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Abstract

Many connective tissue diseases occur more frequently in women, the female:male ratio for systemic lupus erythematosus is 9:1 and for rheumatoid arthritis is 3:1. These diseases frequently afflict young women, many of whom wish to become mothers. While some diseases (for example, rheumatoid arthritis) generally improve during pregnancy, other immune-mediated diseases may be exacerbated by pregnancy, putting both the mother and fetus at risk and making control of maternal disease a top priority. This review examines the current literature pertaining to the use of antirheumatic drugs during pregnancy, including aspirin and nonsteroidal anti-inflammatory drugs, corticosteroids, anticoagulants, the 4-aminoquinoline antimalarial drugs, immunomodulating drugs, antimetabolite drugs and other agents including sulfasazine and anticytokine therapy.

Keywords

aspirin azathioprine complications corticosteroids cyclophosphamide cyclosporine etanercept hydroxychloroquine infliximab inhibitor leflunomide methotrexate mycophenolate mofetil nonsteroidal anti-inflammatory drugs pregnancy sulfasalazine tumor necrosis factor

Autoimmune conditions commonly affect women of childbearing age. Some diseases, for example rheumatoid arthritis, usually improve during pregnancy [1], whereas the course of other autoimmune diseases during gestation is less predictable. Diseases such as systemic lupus erythematosus (SLE), scleroderma, phospholipid antibody (aPL) syndrome and inflammatory bowel diseases may be difficult to manage throughout pregnancy. This is partly due to the effects of pregnancy on the disease, the effects of the disease on pregnancy and, with concerns of teratogenicity and other potentially harmful effects for the fetus, the restricted repertoire of available therapeutic options.

Here we have summarized recent literature on the maternal and fetal effects of anti-inflammatory, immunomodulating, antimetabolic and anticoagulant drug use in pregnancy.

Anti-inflammatory drugs

Aspirin

Aspirin is one of the most widely used drugs in pregnancy and this widespread use is due, in part, to the fact that the lay public do not consider it to be a drug and it is available over the counter. Aspirin is a platelet cyclooxygenase inhibitor and prostaglandin synthesis inhibitor, and it is therefore an antithrombotic and anti-inflammatory drug. This antithrombotic effect has led to extensive use of aspirin during pregnancy in women with prothrombotic states, such as phospholipid antibody syndrome with recurrent pregnancy loss. Some studies have recommended its use to prevent pregnancy-induced hypertension [2]. In low doses, only maternal platelet cyclooxygenase is affected and no neonatal adverse effects are seen [3]. A 1989 study recommends safe use of low-dose aspirin up until birth, although this has been shown to prolong pregnancy [4]. Other reports have suggested an increased risk of gastroschisis in infants exposed to aspirin in utero [5]; however, a recent paper by Norgard and colleagues failed to detect any teratogenic effect associated with the use of aspirin [6].

Full-dose aspirin near term can result in complicated deliveries with an increased incidence of peripartum hemorrhage and anemia [7]. Aspirin readily crosses the placenta and can affect neonatal clotting ability if full-dose aspirin is given 1 week prior to delivery [8]. The recommendation is: safe in low doses, avoid full doses 6–8 weeks prior to delivery.

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to inhibit labor and prolong gestation and are used as tocolytic agents. Animal studies show that NSAIDs can inhibit blastocyst implantation and some human studies have suggested an increased risk of miscarriage in patients taking NSAIDs around the time of conception, leading to the suggestion that they should therefore be avoided in the preconception period [9]

A population cohort study by Li and colleagues determined that prenatal use of NSAIDs and/or aspirin around the time of conception is associated with an increased risk of miscarriage [10]. Previous reports had suggested that NSAID use in humans was not associated with congenital defects, low birthweights or preterm delivery [11,12]; however, other studies have suggested an association between NSAID use and fetal cardiac effects, as well as oral–facial cleft palates [13,14]. Prostaglandin inhibition resulting in adverse renal effects has been reported [15,16], with renal failure described in some infants [16]

Prostaglandin inhibitors used in the third trimester can cause fetal ductus arteriosus constriction and premature closure leading to primary pulmonary hypertension in the newborn. Constriction of the fetal ductus arteriosus can be reversed [17], but pulmonary hypertension may not be reversible. Recommendations are as follows:

Avoid in third trimester owing to neonatal toxicity;

Selective cyclooxygenase (COX) II inhibitors should be avoided due to lack of reliable data;

Possibly associated with the development of spontaneous abortions.

Corticosteroids

Glucocorticoids are frequently used during pregnancy, and form the mainstay of treatment of many inflammatory conditions as the non-fluorinated corticosteroids such as prednisone and solumedrol cross the placenta in only minuscule amounts.

Maternal complications amount to the same as those for nonpregnant patients. Monitoring for hypertension, hyperglycemia in particular, avascular necrosis of bone and osteopenia should be undertaken and supplemental oral vitamin D and calcium is recommended.

Fluorinated steroids (betamethazone and dexamethazone) are commonly used to treat fetal lung immaturity. These compounds are more resistant to placental metabolism, and therefore cross the placenta and are considered safe to use in the third trimester, but recent data have demonstrated that the use of fluorinated corticosteroids can lead to long-term effects in exposed offspring, including reduced brain weight, impaired cerebral function and growth retardation [18].

There is data to suggest a small increase in the occurrence of oral–facial clefts as a result of first trimester exposure to corticosteroids. Epidemiological studies, including a case–control study in 1999, showed a higher odds ratio for oral–facial cleft with corticosteroid use in the periconceptual period [19], which is supported by the findings of Pradat and colleagues [20], and other studies [21,22]. The recommendations are as follows:

Safe but limited use of fluorinated corticosteroids;

Moderately increased risk of developing cleft palate if exposed during first trimester.

Anticoagulants

Pregnancy is a known prothrombotic state, which means an increased risk of clinical thrombotic events in pregnant women with known pre-existing prothrombotic disease states.

Some autoimmune diseases, such as aPL syndrome, also interfere with the normal development of pregnancy, not just by promoting thrombosis with infarction of the placenta, but also by interfering with the process of placentation, the end result being placental insufficiency and, eventually, placental failure. Numerous studies have shown that anticoagulation can improve fetal outcome in patients with aPL syndrome [23,24]. Oral anticoagulants (warfarin and coumadin) cross the placenta and, if used after 6 weeks gestation, can give rise to the neonatal warfarin syndrome that consists of eye and ear defects, hypoplasia of the nose and extremities, as well as congenital heart disease [25]. Therefore, anticoagulation throughout pregnancy is conducted using unfractionated heparin or low-molecular-weight heparin, preferably given twice daily and monitored by partial thromboplastin tine (PTT) tests. In the case of low-molecular-weight heparin, activated Xa levels that are the equivalent of a plasma heparin, should be drawn approximately 4 h after the last heparin dose. Low-molecular-weight heparin has a longer half life and is less protein bound, so the risk of bleeding is increased and patients should be advised to change to unfractionated heparin prior to delivery. Recommendations are as follows:

Oral anticoagulants must be discontinued by week 6 of gestation;

Patients receiving heparin should be monitored closely to ensure adequate anticoagulation if therapeutic anticoagulation is desired.

The 4-aminoquinoline antimalarial drugs

Hydroxychloroquine & chloroquine

Hydroxychloroquine and chloroquine are 4-aminoquinoline antimalarial agents. These drugs have numerous other properties that make them ideal for use in a variety of immunologically-mediated diseases. They are used for the management of SLE, aPL syndrome and rheumatoid arthritis. These drugs are known to cross the placenta and to have a long half-life, and could therefore theoretically be deposited in the fetal-pigmented tissues, even in mothers who have recently ceased therapy. The tissue deposition of chloroquine is higher than that seen with hydroxychloroquine and so hydroxychloroquine use during pregnancy is preferred if at all possible. There have not been any recent reports of fetal malformations with hydroxychloroquine use at the approved dosage. In a case–control study in 2003 looking at 90 pregnant women treated with hydroxychloroquine 200 mg or 400 mg daily, compared with 53 pregnant women with similar disorders who were not taking hydroxycholoroquine, no statistical difference was observed with regards to developmental abnormalities [26].

Table 1.

The use of antirheumatic disease drugs during pregnancy.

Drug	US FDA Code	Fetal effects	Use in lactation	Other comments
NSAIDs	Cm/Bm	Premature closure of the ductus arteriosus if used in the third trimester, possibly associated with spontaneous abortions, fetal cardiac effects and cleft palate	Some agents Yes	Insufficient data available on COX-2 Selective agents. Discontinue all in the third trimester except low-dose aspirin
Prednisone	B	Safe. Crosses the placenta in only minuscule amounts, some association with cleft palate	Yes
Fluorinated corticosteroids (dexamethazone, betamethazone)	C	Crosses the placenta Impaired neurological development and growth retardation	No	Exposure must be limited
Warfarin and coumadin derivatives	D	Neonatal warfarin syndrome	Yes	Contraindicated after 6 weeks gestation
Unfractionated heparin	Cm	None known	Yes
LMW heparin	Bm	None known	Yes
Hydroxychloroquine and chloroquine	C	Safe at usual dosage Theoretical potential for drug deposition in fetal tissues	Yes	Dosage must be minimized Drugs have a long half life in tissues Hydroxchloroquine preferred
Cyclosporin (A)	Cm	Not teratogenic Transient immunosuppression of fetus	No
Mycophenolate mofetil	Cm	Some reports of teratogencity in combination with other drugs	No	D/C 6 weeks prior to conception
Cyclophosphamide	Dm	Teratogenic and embryo toxic in animal studies	No	D/C use 3 months prior to conception Premature gonadal failure
Azathioprine	Dm	Transient immunosuppression of fetus	No	6-mercaptopurine must be avoided
Methotrexate	Xm	An abortofactant and congenital abnormalities occur	No	D/C 3–6 months prior to conception
Leflunomide	Xm	Embryotoxic in animals	No	D/C 3–6 months prior to conception
Sulphasalazine	Bm	Safe – probably safe at 2 g daily or less. Potential for jaundice in premature neonates	Yes	Suppresses spermatogenesis
Anti-cytokine therapy etanercept and infliximab	B	To date no observed adverse effects	No	Insufficient data available

US FDA coding:

Category A: Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.

Category B: Either animal reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).

Category C: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in woman or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.

Category X: Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant. ‘m’ is added to define drugs that have been allocated coding by the manufacturers rather than the FDA.

COX: Cyclooxygenase; D/C: Discontinue; LMW: Low molecular weight; NSAID: Nonsteriodal anti-inflammatory drug.

Discontinuing the 4-aminoquinoline drugs in lupus patients is known to precipitate flares of this disease. The maternal effects of stopping hydroxychloroquine during pregnancy may therefore result in a disease flare in SLE patients, and this could result in fetal loss, as disease activity is one of the factors known to contribute to adverse fetal outcome in patients with SLE. It is therefore considered to be safer to continue hydroxychloroquine in low doses, (preferably 200 mg daily or less) throughout pregnancy, especially in patients at risk for flares of their disease [27,28]. Recommendations are as follows:

Can be used during pregnancy;

Hydroxychloroquine is preferred to chloroquine since there is less tissue deposition;

Benefit outweighs risks during pregnancy when used in low doses.

Immunomodulating drugs

Cyclosporine A

Cyclosporine is a fungally produced antibiotic used to prevent solid-organ transplant rejection. Its main action is to block interleukin (IL)-2 signaling to T cells. It has also been used to treat ulcerative colitis, rheumatoid arthritis and SLE.

Very small numbers of documented fetal exposures to cyclosporine exist in the human literature as a result of autoimmune disease treatment in the mother. However, a review of 75 pregnancies in transplant recipients documented that the main adverse outcome was growth retardation and prematurity [29]. These outcomes have independently been attributed to the co-morbidities of transplant recipients [30]. It has also been shown to exert short-term immunosuppressive effects on the neonate.

Cyclosporine has not been shown to be an animal or human teratogen and its nephrotoxic effects in high doses are not specific to fetal development. Some consider it as safe as azathioprine [31]; however, long-term data and latent effects are not known at this time. Recommendations are as follows:

Potentially immunosuppressive to fetus but not teratogenic;

Can be used during pregnancy if maternal disease indicates this to be necessary.

Mycophenolate mofetil

Mycophenolate mofetil (MMF) is one of the newer antimetabolic immunosuppressive agents that has come to be a standard of care in transplant medicine owing to its tolerance and safety profile. MMF, on oral administration, is readily absorbed and hydrolyzed to its active metabolite, mycophenolic acid. Mycophenolic acid has an inhibitory effect on T and B lymphocyte purine synthesis. It is gaining popularity in the treatment of autoimmune conditions such as SLE where it has been shown to be beneficial in the treatment of severe renal disease.

MMF has been demonstrated to be teratogenic in animals, causing head and eye malformations [32]. Human studies are limited and most cases of pregnancy with exposure to this drug have occurred unwittingly in the first trimester. In 2002, the US National Transplant Registry reported a total of 14 pregnancies exposed to MMF that resulted in six spontaneous abortions and eight live births, of which six were normal. Of the remaining two cases, both were exposed to MMF, prednisone and tacrolimus, one fetus demonstrated hypoplastic nails and short fifth fingers and the other had cleft lip and palate and ear deformities [33]. Since then, a further case report in 2004 documented that a 13-week old fetus exposed to MMF, tacrolimus and prednisone had multiple malformations including agenesis of the corpus callosum, cleft lip and palate, micrognathia and external ear malformations, instigating elective termination at 22 weeks [34]. The authors concluded that as tacrolimus is not associated with an increased incidence of anomalies compared with other regimens, MMF was probably responsible for the malformations. Another recent report documented serious malformations in two infants exposed to MMF [35].

It seems prudent to avoid this drug in pregnancy until further data becomes available. For those patients wishing to conceive whilst being treated with MMF, the European Best Practice Guidelines advise cessation of therapy 6 weeks prior to conception [36]. Recommendations are as follows:

Some reports of teratogenicity in combination with other drugs;

To be avoided during pregnancy;

Discontinue 6 weeks prior to conception.

Cyclophosphamide

Cyclophosphamide is an alkylating antineoplastic agent used in the treatment of rheumatic diseases as well as hematological malignancies. It is a known teratogen, causing fetal malformations involving the skeleton, palate, eyes and limbs following first trimester exposure [37], although normal pregnancies have also been reported. Exposure to cyclophosphamide during the first trimester is associated with significant early fetal loss [38].

A recent review discusses the use of cyclophosphamide during pregnancy in more detail [39].

Cyclophosphamide has long-term effects on male and female reproductive health. The age of the patient (>31 years in women) and the cumulative dosage are critical in determining ovarian failure [40]. Oral contraception and gonadotrophin-releasing hormone agonists can be used to inhibit ovulation during therapy to protect ovarian follicles and cryopreservation of oocytes may also be offered [41].

Male and female patients should be counseled regarding possible infertility and prophylactic options to preserve spermatozoa and oocytes. Treatment with cyclophosphamide should be ceased 3 months prior to attempted conception [42]. Recommendations are as follows:

Teratogenic;

Contraindicated in pregnancy;

Withdraw use 3 months prior to conception.

Antimetabolite drugs Azathioprine

Azathioprine is commonly used in patients with inflammatory bowel disease, following organ transplants and rheumatic diseases including rheumatoid arthritis and SLE. It is converted to its active metabolite, 6-mercaptopurine by the liver.

Although azathioprine readily crosses the placenta, the fetal liver lacks the inosinate pyrophosphorylase enzyme that causes the conversion, and therefore only trace amounts of 6-mercaptopurine have been found in fetal blood [43].

While animal studies have confirmed teratogenicity in rabbits and mice, causing skeletal and visceral anomalies [44], these have not been conclusively proven in humans [45]. However, a recent review documented exposure to azathioprine in 117 infants, with no congenital abnormalities detected in 112 of these exposed offspring [46].

Immunosuppression has been observed in infants, especially those exposed to persistently high maternal serum levels of azathioprine during the third trimester, resulting in leucopoenia and thrombocytopenia. This risk was reduced in a study where azathioprine dosing was reduced in the third trimester [47]. Recommendations are as follows:

If maternal disease dictates, azathioprine can be used during pregnancy but 6-mercaptopurine (the active metabolite) is to be avoided;

Can cause fetal immunosuppression;

Voluntary termination is unnecessary.

Methotrexate

Methotrexate is a folate analogue and antagonist, which reversibly inhibits dihydrofolate reductase (DHFR), an important enzyme in folic acid metabolism. Folates are crucial to purine synthesis, and hence DNA synthesis. Thus, methotrexate and its longer-acting metabolites, methotrexate polyglutamases, cause immunosuppression via inhibition of folate-dependant enzymes.

Methotrexate is widely used in the treatment of rheumatoid arthritis, SLE, psoriasis, juvenile arthritis, leukemias and lymphomas. As such, it poses a potential risk to many women of childbearing age. Of note is its use as an abortifacient [48].

The aminopterin syndrome was first described several years ago after aminopterin (a compound similar in structure to methotrexate) was given to pregnant women between the 4th and 12th gestational week. Fetal malformations in this syndrome include CNS, skeletal and cardiac anomalies. Maternal exposure to low-dose methotrexate resulting in fetal malformations has also been documented. In 1993, Feldkamp suggested that the most vulnerable gestational period is 6–8 weeks and that the threshold dose required to produce defects was 10 mg once-a-week [49]. Donnenfeld used prospective data from 63 centers to support these findings in 1994 [50]. A summary of cases from the literature in 1999 showed that of 42 first-trimester exposures, ten cases of physical abnormalities, including mostly skull and peripheral skeletal defects, were reported [51]. Classical neural tube defects were not seen.

Methotrexate has been found in the liver up to 116 days after exposure. This finding does not appear to be dose related [52], and so there remains a theoretical risk of fetal exposure if methotrexate is taken 4 months prior to conception. Donnenfeld also showed a high rate of spontaneous abortion with maternal exposure to methotrexate within 1 year of pregnancy [50]. The manufacturer's recommendation currently is to avoid conception for 3–6 months following exposure [53]. Avoiding conception for at least 3, preferably 6, months after methotrexate exposure would be prudent. Recommendations are as follows:

Contraindicated in pregnancy;

Ensure contraception on therapy;

Discontinue therapy 3, preferably 6, months prior to conception.

Leflunomide

Leflunomide is a new disease-modifying antirheumatic drug (DMARD) indicated for the treatment of rheumatoid arthritis. It is a pyrimidine synthesis inhibitor that has immunomodulatory effects. Prior to its launch in 1998, the Arthritis Advisory Committee recommended that leflunomide be contraindicated in pregnancy [54] following animal studies that showed dose-related teratogenicity consisting of anophthalmia, hydrocephalus and skeletal malformations in rats and rabbits [55]. Human data are scarce; however, Brent reported teratogenic risks in humans in 2001 [56]. Leflunomide has a sufficiently low molecular weight to cross the placenta, although transplacental passage has not been confirmed.

The active metabolite can take up to 2 years to reach nondetectable plasma levels. Hence the manufacturer advises cholestyramine therapy for 11 days and verification of plasma levels to nondetectable levels on two occasions, 2 weeks apart for women who wish to become pregnant while on leflunomide treatement.

A recent survey by Ostensen (2004) confirms mandatory withdrawal of leflunomide before pregnancy [57]. Recommendations are as follows:

Contraindicated in pregnancy;

Discontinue treatment and systemically eliminate prior to conception.

Other agents Sulfasalazine

Sulfasalazine is a DMARD used in the treatment of rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease. It is metabolized by the colonic bacterial azoreductases to the active compounds sulfapyridine and 5-aminosalycyclic acid. Sulfapyridine readily crosses the placenta to produce fetal concentrations approximating maternal drug levels [58]. Although there is extensive placental transfer, adverse effects have not been decisively linked to sulfasalazine use. Human congenital malformations and neonatal toxicity have not been proven to date, but this a small study [59].

Sulfasalazine has been shown to exhibit adverse effects on spermatogenesis [60]. Recommendation: probably safe for use in pregnancy.

Tumor necrosis factor inhibitors & other biological agents

This class represents the newest group of antirheumatic drugs. Currently, five agents are commercially available, three anti-tumor necrosis factor (TNF) agents, an IL-1 receptor antagonist and a selective costimulation modulator that inhibits T-cell activation. The three TNF antagonists include etanercept, which is a soluble TNF receptor, infliximab, a chimeric human/mouse monoclonal anti-TNF antibody, and adalumimab, a fully human monoclonal antibody against TNF.

TNF is a proinflammatory cytokine and has been implicated in the cytokine-mediated destruction of cartilaginous tissue typical of rheumatoid arthritis. One function of TNFα is to potentiate metalloproteinase gene expression, resulting in collagenolysis.

The TNF inhibitors have been approved for use in patients with rheumatoid arthritis, Crohn's disease, psoriasis and ankylosing spondylitis and they are also being considered for use in a variety of other autoimmune conditions.

Human data is not available on teratogenicity or pregnancy loss for etanercept. Reproduction studies in rats and rabbits have failed to show fetal harm [61].

A study reviewing the infliximab safety database in 2004, looking at 131 women exposed to infliximab before or during pregnancy compared with the general US population of pregnant women with and without connective tissue disease who were not exposed to infliximab, reported that outcomes did not differ between the different groups. No adverse outcomes were noted, although outcome data was only available for 96 of the 131 women receiving infliximab [62]. The study recommended follow-up of larger numbers to exclude fetal risk.

A review of the safety of TNF antagonists in 2004 also stated that at present there is no evidence to implicate increased teratogenicity, embryotoxicity or pregnancy loss [63]. There is now some interest in these agents for use in women with recurrent pregnancy loss, as a successful pregnancy requires immune switching from proinflammatory cytokine production, T-helper (TH)1 to TH2 cytokine production. Recommendation: probably safe but data currently insufficient for definitive guidelines.

Future perspective

Pregnancy may exacerbate or improve a variety of inflammatory disease states. Understanding more about the immunology of pregnancy will eventually lead to a better understanding of the inflammatory mechanisms that result in diseases such as rheumatoid arthritis and SLE.

For the patient with a systemic inflammatory connective tissue disease, maternal disease control is vital for fetal well-being as well as maternal health. Anti-inflammatory drugs may be required to control maternal disease activity during pregnancy and many of these drugs are not safe for use during pregnancy.

Conclusive evidence in the form of sufficiently-powered studies looking at the use of anti-inflammatory drugs in pregnancy is unavailable for most drugs, and it is unlikely that such studies will ever be completed. We therefore have to err on the side of caution.

Although some drugs, such as hydroxycholoroquine and chloroquine, are known to cross the placenta, the current literature suggests that in certain diseases, such as SLE, the benefits of continuing therapy appear to outweigh the risks of disease flare. Hydroxychloroquine is the preferred drug as the tissue deposition of hydroxychloroquine is less than that of chloroquine.

Aspirin and NSAIDs are frequently not considered to be drugs by the lay public, and so are often continued throughout pregnancy. Low-dose aspirin is considered safe for use during pregnancy but NSAIDs and high-dose aspirin should be avoided in the third trimester and preferably around the time of conception. Better education of the lay public is required.

Information resources

A recent more comprehensive review of this topic can be found in Ostensen M, Khamashta M, Lockshin M et al.: Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res. Ther. 8, 209 (2006).

Executive summary

Anti-inflammatory drugs

Aspirin

Safe in low doses, avoid full doses 6–8weeks prior to delivery.

Nonsteroidal anti-inflammatory drugs

Must avoid in third trimester.

Possible association with spontaneous abortions.

Possible rare association with cardiac defects and/or cleft palate.

Avoid selective cyclooxygenase II inhibitors.

Corticosteroids

Prednisone safe.

Fluorinated corticosteroids associated with impaired neurodevelopment and growth retardation.

Small chance of cleft palate if exposed during first trimester.

Anticoagulants

Oral agents

Contraindicated after 6 weeks gestation.

Unfractionated & low-molecular-weight heparins

Safe: low-molecular-weight heparin should be changed to unfractionated heparin at least 2–3days prior to delivery.

Aminoquinoline antimalarial drugs

Hydroxychloroquine & chloroquine

Considered safe, benefits outweigh risk during pregnancy if used in low doses, i.e., preferably hydroxchloroquine 200–400mg.

Hydroxychloroquine is the preferred drug.

Executive summary

Immunomodulating drugs

Cyclosporine A

Potentially immunosuppressive to fetus but not teratogenic.

Mycophenolate mofetil

Insufficient human data for safety. Some reports of teratogenicity in combination with other drugs. Discontinue 6 weeks prior to conception.

Cyclophosphamide

Teratogenic. Contraindicated in pregnancy. Withdraw use 3 months prior to conception.

Antimetabolites

Azathioprine

Can cause fetal immunosuppression. Voluntary termination is unnecessary. Reserve for refractory or life-threatening cases.

6 mercaptopurine, the active metabolite, is to be avoided.

Methotrexate

Contraindicated in pregnancy. Ensure contraception on therapy.

Leflunomide

Contraindicated in pregnancy. Discontinue treatment and systemically eliminate prior to conception.

Other agents

Sulfasalazine

Probably safe.

Tumor necrosis factor & other biological inhibitors

Probably safe. Data currently insufficient for definitive guidelines.

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The Use of Antirheumatic Disease Drugs during Pregnancy

Abstract

Keywords

Anti-inflammatory drugs

Aspirin

Nonsteroidal anti-inflammatory drugs

Corticosteroids

Anticoagulants

The 4-aminoquinoline antimalarial drugs

Hydroxychloroquine & chloroquine

Immunomodulating drugs

Cyclosporine A

Mycophenolate mofetil

Cyclophosphamide

Antimetabolite drugs Azathioprine

Methotrexate

Leflunomide

Other agents Sulfasalazine

Tumor necrosis factor inhibitors & other biological agents

Future perspective

Information resources

References