16 March 2018: Original Paper
Immunological Status of Children Born to Female Liver Recipients
Agnieszka Drozdowska-Szymczak ABCDEF 1, Bronisława Pietrzak E 2, Natalia Czaplińska E 1*, Joanna Schreiber-Zamora B 1, Zoulikha Jabiry-Zieniewicz E 2, Mirosław Wielgoś E 2, Bożena Kociszewska-Najman ABCDEFG 1
DOI: 10.12659/AOT.907930
Ann Transplant 2018; 23:182-189
Abstract
BACKGROUND: Immunosuppressive treatment in pregnant organ recipients can affect functions of the fetal and newborn immune system. The aim of this study was to evaluate the effect of this treatment on selected parameters of the immune system of children born to mothers after liver transplantation.
MATERIAL AND METHODS: The study included 52 children born to liver recipients and 52 children in the control group. The study was conducted in the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw. Children from the 1st day of life to 10 years of age were examined. Serum antibody concentrations of IgG, IgM, and IgA were measured by the immune agglutination method on a Cobas 6000 analyzer.
RESULTS: Comparison of mean IgG, IgM, and IgA levels and with reference values did not show a significant difference between the study and control group (p>0.05). Immunoglobulin concentrations were also analyzed in the groups of children according to their age at the time of the test and the type of calcineurin inhibitor used in the mother’s treatment. The analysis showed a significant difference in the distribution of IgA concentrations in comparison to the normal values (p<0.05), as well as mean IgA (p<0.05) and IgM concentrations (p<0.05) according to the type of immunosuppressive treatment of the mother (tacrolimus or cyclosporin treatment regimen).
CONCLUSIONS: Analysis of the type of immunosuppressive therapy used during pregnancy revealed a possible influence of the type of calcineurin inhibitor on selected parameters of the immune system of the children; however, further research is needed to confirm these findings.
Keywords: Child, Immune System, Immunosuppressive Agents, Liver Transplantation, Pregnancy
Background
AIM:
The aim of this study was to evaluate the effect of different types of immunosuppressive therapy on selected immune system parameters in children born to mothers after liver transplantation.
Material and Methods
The study group (LT) consisted of 52 children born to mothers after liver transplantation, aged between 1 and 10 years, born between December 2001 and July 2013, and examined in the period between December 2010 and July 2013, in the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw. The control group involved 52 children born between March 2001 and July 2013, at similar gestational ages as the children in the study group, whose mothers consented to participate in the study.
Immunosuppressive drugs used by mothers in the study group were tacrolimus, cyclosporine, glucocorticosteroid, and azathioprine. The characteristics of children in the study and control group included their age at the time of examination, gestational age, birth weight, and the type of termination of pregnancy (Table 1).
All mothers of the examined children signed consent for participation in the study, and the study protocol was approved by the Bioethics Committee of the Medical University of Warsaw (KB/174/2009). The research funded by a grant (No. N N407 534938) from the Ministry of Science and Higher Education.
To assess immunity, antibody IgG, IgM, and IgA levels were used. Venous blood samples were taken during a visit to the clinic. After clotting and centrifugation, immunoglobulin IgG, IgM, and IgA concentrations were determined by the immunoturbidimetric method on a Cobas 6000 (Roche) analyzer. The tests were done at the Central Laboratory of the Hospital of Baby Jesus in Warsaw.
To evaluate antibodies, concentration reference values for immunoglobulin concentrations according to the age of children developed by Wolska-Kuśnierz et al. were used (Table 2) [7].
Beside the comparison of the results with respect to the normal value, the mean concentrations of particular immunoglobulins were compared. To compile the collected data, descriptive methods and statistical reasoning methods were used. The chi-square test was used to compare the incidence of individual variants in the studied groups and subgroups and to examine the relationship between the qualitative variables. In the case of small numbers in some fields of the tables, Yates’ correction was used for calculate chi-square analysis.
Before comparing the mean of the measurable variables, the compatibility of their distributions with the normal distribution was checked using the Shapiro-Wolf compatibility test. For the comparison of 2 independent trials, the Mann-Whitney test was used.
Statistically significant values were the differences between the means (or frequencies) and variables for which the calculated test value was equal to or greater than the critical value read from the corresponding tables with the number of degrees of freedom and the probability of error <0.05. The statistic calculations were based on STATISTICA 10 software.
Results
The following table shows the results of IgG, IgM, and IgA levels and the number of children (n) who had results above the normal value, normal, and below the normal value for age, as well as mean concentrations of immunoglobulins in the study and control group, and in groups extracted according to the age of children at the time of study or the regimen of immunosuppressive therapy administered to the mother (Table 3).
There were no statistically significant differences in the IgG, IgM, and IgA concentrations between the study group and control group (p>0.05). The comparison of mean IgG, IgM, and IgA concentrations in the analyzed groups also showed no statistically significant differences (p>0.05).
IgG, IgM, and IgA immunoglobulin concentrations were also analyzed in the groups of children separated according to the age of children at the time of the study. Children were divided into 3 groups: newborns (1 to 28 days), infants (>28 days to 1 year) and children older than age 1 year. There were no statistically significant differences in the IgG, IgM, and IgA distributions in relation to the normal values or mean concentrations of these immunoglobulins between the study and control group (p> 0.05). The results are shown in Table 3.
Also, the results of distribution of antibody concentrations in relation to the normal values in the groups of children separated according to the type of mother’s immunosuppression (tacrolimus or cyclosporin regimen) were analyzed and compared between those groups and with the control group.
There were no statistically significant differences in the IgG, IgM, and IgA concentrations according to the normal values and mean concentrations of these immunoglobulins between the group of children whose mothers used a particular immunosuppressive therapy regimen (based on tacrolimus or cyclosporin) and the control group (p>0.05).
There were no statistically significant differences in the IgG and IgM concentrations between the group of children whose mothers used the tacrolimus-based immunosuppressive regimen and the group of mothers receiving cyclosporine (p>0.05).
Comparing the IgA concentration distribution according to the normal values, a statistically significant difference was found in the IgA distribution according to the type of immunosuppressive regimens (p<0.05). We found that in the tacrolimus-based regimen, up to 70.7% of the subjects were normal and 29.3% were below normal. There were no results above the normal value. On the other hand, in the cyclosporin-based regimen group, the normal results were 54.5% and the results above normal value were observed in 27.3% of children. In this group, 18.2% of the results were below the normal value.
The comparison of mean IgG values in the analyzed groups according to the immunosuppression regimen did not show a statistically significant difference (p>0.05).
The analysis of mean IgM concentrations between the analyzed groups separated according to the mother’s immunosuppressive regimen showed a statistically significant difference (p<0.05). We found that the mean IgM concentration in the tacrolimus-based regimen group was significantly lower than in the group of children born to mothers treated with cyclosporine-based regimen (0.693±0.58 [g/l]
Analysis of mean IgA concentrations according to the immunosuppressive regimen in mothers showed a statistically significant difference (0.390±0.63 [g/l]
Discussion
LIMITATIONS:
Factors that may have had a significant effect on the results in the studied material and limit the value of the study are:
References
1. Surti B, Tan J, Saab S, Pregnancy and liver transplantation: Liver Int, 2008; 28(9); 1200-6, pmid: 18822076
2. Czaplińska N, Kociszewska-Najman B, Schreiber-Zamora J, Analysis of the selected biochemical parameters of liver and kidneys function in children of mothers after liver transplantation: Transplant Proc, 2014; 46(8); 2790-93, pmid: 25380919
3. Durlik M, Rowiński W: Zalecenia dotyczące leczenia immunosupresyjnego po przeszczepieniu narządów unaczynionych, 2010, Warszawa, Fundacja Zjednoczeni dla Transplantacji [in Polish]
4. Schreiber-Zamora J, Kociszewska-Najman B, Borek-Dzięcioł B, Neurological development of children born to liver transplant recipients: Transplant Proc, 2014; 46(8); 2798-801, pmid: 25380921
5. Tendron A, Gouyon J-B, Decramer S, In utero exposure to immunosuppressive drugs: Experimental and clinical studies: Pediatr Nephrol, 2002; 17; 121-30, pmid: 11875675
6. Tartakover Matalon S, Ornoy A, Lishner M, Review of the potential effects of three commonly used antineoplastic and immunosuppressive drugs (cyclophospamide, azathioprine, doxorubicin) on the embryo and placenta: Reproductive Toxicology, 2004; 18; 219-30, pmid: 15019720
7. Wolska-Kuśnierz B, Gregorek H, Zapaśnik A, Wartości referencyjne stężeń immunoglobulin G, A, M i D w surowicy zdrowych dzieci i osób dorosłych, mieszkańców województwa mazowieckiego: Standardy Medyczne/Pediatria, 2010; 7; 524-32 [in Polish]
8. Paris K, Leiva L, Sorensen RU, Antibody deficiency syndromes: Allergy frontiers, 2010; 737-52, Springer
9. Blume C, Pischke S, Versen-Hoynck F, Pregnancies in liver and kidney transplant recipients: A review of the current literature and recommendation: Best Pract Res Clin Obstet Gynecol, 2014; 28; 1123-36
10. Fuchs KM, Coustan DR, Immunosuppressant therapy in pregnant organ transplant recipients: Elsevier Semin Perinatol, 2007; 31; 363-71
11. Deshpande NA, Coscia LA, Gomez-Lobo V, Pregnancy after solid organ transplantation: A guide for obstetric management: Rev Obstet Gynecol, 2013; 6(314); 116-25, pmid: 24826201
12. Wielgos M, Pietrzak B, Mazanowska N, Kociszewska-Najman B, Neonates of mothers who have had kidney or liver transplantation: J Perinat Med, 2016; 44(6); 691-94, pmid: 27049614
13. Kanzaki Y, Kondoh E, Kawasaki K, Pregnancy outcomes in liver transplant recipients: A 15-year single-center experience: J Obstet Gynaecol Res, 2016; 42(11); 1476-82, pmid: 27557727
14. Baskiran A, Karakas S, Ince V, Pregnancy after liver transplantation: Risks and outcomes: Transplant Proc, 2017; 49(8); 1875-78, pmid: 28923640
15. Motta M, Tincani A, Perez-Rodriguez C, Neonates from mother autoimmune disease: Hematol Rep, 2006; 2(10); 55-59
16. Cimaz R, Meregalli E, Biggioggero M, Alterations in the immune system of children from mothers treated with immunosuppressive agents during pregnancy: Toxicol Lett, 2004; 149(1–3); 155-62, pmid: 15093261
17. Motta M, Tincani A, Meroni P, Follow-up of children exposed antenatally to immunosuppressive drugs: Reumatology, 2008; 47; 32-34
18. Motta M, Rodrigez-Oerez C, Tincani A, Neonates born from mothers with autoimmune discords: Early Human Development, 2009; 85; 567-70
19. Schena P, Stallone G, Schena A, Pregnancy in renal transplantation: Immunologic evaluation of neonates from mother with transplanted kidney: Transplant Immunology, 2002; 9; 161-64, pmid: 12180825
20. Drozdowska-Szymczak A, Kociszewska-Najman B, Schreiber-Zamora J, Evaluation of selected markers of the immune system in children of renal transplant recipients: Transplant Proc, 2014; 46(8); 2703-7, pmid: 25380899
21. Biggioggero M, Borghi MO, Gerosa M, Immune function in children born to mothers with autoimmune diseases and exposed in utero to immunosuppressants: Lupus, 2007; 16; 651-56, pmid: 17711903
22. Motta M, Ciardelli L, Marconi M, Immune system development in Infants born to mothers with autoimmune disease, exposed in utero to immunosuppressive agents: Am J Perinatol, 2007; 24(8); 441-47, pmid: 17992710
23. Meregalli E, Biggioggiero M, Borghi O: Arh Hig Rada Toksikol, 2005; 56; 151-56, pmid: 15968830
24. Ersay A, Oygur N, Coskun M, Immunologic evaluation of a neonate born to an immunosuppressed kidney transplant recipient: Am J Perinatol, 1995; 12(6); 413-15, pmid: 8579652
25. Baarsma R, Kamps W, Immunological responses in an infant after cyclosporine A exposure during pregnancy: Eur J Pediatr, 1993; 152; 476-77, pmid: 8335013
26. Østensen M, Khamashta M, Lockshin M, Anti-inflammatory and immunosuppressive drugs and reproduction: Arthritis Res Ther, 2006; 8(3); 209, pmid: 16712713
27. Di Paolo S, Schena A, Morrone LF, Immunologic evaluation during the first year of life of infants born to cyclosporine-treated female kidney transplant recipients: Analysis of lymphocyte subpopulations and immunoglobulin serum levels: Transplantation, 2000; 69(10); 2049-54, pmid: 10852595
28. Prevot A, Martini S, Guignard JP, In utero exposure to Immunosuppressive drugs: Biol Neonate, 2002; 81; 73-81, pmid: 11844873
In Press
Original article
Diagnostic Utility of FAR1 Methylation Levels in Hepatocellular Carcinoma Patients Undergoing Liver Transpl...Ann Transplant In Press; DOI: 10.12659/AOT.951568
Original article
Inferior Long-Term Outcome of Fatty Liver Allografts After Orthotopic Liver TransplantationAnn Transplant In Press; DOI: 10.12659/AOT.950589
Database Analysis
Identification and Validation of Liver Transplantation-Induced Acute Lung Injury Biomarkers Using a Bioinfo...Ann Transplant In Press; DOI: 10.12659/AOT.950289
Original article
Survival and Recurrence in Liver Transplant Patients With Intrahepatic Cholangiocarcinoma and Hepatocellula...Ann Transplant In Press; DOI: 10.12659/AOT.950997
Most Viewed Current Articles
24 Aug 2021 : Review article 18,372
Normothermic Machine Perfusion (NMP) of the Liver – Current Status and Future PerspectivesDOI :10.12659/AOT.931664
Ann Transplant 2021; 26:e931664
05 Apr 2022 : Original article 14,731
Impact of Statins on Hepatocellular Carcinoma Recurrence After Living-Donor Liver TransplantationDOI :10.12659/AOT.935604
Ann Transplant 2022; 27:e935604
22 Nov 2022 : Original article 14,244
Long-Term Effects of Everolimus-Facilitated Tacrolimus Reduction in Living-Donor Liver Transplant Recipient...DOI :10.12659/AOT.937988
Ann Transplant 2022; 27:e937988
29 Dec 2021 : Original article 13,752
Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Sys...DOI :10.12659/AOT.933588
Ann Transplant 2021; 26:e933588