Abstract

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Pharmacotherapy of Rheumatic Diseases in Pregnancy

Farmakoterapia schorzeń reumatoidalnych u kobiet w ciąży

Department of Clinical Pharmacology Silesian Piasts University of Medicine in Wrocław, Poland

Adv Clin Exp Med 2008, 17, 4, 423–431 ISSN 1230−025X

REVIEWS

© Copyright by Silesian Piasts University of Medicine in Wrocław

Abstract

Females are more prone than males to rheumatologic diseases. Degenerative diseases more frequently occur after fertile years, but inflammatory or autoimmune disorders often manifest themselves during women’s childbearing years. Disease which remains active during pregnancy may require drug treatment either for the benefit of the mother or in order to protect pregnancy and/or the fetus. Therapy with non−steroidal anti−inflammatory drugs (NSAIDs), corticosteroids, anticoagulants, immunosuppressive or even cytotoxic drugs may be crucial to acquire control of disease. But the use of antirheumatic drug during pregnancy may lead to increased risk of teratogenoc− ity; possible long−term effects on the infant and maternal side effects which interfere with pregnancy. In the preg− nant women with rheumatic disorders discontinuation of therapy with antirheumatic drugs may have advantages and many disadvantages and any treatment plan must be individually discussed. Cyclophosphamide, leflunomide and methotrexate use during pregnancy should be avoided and therapy should be discontinued at least 3 months before planned conception. Sulfasalazine therapy should be discontinued before planned pregnancy. NSAIDs and anti−malarial therapy can be continued until pregnancy is discovered. ASA and low doses of short acting NSAIDs can be taken during pregnancy and should be withdrawn 6 to 8 weeks before delivery and the treatment should be stopped by week 32 of pregnancy. Paracetamol, prednisolone and azathiopryne are the safest drugs to be used in pregnancy. Information concerning safety of biological treatment during pregnancy is insufficient (Adv Clin Exp Med 2008, 17, 4, 423–431).

Key words: pregnancy, rheumatologic diseases, drugs.

Streszczenie

Choroby reumatyczne częściej występują u kobiet niż u mężczyzn, a schorzenia o charakterze autoimmunologicz− nym i zapalnym, w większości przypadków, mają swój początek u kobiet w wieku rozrodczym. Jeżeli objawy cho− roby utrzymują się w czasie trwania ciąży, to jest wskazane podjęcie lub kontynuacja dotychczasowego leczenia w celu ochrony zdrowia kobiety ciężarnej, ciąży lub płodu. Do rozważenia jest więc zastosowanie leków z grupy niesteroidowych przeciwzapalnych, kortykosteroidów, leków przeciwzakrzepowych, immunosupresyjnych, biolo− gicznych, a nawet cytotoksycznych. Należy jednak mieć na uwadze, że taka terapia może zwiększyć ryzyko wy− stąpienia działań teratogennych, a także odległych niekorzystnych działań niepożądanych u dziecka lub u matki. Tak więc zaniechanie dotychczasowego leczenia lub włączenie nowych leków musi być wnikliwie przeanalizowa− ne. Podsumowując można powiedzieć, że 1) należy unikać stosowania w czasie ciąży cyklofosfamidu, leflunomi− du, metotreksatu; terapia tymi lekami powinna być zakończona na 3 miesiące przed planowaną ciążą, 2) leczenie sulfasalazyną jest najczęściej zakańczane przed zajściem kobiety w ciążę, 3) niesteroidowe leki przeciwzapalne klasy B wg klasyfikacji FDA oraz leki przeciwmalaryczne mogą być stosowane również po rozpoznaniu ciąży, 4) kwas acetylosalicylowy i małe dawki leków przeciwbólowych krótko działających mogą być stosowane w cza− sie ciąży, ale powinny być wycofane z leczenia 6–8 tygodni przed rozwiązaniem, najpóźniej w 32. tygodniu ciąży, 5) paracetamol, prednizolon i azatiopryna są uznawane za najbezpieczniejsze leki dla kobiety ciężarnej i płodu, 6) nie ma wystarczającej ilości informacji dotyczących stosowania leczenia biologicznego u kobiet w ciąży (Adv Clin Exp Med 2008, 17, 4, 423–431).

Słowa kluczowe: ciąża, choroby reumatyczne, leki.

Two types of rheumatologic diseases could be distinguished: inflammatory or autoimmune disor− ders, and degenerative diseases. Females are more

orders often manifest themselves during women’s childbearing years. The interaction of pregnancy and rheumatic disease varies, some conditions benefit, others worsen in response to the immunological and hormonal changes occur− ring during pregnancy (Table 1). Inflammatory rheumatic diseases may cause episodes of arthritis; autoimmune, systemic conditions may flare with symptoms of hematological, dermatological or renal disease or may lead to thromboembolism during pregnancy (Table 2). Disease which remains active during pregnancy may require drug treatment either for the benefit of the mother or in order to protect pregnancy and/or the fetus. Risks and benefits should be carefully analyzed with every patient and the physician should make the informed decision.

Therapy with non−steroidal anti−inflammatory drugs (NSAIDs), acetosalicylic acid (ASA), glico− corticosteroids (GS), anticoagulants, immunosup− pressive or even cytotoxic drugs may be crucial to acquire disease control. The use of antirheumatic

drugs during pregnancy may lead to increased risk of teratogenoicity; possible long−term effects on the infant and maternal side effects which interfere with pregnancy. Disorders of the internal organs and autoimmune conditions are more likely to require aggressive drug treatment than conditions with mainly muscoskeletal manifestations. Indications for treatment of pregnant women suf− fering from rheumatic disease may include differ− ent transient flares of arthritis and life−threatening conditions such as severe renal dysfunction or thromboembolism [1–4].

Rheumatoid arthritis (RA) can occur for the first time during pregnancy or, most commonly, first symptoms may be developed during 12 months following delivery and flare of existing arthritis. Improvement of preexisting RA symptoms has been observed during pregnancy. Continuation of drug treatment in RA is necessary for only 10–30% women with active disease [1, 3, 5–7]. There is little evidence that the presence of RA in the mother affects the development of the fetus but

Table 1. The influence of pregnancy on selected common rheumatoid diseases [1]

Tabela 1.Wpływ ciąży na wybrane choroby reumatyczne [1]

Disease Risk of major organ Increased risk for fetal/ Response of disease to

(Choroba) during pregnancy /neonatal complications pregnancy

(Ryzyko zajęcia ważniejszych (Większe ryzyko powikłań (Reakcja choroby na ciążę) narządów w czasie ciąży) u płodu/noworodka)

Rheumatoid arthritis (RA) rare no improvement

(Reumatoidalne zapalenie stawów)

Ankylosing spondylitis no no active/aggravated

(Zesztywniające zapalenie stawów kręgosłupa)

Systemic lupus erythroma− renal, hematological, CNS fetal loss, neonatal lupus Active

tosus (SLE) erythromatosus (NLE)

(Toczeń układowy)

Antiphospholipid syndrome thrombotic events fetal loss aggravated (Zespół antyfosfolipidowy)

Table 2. Features of various rheumatic diseases [1]

Tabela 2.Charakterystyka chorób reumatycznych [1]

Disease Type of organ involvement Autoimmune features Examples (Choroba) (Zajęty narząd) (Cechy autoimmunologiczne) (Przykłady)

Inflammatory joint disease muscoskeletal few spondyloarhropathies,

(Zapalenie stawów) reactive arthritis

Inflammation of joint muscoskeletal, internal several rheumatoid arthritis + systemic disease organs

(Zapalenie stawów + choroba układowa)

Systemic rheumatic diseases multiorgan disease many systemic lupus erythe−

(Układowa choroba matosus, sclerodermia,

it can affect the natural history of pregnancy. Postpartum recurrence of RA is observed in 85% of women during the following 3 months [3, 8–12]. Systemic lupus erythematosus (SLE) symp− toms are not mitigated by pregnancy, and active disease or even flares are common in pregnant patients. Oral contraceptives have the potential to exacerbate lupus disease. SLE in pregnant women can lead to hematological abnormalities, renal dis− ease, antiphospholipid syndrome with the conse− quence of fetal loss, severe pre−eclampsia, and in the fetus – to neonatal lupus, congenital heart block, intrauterine growth restriction. The risk of SLE flare is highest in the third trimester of preg− nancy and post−partum. Patients with SLE should plan their pregnancy and attempt conception only during the period of well−controlled, quiescent dis− ease. Indications for drug treatment of the preg− nant women with SLE include active disease (muscoskeletal problems, rash, hematological abnormalities, lupus nephritis) or organ damage. For pain reduction paracetamol, glicocorticoids, the use of NSAID’s, hydroxychloroquine and aza− thiopryne are recommended. Antiphospholipid syndrome, as part of SLE (15%), requires low− dose aspirin (ASA) alone, or in combination with heparin (depending on the severity of clinical symptoms). Those who were treated with war− farin/acenokumarol before pregnancy should be switched to low molecular weight heparin (enoxa− parin 40mg/daily, dalaparin 5000 U/daily) prior to 6 weeks gestation to avoid warfarin embryopathy. Heparin should be continued intrapartum and post− partum until the patients are re−warfarined. Women with SLE are at increased risk of fetal loss (20%) due to spontaneous abortion or stillbirth and preterm delivery (24%). Neonatal lupus erhytem− atosus (NLE) can also develop [1, 3, 5, 13–21].

Same authors suggest that fertility may be impaired and the risk of fetal loss during pregnan− cy increased in systemic sclerosis. Prematurity and intrauterine growth retardation were more com− mon in patients with sclerodermia than in controls in one study. The main health problem during pregnancy is renal crisis [7, 10].

Features of Effects

of Selected Rheumatic

Drugs Treatment

During Pregnancy

The Food and Drug Administration (FDA) has provided use−in−pregnancy ratings for drugs [2] (Table 3). Because pregnancy as a rule, is an exclusion criterion for randomized, controlled tri−

als only few such studies for antirheumatic drugs have been performed [1].

Glicocorticoids

Steroids are used during pregnancy mainly to treat systemic lupus erythematosus (SLE) [1, 5, 13, 16].

The treatment with steroids may be continued during pregnancy. In general they belong to cate− gory B according to FDA classification. The rec− ommendation for the class of steroid treatment depends on whether the mother or the fetus needs to be treated. If steroid therapy is indicated for the mother, hydrocortisone, cortisone or prednisolone should be chosen (placental inactivation). Dexamethasone and betamethasone, belonging to category C, according to FDA classification, cross the placenta and similar maternal and fetal con− centrations have been observed. So if the fetus required steroid treatment, those drugs are the drugs of choice [1, 5, 13].

During steroid therapy following adverse effects have been noted:

– fetus: oral clefts with first trimester expo− sure (it is recommended to avoid if possible, to use high dose of prednisolone, 1–2 mg/kg/day, in the first trimester of pregnancy while the hard palate is forming), rare: masculinisation of female infants, growth restriction, neonatal cataracts, adrenal sup− pression. Maternal corticosteroid therapy does not induce general immunosupression in the neonate;

– mother: gestational diabetes, hypertension, sodium retention, oedema, insomia, depression, premature rupture of membranes, and osteopenia or osteoporosis, adrenal gland suppression, increased risk of infection (for prednisone at 5–10 mg/day or higher used for prolonged periods) [1, 16].

On the other hand in pregnant women with systemic lupus erythematosus (SLE) treated with prednisone 10 mg/day, increased rate of birth defects or intrauterine growth retardation have not been observed [1].

To avoid the development of osteoporosis in time of GS treatment, supplementation with calci− um and vitamin D should be given to pregnant women.

During labor, delivery and immediately post− partum, in selected cases stress doses of hydrocor− tisone (50 to 75 mg of hydrocortisone or 10–15 mg of methylprednisolone intravenously on the day of procedure) are suggested.

Salicylates, Nonsteroidal

Anti−Inflammatory Drugs

(“Traditional”

and “Coxyb” NSAIDs)

Some of so called “traditional” NSAID’s are categorized as relatively safe according to FDA category, depending on the stage of pregnancy.

But acetosalicylic acid (ASA) in standard doses is not recommended to be used in pregnant women because of high risk of fetal malformations, pre− mature closure of ductus arteriosus, premature and low birth weight, excessive bleeding and postpar− tum anemia of the mother [13] (Table 4).

NSAID’s are involved in inhibition of prostaglandin synthesis, so in pregnant women

Table 3.Features of antirheumatic drugs treatment in pregnancy

Tabela 3. Charakterystyka leków przeciwreumatycznych stosowanych w ciąży

Drug FDA category Fetal effects Recommendations

(Lek) (Kategorie FDA) (Wpływ na płód) (Zalecenia)

Glucocorticoids in general B oral clefts with 1 st trimester evaluate need for stress dosing, avoid during

(Glikokortykoidy) exposure first trimester

NSAIDs B risk of fetal hemorrhage; prema− discontinue 6–8 weeks prior to delivery, (Niesteroidowe leki ture closure of ductus arteriosus preferably discontinue by week 32 przeciwzapalne)

Selective COX−2 C risk of fetal hemorrhage; prema− discontinue 6–8 weeks prior to delivery, inhibitors ture closure of ductus arteriosus preferably discontinue by week 32 (Selektywne

inhibitory COX−2)

Hydroxychloroquine C probably none may be continued through pregnancy (Hydroksychloro−

china)

Methotrexate X cranial abnormalities; limb discontinue 4 months prior to conception; (Metotreksat) defects, CNS abnormalities supplementation with folic acid during those

4 months and through the whole pregnancy Leflunomide X embryotoxic cholestyramine 8 g tid for 11 days with plasma

(Leflunomid) levels less than 0,02 mg/L on 2 separate tests

2 weeks apart AND wait 3 menstrual cycles prior to conception

Sulfasalazine B, D probably none may be continued through pregnancy (Sulfasalazyna)

Azathiopryne D IUGR (intrauterine growth use with caution if needed to suppress disease (Azatiopryna) restriction), neonatal leukopenia, activity; consider decreasing dose at 32 weeks

hypogammaglobulinemia; infec− tions (CMV and gram−negative)

Cyclophosphamide D embryopathy with growth de− avoid during pregnancy, especially during 1st (Cyklofosfamid) ficiency; developmental delay; trimester

craniosynostosis, cranial defects, distal limb defects

Cyclosporine A C abnormal T, B and NK cell use with caution if needed to suppress disease (Cyklosporyna A) development and maturation activity

Mycophenolate C teratogenic, craniofacial distal avoid if possible during pregnancy

mofetil limb, and other fetal malforma−

(Mykofenolan tions mofetilu)

TNF−antagonists B insufficient data caution if used during pregnancy (Antagoniści TNF)

Anakira B insufficient data; no toxicity in use in pregnancy only if needed to suppress (Anakira) reproductive studies on rats disease activity

and rabbits

Rituximab C insufficient data; case reports avoid if possible during pregnancy

(Rytuksymab) of granulocytopenia and

they can inhibit or relax uterine contractions, pro− long gestation and labor and cause increased maternal blood loss on delivery [1, 2, 13]. Indometacin has been reported to induce oligohy− dramnios and alter urinary output. In case of plat− ed aggregation inhibition by NSAIDs, the risk of fetal hemorrhage and postpartum bleeding increas− es. First−trimester use of various NSAIDs has failed to demonstrate any increase of congenital abnormalities. The use of mentioned drugs in the third trimester promotes premature closure of the ductus arteriosus leading to fetal pulmonary hypertension [5, 7].

During therapy with selective COX−2 inhi− bitors, potentially the same side effect may occur. The whole drug group is classified as C category according to FDA.

It is recommended that NSAIDs drugs should be withdrawn 6 to 8 weeks before delivery and the treatment should be stopped by week 32 of preg− nancy.

NSAID’s most probably do not affect fertility in women with rhematic disease [15].

It has been observed that low dose ASA at 80 mg/day has no influence on neonatal platelet aggregation or renal or ductal blood flow. It should be stopped about 2 weeks before delivery (the risk of premature closure of ductus arteriosus, pul− monary hypertension and intracranial haemor− rhage in the fetus, and bleeding complications dur− ing epidural anesthesia in the mother) [1, 2, 13].

Hydroxychloroquine

Hydroxychloroquine is an antimalarial drug used in the therapy of RA, SLE and connective tis− sue diseases. According to FDA classification it belongs to category C. It is important that the drug is stored in tissues, mainly in the liver and retina, has long half−life time, approximately 8 weeks and passes across the placenta. Therefore fetal exposure cannot be avoided and the therapy is discontinued

after conception [2, 7]. However no drug related real fetal toxicity has been observed at the doses used for the treatment of connective tissue diseases (6,5 mg/kg body weight). The analyzed clinical tri− als did not contain any evidence of visual, hearing, growth or developmental abnormalities observed in children of mothers treated with hydroxychloro− quine during pregnancy. Important conclusion aris− ing from those studies is that it is safer to continue hydroxychloroquine therapy through pregnancy to help stabilize SLE activity rather than risk a flare of the disease in the peripartum period, but there is no benefit from initiating drug therapy at the time of existing pregnancy. Hydroxychloroquine should be the drug of choice in fertile women with rheumatic disease [1, 2, 13, 16].

Methotrexate

Methotrexate (MTX) as folic acid antagonist interferes with folic acid metabolism and purine synthesis. MTX is indicated in the treatment of RA, juvenile rheumatoid arthritis, spondy− loarthropathies, autoimmune inflammatory dis− eases. It has category X according to FDA classi− fication and has documented teratogenic and abor− tifacient property [2, 3, 13]. Women with childbearing potential should use contraception while methotrexate therapy is required. Fetus exposure to this drug at high doses (not used in rheumathology) may demonstrate multiple cranial abnormalities (anencephaly, hydrocephaly, me− ningomyelopathy, cranial ossification, palate) and neural tube defects, especially if the first trimester exposure occurred. One−weekly doses of 5–20 mg methotrexate, as used in rheumatology, may lead to miscarriage and to the development of “aminopterin syndrome”. A follow−up observation till 16.7 years revealed no developmental or other serious health problems [1].

Methotrexate has large volume of distribution, and can be accumulated in the liver for up to

Table 4. Nonsteroidal antiinflamatory drugs and pregnancy

Tabela 4. Niesteroidowe leki przeciwzapalne a ciąża

Drug FDA category, pregnancy trimester Placenta crossing Pregnancy use (Lek) (Kategorie FDA, trymestr ciąży) (Przenikanie (zastosowanie w ciąży)

I II III przez łożysko)

Acetosalicylic acid D D D yes contraindicated beside specific

(Kwas acetylosalicylowy) recommendations

Ibuprofen B B D yes caution if used during pregnancy,

Ketoprofen B B D yes do not indicated in 3rd trimester

Naproxen B B D yes

116 days after exposure, so it is recommended to stop drug treatment for about 4 months before con− ception and additionally folic acid supplementa− tion should be continued during this time and throughout the pregnancy.

Although with low doses of methotrexate used in rheumatology congenital malformations have been not observed, this medication is contraindi− cated during pregnancy because of the potential teratogenic risk [1, 4, 13, 16].

Leflunomide

Leflunomide is an inhibitor of the enzyme required for pyrimidine synthesis. Indications for leflunomide treatment include active rheumatoid disease in adults and psoriasis arthropaty. It belongs to category X according to FDA classifica− tion and has teratogenic and fetotoxic potentials. In animal studies skeletal and central nervous system malformation, embryo lethality and reduced fetal weight have been observed. The drug has long half−life time (14–15 days) and its metabolite undergoes extensive enterohepatic circulation which causes prolonged presence, up to 2 years after exposure, of high serum drug concentration. Therefore women with childbearing potential should have negative pregnancy test before therapy is instituted and should use contraception through− out this period. Because the drug has a long half− life time, discontinuation of the therapy before con− ception may not be sufficient. It is recommended to take cholestyramine orally, 8 g 3 times daily for 11 days, to eliminate the leflunomide from the body and to achieve drug plasma level beyond 0.02 mg/l in two separate tests at least 2 weeks apart. After cholestyramine treatment, women should have at least 3 menstrual cycles before planned conception. But if the pregnancy occurs unexpectedly during leflunomide treatment, taking cholestyramine does not fully protect the fetus to drug exposure in organogenesis time [1, 2].

Sulfasalazine

Sulfasalazine is a dihydrofolate reductase inhibitor. It belongs to category B or D according to FDA classification. Sulfasalazine is indicated for the treatment of RA and spondyloarthropathies. About 75% of the applied drug passes into the colon, where it is metabolized into 5−aminosali− cylic acid and sulfapyridine [7, 13] which cross the placenta and achieve the cord concentration similar to that observed in maternal serum. However none of the mentioned substances influence the neonatal bilirubin serum concentration and cause displace− ment of bilirubin from albumin (as sulphonamides

used to). It is stated that sulfasalazine is safe and does not increase fetal morbidity or mortality. But as a dehydrofolate reductase inhibitor, sul− fasalazine increases the risk of cardiovascular defects and oral clefts in the fetus exposed to the drug in the first and second months of pregnancy [1, 2, 13]. Sulfasalazine treatment may lead to folate deficiency; therefore folic acid supplementa− tion should be performed before and during the pregnancy time. The daily dose of sulfasalazine in the pregnancy period should not exceed 2.0 g. Sulfasalazine therapy is usually discontinued before planned pregnancy [1, 2, 13].

Azathiopryne

Azathiopryne (6−mercaptopurine) is indicated in rheumatology for the treatment of RA and SLE, mostly in women with renal transplant. It belongs to category D according to FDA classification. The drug crosses the placenta but in the fetal liver it is not converted to active metabolite, 6−mercap− topurine with teratogenic properties. Despite earli− er information concerning a negative influence of azathiopryne on the fetus, a retrospective cohort study found no statistical differences in conception failures, miscarriages secondary to birth defect, major congenital malformations, neoplasia or increased infections in women patients treated with doses of 100 mg/day. So azathiopryne is the treatment option for pregnant women with rheumatic disease in case of needed suppression of disease activity. Azathiopryne controls the disease, reduces the rate of pregnancy losses and usually does not cause congenital malformations. Occasionally intrauterine exposure to azathio− pryne may cause slight suppression of the bone marrow expressed by decreased leukocytes and thrombocytes count.

Azathiopryne may be prescribed during preg− nancy without measurable risk of congenital mal− formations [1, 2, 13, 16].

Cyclophosphamide

phamide. The risk of congenital malformations as a consequence of cyclophosphamide therapy dur− ing pregnancy is estimated to 20%. To observed embryopathy belong: growth deficiency, develop− mental delay, craniosynostosis, blepharophimosis, flat nasal bridge, abnormal ears, distal limb defects (hypoplastic thumbs, oligodactyly). Therefore the cyclophosphamide use, as a teratogen should be avoided in the pregnancy time, especially in the first trimester. Attempts at conception should be delayed until 3 months after termination of cyclophosphamide therapy. Summary: cyclophos− phamide is likely to be teratogenic in human when given in large doses during the period of early organogenesis. It should be avoided during preg− nancy. Cyclophosphamide can be a cause of infer− tility in both women and men [1–3, 13, 16].

Cyclosporine A

Cyclosporine A is indicated in rheumatology for treatment of autoimmune diseases, especially RA, SLE and polymyositis in patients who not responded to conventional therapy. It has category D according to FDA classification. Cyclosporine pass the placenta, and is detectable in fetal blood. The meta−analysis of the outcome of drug therapy (doses 1.4–14 mg/kg) during pregnancy revealed that the overall prevalence of major malformations was 4.1% and it did not vary significantly from observed in the general population. The influence of cyclosporine on immunologic function, corre− sponding to the impairment of maturation and development of T, B lymphocytes and NK−cell in newborns of mothers undergoing drug therapy was observed. However newborns were appropriate for the gestational age and the mother did not show systemic hypertension or renal damage. Predo− minant health problems related to cyclosporine therapy during pregnancy were not observed. Major negative outcomes of cyclosporine−treated pregnancies were prematurity (< 37 weeks), in 40–60% and low birth weight (< 2500 g) in 44–65% of cases [1, 2].

It is suggested to use cyclosporine therapy during pregnancy with caution, only if it is needed to suppress the disease activity. There is no evi− dence of human teratogenicity [13].

Mycophenolate Mofetil

Mycophenolate mofetil (MMF) is indicated as an immunosuppressive agent for SLE, lupus nephri− tis, refractory RA. It has category D according to FDA classification. There is little experience con− cerning the exposure of pregnant women to MMF (in 11 pregnancies 4 spontaneous abortions were

reported). The main observations were: mild moth− er pre−eclampsia and renal insufficiency, premature delivery, in the newborns: hypoplastic nails, short fifth fingers, cleft lip and plate, ear deformity, micrognathia, ocular hypertelorism, microtia, left pelvic ectopic kidney, complete agenesis of corpus callosum. Those reports suggested that caution is warranted (appropriate conception), the drug should be avoided if possible, and the MMF should be dis− continued at least 6 weeks before conception [1, 2].

Biological Treatment

in Pregnancy

Tumor Necrosing Factor

Antagonists (TNF−

αα

)

Infliximab (chimeric IgG1 anti−TNF alpha antibody) is especially indicated for RA treatment, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis.

Etanercept (TNF−receptor fusion protein), crosses the placenta and is detectable in fetal cir− culation, but does not interrupt pregnancy or impair fetal development.

Adalimumbad is a recombinant human IgG1 monoclonal antibody. There is no relevant infor− mation concerning the drug behavior in pregnancy. The FDA has classified all mentioned drugs as pregnancy class C. There is no evidence that these drugs posses maternal toxicity, embryotoxicity, or teratogenicity in animal studies. There is little experience concerning the exposure of pregnant women to Tumor Necrosing Factor Antagonists. Among 133 pregnant women exposed to inflix− imab (3 months before conception and during first month of pregnancy) a following outcome was reported: life births – 65%, miscarriages – 17%, therapeutic terminations – 22%, what was similar to findings in general pregnant population. However despite these findings, caution should be taken when using the above agents during preg− nancy, but cessation of treatment has not been sug− gested by the manufacturer [1, 2, 21].

Future observations concerning optimal doses, possibility of treatment of pregnant women, and the use in lactation period, and the influence of the mentioned drugs on fetus and child development are needed [3].

Anakira

gory B according to FDA classification. There is no experience concerning the exposure of preg− nant women to anakira, but animal studies do not deliver evidence of impaired fertility or harm to the fetus. Because of that anakira should be used in pregnancy only if clearly needed [2].

Rituximab

Rituximab (chimeric monoclonal antibody) is indicated in rheumatology for the treatment of SLE and RA. It has category C according to FDA classification. There are only few case reports regarding rituximab treatment in pregnancy. One pregnancy, apart from slight anemia in the woman) was uncomplicated and in the newborn transient granulocytopenia and lymphopenia was observed. In this time, rituximab should be avoided in preg− nancy and may be considered as an option for treatment in the future [2, 3].

Antirheumatic Therapy

in Men, Male Fertility

and the Risk of Conception

There are few data concerning the risk of male infertility with antirheumatic drugs as methotrex− ate, leflunomide, sulfasalazine, cyclosporine, cyclophosphamide (Table 5).

In case of methotrexate outcome, one study revealed no effect on fertility evaluated by semen analysis, testicular histology or spermatogenic activity, another study revealed reversible sterility. The suggestion is that methrotrexate therapy should probably be discontinued 3 months before planned conception [2].

Leflutomide study shows no evidence of the drug influence on male−mediated fetal toxicity and remote male fertility. In case of drug therapy, before planned conception, it is recommended to take cholestyramine orally 8 g 3 times daily for 11 days to eliminate the leflunomide from the body and to achieve drug plasma level beyond 0.02 mg/l in two separate tests at least 2 weeks apart [2].

Sulfasalizine causes reversible men sterility. 86% of analyzed sperm delivered by men treated with sulfasalizine were abnormal and 72% were oligospermic. It was observed that sperm quality improved after the drug was withdrawn for longer than 2 months [2].

For azathiopryne, there is no evidence of reducing male fertility. Changes in semen density, motility, morphology, volume and total sperm count were not observed [2].

Cyclophosphamide decreases men fertility by irreversible influence on germ cell function.

There is no information that cyclosporine or mycofenolate mofetil affect male fertility [2, 15].

In the pregnant women with rheumatic disor− ders, discontinuation of the therapy with antirheumatic drugs may have advantages and many disadvantages and any treatment plan must be individually discussed [14].

Authors conclude that: cyclophosphamide, leflunomide and methotrexate use during preg− nancy should be avoided and therapy should be discontinued at least 3 months before planned conception, sulfasalazine therapy should be dis− continued before planned pregnancy, NSAIDs and anti−malarial therapy can be continued until pregnancy is discovered, ASA and low doses of short acting NSAIDs can be taken during preg− nancy and should be withdrawn 6 to 8 weeks before delivery and the treatment should be stopped by week 32 of pregnancy, paracetamol, prednisolone and azathiopryne are the safest drugs to be used in pregnancy, information con− cerning the safety of biological treatment during pregnancy is insufficient.

Table 5. Immunosupressive drugs and fertility in men and women

Tabela 5.Leki immunosupresyjne a płodność mężczyzn i kobiet

Drug Impairment of fertility

(Lek) (Zmniejszenie płodności)

Prednisone no

(Prednizon) Antimalarias

(Leki przeciwmalaryczne) no

Sulphasalazine women – no, men – yes (Sulfasalazyna)

Azathioprine no

(Azatiopryna)

Methotrexate women – no, men (Metotreksat) – occasionally Cyclophosphamide women and men – yes (Cyklofosfamid)

Leflunomide no

(Leflunomid)

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Address for correspondence:

Ewa Jaźwińska−Tarnawska

Department of Clinical Pharmacology

Silesian Piasts University of Medicine in Wrocław Bujwida 44

50−345 Wrocław Poland

Tel.: +48 71 328 61 70; +48 71 328 61 80 E−mail: [email protected]