in uveitis tended to occur within the first trimester of pregnancy. In a retrospective cohort designed study of 32 women who became pregnant during long-term followup (40 pregnancies) the rate of flare-up was lower than that observed during the nonpregnant period

(1 occurrence per year vs. 2.4 occurrences per year, p < .01). Flare-ups in uveitis when they did occur were more frequent in the first trimester of pregnancy and significantly less during the second and third trimester.4 The reason for these changes in disease activity during pregnancy and postpartum are unknown. Although there is evidence to indicate that changes in immune regulation by cytokines may play a role. Chan et al. have examined cytokine changes during pregnancy in patients with uveitis.5 Previous observations indicated that T helper (Th2) cell cytokines are associated with downregulation of Th1 cytokines and may result in protection from (Th1)-mediated autoimmune diseases, such as uveitis. Pregnancy is associated with a change in the Th1Th2 balance and this change in immune function has been proposed to be important in avoiding fetalmaternal rejection. Such changes in immune function and cytokine balance have been proposed to mediate changes in the activity of various autoimmune diseases, including uveitis. These findings are supported by experimental animal studies of autoimmune uveitis in mice. Agarwal et al.6 found that mice (C57BL/6) immunized during

Received 24 October 2011; revised 07 April 2012; accepted 10 April 2012 Correspondence: Dr. Denis Wakefield, U New South Wales, Medicine, Kensington, Sydney, Australia, E-mail: d.wakefield@unsw.edu.au

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D. Wakefield et al. Women with IED who become pregnant should be encouraged to immediately notify their treating physician of their change in circumstances so that modifications to their treatment may be initiated if needed as early as possible during the pregnancy. Occasionally women with uveitis on immunosuppressive therapy may wish to become pregnant while on relatively safe medication, in which case they should be informed of the potential risks of such treatment to themselves and the fetus (see below) and encouraged to discuss this with their obstetrician. As outlined below, in female patients methotrexate should be stopped at least 3 months before attempting pregnancy. In contrast, it is suggested that other medications, such as rituximab, should be stopped at least 12 months before conception.10,11 Unfortunately, there are few clinical trials and limited patient data to help give informed recommendations with regard to how long before conception certain medications should be stopped.

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pregnancy developed significantly less experimental autoimmune uveitis (EAU) than nonpregnant control animals. Examination of lymph nodes and splenic cells from these animals in response to retinal antigen, interphotoreceptor retinoid binding protein (IRB) immunization indicated that they demonstrated a reduction in interferon gamma and IL12 P40 but unchanged levels of TNF, IL4, IL5, and IL10, indicating a possible Th2 bias in their immune response. Hormonal influence on the cytokine balance may also be important and recent studies have indicated that oral estradiol therapy, for example, may decrease disease activity in patients with a relapsing remitting form of multiple sclerosis.7 It is not known what influence such hormones have on patients with uveitis.8 There is little available literature to help counsel females and males with regard to pregnancy and preservation of fertility during the treatment of severe inflammatory eye disease. Given that these conditions are often managed with immunosuppressive medication, which can affect both fertility and the viability of the fetus, physicians managing such conditions should be aware of the pitfalls and approach to management in such clinical circumstances. This article aims to review the literature and propose guidelines for the management of inflammatory eye disease (IED) in patients who are pregnant or wish to preserve their fertility for future pregnancies after completing a course of systemic therapy for IED.

mAlES AnD ImmunoSuPPRESSIvE ThERAPy

Immunosuppressive therapy may lead to infertility (in both males and females), which in the case of alkylating agents may be irreversible.12 In such circumstances, consideration should be given to the use of alternative therapeutic agents or consideration of sperm storage in the case of men, prior to the commencement of such therapy. Sperm banking is available in the andrology departments of some major teaching hospitals. Males treated with systemic immunotherapy should be made aware of the potential for such drugs to lead to oligospermia and infertility. Several medications used in the treatment of patients with IED can affect male fertility. For example, sulfasalazine, which is often used to treat associated arthritis or to prevent recurrent attacks of anterior uveitis, causes oligospermia, due to the activity of the sulfapyridine component of the drug.13,14 This effect appears to be reversible and successful conception has been reported after sulfasalazine has been stopped or an alternative antiinflammatory therapy has been substituted.15 Methotrexate and alkylating agents may also cause oligospermia, which can be either transient or permanent.12,16 Infertility in men with IED has not been examined systematically. Associated inflammatory diseases may also decrease infertility in patients. For example, data from patients with inflammatory bowel disease (IBD), in a study of men with ulcerative colitis or Crohn disease compared with healthy age-matched controls, show that pregnancy rates were lower in patients with IBD. There was no difference between patients and controls in the probability of achieving a pregnancy in one menstrual cycle.17,18 Evidence suggests that the corticosteroids azathioprine and infliximab are safe to use in men with IED who are trying to conceive, although there is limited data (Table 1).8,10,16,1921 Because of the long half-life of
Ocular Immunology & Inflammation

ADEquATE bIRTh conTRol AnD PREgnAncy PlAnnIng

Education is of paramount importance in the management of patients with inflammatory eye disease who are treated with immunosuppressant therapy. It is incumbent upon the physician to adequately counsel patients with regard to potential toxicities of all therapies used to control ocular inflammation. It is particularly important to discuss plans with regard to preservation of fertility, family planning, and future pregnancies, as inflammatory eye diseases tend to occur in young people of child-bearing age. It is essential to inform both male and female patients of the potential for drugs to cause infertility, miscarriage, or fetal abnormalities.8,9

FEmAlES AnD ImmunoSuPPRESSIvE ThERAPy

It is also critically important that young women of childbearing age who are receiving systemic immunosuppressive therapy take precautions to avoid pregnancy. Adequate birth control should involve consideration of abstinence, barrier methods, and oral contraceptives. Some authorities recommend a combination of both a barrier method and oral contraceptive therapy to prevent pregnancy in patients receiving systemic immunosuppressive therapy.

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Inflammatory Eye Disease Treatment and Pregnancy 279

TABLE 1 Immunosuppressive drugs and pregnancy [from the Australian Therapeutic Goods Administration (TGA) pregnancy classification, www.tga.gov.au/hp/medicines-pregnancy.htm] Class Classification* Generic name Fetal and pregnancy side effects Recommendations Corticosteroids A Prednisone Increased incidence of cleft palette Can be used in pregnancy. Attempt to maintain dosage of prednisoPrednisolone lone 10 mg/d. Anti-metabolites D Azathioprine and No increase in congenital malformations. May cause neonatal Can be used during pregnancy. Dosage azathioprine <2 mg/kg/ 6-mercaptopurine immunosupression and bone marrow suppression day. Careful monitoring required. D Methotrexate(MTX) Methotrexate therapy during the first trimester of pregnancy Stop 3 months before conception for males and females. Continue increases the risk of congenital abnormalities. folic acid after stopping MTX and during pregnancy. Should not be used in pregnancy and should be ceased 3 months D Mycophenolate Congenital malformations, including ear malformations, mofetil (MMF) have been reported in children of patients exposed to MMF. before planned pregnancy. Effective contraception must be used for Studies in rats have shown MMF to be excreted in milk. It is four weeks before beginning MMF therapy, during therapy and for 3 months following discontinuation of therapy. not known if it is excreted in human milk. T-cell C Cyclosporin Although there is no evidence that cyclosporin has a direct Can be used during pregnancy. Dosage 2.55mg/kg/d. Careful monitoring is required during pregnancy. Mothers receiving treatinhibitors teratogenic effect in humans. Cyclosporin therapy during ment with cyclosporin should not breast-feed their infants. pregnancy may cause immunosuppression in the infant. Cyclosporin passes into the breast milk. C Tacrolimus Tacrolimus at oral doses of 0.32 mg/kg during organogenesis Insufficient information to recommend use in pregnancy. in rabbits was associated with maternal toxicity as well as an Tacrolimus is excreted into breast milk. It is, therefore, recommended that mothers should not breast-feed while receiving increase in the incidence of abortions. tacrolimus. Interferon B3 Not teratogenic in animal studies American College of Pediatricians classifies interferon 2-alpha as Interferon-2 safe in pregnancy and breast-feeding. Infliximab is not recommended for use during pregnancy. BreastAnti-TNF C It is not known whether infliximab can affect reproductive feeding should be discontinued for at least 6 months after inflixcapacity or can cause fetal harm when administered to a pregnant woman. It is not known if infliximab is excreted in imab treatment. human milk. Rituximab C There are no adequate and well-controlled data from studies in Insufficient information to recommend use in pregnancy. It is pregnant women. It is not known whether rituximab is excreted recommended that a lactating woman discontinue breast-feeding in human milk. In monkey studies, rituximab was excreted in while undergoing treatment with rituximab. the milk and was detected in the serum of breast-fed infants. Alkylating D Cyclophosphamide Cyclophosphamide crosses the placenta and can cause fetal Contraindicated in pregnancy. Stop as soon as pregnancy is diagagents Chlorambucil toxicity when administered to pregnant women. nosed or 3 months before planned pregnancy. Cyclophosphamide is excreted in breast milk and breast-feeding should be terminated prior to institution of cyclophosphamide therapy. Note. The Australian categorization consists of the following categories: Category A: Drugs that have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed. Category B1: Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage. Category B2: Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage. Category B3: Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. Category C: Drugs that, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Category D: Drugs that have caused, are suspected to have caused, or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Category X: Drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy.

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D. Wakefield et al. use in pregnancy substituted (Figure 1), if necessary for disease control. The Australian Therapeutic Drugs Administration has classified a large number of drugs based on evidence that they may cause harm to the fetus in utero (Table 1). Drugs classified as A are generally considered safe to use in pregnancy. For drugs in the B1, B2, and B3 categories, human data are lacking or inadequate and subcategorization is therefore based on available animal data. The allocation of a B category does NOT imply greater safety than the C category. Drugs in category D are not absolutely contraindicated in pregnancy (e.g., azathioprine). Moreover, in some cases the D category has been assigned on the basis of "suspicion." Due to legal considerations, sponsor pharmaceutical companies have, in some cases, applied a more restrictive category than can be justified on the basis of the available data (www.tga.gov.au/hp/medicinespregnancy.htm). For several of the immunosuppressive drugs and biologicals their effects on the fetus and presence in breast milk is unknown.

MTX it is recommended that methotrexate therapy should be stopped in males at least 3 months before attempting conception to minimize the effects of methotrexate on semen, although limited studies indicate that this effect is minimal.13,2225 Several other factors may contribute to infertility in men with IED, including associated systemic disease, smoking, excessive alcohol consumption, and other drug therapy. All patients should be informed that it is imperative that they stop certain immunosuppressive therapies prior to conception.27 The duration of abstinence of immunosuppressive therapy before contemplating conception varies among drugs.

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DRugS conTRAInDIcATED AnD oF unknown SAFETy In PREgnAncy

Several commonly used immunosuppressive drugs have been reported to be teratogenic and should be avoided in pregnant women with inflammatory eye disease (Table 1, Figure 1). If a woman becomes pregnant while taking one of these drugs careful consideration should be given to the riskbenefit associated with continuing this medication and the patient and her obstetrician should be consulted and fully informed of the potential complications associated with the medication. This will often require that the immunosuppressive medication be stopped and another drug considered to be safe to

mEThoTRExATE
Methotrexate (MTX) (D classification, Table 1) is contraindicated in pregnancy and has been used to induce abortions.23 Extensive experience with the use of once-weekly, low-dose (less than 20 mg) methotrexate in patients with rheumatic disease indicates that congenital abnormalities after first trimester exposure to

FIGURE 1 Algorithm for managing patients with IED who either become pregnant or plan a pregnancy. Ocular Immunology & Inflammation

Inflammatory Eye Disease Treatment and Pregnancy this drug occur in 510% of pregnancies. Fortunately, previous exposure to methotrexate has not been shown to have a fetal toxic effect in subsequent pregnancies. Methotrexate treatment during the first trimester of pregnancy increases the risk of congenital abnormalities involving the central nervous system, cranial bones, as well as limb and palate development, and growth retardation has been observed both in animal experiments and in humans.25,28,29 The active metabolites of methotrexate have a long half-life and may remain in cells for several months. The toxic effects of methotrexate on the developing fetus occur between 5 and 11 weeks of pregnancy, although the drug should be avoided for the duration of the pregnancy and during breastfeeding.30,31 Thus, women of child-bearing potential should be advised to use adequate contraception while taking MTX and for at least 3 months after stopping MTX treatment.30 Because of the long half-life of MTX metabolites, folic acid therapy should be continued for 3 months after ceasing methotrexate and may be taken for the duration of the pregnancy in women previously treated with MTX.

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mycoPhEnolATE moFETIl (mmF)

MMF (D classification) is associated with increased risk of first-trimester pregnancy loss and increased risk of congenital malformations, especially external ear and facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney.11,28,29,32 MMF should not be used in pregnant patients with inflammatory eye disease. Given the relatively long half-life of MMF it should be stopped at least 3 months before planned pregnancy or immediately after becoming pregnant. There is limited data on the effect of MMF on male fertility and no evidence of the effect on children fathered by patients receiving this medication.33 Similarly, there is little evidence of the effect of MMF and breast-feeding, although animal studies indicate that MMF is in breast milk, and it is recommended that it not be used while breast-feeding.34

In animal studies oral contraceptives and inhibitors of gonatotrophin releasing hormone protect ovarian function from the cytotoxic effects of alkylating agents.40 It has been suggested that consideration be given to their use in female patients treated with this medication, although the efficacy of this approach in humans has not been established.41 The use of cyclophosphamide is associated with significant toxicity, which has limited its use in treating patients with inflammatory eye disease.35,42 The main side effects associated with this drug include increased risk of carcinogenesis, infertility, bone marrow toxicity, and hemorrhagic cystitis. The risk of infertility and azoospermia increases with increasing age of the patient, duration of therapy, and total cumulative dosage (and it is common in males who have received a total dose of cyclophosphamide more than 18 g). Thus, the total dose of cyclophosphamide should be limited and carefully monitored in males who wish to father children. Amenorrhea develops in a quarter of women treated with long-term cyclophosphamide therapy, and is often irreversible. The dosage of cyclophosphamide that induces amenorrhea decreases with increasing age. In women 2029 years of age a dosage more than 20 g of cyclophosphamide produced amenorrhea, while in the 3039 age group the dosage was greater than 9 g, and in women 4049 years of age more than 5 g total dose of cyclophosphamide induced amenorrhea.42 It is recommended that alkylating agents such as cyclophosphamide should be stopped immediately as soon as it is ascertained that a patient with IED has become pregnant and for 3 months prior to planned conception in nonpregnant females. Cyclophosphamide is excreted in breast milk and breast-feeding should be stopped prior to institution of cyclophosphamide therapy.

TAcRolImuS
There is limited clinical experience with the use of tacrolimus (C classification) in patients with severe IED. Exposure to tacrolimus during pregnancy has been documented in patients undergoing transplantation of solid organs. Recent studies confirm the absence of an increased risk of miscarriage or congenital anomalies in patients exposed to tacrolimus therapy during pregnancy.43,44 There is no experience with the use of this medication in patients with IED who become pregnant, thus its effects under these circumstance are unknown and its use cannot be recommended. Tacrolimus is excreted into breast milk. It is, therefore, recommended that mothers should not breast-feed while receiving tacrolimus.44 There are insufficient data to make recommendations with regard to the preconception use of tacrolimus in males.34

AlkylATIng AgEnT
Alkylating agents such as cyclophosphamide and chlorambucil (D classification) are contraindicated during pregnancy because of their teratogenic effects.9,25,32,35-38 The most common severe side effects from chlorambucil therapy are dose-related bone marrow suppression and infertility. The risk of infertility, amenorrhea, and azoospermia increases with duration of therapy, cumulative dose, and age of the patient.39 Women may also develop infertility and drug-induced menopause. The frequency of infertility in males is high, with a lower rate in females who receive treatment with chlorambucil.
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D. Wakefield et al.

InTERFERon
Recent studies have demonstrated the effectiveness of interferon therapy (B3 classification) in patients with uveitis, especially Behet disease.45,46 The drug manufacturer recommends that men and women receiving interferon-2 should practice effective contraception.47 In pregnancy, interferon-2 should be avoided or administered only if the benefit to the woman justifies the potential risk to the fetus. Although animal studies do not indicate that interferon-2 is a teratogen, harm to the fetus from use during pregnancy cannot be excluded. When doses greatly in excess of the recommended clinical dose were administered to pregnant rhesus monkeys an increased rate of abortion was observed. Male fertility and evaluation of the risk of teratogenic effects on the fetus have yielded no significant adverse effects to date. However, in view of the limited data available in patients with uveitis, interferon-2 therapy is best avoided and therapy with medications that have an established profile of use in pregnancy should be used. It is not known if interferon is excreted in breast milk and thus should not be used in breast-feeding mothers. Similarly, there is no evidence that interferon has a deleterious effects on males in the preconception period (www.tga.gov.au/hp/medicinespregnancy.htm).

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antibodies are known to cross the placenta and it has been shown that monoclonal antibodies, such as infliximab and adalimumab, cross the placenta during the second trimester and onward, leading to increase in cord blood levels of these antibodies. Women treated with infliximab throughout their pregnancies have given birth to healthy children.56 Controlled studies have shown similar rates of congenital malformations and miscarriages in patients receiving anti-TNF therapy and nontreated subjects.57 In contrast, congenital abnormalities have been reported in children born to women exposed to anti-TNF therapy (infliximab and etanercept) during pregnancy.54 Such congenital abnormalities were similar to those reported in the normal population and occurred at a rate of 35% of live births. At the present time human studies have not shown an increased rate of adverse outcomes in patients exposed to TNF inhibitors during pregnancy.54 However, it has been recommended by the manufacturer that such therapy should be stopped in women during pregnancy until more definitive data are available. There is no information of the effect of TNF inhibitors on males in the preconception period.

RITuxImAb
Rituximab (anti-CD 20) (C classification) is a chimeric, humanized monoclonal antibody (IgG 1 subclass) that has a potent effect in depleting B cells. Rituximab has recently been reported in the treatment of patients with inflammatory eye disease.58 Caution should be exercised in the use of this drug in patients who are pregnant or planning pregnancy. At the present stage the manufacturers recommend stopping rituximab therapy 1 year before a planned pregnancy and although no abnormalities have been detected with the use of this therapy during the second or third trimester, there was insufficient data on which to make a responsible clinical decision.59 In clinical studies of patients with rheumatoid arthritis three pregnancies occurred in patients treated with rituximab and MTX resulting in two spontaneous abortions. It is recommended that rituximab should not be given to a pregnant woman, unless the potential benefit outweighs the potential risk. Individuals of childbearing potential should use effective contraceptive methods during treatment and for up to 12 months following rituximab therapy. As with other IgG antibodies, rituximab crosses the placenta and has been found in significant levels in fetal serum. There has been limited experience with the use or exposure of pregnant women to this antibody therapy. There are reports of only a small number of pregnant women treated during the second and third trimester of their pregnancy, indicating that apart from a B-cell lymphopenia that reversed to normal within 6 months of the birth of the child no other significant abnormalities were detected in the offspring of patients
Ocular Immunology & Inflammation

AmInoSAlIcylATES
Aminosalicylates (sulfasalazine) are used mainly in patients with severe recurrent anterior uveitis or patients with associated inflammatory bowel disease (IBD) and/or seronegative arthritis.4850 Case reports related to the deleterious effects of sulfasalazine suggested an association with cardiovascular, genitourinary, and neurologic abnormalities, but larger series and a population-based study (Hungarian Case Control Surveillance of Congenital Abnormalities database) failed to find a significant increase in congenital abnormalities in women with IBD treated with sulfasalazine.18,5153 Thus, sulfasalazine is probably safe to use in pregnancy and during breast-feeding. There is no evidence of deleterious effects in males in the preconception period.

TumoR nEcRoSIS FAcToR (TnF) InhIbIToRS

TNF inhibitors (C classification) have now been used in a large number of patients with a variety of inflammatory eye diseases, mostly in the setting of uncontrolled case series of patients with uveitis. There is more extensive information on the potential complications of such therapy in pregnant women with rheumatic disease, who have received infliximab therapy.54,55 IgG

Inflammatory Eye Disease Treatment and Pregnancy treated with rituximab.58-60 Toxicity studies performed in cynomolgus monkeys showed no evidence of congenital abnormalities at exposure levels similar to that anticipated in humans. It is not known if rituximab is excreted in human breast milk, although this seems likely, as in monkey studies rituximab is excreted in breast milk and is detected in the serum of breast-fed infant monkeys. Reversible B-cell lymphopenia was observed in all monkey infants exposed to rituximab during gestation or after breast-feeding. It is thus recommended that lactating women should discontinue breast-feeding while undergoing rituximab therapy.61 There is no information of the effect of rituximab on males in the preconception period.
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intolerance, hypertension, and delayed fetal growth. Rare cases of transient fetal adrenal suppression have been reported, so infants should be monitored in the postpartum period.64 Breast-feeding is safe, with clinically insignificant amounts of the drug being concentrated in breast milk. There is no effect on male fertility and corticosteroids can be administered to males attempting to father children.6568

Azathioprine and 6-mercaptopurine

Azathioprine and 6-mercaptopurine (D classification) are relatively safe to use in pregnancy and are often used as steroid-sparing drugs in patients with severe inflammatory eye disease.19,25,32 That is, they are usually used in combination therapy with corticosteroids to control ocular inflammation. There is extensive clinical experience in the transplant literature on the use of azathioprine in pregnancy. For example, in large prospective case control studies there is no evidence of an increased rate of congenital abnormalities in children (n = 160) exposed to azathioprine (50100 mg per day) in utero when compared to children not exposed to azathioprine in utero.69,70 Similarly, a study of patients with Crohn disease who had been treated with azathioprine or 6-mercaptopurine showed no significant increased risk of congenital abnormalities.71 It has been recommended that azathioprine can be used during pregnancy and that the daily dose should be less than 2 mg/kg/day. As in all patients with IED treated with azathioprine, it is important to carefully monitor patients for hematological and hepatic complications of this therapy. A recent study indicates that although 5-MP is detected in breast milk of patients taking azathioprine it is safe to breast-feed while taking this drug.72 There is no evidence of a deleterious effect on male fertility, and azathioprine can be administered to males attempting to father children.65-68

ImmunoSuPPRESSIvE AnD AnTIInFlAmmAToRy DRugS uSED In PREgnAncy corticosteroids

Corticosteroid (A classification) therapy is the mainstay of anti-inflammatory and immune therapy in patients with severe IED and this is also true in patients who become pregnant and have severe ocular inflammation. Systemic and local corticosteroid therapy is not contraindicated during pregnancy. However, as there is an increased risk of cleft palate, the daily dosage should be reduced to the lowest most effective dose and to less than 10 mg prednisolone a day if possible.25,62,63 The risk of oral cleft is increased in patients exposed to corticosteroids during the first trimester of the pregnancy. The risk of cleft palate is 1 per 1000 live births without any exposure to corticosteroids and this risk increased to 1.33.3 per 1000 live births with exposure to corticosteroids during the first trimester. It is recommended that the dosage of corticosteroids should be increased during the period immediately prior to delivery (24, 12, and 1 h prior to delivery) of the child to counteract the effect of stress and may be required to be continued for several weeks during the postpartum period when there is an increased risk of disease relapse. Careful attention should be given to observing patients for pregnancy-induced glucose
TABLE 2 Management of flare of IED in pregnancy. Scenario 1st-line treatment Mild disease previously controlled Local steroid injection. with topical steroids and mydriatics Severe disease previously controlled Increase dose of prednisolone by oral corticosteroids up to 1 mg/kg/day.

cycloSPoRIn
Cyclosporin (C classification) and other calcineurin inhibitors are commonly used as steroid-sparing agents or second-line therapy in patients with severe IED (see Table 2, Figure 1). Although there is little evidence for

2nd-line treatment 3rd-line treatment Prednisolone (up to 50 mg/d). Add azathioprine or cyclosporin. Add azathioprine or cyclosporin. Add second immunosuppressive agent to azathioprine and steroids. Add second immunosuppressive agent to azathioprine and steroids. Consider biological agents if disease not controlled.

Severe disease previously controlled Increase dose of prednisolone Substitute azathioprine for cyclosporin or vice versa. by oral corticosteroids and azathio- up to 1 mg/kg/day. Consider IVIg therapy. prine or cyclosporin

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D. Wakefield et al. anterior uveitis.80,81 Apart from their common systemic side effects, NSAIDs may impair fertility by interfering with ovulation.82 They are not teratogenic but can impair fetal renal function after 20 weeks gestation and cause constriction of the ductus arteriosis.83 They are secreted in low concentration in breast milk but usually produce no adverse effects on the infant. The American Academy of Pediatricians considers ibuprofen, naproxen, and indomehtacin compatable with breast-feeding.84 There is no evidence that nonsteroidal anti-inflammatory drugs have an effect on males fathering children, although, based on animal studies, they can have slight effects on spermatogenesis.85,86

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the safe use of cyclosporin in the treatment of pregnant patients with IED there is extensive experience with the use of cyclosporin in patients who have undergone a solid organ transplants and become pregnant.73 The U.S. National Transplantation Pregnancy Registry has data on over 2400 such patients. Congenital malformations have been observed in 3% of patients treated with cyclosporin during pregnancy.73 This rate is not significantly different from the reported rate of congenital malformations in the general population. No recurring pattern of congenital abnormalities has been associated with treatment with cyclosporin in pregnancy. It is recommended that cyclosporin (2.55 mg/kg/day) can be used in pregnant women who have or who develop severe IED requiring immune-suppressive therapy. As is the case with azathioprine, cyclosporin is usually used in combination with systemic corticosteroids. It is essential that all patients treated with cyclosporin be carefully monitored for severe side effects (hypertension, increased creatinine, and lymphoma). In a study of breast-fed infants of mothers treated with CsA after kidney transplantation there were no demonstrable nephrotoxic effects or other side effects on the child. Thus, women treated with cyclosporin could be allowed to breast-feed.74 There is no evidence that cyclosporin has an effect on males fathering children.

mAnAgEmEnT oF ExAcERbATIonS oF InFlAmmAToRy EyE DISEASE DuRIng PREgnAncy AnD PoSTPARTum

Several clinical scenarios may be associated with an exacerbation of IED during pregnancy and in the postpartum period (Table 2). These range from patients with previously mild disease treated with topical medication (corticosteroids) to those on systemic corticosteroids, with or without a steroid-sparing agent, who experience a significant vision-threatening exacerbation of their ocular inflammation. In patients where IED is not adequately controlled with topical therapy, local steroid injections should be tried initially, if appropriate. If this approach is not effective or appropriate, systemic corticosteroids should be commenced (initial dose prednisolone 1 mg/kg/day) and progressively reduced to less than 10 mg/day of prednisolone when the IED is controlled. In patients already on systemic corticosteroid therapy, the dosage should be increased (initial dose prednisolone 6080 mg/day) and gradually decreased to <10 mg/day as the disease is controlled. If there is still inadequate control of ocular inflammation or high doses of steroids are required for disease control, then a steroid-sparing agent should be added. Our preference is to use azathioprine (2 mg/ kg/day) first, followed by cyclosporin (2.55 mg/kg/ day) if the former is ineffective. Occasionally combination therapy is required to control disease or allow a safer dose of corticosteroid (prednisolone <10 mg/ day) to be used. In a recent review of the use of anti-rheumatic drugs in pregnancy and in lactation, Temprano et al. concluded that methotrexate is contraindicated during pregnancy and lactation.10 Similarly, cyclophosphomide and mycophenolate should be avoided during pregnancy and lactation, while azathioprine and cyclosporin could be used with caution during pregnancy if there is clinical need to suppress disease activity. It was also concluded by these authors that there is insufficient data regarding tumor necrosis factor antagonists, anakinra, and rituximab in relation to pregnancy and lactation.10
Ocular Immunology & Inflammation

Intravenous Immunoglobulin Therapy (IvIg)

Intravenous immunoglobulin therapy has been used to treat a number of uveitis syndromes, including birdshot retinopathy, and also in the management of ocular cicatricial pemphigoid.75 In addition, IVIg has been used as rescue therapy in patients with severe uveitis that have not responded to other immunosuppressive therapy.76 IVIg has a good safety profile and has been used in pregnancy to treat recurrent miscarriage, congenital heart block, and Wegener granulomatosis.77,78 It is probably secreted into breast milk of lactating women but has not been found to cause adverse effects in the infants.79 Thus, IVIg may represent a reasonable alternative form of therapy in patients with severe IED requiring immunosuppressive therapy who are pregnant or contemplating pregnancy. This form of therapy warrants further evaluation in the treatment of woman with severe inflammatory eye disease during pregnancy. There is no evidence that IVIg therapy affects male fertility or causes problems in the preconception period in males.

nonsteroidal Anti-inflammatory Therapy

Systemic NSAIDs, while not immunosuppressive and not usually used in the management of severe IED, are commonly used to treat mild to moderate scleritis and to prevent recurrence in patients with nongranulomatous

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Follow-uP oF chIlDREn ExPoSED AnTEnATAlly To ImmunE SuPPRESSIvE DRugS

There is concern about the long-term consequences to children born to mothers who have been treated with immune suppressive medications during pregnancy for autoimmune diseases, such as uveitis. Preliminary data from a study by Motta et al. indicated that such immune-suppressive therapy during pregnancy did not significantly impair immunity in exposed children.1 This is of significant interest as maternal treatment with immunosuppressive medications, such as steroids and cyclosporin, may increase the risk of gestational complications, including hypertension, diabetes, and low-birth-weight offspring. Thus, these results indicating that offspring of children exposed to such immunosuppressive medications antenatally do not suffer long-term consequences is reassuring, although larger more definitive studies are required. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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