Anti-inflammatory and immunosuppressive drugs and reproduction

Note

Data on breastfeeding or fertility are presented in the text only when studied in humans. Otherwise the information is given exclusively in the tables. With regard to biological drugs, sufficient data on which to base recommendations exist only for etanercept and infliximab. Other biological drugs are therefore not included in this survey.

NSAID and outcome of pregnancy

A Danish case-control study showed a link between the use of NSAID during pregnancy and miscarriage [2]. Odds ratios ranged from 1.3 for NSAID use 10 to 12 weeks before miscarriage to 7.0 for use 1 week before miscarriage. Potential bias and confounders of the study were the validity of the registry variables, confounding by indication for treatment, and the fact that prescription and not drug consumption had been recorded [3]. A second population-based cohort study including 1,063 women confirmed an increased risk of miscarriage for the use of NSAID (including aspirin) but not of paracetamol during pregnancy [4]. The odds ratio (OR) was 1.8, but increased to 5.6 when taken around conception and to 8.1 when used for more than 1 week. Interference of NSAID with implantation and placental circulation was suspected as the explanation for the findings. By contrast, a meta-analysis of low-dose aspirin during the first trimester did not find an increase in miscarriage [5]. The risk for miscarriage did not differ between women treated with aspirin or placebo (relative risk (RR) 0.92; 95% confidence interval (CI) 0.71 to 119).

By stimulating uterine contractions and enhancing cervical ripening, prostaglandins are important mediators in parturition. Inhibitors of cyclo-oxygenases (COX) can prolong gestation and labour. Indomethacin, aspirin, ibuprofen, sulindac, diclofenac and ketoprofen [6–8] as well as the preferential COX-2 inhibitors nimesulide and meloxicam [8, 9] have been used successfully for the inhibition of premature labour. Similarly, celecoxib has been found to be as effective as indomethacin as a tocolytic agent [10].

Potential mutagenic and teratogenic effects

Effects on the ductus arteriosus

Both COX-1 and COX-2 are expressed in endothelial and smooth muscle cells of the ductus arteriosus [19] and hence the constriction or premature closure of the ductus is a risk with all NSAID. No constriction of the ductus arteriosus occurred in the only human study of 12 pregnancies exposed to celecoxib [10]. Effects on ductal blood flow have been shown for most of the non-selective COX inhibitors occurring as early as 4 hours after administration of the drug [20, 21]. Several studies with fetal echocardiography found an increasing rate of constriction of the ductus arteriosus from 0 before gestational week 27 to 43% in the period 27 to 30 weeks of gestation and 61% between 31 to 34 weeks of gestation during treatment with indomethacin independently of the fetal serum concentration [22–24]. The constriction frequently reversed within 24 to 48 hours after the cessation of therapy. However, several studies have shown a significant association between pulmonary hypertension in newborn infants and antenatal exposure to aspirin, naproxen or ibuprofen in the third trimester. The severity of pulmonary hypertension was dose related [24, 25].

Effects on fetal and neonatal renal function

COX-1 is expressed in renal tubuli and COX-2 in renal medulla [19]. The blockade of prostaglandin synthesis by NSAID and the decreased activation of prostaglandin receptors cause reduced renal perfusion and oligo-hydramnios. Adverse effects on fetal renal function have been reported for non-selective and selective COX inhibitors [24, 26–28]. A marked decline in fetal urine output has been observed within 5 hours of indomethacin ingestion, and oligohydramnios developed in 70 to 82% of pregnancies during the first week of treatment, but disappeared after discontinuation of the drug. Development of oligohydramnios has been shown to be dose dependent [26]. Short-term treatment with celecoxib reduced fetal urine production, but less than indomethacin [10]. Transient anuria, but also fatal persistent anuria and irreversible end-stage renal failure, has been reported in newborn infants exposed to indomethacin or nimesulide [27–29].

Other fetal/neonatal effects

High-dose aspirin and indomethacin given close to delivery have been shown to cause bleeding tendencies and haemorrhage in the central nervous system in the newborn infant [24, 30]. Clotting abnormalities have also been detected in newborn infants exposed to 325 to 650 mg of aspirin within 1 week before delivery [15].

Low-dose aspirin (LDA)

Adverse effects of LDA (less than 325 mg/day) on pregnancy outcome were studied in a meta-analysis [5]. Women who took aspirin had a significantly lower risk of preterm delivery than did those treated with placebo (RR 0.92; 95% CI 0.86 to 0.98). There was no significant difference in perinatal mortality (RR 0.92; 95% CI 0.81 to 1.05) and in the rate of small-for-gestational-age infants (12 studies; RR 0.96; 95% CI 0.87 to 1.07) among offspring of mothers treated with aspirin and those of mothers treated with a placebo [5]. More than 10,000 pregnancies exposed to aspirin at 60 to 80 mg/day during the second and third trimester up to term have been reported without any increase in impaired renal function, pulmonary hypertension or clotting ability of the newborn infant [31]. Doppler investigation of fetuses aged 15 to 40 weeks exposed to 60 mg of aspirin daily during the second and third trimesters did not reveal any effect on the ductus arteriosus [32]. One study found that LDA (less than 100 mg) given to the mother could suppress platelet thromboxane A₂ formation in the newborn infant that recovered within 2 days after discontinuation of the drug [33]. There are some reports on epidural haematoma in patients who, while on LDA, underwent epidural anaesthesia; however, prospective studies have not found an increased risk for this complication [34].

Effects of NSAID on fertility

COX-1 and COX-2 are involved in ovulation and implantation [34, 35]. Several case reports and small series have described transient infertility after treatment with non-aspirin NSAIDs such as indomethacin, diclofenac, piroxicam and naproxen [36–38]. Studies in animals and humans have shown that NSAID can inhibit the rupture of the luteinized follicle and thereby cause transient infertility. A prospective, randomized trial of ibuprofen in 12 women detected a delay of 2 days or more in follicle rupture in a small number of treated women [38]. However, no alterations of serum progesterone or luteinizing hormone levels were observed. In a study of 13 healthy women, 6 of whom were given the selective COX-2 inhibitor rofecoxib, delayed follicle rupture was observed in 4 of them [39].

A study of men attending an infertility clinic found a decrease in sperm count and quality in non-prescription, chronic users of NSAID (mostly aspirin) at low or moderate doses [40].

Breastfeeding

Most NSAID are excreted in very small quantities into human breast milk [41, 42]. The American Academy of Pediatrics (AAP) considers flufenamic acid, ibuprofen, indomethacin, diclofenac, mefenamic acid, naproxen, piroxicam and tolmetin to be compatible with breastfeeding [43]. Aspirin at more than 100 mg/day should be used cautiously because of potential adverse effects in the nursing infant [43]. Feeding immediately before a dose can help to minimize infant exposure to NSAID.

Conclusion and recommendation Tables (1 and 2)

Conclusion and recommendation

Side effects with special relevance to pregnancy

Corticosteroid side effects in pregnant women include all that are present in non-pregnant subjects taking corticosteroids. Side effects such as increased blood pressure, osteopenia, osteonecrosis and susceptibility to infection are of special relevance in pregnancy. Pregnancy induces insulin resistance at later stages, and the resulting glucose intolerance is further enhanced by exogenous glucocorticoids with an increased risk of gestational diabetes. Pregnancy-specific complications are premature rupture of the membranes, frequently reported in corticosteroid-treated patients with systemic lupus erythematosus (SLE) and in one controlled study comparing treatment with corticosteroids with treatment with heparin in pregnant antiphospholipid-antibody-positive patients [54].

Potential mutagenic and teratogenic effects

Hydrocortisone produces dose-related teratogenic and toxic effects in genetically susceptible experimental animals, with increased rates of cleft palate, cataract, fetal loss and fetal growth restriction [55, 56].

In the human, results from case-control and prospective studies indicate that exposure to hydrocortisone and prednisone during the first trimester can lead to a small increase in oral clefts [57–61]. A meta-analysis found a 3.3-fold increased OR of oral clefts after first-trimester exposure to corticosteroids [62]. Similar results were reported by the Spanish Collaborative Study of Congenital Malformations [57] and by two additional studies [59, 61], but a reporting bias might exist because several large studies found no statistically increased rate of oral clefts [60, 63]. Available data do not allow a conclusion to be drawn about the specific oral cleft phenotype associated with glucocorticoid exposure in humans (cleft lip, cleft palate or both). Since oral clefts occur at about 1:1,000 births in the general population, the possible increase to 3 or 4 for every 1,000 births after embryonic exposure to corticosteroids is minimal [62]. On the whole, corticosteroids do not seem to increase the risk of congenital abnormalities noticeably in humans.

The influence of corticosteroids on intrauterine growth has been controversial. Some authors have demonstrated an increased incidence of low-birthweight babies in mothers on corticosteroids [56, 64], whereas others have not [65]. Infections in newborn infants after antepartum exposure to corticosteroids occur rather infrequently [66] and maternal corticosteroid therapy does not induce general immuno-suppression in the newborn infant [67]. The possible induction of hypertension in adult life by antenatal exposure to corticosteroids has not been proven in humans [68]. Other rare adverse events reported for antenatal exposure to corticosteroids are neonatal cataract [69] and adrenal suppression in children born to women taking high doses of steroids during pregnancy [70, 71].

Antenatal exposure to synthetic fluorinated corticosteroids betamethasone and dexamethasone

A single course of fluorinated corticosteroids (betamethasone or dexamethasone, 24 mg) to pregnant women at risk for preterm delivery, between 24 and 34 weeks of gestational age, clearly reduced the risk of death, respiratory distress syndrome and cerebral haemorrhage in their preterm infants [72]. In the meantime, however, evidence has accumulated on the potential harm of repeated courses of steroids for the mother and the fetus. Findings in animals widely suggest that repeated antenatal steroid doses can interfere with the growth and development of the immature brain [73, 74], and observations on humans suggest that antenatal and postnatal dexamethasone may negatively affect the child's neuro-psychological development [75–78]. In view of this concern, a further NIH consensus conference in 2000 confirmed the previous statement of the advantages of one course of antenatal corticosteroids but also made it clear that, in view of their potential hazard, repeated courses should not be given routinely but be reserved for patients in randomized controlled clinical trials [79].

The possible negative effects seem linked more to dexamethasone than to betamethasone [80]. In addition, a separate meta-analysis of the data in the Cochrane review showed that only betamethasone, and not dexamethasone, significantly reduces neonatal mortality [81]. For these two reasons it has been suggested that betamethasone should be preferred when available [82]. Adverse effects on neuropsychological development in children have not been observed after exposure to steroids that are inactivated by placental enzymes [83].

Breastfeeding

Only trace amounts of hydrocortisone are excreted into human breast milk [84]. In six lactating women, prednisolone doses of 10 to 80 mg/day resulted in milk concentrations ranging from 5% to 25% of maternal serum levels [85]. Even at a maternal dose of 80 mg/day, the nursing infant would ingest only 10 μg/kg which corresponds to <10% of the infant's endogenous cortisol production. No data are available for dexamethasone or betamethasone in lactating women [43].

Conclusion and recommendation Tables (1 and 2)

Potential mutagenic and teratogenic effects

CQ was embryotoxic and fetotoxic in high doses (250 to 1,500 mg/kg) in experimental animals. Eye malformations occurred in 45% of animals at 1,000 mg/kg [92]. CQ accumulated preferentially in melanin-containing structures in the fetal uveal tract and inner ear when given during pregnancy [92].

CQ and HCQ cross the placenta with no significant difference in the mean concentration in maternal and cord blood [93]. Weekly malaria prophylaxis with 300 mg of CQ throughout gestation did not increase the congenital malformation rate [94]. In the rheumatism literature, reports on several hundred pregnancies exposed to CQ 250 mg daily or HCQ 200 to 400 mg daily during the first trimester did not find an increase in congenital malformations or cardiac conduction disturbances in children exposed antenatally to antimalarials [88, 95–100]. Malformations of the inner ear and other abnormalities after treatment with higher than the recommended dose of CQ throughout pregnancy were reported after intrauterine exposure to 500 mg daily of CQ in three siblings born to a mother with SLE [101]. HCQ has not been associated with congenital malformations.

Breastfeeding

Three studies examined the presence of CQ after the administration of single doses (5 mg/kg and 600 mg) in lactating women [100, 102]. Daily ingestion of CQ by a nursing child was calculated as 2.2 to 4.2% of the maternal dose. Two case reports measured the secretion of HCQ during lactation and found 0.35% and 0.0005% of the maternal dose in human breast milk [103, 104].

Long-term effects in children

Several studies have investigated long-term effects in children exposed in utero or during lactation to HCQ. No decrease in visual acuity, visual field or colour vision, or alterations in electroretinogram and electro-oculogram or hearing impairment, were detected in children studied during the first year of life or up to 4 years of age [105–108]. A case-control study of 133 pregnancies exposed to HCQ found no visual, hearing, growth or developmental abnormalities in children followed up for 108 months. Electrocardiograms of exposed children were normal [99].

Conclusion and recommendation Tables (3 and 4)

Potential mutagenic and teratogenic effects

Reproduction studies with SSZ in rats and rabbits at doses up to six times the human dose have not shown impaired female fertility or harm to the fetus.

A population-based case-control study demonstrated no significant increase in selected congenital abnormalities in the children of women treated with SSZ during pregnancy [109]. A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In 186 pregnancies of women treated with SSZ alone or with concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable both with that of 245 untreated IBD pregnancies and with pregnancies in the general population [110]. Additional studies of pregnancies in women with IBD confirmed these results [111–114]. There have been isolated reports on children born with congenital malformations to mothers treated with SSZ during pregnancy [115]. A study comparing fertility rates and fetal abnormalities of patients with IBD with the general population found a higher rate of malformations among offspring (particularly of men) in patients treated with SSZ [115]. Because SSZ inhibits the gastrointestinal and cellular uptake of folate, a possible role of folate deficiency cannot be ruled out [116].

Some experts have advised the cessation of SSZ in the last trimester, fearing it could displace bilirubin from albumin and thus induce neonatal pathological jaundice. Yet the bilirubin-displacing capacity of sulphapyridine and SSZ at the low concentrations measured in cord blood is negligible [117]. Kernicterus in the newborn infant after exposure to SSZ in utero has not been reported. Aplastic anaemia was found in an aborted fetus exposed during the first trimester to SSZ [118], and another case reported congenital severe neutropenia in an infant whose mother was taking 3 g of SSZ daily throughout pregnancy [119].

Breastfeeding

Insignificant amounts of uncleaved SSZ have been found in milk, whereas the sulphapyridine levels in milk were about 30 to 60% of those in maternal serum [120]. Diarrhoea and rash were reported in a breastfed infant whose mother was receiving SSZ [121]. Exposure to sulphonamides through breast milk apparently does not pose a significant risk for the healthy, full-term newborn infant, but it should be avoided in ill, stressed or premature infants and in infants with hyper-bilirubinaemia or glucose-6-phosphate dehydrogenase deficiency [43].

Fertility

SSZ does not impair fertility in women. Treatment with SSZ leads to oligospermia, reduced sperm motility, an increased proportion of abnormal forms, and infertility in men and rats [122]. The effect is due to sulphapyridine and cannot be abrogated by folate supplementation. Spermatogenesis recovers at about 2 months after withdrawal of the drug [122].

Conclusion and recommendation Tables (3 and 4)

Potential mutagenic and teratogenic effect

Leflunomide given to pregnant rats and rabbits in doses equivalent to human doses induced malformations of the skeleton and central nervous system in the offspring. Prenatal exposure to about 1% of the human dose resulted in decreased birthweight and increased perinatal mortality in the offspring [123].

In a retrospective study, 10 pregnancies occurred in RA patients treated with leflunomide. No congenital malformation occurred in the five pregnancies with known outcome [124]. An unpublished safety update of the manufacturer in September 2004 reported 428 exposures during pregnancy, with known outcome for 165 pregnancies. Twenty-one pregnancies occurred while the male partner was receiving leflunomide. Termination was performed in 44 cases, miscarriage occurred in 36 cases and 85 pregnancies went to term. Congenital malformations occurred in seven children. A Canadian prospective cohort study is currently in progress to investigate possible fetal and neonatal side effects of leflunomide exposure during pregnancy. At present, the study includes a total of 246 pregnancies with known outcome. No significant differences between exposed and non-exposed pregnancies were noted with regard to spontaneous abortion or major structural defects in newborn infants.

Conclusions and recommendations Tables (3 and 4)

Potential mutagenic and teratogenic effect

The fetal liver lacks the enzyme inosinatopyrophosphorylase, which converts azathioprine to its active form and therefore should be theoretically protected from azathioprine crossing the placenta [125].

Azathioprine injected intraperitoneally in doses equivalent to 4 to 13 times the therapeutic human dose caused skeletal defects and multiple malformations in mice and rabbits exposed during gestation [125]. In rodents exposed in utero to 1 to 62.5 times the human dose of 6-MP, cleft palate, dilatation of cerebral ventricles and hydrocephalus were observed. Female and male offspring of mice receiving 6-MP in pregnancy had a decreased number of germ cells in the gonads, with resulting decreased fertility [126].

Studies in pregnant transplant recipients receiving azathioprine and prednisone and in pregnant patients treated for IBD with azathioprine or 6MP showed no increase in pregnancy complications or congenital malformations [127–129]. Intrauterine growth restriction has been reported in 40% of renal graft recipient mothers taking both cortico-steroids and azathioprine [64]. Anecdotal experience has associated prenatal exposure to azathioprine with different congenital anomalies, but none of them were clearly linked to the drug. Other reported events after antenatal exposure to azathioprine were transient chromosomal anomalies in clinically normal infants [130], transient lymphopenia [130, 131], severe immune deficiency and cytomegalovirus infection [131], and depressed haematopoiesis in infants whose mothers were treated with more than 2 mg/kg azathioprine daily [132].

One group reported an increased incidence of spontaneous abortions and congenital malformations in pregnancies fathered by 13 men treated with 6-MP for IBD at conception or in the 3 months previously [133]. However, it is uncertain whether the control group of untreated IBD male patients was comparable. In addition the overall rate of congenital malformations was within the baseline incidence. Another study did not find any increase in adverse outcomes in men and women treated for IBD with 6-MP before or during the first trimester [134].

Breastfeeding

Azathioprine and its metabolites were found in milk, exposing the child to 0.1% of the maternal dose [135]. Nine children were nursed without side effects.

Fertility

Azathioprine does not adversely affect the fertility of women. A recent study in men found semen quality and quantity to be normal despite long-term treatment with azathioprine [136].

Long-term effects in offspring

Postnatal enhancement of T cell maturation, but otherwise normal immunological development, was detected in children exposed to azathioprine in utero [137]. A recent case report found the development of autoimmunity in a daughter of a patient with SLE who had received azathioprine during pregnancy and regarded this as a possible long-term effect of exposure in utero [138]. However, a genetic predisposition as the cause of the daughter's SLE cannot be ruled out.

Conclusion and recommendations Tables (3 and 4)

Potential mutagenic and teratogenic effect

MTX is a methyl derivative of the folate antagonist aminopterin. Active metabolites of MTX remain in cells or tissues for several months after the cessation of therapy [139]. Closure of the neural tube takes place during week 5; the embryo is therefore 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 ossification, the limbs and the palate and growth retardation [140–142].

Experience with MTX in human pregnancy has been derived mainly from patients treated for cancer with multiagent therapy or when MTX or aminopterin was used unsuccessfully as an abortifacient to terminate a pregnancy [143, 144]. In most of these reports, doses of MTX exceeded the low-dose weekly pulses (5 to 20 mg) applied in rheumatology. Three infants exposed to MTX during the first trimester had multiple cranial anomalies [143–145]. Chromosomal aberrations were detected in a healthy newborn infant exposed to MTX and other cytotoxic drugs during pregnancy [144]. In seven cases, MTX had been given during the second and third trimester; six normal children were born and one child had pancytopenia [145].

Reviewing the rheumatology literature of first-trimester exposure to once-weekly doses of 20 mg of MTX or less, disclosed 63 pregnancies [124, 146–151]. In the pregnancies not terminated electively, 11 (17%) ended in miscarriage, and of the 33 that proceeded to delivery, four children (12%) had congenital anomalies, including one child with multiple skeletal abnormalities [149]. Birthweights of the full-term infants were within normal range. Previous treatment of women with MTX has no harmful effect on subsequent pregnancy outcomes [152, 153]. So far there are no reports of adverse pregnancy outcomes among men exposed to MTX before conception [154].

Breastfeeding

MTX is excreted into breast milk in low concentrations, with a milk:plasma ratio of 0.08 [155]. The significance of this small amount for the nursing child is unknown.

Fertility

MTX does not impair female fertility. There is no indication that monotherapy with MTX induces infertility in men [156], although a case report has described oligospermia in a male patient treated with MTX for psoriasis [157].

Long-term effects in children

A follow-up study of children exposed antenatally to cytotoxic drugs including MTX showed physical, neurological, psychological, haematological, immune function and cytogenetics to be normal after 3 to 19 years [158]. A follow-up ranging from 0.1 to 16.7 years of an additional seven children revealed no developmental or other serious health problems [146].

Conclusions and recommendations Tables (3 and 4)

Potential mutagenic and teratogenic effect

CYC is teratogenic in all animal species studied, including mice, rats, rabbits and monkeys [159]. Abnormalities induced in animals by specific dose ranges and at specific periods of gestation showed a rather consistent pattern of brain malformation, defective limbs and facial abnormalities.

CYC has an unpredictable effect on the human fetus because it does not always cause malformations when given during the first trimester [160–163]. CYC embryopathy has been reported in nine cases, including defects of the calvaria, anomalies of craniofacial structures, ears and limbs, visceral organs, growth retardation and developmental delay during childhood [160–168]. CYC given in the second and third trimester does not result in structural abnormalities but it may cause growth restriction, impair neurological development and suppress haematopoiesis in the infant [164, 169]. Therapy with CYC completed before pregnancy does not increase the rate of miscarriage or congenital abnormalities in offspring [170].

Little information is available about the outcome of children born to men taking CYC. Isolated reports of congenital abnormalities have been associated with paternal use of CYC, but a direct relationship is difficult to prove [171].

Breastfeeding

CYC is excreted into human breast milk [172]. Suppression of haematopoiesis has been reported in a breastfed infant nursed by a mother who received CYC [169].

Fertility

CYC is gonadotoxic in both women and men, depending on the cumulative dose and the age of the patient. Impairment of fertility follows both daily oral and intermittent pulse therapy [173]. In women, sustained amenorrhoea after a total dose of 3.5 to 7 g of CYC was rare under the age of 25 years, increased to 12% for patients aged 26 to 30 years and to 25% for patients aged 31 years or older [174]. Women older than 32 years have a substantial risk for amenorrhoea at 8 g/m², which increases to sustained amenorrhoea for 90% of women at 12 g/m² [175]. In men, gonadotoxicity of CYC is present even before puberty [176]. There is no safe threshold of the cumulative dose, and it is not possible to predict which patients will become sterile and which will recover testicular function [177].

Preservation of gonadal function during CYC therapy in women is best done by concomitant treatment with a gonadotrophin-releasing hormone agonist, as a case-control study has shown [178]. Cryopreservation of sperm and sperm banking is the method of choice in men who have no children or have not completed their families.

Long-term effects in children

A case of a papillary thyroid cancer at the age of 11 years and a neuroblastoma at age 14 years in a male twin exposed to CYC in utero has been reported. The female twin was unaffected [164]. A population-based study did not find any increase in chromosomal abnormalities in offspring of childhood cancer survivors in Denmark treated with cytotoxic drugs including CYC, nor an increase in Down syndrome or Turner syndrome [179].

Conclusion and recommendation Tables (3 and 4)

Potential mutagenic and teratogenic effect

CsA was not toxic to the exposed fetuses at the maternal dosage of 10 mg/kg per day, whereas it was embryotoxic at dosages of 25 to 100 mg/kg per day [180].

More than 800 pregnancies receiving CsA have been reported, mainly in transplant recipients [181–185]. 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 newborn infants exposed to CsA in utero [186]. A meta-analysis evaluated the risk of congenital malformations, preterm delivery or low birthweight from CsA treatment during pregnancy [187]. The calculated OR of 3.83 for malformations did not achieve statistical significance. The overall prevalence of 4.1% of malformations in the study population did not vary substantially from that reported in the general population. The OR for prematurity did not reach statistical significance, although the overall prevalence rate was 56.3%. It is not clear whether maternal therapy with CsA or the underlying maternal disease was associated with increased rates of prematurity and low birthweight (less than 2,500 g).

Breastfeeding

Small amounts of CsA are excreted in breast milk. Successful breastfeeding without side effects has been reported in 15 children [188].

Long-term follow-up of children

Follow-up for 1 to 12 years of 175 children registered in the National Transplantation Pregnancy Register (USA) found normal development in 84% of offspring exposed to CsA in utero [189]. The high incidence of prematurity was suspected to be involved in the mental developmental delay observed in 16% of the children. Because CsA can induce autoimmunity in rodents after exposure in utero, several studies have addressed this issue in children of transplant recipients. The maturation and development of T cells, B cells and NK cells can be impaired during the first year of life [137], and transient B cell depletion has been described in several infants [190]. A case-control study of the immune function of children born to mothers with connective tissue diseases found normal blood cell counts, immunoglobulin levels and lymphocyte subpopulations in offspring of mothers treated with immunosuppressive drugs (including CsA) [191]. All children responded satisfactorily to hepatitis B vaccination. A paediatric follow-up ranging from 3 months to 11 years of age found three cases with long-term developmental difficulties, but no learning disability (mental retardation) among 31 children exposed to CsA during pregnancy [192].

Conclusion and recommendation Tables (3 and 4)

Tacrolimus

Breastfeeding

According to one case report, only 0.02% of the mother's dose of tacrolimus is transmitted to the breastfed baby [197].

Conclusion and recommendation Tables (3 and 4)

Potential mutagenic and teratogenic effect

Treatment of pregnant rats and rabbits with 30 to 50% of the human dose has resulted in birth defects in the offspring, comprising the central nervous system, cardiovascular and renal system [198].

No controlled studies on pregnancy during treatment with MMF are available, but data exist in drug company files (Roche Pharma, safety update). By April 2005, 119 pregnancies under maternal treatment with MMF had been reported; however, the outcome is known for only 76 of these. Twenty miscarriages and 13 terminations of pregnancy were reported. Twenty-two deliveries resulted in healthy newborn infants. Abnormalities at birth were observed in 10 newborn infants, yet a causative role for MMF could not be established. Sixty-nine pregnancies occurred after paternal exposure, with a known outcome for 45 of these. Six congenital anomalies such as foot malformation, hand malformation, bladder anomaly and chromosomal abnormality were reported; 36 newborn infants were healthy.

Two newborn infants with structural congenital anomalies were reported from the National Transplantation Pregnancy Registry after in utero exposure to MMF [199, 200]. One child had hypoplastic nails and short fifth fingers, normal chromosomes, and normal growth and development [199]. A terminated pregnancy of a patient treated with MMF before conception and during the first trimester of pregnancy disclosed multiple fetal malformations, specifically facial dysmorphology and midline anomalies, including agenesis of the corpus callosum [198].

Conclusion and recommendation Tables (3 and 4)

Conclusion and recommendation Tables (3 and 4)

Etanercept

Infliximab