Immunosuppression, rheumatic diseases, multiple sclerosis, and Wilson’s disease

Cyclosporine

The calcineurin inhibitor, ciclosporine or cyclosporine A (CyA) is among the well-studied immunosuppressants. CyA was first approved for use in organ transplant patients and is, meanwhile, also used for severe courses of some autoimmune diseases. Some 30–64% of the maternal concentration of the substance can reach the fetus.

Experience of a large number of case reports and series, and from the transplantation registries ( , , ) have not revealed teratogenic risk. Intrauterine growth retardation, a higher rate of caesarean deliveries, prematurity and increased maternal complications, such as, for instance, hypertension and preeclampsia have been described ( ); however, these adverse outcomes might well be a consequence of maternal illness. In two case series, no effects on the infant immune system were found in children of mothers with autoimmune diseases and immunosuppressive therapy during pregnancy ( , ). This is in line with the findings of earlier studies (e.g. ). A hepatoblastoma in a 2-year-old child is the only case described of a malignancy after continuous maternal treatment ( ).

In a cohort study, in which 39 intrauterine CyA-exposed children were compared with non-exposed children with respect to possible long-term effects, no differences in intelligence, visual motor abilities and behavior could be determined ( ).

Mycophenolate (MMF)

The selective immunosuppressants mycophenolate mofetil and mycophenolic acid are used after organ transplants, for rheumatoid arthritis and for systemic lupus erythematosus (SLE). Mycophenolate mofetil is quickly absorbed after oral intake and rapidly changed into its active metabolite, mycophenolic acid. The metabolite has a mean half-life of 12–16 hours and it appears to cross the placenta ( ).

MMF is the most recently recognized human teratogen. The specific pattern of birth defects consists of malformations of the ear, in particular, microtia and atresia of the external ear, cleft lip, and other malformations such as tracheal-esophageal atresia ( ) or heart defects ( ).

The experiences with pregnancy are based on transplantation registries ( , ), the manufacturer’s (Roche) database (77 pregnancies) and retrospective case reports, which describe 20 children or fetuses with a distinct pattern of malformations (e.g. ). Some of these pregnancies were also recorded by the Roche database or the transplantation registry. In a study by the European Network of Teratology Information Services (ENTIS), 57 prospectively ascertained pregnancies with maternal MMF treatment were evaluated: a spontaneous abortion risk of about 45% and an increased risk for major birth defects of 26% were observed, of which at least four fetuses/infants had a clinical phenotype consistent with mycophenolate embryopathy ( ).

Paternal exposure: An evaluation of the National Transplantation Pregnancy Registry could identify 152 male transplant recipients with MMF therapy who fathered 205 pregnancies. There was neither an increased rate of major birth defects nor a distinct pattern of anomalies ( ).

Tacrolimus

Tacrolimus ( FK-506 ) is a macrolide obtained from Streptomyces, which is used orally as an immunosuppressant after organ transplantation or locally for skin diseases ( Chapter 2.17 ). It crosses the placenta with in utero exposure being approximately 71% of maternal blood concentrations. Its pharmacokinetic is altered during pregnancy. Due to decreased albumin level during pregnancy unbound tacrolimus concentration increases (e.g. ).

The experience in pregnancy rests on retrospective case reports (e.g. , ), case series and studies (e.g. , , ), including a small prospective study with 49 children of 37 mothers with liver transplants ( ), and on the National Transplantation Registry established in 1991 by the drug manufacturers ( ). Altogether, more than 250 pregnancies with tacrolimus have been documented, from which no teratogenic risk can be deduced. The malformations observed up to now do not occur frequently, and there is no recognizable pattern.

As with therapy with other immunosuppressants, preeclampsia, premature births, lower birth weights and caesarean sections have been observed more frequently; however, these adverse outcomes might well be a consequence of maternal disease. Gestational diabetes appears to occur more frequently with tacrolimus, and newborns with decreased kidney function and hyperkalemia have been described frequently (e.g. ). A case of anuria which continued for 36 hours was the gravest finding ( ).

Further selective immunosuppressants

Everolimus is a derivative of sirolimus and is used in transplant patients, and in higher doses, as an antineoplastic drug. There are only a few documented case reports on its use during pregnancy, all with favorable outcome ( , , ).

Sirolimus inhibits the T-cell proliferation via another mechanism in comparison with cyclosporine or tacrolimus. More than 10 case reports give no indications of any teratogenicity (e.g. , , , ).

Paternal exposure: There is evidence that sirolimus can lead to oligospermia, which was reversible in some patients after ceasing the therapy ( , ).

There is no documented experience for the selective calcineurin inhibitor pimecrolimus during pregnancy. After dermal use, no relevant systemic concentrations are expected, and thus effects on the expected child appear unlikely ( Chapter 2.17 ).

Adalimumab

Adalimumab (ADA), a fully human monoclonal IgG1-antibody and tumor necrosis factor α-(TNF α-) blocker with a half-life of 14 days, is used in severe forms of rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriasis-arthritis or Crohn’s disease, as a rule after failure of established immunosuppressants.

In total, approximately 270 pregnancies (abstracts included) exposed during the first trimester are published in case reports (e.g. ), case series (e.g. , , ), a small study on 83 anti-TNF-α-exposed pregnancies of which 23 were adalimumab exposed ( ), and a study currently conducted by the North American Teratology Centers (OTIS, Organization of Teratology Information Specialists) for which an interim report on 161 pregnancies is available ( ). Even though malformations were described in a few pregnancies, there is no distinct pattern.

The high molecular weight of 148,000 Da makes placental transfer during embryogenesis unlikely. Nevertheless, through an active process, there is an increasing transfer of the monoclonal antibody by the mature placenta after the twentieth week of pregnancy. Because TNF-α plays an important role in the development of the fetal immune system, there are theoretical concerns about its use, especially in the late second and third trimester. Thirty-five pregnancy courses to date on continuous adalimumab therapy, or on treatment in the second half of the pregnancy, have shown that therapeutic concentrations can be reached in the newborn ( , , ). determined the cord blood concentrations in 13 pregnancies in which ADA therapy already ended before gestational week 30. In only 5 out of 13 samples ADA was detected in cord blood. The median ratio of infant’s ADA drug level to mother’s was 179% (range 98–293%) ( ).

The experience with a longer follow-up period after therapy in late pregnancy is considerably sparser (e.g. , , ). Up to now, there is only one case reporting adverse effects on the infant immune system after maternal TNF-inhibitor therapy. reported on a boy born healthy, whose mother was treated for Crohn’s disease throughout pregnancy with infliximab. At the age of 3 months, he received a BCG live vaccine, which led to a disseminated BCG infection and ultimately to the child’s death. On the contrary, a recently published case report of a 3-month-old preterm infant with chicken pox who fully recovered is reassuring ( ). His mother received ADA until gestational week 34 and went into labor 2 days later.

Paternal exposure : Six pregnancies fathered by men on adalimumab with apparent favorable pregnancy outcome were reported by .

Certolizumab pegol

Certolizumab pegol (CZP) is a pegylated (polyethylene glycol) antigen-binding fragment (Fab) of a recombinant humanized anti-TNF-α monoclonal antibody, which is approved for severe courses of rheumatoid arthritis (in some countries only together with MTX) and by the FDA also for Crohn’s disease. Its half-life is 14 days. The molecular structure of CTZ is different from infliximab (IFX) and ADA. It lacks an Fc portion which among others is necessary for an active transport across the placenta.

Experience during the first trimester is limited to less than 20 published pregnancies which did not indicate a teratogenic risk as yet (e.g. review by ). In addition, 59 pregnancies were reported from clinical trial reports and 82 from spontaneous post-marketing reports. According to an analysis by the manufacturer, no particular fetal risks have been reported; however, data quality does not seem to be high ( ).

CZP has a low placental transfer which was shown by . Ten mothers of 12 infants (including twins) had received their last CZP dose in median 19 days before delivery. The median ratio of cord blood to maternal drug concentration was 3.9% (range 1.5–24%). The mechanism of transfer is not yet known.

Etanercept

Etanercept is approved for treatment of moderately severe to severe courses of rheumatoid arthritis, with or without methotrexate, as well as for psoriasis-arthritis, plaque-psoriasis, Bechterew’s disease (ankylosing spondylitis) and juvenile idiopathic arthritis, following insufficient response to the usual basic therapeutics. It is a functionally soluble TNF-α-inhibitor, a fusion protein, consisting of a portion of the human TNF-receptor and the Fc domain of human IgG1, which among others, leads to a placental transfer. It has a half-life of about 70 hours.

Meanwhile, published experience covers more than 300 pregnancies. However, most data come from abstracts (e.g. ), posters ( ), case descriptions (e.g. , ), case series (e.g. ) or registries ( , ). Most of the children described here were exposed in the first trimester and born healthy.

Preliminary results of an OTIS study of 139 pregnancies exposed in the first trimester were published as poster ( ). A higher number of malformations than expected was observed, but the malformations were heterogeneous. Confounders such as co-medication, e.g. methotrexate, have not been considered in the preliminary findings. A small cohort study on 83 anti-TNF-α-exposed pregnancies among them 25 with etanercept, did not find an increased malformation risk ( ). An evaluation of the British Society for Rheumatology Biologics Register included 71 prospectively recorded pregnancies with anti-TNF therapy, among them 48 with etanercept, nine with infliximab and 14 with adalimumab, and revealed a 27% miscarriage rate. Even if only pregnancies without MTX as a co-medication were considered, the miscarriage rate remained high. However, the total number of pregnancies evaluated was small, the group of drugs was heterogeneous and the results have not been confirmed by other studies up to now ( ). Furthermore, since TNF-α can play an important role in causing spontaneous abortions, the TNF-α inhibitors adalimumab or etanercept were used in patients with IVF treatment or recurrent miscarriage ( , ). Thereby, no negative effects on the pregnancy were observed. This also argues against an increased spontaneous abortion rate after etanercept therapy.

A report ( ) on a child with VACTERL syndrome (V: vertebral defects; A: anal atresia; C: cardiac anomalies; T: tracheal-esophageal fistula; E: esophageal atresia; R: radial and renal problems; L: limb anomalies) following continuous intrauterine exposure has led to discussion. However, there are no further comparable observations after etanercept treatment. Also the analysis of the FDA data base ( ) was unable to turn up any additional children with a VACTERL syndrome among the 22 retrospectively recorded pregnancies with anomalies. However, the authors assessed isolated malformations, such as septal heart defects as part of the VACTERL syndrome. Furthermore, this publication has grave methodological shortcomings in that, for instance, the respective exposure periods were not mentioned.

With continuous treatment, etanercept crosses the placenta in limited amounts as indicated through simultaneous measurements in the mother’s blood and the cord blood. In the cord blood 1/30 ( ) and 1/14 ( ) of the maternal concentration was found. The experience of use in later pregnancy is very limited, with fewer than 20 cases, but does not indicate any negative effects on the newborn (e.g. ).

Paternal exposure: Forty pregnancies fathered by men on etanercept with mostly favorable outcomes were reported ( ). Among those was one child with a septal heart defect and penoscrotal malformation.

Infliximab

Infliximab (IFX) is a TNF-α inhibitor and full IgG1-antibody which is approved for severe cases of rheumatoid arthritis, together with methotrexate, for pronounced psoriasis and psoriasis-arthritis, ankylosing spondylitis as well as for chronic inflammatory bowel disease. It has an average terminal half-life of about 9 days, and is still detectable to some extent in the serum after 12 weeks, and in steady-state, is infused every 6 to 8 weeks.

The approximately 500 pregnancy courses after treatment in the first trimester come from registries ( , ), case series (e.g. , ), case reports (e.g. ) and a small prospective cohort study among which were 35 infliximab exposed pregnancies ( ). Up to now, there are no larger controlled studies. No teratogenicity has been observed as yet.

The high molecular weight of 144,200 Da makes placental transfer during embryogenesis unlikely. Nevertheless, through an active process, there is an increasing transfer of the monoclonal antibody by the mature placenta after the twentieth week of pregnancy. Because TNF-α plays an important role in the development of the fetal immune system, there are theoretical concerns about its use, especially in the late second and the third trimester. The few publications to date on continuous therapy or on treatment in the second half of the pregnancy, have shown that therapeutic concentrations can be reached in the newborn ( , ). determined the cord blood concentrations in 18 cases. In most of these cases, IFX therapy ended before gestational week 30. The mean IFX cord levels were significantly lower when the treatment had been stopped 10 weeks or more before delivery. The median ratio of infant’s IFX drug level to mother’s was 160% (range 87–400%) ( ). In one infant, a slow postpartum clearance was documented with measurable levels up to 6 months of age. This argues for an increased half-life in fetuses, neonates and young infants. Antibodies against IFX, which about 60% of the patients in treatment develop, were not observed in this child at the age of 6 months ( ). There is currently only one case reporting adverse effects of the infant immune system after maternal IFX. As has been noted previously, reported on a boy born healthy, whose mother was treated for Crohn’s disease throughout pregnancy with IFX. At the age of 3 months, he received a BCG live vaccine, which led to a disseminated BCG infection and ultimately to the child’s death. However, a recently published case report of a 3-month-old preterm infant with chicken pox who fully recovered is reassuring ( ). His mother had received ADA until gestational week 34 and went into labor 2 days later.

Paternal exposure: In two small case series/case reports, changes of form and motility of the sperm were described after the father’s infliximab therapy ( , ). However, a comparative analysis of semen samples of 26 men on TNF-antagonists and healthy volunteers, showed no significant impairment in the patients with inactive disease receiving long-term TNF-inhibitors ( ). Saougou reported about 14 healthy children fathered by men on infliximab therapy ( ).