The advances in transplantation medicine render it possible for recipient women to fulfill their dream of having their own baby. However, the pregnancy, the delivery, and the transplanted organ need special medical care due to a high risk of complications, including preterm delivery and all its implications, as well as rejection of the transplant. In addition, the fetus is constantly exposed to the harmful factors related to the mother’s main disease as well as the immunosuppressant therapy during the pregnancy. We still do not fully know what will the effects of the immunosuppressant therapy be on the developing organs of the fetus and the effects on the overall development of the child in the future. One of the most sensitive organs of the developing fetus is the ophthalmic organ. The human eye is also the most important sensory organ that allows the contact with the outside world, conditioning the proper development of the child. Preterm neonates mainly belong to the risk group of ophthalmologic disorders due to a series of complications related to the shortened pregnancy period. The aim of the study was the analysis of ophthalmologic disorders in children born to mothers that had a renal transplantation (RTx) or liver transplantation (LTx) in addition to the analysis of certain selected parameters of the labor period including the postpartum state according to the Apgar score, the frequency of preterm deliveries, and the variations in immunosuppressant therapy during pregnancy in women after LTx or RTx.
In the LTx group, the gestational age at delivery was between 33 and 41 weeks with an average of 37 weeks of gestation (wg) and the birth weight was between 1420 and 4100 g with a median of 2930 g. In the RTx group, the gestational age at delivery was between 27 and 39 weeks with an average of 36 wg and the birth weight at delivery was between 580 and 3450 g with a median of 2530 g. In the control group, the gestational age at delivery was between 27 and 41 weeks with an average of 37 wg, whereas the weight of the neonate at delivery was between 1190 and 4720 g with a median of 3065 g. Statistical analysis showed that there is a statistically significant difference in the median values of the gestational age between the groups (37 for LTx and 36 for RTx; P=0.03052). Similarly, there is a statistically significant difference in the median values the birth weight between LTx (2930 g) and RTx (2530 g; P=0.000923; Fig. 1). There is a difference in the median values in the study group as a whole and the control group regarding the birth weight. For the control group, the median value of the birth weight is 3065 g, whereas in the LTx+RTx the median birth weight is 2720 g (P=0.006334).
Comparing the well-being of the neonates from recipient mothers in the first minute of life showed no significant statistical differences: a good state according to the Apgar score at 1 min after birth was noted in 89.2% of children of mothers after LTx and 97.1% of children of mothers after RTx (P=0.358, Fisher’s test). Comparing the well-being of neonates of recipient mothers (LTx and RTx together) with the control group, a good state of neonates according to the Apgar score at 1 min after birth was noted in 93.1% in the recipient mother group versus 86.4% in the control group. This difference was not statistically significant (P=0.2611, Fisher’s test). Analyzing the well-being of neonates at 5 min after birth, a good state according to the Apgar score was noted in 97.3% of neonates of mothers after LTx and 97.1% of neonates mothers after RTx; no significant difference was shown (P=1.00, Fisher’s test). Similarly, analyzing in the fifth minute the well-being of neonates born to recipient mothers (LTx and RTx together) in comparison with the control group, also no statistical difference was shown (P=0.4973, Fisher’s test; Table 1).
Comparing the percentage of prematurity, it was noted that, for neonates from the LTx group, it was lower (43.2%) than for children from the RTx group (68.6%). This difference was statistically significant (P=0.0306, χ2 test). Analyzing the percentage of prematurity in the whole group of children of recipient mothers (LTx and RTx) in comparison with the percentage of premature deliveries of the control group, it was noted that the difference was not statistically significant (P=0.5137, χ2 test; Table 1).
Comparing the percentage of drugs and the combination of immunosuppressant drugs given to mothers from the LTx and RTx groups showed that tacrolimus (TAC)+glucocorticosteroids (GS) were more often given in the LTx group (54.5%) than in the RTx group (22.86%). This difference was statistically significant (Fisher’s test). Statistically significant also was the difference in the percentages of different drug schemes: azathioprine (AZA)+cyclosporine (CSA)+GS in the LTX group (2.7%) was lower than in the RTx group (28.57%; Table 2). Analyzing each immunosuppressant drug alone, it was shown that there are statistical differences in the frequency of applying the drugs TAC and AZA, and for CSA the difference is at the edge of statistical significance, in the study groups LTx and RTx (Fisher’s test). TAC was more often given in the LTx group (70.7%) than in the RTx group (42.86%; P=0.0315, χ2 test), whereas CSA was more often given in the RTx group (54.29%) than in the LTx group (28.73%; P=0.0551). Similarly, AZA was more often given in the RTx group (45.71%) than in the LTx group (only 2.7%; P=0.0000; Table 2).
Because the ophthalmologic examinations were done between 01 January 2010 and 30 June 2012, the children from the LTx, RTx, and control groups were examined at different stages of life. Children were examined in the following stages of life: neonatal (1–4 weeks of age), babyhood (2–12 months), early stages of kindergarten (1–3 years of age), later stages of kindergarten (4–6 years of age), and school years (>6 years of age). In the neonatal stage, ophthalmologic examinations were mainly done on neonates born prematurely that were in danger of developing retinopathy of prematurity. The rest of the children had examinations done later in life. The largest number of examined children was at the later kindergarten stage (4–6 years of age; Fig. 2).
The statistical analysis with the Fisher’s test showed that there is no significant difference between the percentage of pathologic findings in the ophthalmologic examination of children from the LTx group (16.2%) and the RTx group (17.1%; P=1.00). Furthermore, statistical analysis (χ2 test) showed that the percentage of pathologic findings in the ophthalmologic examination in the group of children of recipient mothers (LTx and RTx) did not differ statistically from the percentage of pathologic findings in the control group (P=0.6206). The disorders that were noted during the ophthalmologic examination are listed in Table 3.
Neonates of recipient mothers are patients that need special medical observation. This medical observation starts right after delivery when the well-being of the newborn is assessed according to the Apgar score: appearance (skin color), pulse, grimace (reflex irritability), activity (muscle tone), and respiration. Evaluation in the first and fifth minutes renders it possible to assess the well-being of the neonate and take a decision in the further management of the newborn. The analysis done on the assessment of the clinical state of neonates at delivery according to the Apgar score has shown that most children were born in a good state and did not need any resuscitation maneuvers. The well-being of 89.2% of neonates from the LTx group and 97.1% of neonates from the RTx group in the first minute after birth and in more than 97% of neonates from the LTx and RTx group was good. There were no significant statistical differences in the evaluation of the well-being of neonates directly after birth whether at the first or fifth minute of life in comparison with the control group.
In pregnant women after transplantation of an organ, preterm deliveries, intrauterine growth restriction, and associations with low birth weight are more commonly observed (1–5). In the analyzed group of LTx and RTx patients, the percentage of preterm deliveries was high. Deliveries before 37 wg were noted in 40 patients (16 in the LTx group and 24 in the RTx group) of 82 transplant recipient patients, which accounted for 48.8%. As a comparison, the percentage of neonates delivered prematurely at the same time was 20.5% in the Obstetrical Department and 5.7% in the Mazovia region. Furthermore, it was found that preterm deliveries were by far more common in the RTx group (68.8%) than in the LTx group (43.2%). The difference was statistically significant (P=0.0306, χ2 test).
The type of immunosuppressant therapy used during pregnancy in women after LTx or RTx was also analyzed. It is widely considered that the use of immunosuppressant therapy used to keep the function of a transplanted organ has adverse effects. Some of the immunosuppressant drugs are contraindicated during pregnancy due to proven adverse or even teratogenic effects on the developing fetus (6, 7). The placental barrier between the mother and the fetus is a deceiving term that should not be taken literally. All immunosuppressant drugs pass through the placenta. GS such as nonfluorinated derivatives, prednisone and methylprednisolone, used in immunosuppressant schemes are mostly metabolized by the placental dehydrogenase 11-β-hydroxysteroid and are present in the fetal blood in small concentrations. CSA and TAC pass through the placenta in considerable quantities. There are data suggesting that CSA in the fetal blood reaches half the concentration present in the maternal blood, whereas other studies showed that fetal serum from mothers treated with CSA have the ability of inhibiting lymphocyte T function, which may portray its clinically significant presence (5, 8, 9). TAC, on the other hand, gathers mainly in the placenta and its concentration in the fetus does not reach half of the concentration in the maternal blood (5, 8). AZA passes through the placenta; however, its active metabolite 6-mercaptopurine is not detected in the fetal blood due to the lack of the enzyme that would convert the drug to its teratogenic active metabolite (5, 8).
In the liver or renal transplant recipient mothers, the immunosuppressant drugs that were used are TAC, CSA, and AZA in monotherapy and in schemes of two or three drugs in combination with GS or other immunosuppressant drugs. In the analyzed schemes of immunotherapy of pregnant recipient women, there were statistically significant differences in using some of the immunosuppresant drugs in monotherapy and in schemes of two or three drugs between the LTx and the RTx groups. TAC was given more often in the LTx group than the RTx group in monotherapy (70.27% vs. 42.86%) as well as in two drug schemes combined with GS (54.05% vs. 22.86%). In both cases, the difference was statistically significant (P=0.0315 vs. 0.0084). Whereas AZA given in monotherapy was significantly more often used in the RTx group than in the LTx group (P=0.0000), the combination of AZA+CSA+GS was used only in 1 patient after LTx and in 10 patients after RTx (P=0.0065).
Right after delivery, it is difficult to assess and predict the long-term effects of immunotherapy during fetal life on the development and function of the children’s organs. In the medical databases, few reports were found concerning the development of newborns of recipient mother (10–13). These reports are usually restricted to the neonate and early babyhood and are done on a small group of children. In the available literature, there are no data about the long-term effects on the children’s overall well-being and authors stress the need of performing more studies. In the analyzed group of neonates and children of recipient women, ophthalmologic disorders were examined. In all the groups of children, LTx, RTx, and the control groups examined by an ophthalmologist, in more than 80%, no disorders were detected (83.8% vs. 82.9% vs. 86.4%). The disorders that were detected in the LTx and RTx groups as well as the control group were similar. The most common disorders detected were convergence disorders, convergent strabismus, or exotropia and hyperopia.
Convergence disorder, which frequently occurs, is characterized by the simultaneous inward movement of both eyes toward each other mediated by the medial rectus muscle, which is innervated by the oculomotor nerve. It is due to an effort done to view objects lying close to the eye. As a result, symptoms as double vision, eye pain, headache, blurred vision, difficulty sustaining near-visual function, and abnormal fatigue appear. Another common disease occurring in children is strabismus, which is determined by the inappropriate alignment of the eyes as a result of ocular muscle weakness. Strabismus might be caused by refractive errors, retina diseases, lesion of the optic nerve, congenital cataracts, congenital or acquired traumatic lesion of the ocular muscles, perinatal injuries, brain microtrauma, and genetic effects. Any strabismus occurring in children at the age of 12 weeks or more requires a diagnosis because an untreated disease may lead to irreversible eye damage. Moreover, hyperopia is a defect of vision caused either when the eyeball is too short or when the optical power needed to keep the image focused on the retina is insufficient. Hyperopia observed in children up to 3 years old is physiologic and is relevant to a small eyeball, which grows to its final size by the age of 6 to 8 years. Constant accommodative excess might be the cause of a coordination lack between the ocular muscles and hence resulting in convergent strabismus or vision deficiency. Because accommodation is very strong in children and optical power is pressurized, hyperopia is often latent (14–18). Among the children in the study groups LTx and RTx, the most common disorders observed were convergence insufficiency (6 of 72), strabismus (2 of 72), and hyperopia (2 of 72). Statistically significant differences were not found between the percentage of the disorders in the eye examination in the LTx and RTx groups (P=1.00). Another similar disorder in the ocular was observed in children in the control group. The most common disorders in this group included strabismus (7 of 66) and convergence insufficiency (2 of 66). However, the percentage of the disorders determined in both LTx and RTx groups did not significantly differ statistically from the percentage of the disorders found in the control group (P=0.6206).
Prematurity, small birth weight, and early respiratory disorders requiring intubation and artificial ventilation are risk factors of retinopathy of prematurity in infants. It is caused by disorganized growth of the retinal blood vessels and the fibrous tissue in the retina and the vitreous humor. This concerns the prematurely born babies especially those born at less than 28 weeks of gestation and is the main cause of blindness in young children. Although, in most premature infants, retinopathy pulls back spontaneously, in some children it progresses and could lead to retinal detachment and blindness (19–21). As a matter of fact, not even a single cause of retinopathy of prematurity was determined in the LTx and control groups. This disease was diagnosed only in two infants in the RTx group, which were actually extremely immature infants. Both have had laser eye surgery resulting in good effects.
In summary, having an organ transplant in a mother (liver or renal) does not significantly affect the development of the fetus ocular organ and its state in the examined children. Moreover, immunosuppressive treatment during pregnancy, regardless of kind, did not affect the ocular organ’s development.
MATERIALS AND METHODS
Certain parameters of the labor period in liver or renal recipient mothers and neonates delivered at the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, from 01 January 2001 to 30 June 2012 were retrospectively analyzed. The study group encompassed 37 neonates of mothers after LTx and 35 neonates of mothers after RTx. The control group included 66 neonates of nontransplanted mothers that agreed to participate in the study, born consecutively after newborns from the study group and at the same gestational age. The condition of the neonate at the first and fifth minutes according to the Apgar score, the percentage of preterm deliveries, and the type of immunosuppression in women after LTx or RTx used during pregnancy were all evaluated. Ophthalmic examinations in the analyzed group were performed later in the life of the child. Such examinations were performed by a pediatric ophthalmologist in the period between 01 January 2010 and 30 June 2012 during control visits in the ophthalmologic clinic. For the statistical analysis evaluating the significance of differences between fractions of elements in the studies performed (prematurity rate, comparison of the neonates condition in the Apgar score, etc.), Fisher’s test was used for a small sample size, whereas, in differences of a large sample size such as the analysis of immunotherapy drugs, chi-square test was used. For the evaluation of the significance of median differences (week gestation and birth weight) between studied groups, Mann-Whitney test was used. For all calculations, statistical package Statistica 9.0 was applied, and P<0.05 was considered as significant.
1. Blowey DL, Warady BA. Outcome of infants born to women with chronic renal disease. Adv Chronic Renal Dis
2007; 14: 199.
2. Fuchs KM, Wu D, Ebcioglu Z. Pregnancy in renal transplant recipients. Semin Perinatol
2007; 31: 339.
3. Jabiry-Zieniewicz Z, Bobrowska K, Pietrzak B, et al.. Mode of delivery in women after liver transplantation. Transplant Proc
2007; 39; 2796.
4. Kociszewska-Najman B, Pietrzak B, Cyganek A, et al.. Intrauterina hypotrophy and premature births in neonates delivered by female renal and liver transplant recipients. Transplant Proc
2011; 43: 3048.
5. McKay DB, Josephson MA. Pregnancy in recipients of solid organs—effects on mother and child. N Engl J Med
2006; 354: 1281.
6. Armenti VT, Moritz MJ, Cardonick EH, et al.. Immunosuppression in pregnancy: choice for infant and maternal health. Drugs
2002; 62: 2361.
7. Danesi R, Del Tacca M. Teratogenesis and immunosuppressive treatment. Transplant Proc
2004; 36: 705.
8. Fuchs KM, Coustan DR. Immunosuppressant therapy in pregnant organ transplant recipients. Semin Perinatol
2007; 31: 363.
9. Diaz JM, Canal C, Gimenez I, et al.. Pregnancy in recipients of kidney transplantation: effects on the mother and child. Nefrol
2008; 2: 174.
10. Areia A, Galvao A, Pais MS, et al.. Outcome of pregnancy in renal allograft recipients. Arch Gynecol Obstet
2009; 279: 273.
11. Armenti VT, Constantinescu S, Moritz MJ, et al.. Pregnancy after transplantation. Transplant Rev (Orlando)
2008; 22: 223.
12. Dei Malatesta MF, Rossi M, Rocca B, et al.. Pregnancy after liver transplantation: report of 8 new cases and review of the literature. Transpl Immunol
2006; 15: 297.
13. Xia D, He HY, Xu L, et al.. Pregnancy after liver transplantation: four-year follow-up of the first case in mainland China. World J Gastroenterol
2008; 14: 7264.
14. Barrett BT, Panesar GK, Scally AJ, et al.. A limited role for suppression in the central field of individuals with strabismic amblyopia. PLoS One
2012; 7: e36611.
15. Donnelly UM. Horizontal strabismus worldwide—what are the risk factors? Ophthalmic Epidemiol
2012; 19: 117.
16. Larsson E, Rydberg A, Holmström G. Accommodation and convergence in 10-year-old prematurely born and full-term children—a population-based study. Strabismus
2012; 20: 127.
17. Mohan K, Sharma A. Development of refractive accommodative esotropia in children initially diagnosed with pseudoesotropia. J AAPOS
2012; 16: 266.
18. Settas G, Settas C, Minos E, et al.. Photorefractive keratectomy (PRK) versus laser assisted in situ keratomileusis (LASIK) for hyperopia correction. Cochrane Database Syst Rev
2012; 6: CD007112.
19. Don W, Warren DF. Research in the diagnosis and treatment of ROP has greatly enhanced our knowledge of the disease. Rev Optom
2006; 143: 155.
20. Martinez-Cruz CF, Salgado-Valladares M, Poblano A, et al.. Risk factors associated with retinopathy of prematurity and visual alterations in infants with extremely low birth weight. Rev Invest Clin
2012; 64: 136.
21. Tasman W, Patz A, McNamara JA, et al.. Retinopathy of prematurity: the life of a life time disease. Am J Ophthalmol
2006; 141: 167.