Follow-up of children exposed antenatally to immunosuppressive drugs
1Neonatology and Neonatal Intensive Care, Children's Hospital of Brescia, 2Rheumatology and Clinical Immunology, Spedali Civili, University of Brescia, 3IRCCS Istituto Auxologico Italiano, University of Milano and 4Pediatric Rheumatology, Meyer Children's Hospital and University of Florence, Italy.
Correspondence to: M. Motta, Neonatology and Neonatal Intensive Care, Children's Hospital of Brescia, Pzz. le Spedali Civili – 25123 Brescia, Italy. E-mail: lvmott{at}tin.it
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Abstract |
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 Top Abstract IntroductionImmunosuppressive drugs during...Prematurity, intrauterine growth...Development of immune function...Long-term effects of in...ConclusionsReferences |
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Antenatal exposure to immunosuppressive drugs given to mothers during pregnancy to treat autoimmune diseases raises some questions about the fetal development and the long-term outcome of children. Studies in humans showed that glucocorticoids (GCs), CsA and HCQ do not seem to increase the risk of congenital abnormalities; in contrast, cyclophosphamide, LEF and MTX are contraindicated during pregnancy. The risk of gestational complications, including pre-term delivery, intrauterine growth retardation (IUGR) and low birth weight (LBW), is higher in autoimmune diseases rather than in the general population and probably this finding is related to both maternal disorder and immunosuppressive therapy. Recently, results of our studies suggest that immunosuppressants given during pregnancy do not impair significantly the development of immunity in exposed children. Moreover, preliminary data on neurodevelopmental outcome seem to exclude a causative role of in utero exposure to immunosuppressive agents on the cognitive impairment observed in some of these children; however, our data need to be confirmed with further observations.
KEY WORDS: Pregnancy, Autoimmune disease, Immunosuppressive drugs, Children
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Introduction |
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TopAbstractIntroductionImmunosuppressive drugs during...Prematurity, intrauterine growth...Development of immune function...Long-term effects of in...ConclusionsReferences |
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Women with autoimmune diseases frequently require the administration of long-term immunosuppressive therapy to control an active disease or even a flare during pregnancy.
Immunosuppressive drugs and their metabolites can cross the placental barrier and enter into the fetal circulation [1]; this finding raises questions about the fetal development and the long-term outcome of children exposed to these agents in utero. Potential adverse effects associated with pre-natal exposure to immunosoppressive medications range from congenital malformations to other complications such as transient immunological deficit or neurocognitive impairment.
To assess the relative effects of immunosuppressive agents may be difficult, since the diagnoses of underlying maternal diseases as well as the concurrent use of other medications inevitably may confound interpretation of pregnancy outcome.
Moreover, randomized trials to evaluate the safety of medications during pregnancy in autoimmune diseases cannot be designed easily, for both ethical and practical reasons. Thus, at present, observational studies guide clinical decisions, although the low prevalence of adverse outcomes makes such studies difficult to interpret.
In this review, we will summarize the general concepts regarding fetal exposure to immunosuppressive medications as well as the information available regarding pregnancy outcome in patients with autoimmune disease and the long-term follow-up of their children.
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Immunosuppressive drugs during pregnancy |
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TopAbstractIntroductionImmunosuppressive drugs during...Prematurity, intrauterine growth...Development of immune function...Long-term effects of in...ConclusionsReferences |
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The Food and Drug Administration has developed a classification that codifies the safety categories of immunosuppressive medications [2]. This classification is difficult to apply in the setting of chronic autoimmune disease during pregnancy, particularly since many of the data are derived from experimental and pre-clinical animal studies.
Data collected in transplanted women treated with immunosuppressive drugs has determined no consistent pattern of congenital malformations in the offspring and the documented prevalence of major structure malformations has been found to be 4–5%, similar to the 3% documented in healthy women [3].
Recently, a consensus conference on anti-inflammatory and immunosuppressive drugs during pregnancy and lactation with a focus on patients with rheumatic diseases was organized and results have been published [4].
Despite early studies in animals showing that immunosuppressive drugs may be teratogenic, glucocorticoids (GCs), CsA and HCQ do not seem to increase the risk of congenital abnormalities in humans. Concerns have been raised about AZA, since its use has been associated with fetal anomalies in animals. However, anecdotal experience has associated pre-natal exposure to AZA with different congenital anomalies, but none of them were clearly linked to the drug. Cyclophosphamide, LEF and MTX are contraindicated during pregnancy [1, 4, 5].
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Prematurity, intrauterine growth retardation and low birth weight |
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TopAbstractIntroductionImmunosuppressive drugs during...Prematurity, intrauterine growth...Development of immune function...Long-term effects of in...ConclusionsReferences |
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Systemic autoimmune maternal disease may cause defective placentation with decreased uteroplacental blood flow that may result in intrauterine growth retardation (IUGR) and premature delivery [6, 7].
Moreover, maternal use of immunosuppressive medications may increase the risk of gestational complications. For example, CsA and GCs are associated with hypertension, diabetes mellitus, lower mean birth weight and IUGR [8–10].
As a consequence, infants born to mothers with autoimmune diseases, taking immunosuppressants during gestation, are more likely to be pre-term (born before 37 weeks of gestation), LBW (<2500 g) and small for gestational age (SGA) when compared with the general population (Table 1) [11–18].
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Pre-term and LBW infants are at increased risk for perinatal morbidity and mortality and they appear to have more problems during childhood as well [17, 18].
However, as consequence of improvement of maternal treatment and advances in neonatology, neonatal complications are rare in near-term infants and usually they are described in very low birth weight (<1500 g) or very premature infants (born before 32 weeks of gestation).
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Development of immune function and maturity |
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TopAbstractIntroductionImmunosuppressive drugs during...Prematurity, intrauterine growth...Development of immune function...Long-term effects of in...ConclusionsReferences |
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Studies on the influence of pre-natal administration of immunosuppressants on the babies’ immune system are scanty. Most of the published papers deal with the offspring of women treated for solid organ transplantation.
We have recently performed immune function evaluations, in both humoral and cellular compartments, in children of patients with autoimmune disorders followed in our centres. Overall, in utero exposure to immunosuppressants did not influence significantly the babies’ immune system.
Initially, we had evaluated nine babies, whose mothers had been taking CsA, AZA and dexamethasone during pregnancy, together with 14 babies from mothers with similar diseases but who had not been treated (controls) [19]. Complete blood count, immunoglobulin (Ig) serum levels, IgG subclasses and lymphocyte subpopulations were determined at about 1 yr of age. Serum levels of anti-hepatitis B surface antibody, as in vivo response marker of vaccination, and presence of autoantibodies (ANAs and extractable antinuclear antigen antibodies) were also evaluated. None of the parameters tested resulted significantly different in patients than in controls, and all children responded satisfactorily to hepatitis B vaccination.
We subsequently expanded these observations on a larger cohort of children and by adding more detailed immunological investigations, such as in vitro cytokine production [20]. In this recent study, we evaluated 14 babies (seven males and seven females) born to mothers with autoimmune diseases and exposed to immunosuppressive therapy during pregnancy. The age of the babies at the moment of the study ranged from 1 to 24 months (mean, 11 months), and was matched between patients and controls. Ten patients were also followed longitudinally during the first year of life. Laboratory evaluation included, in addition to all tests performed in our previous study, the secretion of IL-2 and IFN
in supernatants of resting or activated cultured peripheral blood mononuclear cells.
Complete blood counts were in the normal ranges for all babies, except one who was exposed in utero to CsA, who presented neutropenia (880 neutrophils/mm3) that resolved within the first year of life. Also in this study, the differences in serum Ig levels and IgG subclasses between exposed and non-exposed babies were not statistically significant. No relationship between Ig levels and specific drug administration was found by analysing the data as a whole. Basal and longitudinal determinations of lymphocyte subpopulations (CD3+, CD4+, CD8+, CD16+/56+ and CD19+ cells) were comparable in exposed and non-exposed babies as well. Finally, as measure of immune competence, the in vitro production of the cytokines IL-2 and IFN and the response to recombinant hepatitis B vaccine were not impaired in our study subjects. It is also worth noting that, although in utero exposure to immunosuppressants has been suggested to increase the susceptibility to autoimmune diseases in adult life because of a defect in deleting autoreactive T cells, none of the children included in our study has developed autoantibodies or clinical symptoms of autoimmune disease. Moreover, no child suffered from serious infections during the follow-up.
Similar results were obtained in an independent sample of subjects seen in Brescia at birth and followed periodically during the first year of life [21]. Absolute lymphocyte count and subpopulations, as well as Ig production were not different in 19 children exposed in utero to GCs alone or in combination with AZA, CsA or HCQ when compared with those obtained in 15 age-matched controls not exposed to immunosuppressants.
In the previously mentioned study, we had evaluated the response to hepatitis B vaccination, while in another report we have analysed the response to another type of compulsory vaccine, the anti-tetanus [22]. Twenty-two babies born from mothers with autoimmune diseases who had been taking immunosuppressive drugs during pregnancy were evaluated for their response to vaccination with Clostridium tetani toxoid. Six babies born from mothers receiving low-dose aspirin only were used as controls. The immune response to C. tetani vaccination was evaluated by ELISA. Five children out of 28 (17%) did not achieve a protective titre of anti C. tetani toxoid IgG, but no relationship was found between specific drug exposure and antibody response.
In another group of patients, we have evaluated the immune function of babies exposed to immunosuppressants in utero by characterizing the production, function and survival of T lymphocytes of children with prolonged fetal exposure to dexamethasone for anti-Ro-associated congenital complete heart block [23]. The analysis of thymic function was studied by measuring the level of T-cell receptor excision circles (by real-time PCR), and the T-cell diversity (by heteroduplex analysis). T-cell competence was gauged at two functional levels by determining the proliferation and the number of T-cell divisions and by measuring INF production after mitogenic stimulation. All parameters studied were comparable with those of age-matched control, except for a restriction of T-cell receptor diversity in some patients.
Overall, these data suggest that immunosuppressants given during pregnancy for autoimmune diseases do not impair significantly the development of immunity in babies. This finding is in contrast with the results obtained in infants born to mothers who received organ transplants, which showed an impaired immunity in offspring [24, 25]. This may be explained by the different immunosuppressive treatment and the different drug dosages in these two conditions. In fact, in autoimmune diseases, the immunosuppressive therapy is usually characterized by the use of a single drug in a lower dose range, while in organ transplantation immunosuppessive treatment may require higher doses or combination of different immunosuppressive agents.
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Long-term effects of in utero exposure to immunosuppressive medications |
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TopAbstractIntroductionImmunosuppressive drugs during...Prematurity, intrauterine growth...Development of immune function...Long-term effects of in...ConclusionsReferences |
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The long-term follow-up of children exposed in utero to immunosuppressive medications is obviously the most interesting information that might give a final answer to pregnant patients and to physicians. Unfortunately, limited data are available on the long-term observation and neurocognitive development of children exposed in utero to immunosuppressive agents. Neurodevelopmental dysfunctions, such as learning disabilities (LDs) or attention deficit, were described in male offspring of mothers with SLE [26, 27]. Moreover, findings in animal and in human studies have suggested that antenatal administration of GCs may interfere with the normal development of the immature brain [28]. In particular, observations in humans have suggested that antenatal dexamethasone exposure could negatively affect the child's neuropsychological development [29].
On the other hand, we have performed a study showing a normal neuropsychological development in 11 children exposed in utero to high-dose dexamethasone for congenital complete heart block [30]. In addition, in another study we have observed that the occurrence of LD seemed to be related to maternal antibody profile (i.e. aPLs), rather than medications administered during pregnancy, including GCs [31]. Adverse effects on neuropsychological development in children have not been observed after exposure to prednisone or prednisolone that is inactivated by placental enzymes [4].
Recently, we have arranged a national survey in order to collect data on pregnancy in rheumatic diseases and related long-term complications in offspring. A detailed questionnaire was prepared and addressed to patients who get pregnant after the diagnosis of rheumatic disease: data on 72 children, with a mean observation period of 44 months, were collected. Children were exposed in utero to immunosuppressive drugs, mainly GCs, in a 30% of cases. The preliminary data analysis showed no recurrent infections during childhood; one case of autoimmune thyroiditis and one case of coeliac disease were reported (A. Tincani, unpublished data).
The use of anti-malarial agents can give retinal toxicity and seldom ototoxicity; however, their use during gestation does not seem to increase the risk of adverse effects in infants that were exposed to either chloroquine or HCQ prenatally. In particular, no visual or hearing impairment have been described in exposed infants [15, 32, 33].
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Conclusions |
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TopAbstractIntroductionImmunosuppressive drugs during...Prematurity, intrauterine growth...Development of immune function...Long-term effects of in...ConclusionsReferences |
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Even if successful pregnancy outcomes are possible in autoimmune diseases, when immunosuppressive medications are required to treat maternal disease health care professionals and patients should consider the potential risks of pregnancy complications as well as the risks for the offspring. Immunosuppressive therapy with selected drugs does not apparently increase the risk of birth defects; however, gestational complications, including premature delivery, IUGR and LBW may be more frequent. In recent years, we extensively studied the possible immunosuppressive effects of antenatal exposure to immunosuppressant on children's immunity, showing a substantial lack of interference. Limited data are available on long-term follow-up of children exposed in utero to immunosuppressants, in particular, for neurological outcome; further studies to improve the current state of knowledge are certainly needed.
Disclosure statement: The authors have declared no conflicts of interest.
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References |
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TopAbstractIntroductionImmunosuppressive drugs during...Prematurity, intrauterine growth...Development of immune function...Long-term effects of in...ConclusionsReferences |
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- Little BB. Immunosuppressant therapy during gestation. Seminars Perinatol (1997) 21:143–8.[CrossRef]
- Meadows M. Pregnancy and the drug dilemma. FDA Consum (2001) 35:16–20.[Medline]
- McKay DB, Josephson MA. Pregnancy in recipients of solid organs – effects on mother and child. N Engl J Med (2006) 354:1281–93.
[Free Full Text] - Ostensen M, Khamashta M, Lockshin M, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther (2006) 8:209.[CrossRef][Medline]
- Danesi R, Del Tacca M. Teratogenesis and immunosuppressive treatment. Transplant Proc (2004) 36:705–7.[CrossRef][Web of Science][Medline]
- Meroni PL, di Simone N, Testoni C, D’Asta M, Acaia B, Caruso A. Antiphospholipid antibodies as cause of pregnancy loss. Lupus (2004) 13:649–52.
[Abstract/Free Full Text] - Stone S, Khamashta MA, Poston L. Placentation, antiphospholipid syndrome and pregnancy outcome. Lupus (2001) 10:67–74.
[Abstract/Free Full Text] - Armenti VT, Moritz MJ, Cardonick EH, Davison JM. Immunosuppression in pregnancy: choices for infant and maternal health. Drugs (2002) 62:2361–75.[CrossRef][Web of Science][Medline]
- Scott JR. Fetal growth retardation associated with maternal administration of immunosuppressives. Am J Obstet Gynecol (1977) 128:668–76.[Web of Science][Medline]
- Lockshin MD, Sammaritano LR. Lupus pregnancy. Autoimmunity (2003) 36:33–40.[CrossRef][Web of Science][Medline]
- Gimovsky ML, Montoro M, Paul RH. Pregnancy outcome in women with systemic lupus erythematosus. Obstet Gynecol (1984) 63:686–92.[Web of Science][Medline]
- Lê Huong D, Wechsler B, Vauthier-Brouzes D, et al. Outcome of planned pregnancies in systemic lupus erythematosus: a prospective study on 62 pregnancies. Br J Rheumatol (1997) 36:772–7.
[Abstract/Free Full Text] - Lima F, Buchanan NM, Khamashta MA, Kerslake S, Hughes GR. Obstetric outcome in systemic lupus erythematosus. Semin Arthritis Rheum (1995) 25:184–92.[CrossRef][Web of Science][Medline]
- De Bandt M, Palazzo E, Belmatoug N, et al. Outcome of pregnancies in lupus: experience at one center. Ann Med Interne (2000) 151:87–92.[Medline]
- Motta M, Tincani A, Faden D, et al. Follow-Up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation. J Perinatol (2005) 25:86–9.[CrossRef][Medline]
- Hamilton BE, Miniño AM, Martin JA, Kochanek KD, Strobino DM, Guyer B. Annual summary of vital statistics: 2005. Pediatrics (2007) 119:345–60.
[Abstract/Free Full Text] - Kinzler WL, Kaminsky L. Fetal growth restriction and subsequent pregnancy risks. Semin Perinatol (2007) 31:126–34.[CrossRef][Web of Science][Medline]
- Fang S. Management of preterm infants with intrauterine growth restriction. Early Hum Dev (2005) 81:889–900.[CrossRef][Web of Science][Medline]
- Cimaz R, Meregalli E, Biggioggero M, et al. Alterations in the immune system of children from mothers treated with immunosuppressive agents during pregnancy. Toxicol Lett (2004) 149:155–62.[CrossRef][Web of Science][Medline]
- Biggioggero M, Borghi MO, Gerosa M, Trespidi L, Cimaz R, Meroni PI. Immune function in children born to mothers with autoimmune diseases and exposed in utero to immunosuppressants. Lupus (2007) 16:651–6.
[Abstract/Free Full Text] - Motta M, Ciardelli L, Marconi M, et al. Immune system development in infants born to mothers with autoimmune disease, exposed in utero to immunosuppressive agents. Am J Perinatol (2007) 24:441–7.[CrossRef][Web of Science][Medline]
- Cimaz R, Meregalli E, Biggioggero M, et al. Response to tetanus vaccination in infants exposed in utero to immunosuppressants for maternal autoimmune disorders. Lupus (2007) 16:129–32.
[Abstract/Free Full Text] - Airò P, Scarsi M, Brucato A, et al. Characterization of T-cell population in children with prolonged fetal exposure to dexamethasone for anti-Ro/SS-A antibodies associated congenital heart block. Lupus (2006) 15:553–61.
[Abstract/Free Full Text] - Takahashi N, Nishida H, Hoshi J. Severe B cell depletion in newborns from renal transplant mothers taking immunosuppressive agents. Transplantation (1994) 57:1617–21.[Web of Science][Medline]
- Di Paolo S, Schena A, Morrone LF, et al. Immunological evaluation during the first year of life of infants born to cyclosporine-treated female kidney transplant recipient. Trasplantation (2000) 69:2049–54.[CrossRef]
- McAllister DL, Kaplan BJ, Edworthy SM, et al. The influence of systemic lupus erythematosus on fetal development: cognitive, behavioral, and health trends. J Int Neuropsychol Soc (1997) 3:370–6.[Medline]
- Ross G, Sammaritano L, Nass R, Lockshin M. Effects of mothers’ autoimmune disease during pregnancy on learning disabilities and hand preference in their children. Arch Pediatr Adolesc Med (2003) 157:397–402.
[Abstract/Free Full Text] - Matthews SG. Antenatal glucocorticoids and programming of the developing CNS. Pediatr Res (2000) 47:291–300.[Web of Science][Medline]
- Spinillo A, Viazzo F, Colleoni R, Chiara A, Cerbo RA, Fazzi E. Two-year infant neurodevelopmental outcome after single or multiple antenatal courses of corticosteroids to prevent complications of prematurity. Am J Obstet Gynecol (2004) 191:217–24.[CrossRef][Web of Science][Medline]
- Brucato A, Astori MG, Cimaz R, et al. Normal neuropsychological development of children with congenital complete heart block exposed or not in utero to high dose dexamethasone. Ann Rheum Dis (2006) 65:1422–6.
[Abstract/Free Full Text] - Neri F, Chimini L, Bonomi F, et al. Neuropsychological development of children born to patients with systemic lupus erythematosus. Lupus (2004) 13:805–11.
[Abstract/Free Full Text] - Cimaz R, Brucato A, Meregalli E, Muscará M, Sergi P. Electroretinograms of children born to mothers treated with hydroxychloroquine during pregnancy and breast-feeding: comment on the article by Costedoat-Chalumeau et al. Arthritis Rheum (2004) 50:3056–7.[CrossRef][Web of Science][Medline]
- Borba EF, Turrini-Filho JR, Kuruma KAM. Chloroquine gestational use in systemic lupus erythematosus: assessing the risk of child ototoxicity by pure tone audiometry. Lupus (2004) 13:223–7.
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