Rheumatological disorders

Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 15, No. 6, pp. 953±969, 2001

doi:10.1053/beog.2001.0240, available online at http://www.idealibrary.com on

10 Rheumatological disorders Monika éstensen*

MD PhD

Department of Rheumatology and Clinical Immunology/Allergology, University Hospital of Berne, Switzerland

Rheumatic diseases occur frequently in women of childbearing years, necessitating drug treatment during a concurrent pregnancy in order to control maternal disease activity and to ensure a successful pregnancy outcome. In¯ammatory rheumatic diseases with mainly musculoskeletal involvement may cause acute episodes of arthritis. Autoimmune, systemic diseases may ¯are with manifestations of haematological, dermatological or renal disease or give rise to thromboembolism during pregnancy. Treatment with non-steroidal antiin¯ammatory drugs, corticosteroids, anticoagulants, immunosuppressive or even cytotoxic drugs may be required to acquire disease control. Unfortunately, controlled studies on the use of antirheumatic drugs during gestation exist only for a few drugs. This chapter presents data on the use of antirheumatic drugs during pregnancy, addressing the risk of teratogenicity, possible long-term e€ects on the infant exposed to drugs antenatally, and maternal side-e€ects which interfere with pregnancy. Recommendations for pre-pregnancy counselling and necessary adjustment of drug treatment before and during pregnancy are given. Key words: rheumatic disease; non-steroidal anti-in¯ammatory drugs; corticosteroids; immunosuppressive drugs; cytotoxic drugs; biological agents.

Rheumatic diseases have a predilection for the female sex and often become manifest during women's childbearing years. The spectrum of rheumatic diseases comprises in¯ammatory and autoimmune disorders (Table 1) and degenerative diseases. The latter occur usually after women's fertile years. The interaction of pregnancy and Table 1. Di€erences between various rheumatic diseases. Type of organ involvement

Autoimmune features Examples

In¯ammatory joint diseases

Musculoskeletal

Few

Spondylarthropathies, reactive arthritis

In¯ammation of joints ‡ systemic disease

Musculoskeletal, internal organs

Several

Rheumatoid arthritis

Systemic rheumatic diseases

Multi-organ disease

Many

Systemic lupus erythematosus, scleroderma, antiphospholipid syndrome

Disease

*Correspondence to: Department of Rheumatology and Clinical Immunology/Allergology, University Hospital, CH-3010 Berne, Switzerland. 1521±6934/01/060953‡17 $35.00/00

c 2001 Harcourt Publishers Ltd. *

954 M. éstensen Table 2. Interaction between pregnancy and some common rheumatic diseases.

Presence of SSA/SSB

Increased risk for fetal/ neonatal complications

Prevailing response of disease to pregnancy

Reference

Rheumatoid arthritis Rare

Rare

No

Improvement

1

Ankylosing spondylitis

No

No

No

Active/ aggravated

2

Juvenile chronic arthritis

No

Rare

No

Improvement

1

Systemic lupus erythematosus

Renal, haematological, In 30% CNS

Fetal loss, NLEb

Active

3±6

Connective tissue diseasesa

Renal, haematological, Yes CNS

Fetal loss, NLEb

Active

7

Antiphospholipid syndrome

Thromboembolic events

Fetal loss

Aggravated

6

Risk of major organ involvement during pregnancy

Disease

aMixed

No

connective tissue disease, poly/dermatomyositis, scleroderma. lupus erythematosus.

bNeonatal

rheumatic diseases varies, some conditions bene®t, others worsen in response to the immunological and hormonal alterations of pregnancy (Table 2). Diseases that remain active during pregnancy may need drug treatment either for the bene®t of the mother or in order to protect pregnancy and the fetus. Indications for treatment of a pregnant patient vary between transient ¯ares of arthritis and life-threatening conditions such as severe renal disease and thromboembolism. In general, disorders associated with involvement of internal organs and autoimmune phenomena are more likely to require aggressive drug treatment than conditions with mainly musculoskeletal manifestations (Table 3). Experience from systemic connective tissue diseases indicates that uncritical withdrawal of drugs before a pregnancy augments the risk of a ¯are which may compromise both maternal and fetal health.

SOURCE OF DATA AND PRESENTATION The databases Embase, Medline and Cochrane were searched for the period 1960±2000 under the following terms: any of the rheumatic diseases discussed in this survey, each drug, pregnancy, teratogenicity and immunosuppression. Because of the scarcity of data, all types of original observations were accepted provided they were published in English, French, German or Spanish. Because pregnancy, as a rule, is an exclusion criterion for randomized, controlled trials, only few controlled studies for some widely used antirheumatic drugs exist. In addition to the often small number of drug exposures reported, interpretation of data is hampered by the diculty of ascribing observed negative events in the fetus or neonate to drugs, given the fact that the mother has a chronic disease.

Rheumatological disorders 955 Table 3. Drug treatment of in¯ammatory rheumatic diseases. Drugs

Rheumatoid arthritis

Connective tissue diseasesa

Spondyloarthropathies

NSAID

‡

‡

‡

Glucocorticosteroids

‡

‡

‡

Immunosuppressives Gold D-Pencillamine Antimalarials Sulfasalazine Azathioprine Cyclosporine Le¯unemide TNF-a antagonists Mycophenolate

‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡

Cytotoxics Methotrexate Cyclophosphamide

‡ ‡

Anticoagulants

‡ ‡ ‡ ‡ ‡ ‡ ‡

‡ ‡ ‡

‡

‡

a

Systemic lupus erythematosus, antiphospholipid syndrome, poly-, dermatomyositis, scleroderma, mixed connective tissue disease.

The survey presents treatment of selected rheumatic conditions during pregnancy and classes of antirheumatic drugs. Important maternal and fetal/neonatal aspects for each drug are presented and a comment is given. Maternal e€ects are addressed only if they interfere with pregnancy. It is important to note that, because of lack of data, recommendations supported by evidence-based medicine cannot be provided. TREATMENT OF SELECTED RHEUMATIC CONDITIONS DURING PREGNANCY Treatment of acute arthritis and tenosynovitis In all rheumatic disorders with musculoskeletal involvement, acute synovitis of a joint or a tendon sheath may occur occasionally during pregnancy. In the spondyloarthropathies, a ¯are of arthritis is frequently encountered in the second trimester. In¯ammation of joints induces pain and sti€ness, reduces mobility and impairs function. As a rule, in¯ammation of joints or tendon sheaths can be controlled by non-steroidal anti-in¯ammatory drugs or local injection with a glucocorticosteroid. Treatment of rheumatoid arthritis Rheumatoid arthritis (RA) is an autoimmune chronic in¯ammatory disorder characterized by symmetrical polyarthritis and sometimes extra-articular manifestations. As the majority of women with RA experience improvement of disease symptoms during pregnancy, continuation of drug treatment is necessary for only 10±25% of women

956 M. éstensen

with continuous active disease. However, a frequently asked question is whether immunosuppressive treatment should be withdrawn before a planned pregnancy. Drug treatment of RA has profoundly changed during the last 20 years. Treatment with gold, antimalarials and penicillamine has been replaced by methotrexate, sulfasalazine and combination therapies (Table 3). New drugs such as TNF-a antagonists and le¯unemide have recently been introduced. The physician treating an RA patient in her fertile years must decide which drug regimen is compatible with pregnancy.

Systemic lupus erythematosus during pregnancy Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with rash, arthritis and glomerulonephritis as the most typical features. The symptoms of SLE are not mitigated by pregnancy, and active disease or even ¯ares are common in pregnant patients. Manifestations such as haematological abnormalities, renal disease or the presence of antiphospholipid antibodies may negatively in¯uence the course of pregnancy and compromise fetal outcome (Table 4). It is generally recommended that patients with SLE should plan their pregnancies and attempt conception only in a period of well controlled, quiescent disease. Even then the risk of a ¯are is present. Indications for treatment of the pregnant patient with SLE are active disease or organ damage. Frequent manifestations of active disease in pregnancy are musculoskeletal problems, rash, haematological abnormalities, and lupus nephritis (see Chapter 6). Treatment of the antiphospholipid syndrome requires low-dose aspirin alone or in combination with heparin (see Chapter 3).

Table 4. High-risk SLE pregnancies. Manifestation

Risk for complications

Renal involvement with or without hypertension

Pre-eclampsia, prematurity, increased fetal loss

Secondary antiphospholipid syndrome

Thromboembolism, thrombocytopenia, fetal loss, severe pre-eclampsia, interuterine growth restriction

Anti-SSA/SSB antibodies

Neonatal lupus, congenital heart block

Active SLE at conception

SLE-¯ares, compromised fetal outcome

Non-steroidal anti-in¯ammatory drugs (NSAIDs) NSAIDs are inhibitors of cyclo-oxygenases COX-1 and COX-2. Whereas the antiin¯ammatory and analgesic e€ects of the non-selective and COX-2-selective NSAIDs are comparable, the safety pro®le of non-selective COX inhibitors and preferential COX-1 inhibitors di€ers from that of selective COX-2 inhibitors. The latter have signi®cantly fewer gastrointestinal side-e€ects and they do not exert any antiplatelet e€ects. A number of pregnancy-related conditions such as premature labour, polyhydramnios and pregnancy-induced hypertension have been successfully treated with NSAIDs.8

Rheumatological disorders 957

Mother In the mother, reported adverse e€ects of continuous treatment with inhibitors of cyclo-oxygenase in the 3rd trimester are: prolongation of pregnancy and labour and increased maternal blood loss associated with delivery.9,10

Fetus/newborn The classical non-selective NSAIDs, including low-dose aspirin, do not induce congenital malformation, but, given in the latter part of gestation, they can a€ect pregnancy and the fetus. First-trimester use of various NSAIDs, has been studied prospectively in several national drug surveillance projects (American Collaborative Perinatal Project, the Michigan Medicaid surveillance study, Swedish Registry for Drug use in Pregnancy), including several hundred thousand completed pregnancies and has failed to demonstrate any increase in congenital abnormalities.11 The major pharmacological action of NSAIDs on the fetus is mediated through inhibition of prostaglandin synthesis. Prostaglandin E2 induces relaxation of systemic and pulmonary vessels as well as the ductus arteriosus. Locally produced prostaglandins also in¯uence circulation within various organs, including the kidney, the lung and the CNS. Adverse e€ects of NSAIDs on the fetus are therefore most frequent in the latter part of gestation, with an additional risk in case of prematurity. Reduction of renal blood ¯ow and constriction of the fetal ductus arteriosus have been described for most non-selective COX-inhibitors.12 The risk of ductal constriction increases markedly after week 32 of gestation. Exposure to NSAIDs close to delivery may result in pulmonary hypertension of the newborn.13 In lambs and baboons, COX-2 regulates the tone of the fetal ductus arteriosus and is present in the fetal kidney. Consequently, fetal cardiovascular and renal side-e€ects must also be expected of the new, selective COX-2 inhibitors. In general, the vascular e€ects of NSAIDs on the fetal circulation normalize within one to several days after cessation of therapy. A risk of blood clotting abnormalities or haemorrhage in the newborn exists if maternal treatment with a non-selective COX-inhibitor or high-dose aspirin continues until delivery. Low-dose (60±80 mg/day) aspirin does not impair neonatal platelet aggregation nor does it impair renal or ductal blood ¯ow.14,15

Corticosteroids The main indications for treatment with corticosteroids during pregnancy are allografts, asthma, idiopathic thrombocytopenia, and SLE. Short-term corticosteroid therapy to enhance fetal lung maturation prior to preterm delivery is an additional indication. Numerous reports exist about the use of corticosteroids in pregnant patients with SLE; however, most of these are not controlled studies.16

Mother The maternal risks of prolonged and high doses (1±2 mg/kg/day) of corticosteroids include diabetes, elevated blood pressure, insomnia, depression, osteopenia, adrenal gland suppression and susceptibility to infection.

958 M. éstensen

Fetus/newborn Treatment with corticosteroids in a number of animal species produces various deleterious e€ects on the o€spring.17 Most studies, including a limited number of patients, and often without controls, did not ®nd evidence for an increased rate of congenital abnormalities in humans.17 However, a recent meta-analysis of epidemiological studies found a signi®cantly increased risk for oral clefts after ®rst-trimester exposure to corticosteroids.18 Other, though rare, adverse events reported for antenatal corticosteroid exposure are masculinization of female infants, growth restriction, neonatal cataracts, and adrenal suppression in children born to women taking high doses of steroids during pregnancy. Treatment with 5 to 100 mg of prednisolone daily in SLE pregnancies did not increase the rate of birth defects nor cause intrauterine growth restriction.5,6,16 The in¯uence of corticosteroids on intrauterine growth has been controversial. Some authors have demonstrated an increased incidence of low-birth-weight babies in mothers on corticosteroids,19,20 while others have not.5 Premature rupture of membranes has been found in SLE pregnancies and in one controlled study comparing treatment with corticosteroids to heparin.6,21 Infections in newborns after antepartum exposure to corticosteroids occur infrequently.22,23 Maternal corticosteroid therapy does not induce general immunosuppression in the neonate.24 The possible induction of hypertension in adult life by antenatal corticosteroid exposure has not been proven in humans.25 Comment High doses (1±2 mg/kg/day) should be avoided in the ®rst trimester. At prolonged or high-dose medication with corticosteroids, the mother must be monitored for the above mentioned side-e€ects. Calcium supplementation for prevention of osteopenia is advisable. Supplemental corticosteroids must be given during delivery. IMMUNOSUPPRESSIVE DRUGS The immunosuppressive drugs discussed below are used for various rheumatic diseases, as shown in Table 3. Indications for gold and penicillamine are now limited to a few conditions whereas antimalarials, sulfasalazine and cyclosporine have broader indications and are increasingly used in combination therapies, often together with methotrexate and corticosteroids. Unfortunately, data on the use of immunosuppressives in pregnancy are mainly derived from diseases other than rheumatic disorders such as prevention of allograft rejection. Gold compounds Sodium aurothiomalate, aurothioglucose and aurano®n (oral gold) are used for the treatment of several polyarticular in¯ammatory rheumatic diseases. Fetus/newborn Uneventful pregnancies concluding in the delivery of healthy children have been reported in women receiving gold therapy.26 Except for two children with hip

Rheumatological disorders 959

abnormality, no congenital malformations were observed in 102 children born to patients who had terminated gold therapy in early to mid-pregnancy, or in the o€spring of 26 patients treated with gold throughout pregnancy.26 One case of multiple fetal malformations in a mother who received 20 mg of aurothiomalate weekly during the ®rst 20 weeks of pregnancy has been reported, but a relationship to gold therapy has been disputed.27 To date, little is known about the e€ect of oral gold (aurano®n) on the human fetus. Six women who received aurano®n while pregnant delivered normal children.28 Comment Information on the safety of gold during human pregnancy is insucient. There are no data to support the necessity of prophylactic cessation of therapy before a planned pregnancy. In patients on monthly injections, intramuscular gold can be given on the ®rst day of menses in order to stop therapy as soon as pregnancy is recognized. In view of the lack of human data, didactic statements on peroral gold cannot be made. It seems wise to stop therapy when pregnancy is diagnosed, and not to start aurano®n during gestation. Antimalarial drugs Antimalarial drugs containing 4-aminoquinoline compounds are used to treat rheumatoid arthritis, SLE and discoid lupus. Fetus/newborn Chloroquine crosses the placenta and accumulates preferentially in melanin-containing structures in the fetal uveal tract and inner ear. Abnormalities in the retina and the inner ear have been reported in ®ve infants exposed to higher than the recommended daily doses of chloroquine throughout pregnancy.29 No increase in the rate of congenital malformations, prematurity or fetal growth restriction has been found when 300 mg chloroquine weekly was given throughout gestation for malaria prophylaxis.30 In the rheumatic literature, more than 100 pregnancies treated with either chloroquine 250 mg or hydroxychloroquine 200± 400 mg daily during the ®rst trimester were not associated with an increase in congenital abnormalities.31±34 Comment Although antimalarials have been used safely in pregnant patients without producing congenital abnormalities, their long elimination half-life and their tendency to accumulate in certain tissues, including the retina, restricts their gestational use. Discontinuation of antimalarials in pregnant SLE patients may precipitate a ¯are with harmful consequences for mother and child. Furthermore, discontinuation in early pregnancy will not prevent ®rst-trimester exposure of the fetus in view of the long half-life. It seems therefore reasonable to continue antimalarials during pregnancy. Hydroxychloroquine which has not been associated with congenital malformations should be the drug of choice in fertile women with rheumatic disease.

960 M. éstensen

Penicillamine Experience with the use of penicillamine in human pregnancy relates mainly to treatment of pregnant women with Wilson's disease, cystinuria and RA.35 Fetus/newborn In rats, hamsters and mice, high doses of penicillamine during the ®rst trimester caused a variety of malformations, including loose skin. Among about 100 pregnancies treated with penicillamine for Wilson's disease, cystinuria, or RA for 1±9 months, and in doses varying between 0.5 and 2.25 g daily, congenital collagen defects were detected in ®ve infants. Two of the neonates had generalized abnormalities of connective tissue and died of sepsis. In the other infants, the cutis laxa observed at birth was transient.36 Comment The use of penicillamine is crucial for a successful outcome of pregnancy in patients with Wilson's disease. In these patients the bene®t of continued treatment seems to outweigh the approximately 5% risk of a congenital collagen defect associated with gestational use of penicillamine. This risk may not be acceptable to a woman with in¯ammatory rheumatic disease where the bene®t of continued treatment is less obvious and other treatment modalities exist. As a consequence, penicillamine should be stopped before a patient with rheumatic disease tries to conceive, or it should be withdrawn immediately when pregnancy is diagnosed. Sulfasalazine Reports regarding the use of sulfasalazine during and after pregnancy originate exclusively from experience in patients with in¯ammatory bowel disease (IBD). Fetus/newborn More than 300 pregnancies in patients with ulcerative colitis and nearly 800 in patients with Crohn's disease treated with either sulfasalazine alone or in combination with corticosteroids at some time during pregnancy have been reported. No increase in birth defects, or small-for-gestational-age babies was detected.37 In spite of being a sulphonamide, the bilirubin-displacing ability of sulfasalazine is small,38 and published reports have not found an increase in pathological jaundice in the antenatally exposed neonates. Sulfasalazine is a dihydrofolate reductase inhibitor and as such increases the risk for cardiovascular defects and oral clefts in the fetus exposed during the second and ®rst month of pregnancy.39 Comment Sulfasalazine may induce folate de®ciency and folic acid supplementation should therefore be given before and throughout pregnancy. If control of disease activity requires it, sulfasalazine may be continued at doses not exceeding 2 g daily throughout pregnancy.40

Rheumatological disorders 961

Azathioprine Experience with azathioprine in human pregnancy is derived mostly from prevention of allograft rejection, pregnant patients with SLE and in¯ammatory bowel disease. Lacking the enzyme inosinate pyrophosphorylase, the fetal liver is unable to convert azathioprine to its active form. Therefore, the fetus should theoretically be protected from the e€ects of azathioprine and its active metabolite, 6-mercaptopurine, in early pregnancy.41 Fetus/newborn Accumulated data from renal transplant centres in North America and Europe on pregnancies in renal allograft recipients treated with corticosteroids and azathioprine found no predominant or frequent birth defect.42 In a European survey on transplant recipients, birth anomalies were present in seven of 103 children.43 Mothers of abnormal babies had taken signi®cantly higher doses of azathioprine (2.64 mg/kg versus 2.02 mg/kg) than those with healthy babies. Case reports have described congenital malformations and immunosuppression in several infants; however, a causal relationship to azathioprine has not been proven.44 Fetal growth restriction has sometimes been related to the gestational use of azathioprine and corticosteroids.20 The possible contribution of the underlying maternal disease is unclear. Studies of pregnancies in SLE and IBD showed that azathioprine controlled disease, reduced the rate of pregnancy losses and did not cause congenital malformations.16,41,45 Intrauterine exposure to azathioprine may occasionally cause slight suppression of the bone marrow as shown by decreased leukocyte counts and thrombocytopenia at birth.46 T-cell development is enhanced in the newborn after antenatal azathioprine exposure, but at later ages no induction of autoimmunity or immunde®ciency is seen.47 Follow-up of children exposed antenatally showed normal development during infancy and into adolescence.47 Comment There is no indication that azathioprine in doses 1.5±2 mg/kg/day is a strong teratogen or causes lasting immunosuppression in the neonate. Adjustment of the maternal leukocyte count during pregnancy by dose reduction avoids neonatal depression of haemopoiesis. Cyclosporine Cyclosporine is used primarily as an immunosuppressive drug to prevent rejection of organ transplantation. The ecacy of cyclosporine has been demonstrated in patients with rheumatoid arthritis and SLE whose conditions have not responded to conventional therapy. Fetus/newborn When cyclosporine was administrated 10 mg/kg/day to pregnant rats throughout gestation, the drug was not toxic to the exposed fetuses. However, it was embryotoxic at dosages of 25 to 100 mg/kg/day.48 In mice, development of autoimmune disease has been observed in antenatally exposed o€spring.

962 M. éstensen

More than 600 pregnancies exposed to cyclosporine for several weeks, or throughout gestation, have been reported. The majority of the treated mothers were transplant recipients. Daily doses ranged from 1.4 to 14 mg/kg with a mean dose of 5 mg/kg. The observed rate of 3% of congenital malformations has not exceeded the rate reported in the general population nor has any particular pattern of abnormalities emerged. Renal and liver function were normal in 166 neonates exposed to cyclosporine in utero. Major problems of cyclosporine-treated pregnancies were prematurity (537 weeks) in 40±46% and low birthweight (52500 g) in 44±65% of cases. It has been dicult to ascribe a causative role to drug treatment or the underlying maternal disorder.49±52 Follow-up for 1 to 12 years of 175 children registered in National Transplantation Pregnancy Register (USA) found normal development in 84% of o€spring exposed to cyclosporine in utero.53 The high incidence of prematurity was suspected to be involved in the mental developmental delay observed in 16% of the children. Because cyclosporine can induce autoimmunity in rodents after exposure in utero, several studies have addressed this issue in children of transplant recipients. Though T, B and NK-cell maturation and development can be impaired during the ®rst year of life, a follow-up ranging from 0.5 to 9 years of age found normal immune function in 10 children exposed to cyclosporine throughout pregnancy.47

NEW IMMUNOSUPPRESSIVE DRUGS Mycophenolate mofetil (MMF) (Cellcept), an inhibitor of purine synthesis, has been successfully employed to prevent transplant rejection. Most often the drug has been administered in combination with cyclosporine and prednisone. As an immunosuppressive agent with a more pronounced e€ect on T and B cells, MMF has also been used for the treatment of immunological disorders such as severe, refractory RA and lupus nephritis with some promising results.

Fetus/newborn In animal studies, treatment of pregnant rats and rabbits with 0.3±0.5 of the human doses have resulted in birth defects comprising the CNS, cardiovascular and renal systems.54 MMF is only recommended for use in women of fertile years with concurrent reliable contraception. However, pregnancy during treatment with MMF has occurred. Published reports are not available, but data exist on drug company ®les. By January 2001, 44 pregnancies under treatment with MMF had been reported; however, the outcome is known for only 18 of these pregnancies. Thirteen deliveries resulted in healthy neonates. Abnormalities at birth were observed in ®ve neonates, yet a causative role for MMF could not be established.

Comment Because of these ®ndings, and the very limited experience in human pregnancy, MMF is contraindicated during pregnancy.

Rheumatological disorders 963

CYTOTOXIC DRUGS Methotrexate (MTX) MTX is a folic acid antagonist which impairs dihydrofolate reductase and interferes with the production of purines. MTX is widely used for in¯ammatory and autoimmune rheumatic diseases, either as monotherapy or in combination with other immunosuppressive drugs. Experience with MTX in human pregnancy has derived mainly from patients treated for cancer, or when MTX or aminopterin was unsuccessfully used to terminate a pregnancy. In most of these reports, doses of MTX exceeded the low-dose weekly pulses (5±20 mg weekly) applied in rheumatology.55 Fetus/newborn Absolute or functional folic acid de®ciency during early pregnancy may lead to neural tube defects in the o€spring. Closure of the neural tube takes place during week 5, and therefore the embryo is probably most vulnerable to anti-folate drugs at this time. The congenital anomalies observed in animals and humans exposed to MTX in utero usually involved the central nervous system, cranial ossi®cation, and the palate.56 Three infants exposed to MTX during the ®rst trimester had multiple cranial anomalies. In seven cases, MTX had been given during late pregnancy; six normal children were born, and one child had pancytopenia.56 Reviewing the rheumatology literature of ®rst-trimester exposure to once-weekly doses of 20 mg of MTX or less disclosed 20 pregnancies.56 In the pregnancies not terminated electively, four (22%) ended in miscarriage, and of the 12 which proceeded to delivery, one child (8%) was born with the `aminopterin syndrome'. Birthweights of the full-term infants were within normal range. A follow-up ranging from 0.1 to 16.7 years of seven of the children revealed no developmental or other serious health problems. Comment MTX is contraindicated during pregnancy and should be prescribed to fertile women only under the cover of safe contraception. Due to the possibility that active metabolites remain in cells or tissues for about 2 months after cessation of therapy, conception should be postponed until 3 months after withdrawal of the drug. Folate supplementation should be continued antenatally and throughout pregnancy. Cyclophosphamide Severe forms of systemic rheumatic diseases, such as SLE, juvenile chronic arthritis (JCA) and RA are sometimes treated with cyclophosphamide either orally or, as in lupus nephritis, as intravenous pulse therapy. Fetus/newborn Cyclophosphamide is an alkylating agent which is teratogenic in all animal species studied. The e€ect on human pregnancy seems to be unpredictable as both normal children and children with congenital anomalies have been reported. The picture is

964 M. éstensen

complicated by concurrent treatment with other cytotoxic agents or radiation therapy in pregnant patients with malignancies. Birth defects have been reported in human fetuses after ®rst-trimester exposure to cyclophosphamide with facial, skin, musculoskeletal, and visceral organ anomalies, growth restriction and developmental delay during childhood.57 Intravenous cyclophosphamide therapy given during the ®rst trimester in seven pregnancies of six women with lupus nephritis resulted in two miscarriages, one elective termination of pregnancy, two children with multiple anomalies, one child with short arms and legs and one healthy child. Comment Cyclophosphamide is a human teratogen. Safe contraception is necessary when fertile women are treated with the drug. Attempts at conception should be delayed until 3 months after cessation of therapy.

NEW DRUGS FOR THE TREATMENT OF RA Since 1998, new drugs for the immunosuppressive treatment of RA have been registered. These are le¯unemide and the TNF-a antagonists in¯iximab and etanercept. Le¯unemide Fetus/newborn Studies in pregnant rats and rabbits with doses equivalent to human doses have found teratogenicity and fetotoxicity of le¯unemide. Both skeletal and central nervous system malformations have been observed. In addition, increased embryo lethality and reduced fetal weight were noted.58 One abstract has reported the occurrence of human pregnancy during treatment with le¯unemide. Of the 25 pregnancies exposed, 22 were interrupted, three pregnancies went to delivery, but details of neonatal health are not known.59 Comment Le¯unemide is contraindicated during pregnancy, and women of childbearing potential should be started on the drug only under safe contraception. Due to its long half-life and protracted elimination from plasma, le¯unemide must be withdrawn before a planned pregnancy, and conception ®rst attempted after successful elimination of the drug by cholestyramine or active charcoal. TNF-a a antagonists Pharmacological TNF-a inhibition can be achieved by monoclonal antibodies (in¯iximab) or by soluble TNF-a receptors (TNF-R) (etanercept). Thus far, there are few reports on completed human pregnancies exposed to TNF-a inhibitors.

Rheumatological disorders 965

Etanercept Fetus/newborn. Soluble TNF-R cross the placenta and gain access to the fetal circulation in mice, but do not interrupt pregnancy or impair fetal development.60 Pregnancy studies in rats and rabbits with 60±100 times the human dose of etanercept did not ®nd teratogenicity or fetotoxicity. Pregnancy proceeds normally in TNF-a knockout mice. Comment. Due to lack of human data, the use of etanercept during pregnancy is not recommended; however, prophylactic cessation of therapy has not been suggested by the manufacturer. In¯iximab Fetus/newborn. No embryo- or fetotoxicity was noted in mice treated with an antibody analogue to the human monoclonal antibody. One case of pregnancy during treatment with in¯iximab has been reported in a patient with psoriatic arthritis, but the outcome of this pregnancy is not known. In an abstract, exposure to in¯iximab has been reported for 42 pregnancies; outcome data were available for 35 pregnancies. No increase in birth defects or adverse pregnancy outcomes have been reported.61 Comment. The safety of in¯iximab during pregnancy has not been suciently documented. Safe contraception during treatment is therefore recommended by the manufacturer.

SUMMARY Treatment of a pregnant patient with rheumatic disease requires ecient control of disease activity. Acute ¯ares of arthritis can be controlled by NSAIDs or by shortterm treatment with corticosteroids. Disorders associated with involvement of internal organs and autoimmune phenomena may need immunosuppressive, or, in severe cases, cytotoxic drugs. Maternal side-e€ects of prolonged treatment with cyclo-oxygenase inhibitors are prolongation of gestation and labour and a tendency to bleeding. Constriction of the fetal ductus arteriosus, pulmonary hypertension in the neonate, impairment of fetal renal function and haemorrhage in the neonate are risks of third-trimester exposure to all inhibitors of cyclo-oxygenase. Corticosteroids may be necessary to control ¯ares of rheumatic disease and for the prevention of serious organ manifestations. High doses should be avoided in the ®rst trimester. Insucient data exist for de novo treatment of pregnant patients with gold, antimalarials, D-penicillamine and new immunosuppressives such as mycophenolate mofetil. The severity of the disease under treatment determines whether continuation of one of these drugs is justi®ed. In view of the lack of safety data on le¯unemide, and the TNF-a inhibitors recently introduced for the treatment of rheumatoid arthritis, these drugs should be avoided during pregnancy. Prophylactic withdrawal of drugs before pregnancy is mandatory for le¯unemide and the cytotoxic agents methotrexate and cyclophosphamide. Pre-pregnancy counselling and careful monitoring during pregnancy help to ensure necessary tailoring of drug treatment for the bene®t of mother and child.

966 M. éstensen

Practice points . aim: ensure a healthy pregnancy . management: clarify wish for children in fertile women with rheumatic disease. No prophylactic withdrawal of all drugs before pregnancy. Adjustment of drug treatment prenatally, cessation of known or potentially teratogenic drugs. Institution of ecient treatment compatible with pregnancy to prevent a ¯are of disease. Careful monitoring of disease activity during pregnancy and fetal monitoring . aim: prevention of a lupus ¯are in pregnancy . clinical features: musculoskeletal problems, rash, haematological abnormalities, lupus nephritis, secondary antiphospholipid syndrome . management: NSAIDs, antimalarials, local or systemic corticosteroids, azathioprine, antihypertensive drugs, anticoagulants. In severe cases, cyclophosphamide after the 1st trimester . aims: safe treatment with NSAIDs in pregnancy . management: only NSAIDs with a known safety record and a short half-life; ibuprofen, diclofenac, mefenamic acid; use the smallest e€ective dose; treat until subsidence of symptoms is achieved; stop treatment at gestational week 32; if continuation of treatment is necessary monitor fetal renal function and ductus arteriosus by ultrasound . caution: be aware of over-the-counter sale of NSAIDs and multi-ingredient pain medications. Judicious use of NSAIDs in mothers with increased risk of premature delivery . aim: minimize maternal and fetal side-e€ects of immunosuppression . management: reserve immunosuppressives for patients with systemic disease and a risk for ¯ares. Treat with the lowest e€ective dose. Counsel patient to avoid contact with infectious diseases

Research agenda Short- and long-term e€ects of antenatal exposure to corticosteroids to be investigated: . permanent alteration of immune function in the fetus . impairment of brain development . induction of hypertension in adulthood Investigation of long-term e€ects of maternal immunosuppression in o€spring: . cause of fetal growth restriction . e€ect on germ cells and reproductive function . increase in malignancies

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