http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(2): 162–167 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.909804
ORIGINAL ARTICLE
Obstetrical and neonatal outcomes in renal transplant recipients Kholoud Arab1, Lisa Oddy2, Valerie Patenaude2, and Haim Arie Abenhaim1,2 1
Department of Obstetrics and Gynecology, Jewish General Hospital, McGill University, Montreal, Canada and 2Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, Montreal, Quebec, Canada Abstract
Keywords
Objective: To measure the incidence and outcomes of pregnancies in renal transplant (RT) patients and to identify risk factors of adverse pregnancy outcomes. Methods: We conducted a population-based retrospective cohort study using the United States Nationwide Inpatient Sample from 2003–2010. The incidence of pregnancies in women with RT was measured and logistic regression analysis was used to estimate the adjusted effect of RT on maternal and fetal outcomes. Results: We identified 375 deliveries in patients with a RT among 7 094 300 births for an overall incidence of 5.3 cases per 100 000 births over 8 years. Maternal complications, including preeclampsia OR ¼ 9.87 (7.76, 12.55) and blood transfusion OR ¼ 2.29 (1.69, 3.12) were more common in women with RT as compared to in women without. RT pregnancies were also complicated by an increased risk of preterm birth OR ¼ 4.65 (3.72, 5.81), intrauterine fetal death OR ¼ 3.67 (1.89, 7.15) and fetal congenital anomalies OR ¼ 5.28 (2.81, 9.90). Among women with RT and pre-existing hypertension, the risk of intrauterine growth restriction (IUGR) was considerably increased from 4.3% to 21.8%, OR ¼ 3.79 (1.67, 8.62). Conclusion: Pregnancies in RT patients are associated with an increased risk of maternal and fetal morbidities. Among women with RT, pre-existing hypertension strongly increases the risk of IUGR.
Fetal outcomes, maternal outcomes, pregnancy, renal transplant, risk factors
Introduction The first successful organ transplant, described in the 1950s, was a renal transplant (RT) between two identical twins in Boston, United States [1]. The first successful pregnancy in a RT recipient was delivered by caesarean delivery (CD) in 1963 [2]. It is estimated that 1 in 50 women who have received an organ transplant will become pregnant [3,4]. The reported mean age of renal transplantation in women is 30.2 years, with a transplant-pregnancy interval of about 2 years [5,6]. Female patients with end stage renal disease experience decreased fertility as a result of amenorrhea. Fertility levels rise within a few months following a RT, due to restoration of the hypothalamic gonadal axis [6–8]. The reported overall post RT live birth rate ranges between 66.7%–73.5% [9–11]. Previous studies, mostly case series and few population-based studies, have found an increased risk of adverse pregnancy outcomes among RT patients [10,12]. The purpose of our study was to carry out a population-based
Address for correspondence: Haim Arie Abenhaim, Jewish General Hospital, Obstetrics & Gynecology, McGill University, Pav H, Room 325, 5790 Cote-Des-Neiges Road, Montreal, Quebec H3S 1Y9, Canada. Tel: +51 43408222 x5488. Fax: +51 43407941. E-mail: [email protected]
History Received 18 November 2013 Revised 6 March 2014 Accepted 26 March 2014 Published online 29 April 2014
cohort study to better understand the risks and outcomes of pregnant RT patients and their offspring.
Methods We carried out a population-based retrospective cohort study using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS), which includes approximately 8 million hospital stays each year in the United States [13]. The collected data represents 20% of in-patient admissions, covering approximately 1000 hospitals including specialty institutes in obstetrics and gynecology, public hospitals and academic centers. Several studies have assessed the quality of the available data by evaluating the database indicators [14]. While coding errors, which vary according to the method of data collection, can be identified within patient demographic groups, the quality of the database is considered appropriate in light of improvements that have been made following several adjustments over recent years [13]. Ethics approval for the use of this database was obtained by the Medical Research Ethics Department of the Jewish General Hospital, McGill University. The HCUP-NIS was chosen for its large sample size. We created a cohort that included 7 094 300 million births from 2003 to 2010. Changes occurred from 2003 onwards with respect to the sampling and weighting strategy used in the
Obstetrical and neonatal outcomes in renal transplants
DOI: 10.3109/14767058.2014.909804
NIS database. As a result we elected not to include data from 2002 and earlier to allow for consistency in our data analysis. We identified births using all discharges with a delivery code (65.x, 66.x or V27.x). We defined our exposure (renal transplant) using the ICD-9-CM (International Classification of Diseases 9) diagnosis code of (V42.0). The control group was defined as all deliveries not associated with the diagnosis of RT. We used the ICD-9-CM diagnosis and procedure codes to identify all deliveries associated with adverse pregnancy outcomes. The clinical outcomes were classified into maternal and fetal categories. Maternal outcomes were further sub classified into: antepartum (preeclampsia (PET), gestational diabetes (GDM), premature rupture of membrane (PROM), preterm birth, placental abruption and urinary tract infection (UTI)); intrapartum (caesarean delivery (CD), instrumental delivery, chorioamnionitis, anaesthesia complications, postpartum haemorrhage (PPH) and blood transfusion) and postpartum (postpartum endometritis, wound infection and thromboembolic events). The fetal outcomes included intrauterine growth restriction (IUGR), fetal congenital anomalies and intrauterine fetal death (IUFD). Our analysis was carried out in the following manner: first, the incidence of pregnancies complicated by RT was measured and descriptive statistics of baseline characteristics were carried out among women with and without a history of RT. Second, we conducted logistic regression analysis to estimate the effect of RT on maternal and fetal outcomes. Regression analyses adjusted for the following confounding variables: age, race, smoking, obesity, pre-existing hypertension and diabetes. A subset analysis among women with RT was carried out to evaluate the effect of pre-existing hypertension on IUGR and IUFD. The statistical software used for the analysis was SAS V9.2 (SAS Institute, Cary, NC). Statistical significance was defined as p50.05.
Results 375 cases of renal transplants were identified among 7 094 300 million births giving an overall incidence of 5.3 cases in 100 000 births over 8 years. The incidence varied and Figure 1. Incidence of pregnancy among renal transplant patients over 8 years. The incidence varied throughout the study period and there was no specific trend.
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no specific trend was noted throughout the study period (p ¼ 0.21) (Figure 1). When comparing baseline characteristics; diabetes, pre-existing hypertension and advanced maternal age (older than 35 years) were more common among patients with a RT than those without (Table 1). The adjusted effects of RT on maternal outcomes are listed in Table 2. Women with a RT were more likely to develop PET, preterm labor and PPH compared to those without a transplant. In addition, women with a history of RT were more likely to have CD and require blood transfusion. RT patients were not more likely to experience the following maternal morbidities; GDM, gestational hypertension, eclampsia, placental abruption or previa, intrapartum or postpartum infection, wound infection, thromboembolic events and labor anesthesia complications. No maternal deaths were recorded in this study. The effect of RT on fetuses and newborns is listed in Table 3. Prematurity, IUFD, fetal congenital anomalies and IUGR were all more common among births of women Table 1. Baseline characteristics of pregnant women with and without a renal transplant.
Characteristics Age 525 25–34 4¼35 Race White Black Hispanic Other Habits Smoking Alcohol Comorbidities Obesity Diabetes HTNa a
Renal transplant n ¼ 375 (%)
No renal transplant n ¼ 7 094 025 (%)
14.67 54.40 30.93
34.54 50.59 14.78
38.67 10.93 21.60 7.20
39.98 10.47 18.86 8.09
1.33 0.00
2.64 0.09
0.11 1.00
1.60 10.13 32.27
1.60 0.96 1.33
1.00 50.01 50.01
p Value 50.01
0.69
Pre-existing hypertension.
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J Matern Fetal Neonatal Med, 2015; 28(2): 162–167
Table 2. Effect of renal transplant on maternal outcomes, adjusted for age, race, smoking, obesity, pre-existing hypertension and diabetes.
Outcomes Antepartum complications Gestational hypertension Preeclampsia Eclampsia Gestational diabetes Premature rupture of membrane Chorioamnionitis Urinary tract infections Placental abruption Threatened preterm labor Intrapartum complications Caesarian delivery Anesthesia complications Instrumental delivery Postpartum complications Postpartum hemorrhage Blood transfusion Postpartum infections/pyrexia Wound complications VTE Maternal death Mental disorders
Renal transplant n ¼ 375 (%)
No renal transplant n ¼ 7 094 025 (%)
2.93 26.13 0.27 8.80 5.07 2.67 1.60 1.60 2.13
3.06 3.85 0.08 5.20 3.74 1.73 0.86 1.09 0.95
51.73 0.53 4.53
30.66 0.44 6.55
5.33 12.53 1.33 0.27 1.07 0.00 5.07
2.86 5.53 0.85 0.36 0.68 0.01 4.25
Adjusted OR (95% CI) 1.18 9.87 4.53 1.08 1.40 1.63 1.90 1.26 1.75
(0.64, (7.76, (0.64, (0.75, (0.88, (0.87, (0.85, (0.56, (0.87,
2.15) 12.55) 32.34) 1.56) 2.23) 3.05) 4.26) 2.82) 3.54)
Adjusted p value NS 50.001 NS NS NS NS NS NS NS
1.80 (1.47, 2.22) 1.16 (0.29, 4.66) 0.77 (0.47, 1.25)
50.001 NS NS
1.90 2.29 1.61 0.52 1.43
50.01 50.001 NS NS NS – NS
(1.21, (1.69, (0.67, (0.07, (0.53, – 1.02 (0.64,
2.99) 3.12) 3.90) 3.73) 3.83) 1.63)
VTE – Venous thromboembolism.
Table 3. Effect of renal transplant on fetal outcomes, adjusted for age, race, smoking, obesity, pre-existing hypertension and diabetes.
Outcomes Preterm birth spontaneous Intrauterine fetal death Congenital anomalies Intrauterine growth restriction
Renal transplant n ¼ 375 (%)
No renal transplant n ¼ 7 094 025 (%)
30.67 2.40 2.67 7.73
7.34 0.42 0.37 1.95
Adjusted OR (95% CI) 4.65 3.67 5.28 3.25
(3.72, (1.89, (2.81, (2.21,
5.81) 7.15) 9.90) 4.76)
Adjusted p value 50.001 50.001 50.001 50.001
Table 4. Effect of hypertension among renal transplant patients on fetal outcomes, adjusted for age, race, smoking, obesity, preexisting hypertension and diabetes.
Outcomes Intrauterine growth restriction Intrauterine fetal death
Hypertension n ¼ 121 (%)
No Hypertension n ¼ 254 (%)
Adjusted OR (95% CI)
Adjusted p value
21.8 4.1
4.3 1.6
3.79 (1.67, 8.62) 2.03 (0.55, 9.56)
50.01 NS
with RT. The effect of pre-existing hypertension among women with RT showed that risk of IUGR was considerably increased among women with pre-existing hypertension (Table 4).
Discussion Pregnancy in patients with a RT is considered rare in general obstetric practice. The existing literature suggests increased risks of obstetrical complications among RT recipients, however most of the studies are case series and few are population-based studies [2,4–6,9–12]. Studies published in transplant journals often do not address obstetrical issues surrounding pregnancy in RT recipients. We conducted a retrospective cohort study using a large population-based administrative database to measure the incidence of
pregnancy in RT patients and to evaluate common obstetrical outcomes. Our results suggest that RT births have been stable over the last several years however they continue to be associated with increased adverse maternal and fetal outcomes. Our exposure, RT, was assigned using the ICD-9-CM diagnosis code of V42.0. Numerous studies evaluating RT used V42.0, confirming the validity of this code. No alternative or supplementary coding for RT is available. Studies having used the HCUP-NIS database also used the same coding to identify patients with RT, including one recent study on the economic burden of RT in the United States [15]. To the best of our knowledge, this single ICD-9-CM code is a reliable and useful way to identify the cohort of RT patients in our study.
DOI: 10.3109/14767058.2014.909804
Our incidence measured at 5.3 cases per 100 000 births was calculated using the number of births and not pregnancies among RT patients. We set the cohort entry to be delivery rather than admissions in pregnancy to avoid an overrepresentation of renal failure given that these women are more likely to have multiple admissions in pregnancy but only one admission for delivery. The effect of renal transplantation on maternal and fetal outcomes was measured and an increased risk of maternal complications was found among RT patients, corroborating findings from previous studies in the literature. PET represents a major concern among patients with a RT. In a metaanalysis by Deshpande et al. the incidence of PET among pregnant RT patients was 27%. In our study, 26% of pregnant RT patients developed PET; however they were not more likely to develop eclampsia [10]. In addition, there was no increased risk of developing gestational hypertension among RT recipients. Many RTs are performed during childhood as a consequence of congenital renal abnormalities [16]. There is a known association between renal and genital malformations. Pregnant RT recipients may have concurrent uterine or cervical anomalies, potentially contributing to an increased risk of premature delivery [17]. Iatrogenic preterm delivery for maternal or fetal indications may contribute to the increased incidence of prematurity among RT recipients. Severe PET, graft rejection and severe growth restriction are major concerns among RT patients. Pregnant RT recipients need to be aware of possible adverse outcomes including premature delivery and prolonged neonatal intensive care unit (NICU) admission. We were unable to identify the actual risk of delivering prematurely however we identified an overall 30.6% increased risk of delivery before 37 weeks were completed among pregnant women with a RT. Celik et al. reported a 58% risk of prematurity among women with a RT, whereas Sibanda reported a 44% risk of premature delivery [12,18]. In a meta-analysis by Deshpande et al., there was a 45.6% risk of prematurity among RT recipients [10]. Additional data is required to differentiate late preterm cases and extreme prematurity in order to further facilitate the parental counseling process. In our study, 51% of women with RT gave birth by CD. This high rate of CD has previously been reported by Sibanda who measured the rate at 72% and in a meta-analysis by Deshpande et al. a reported 56.9 % of women with RT required CD [10,12]. Whether or not this was due to an increase in elective caesareans versus intrapartum is unknown. Most studies published in the literature did not report whether caesareans were elective or not. In a study by Cruz Lemini et al. on 75 RT pregnancies a reported 30% of CDs were performed electively [19]. It is possible that the increase is in part due to an advanced maternal age among women with RT as well as the increased risk of congenital anomalies and fetal growth abnormalities that is more common among women with a RT. We did not observe an increased risk of infectious morbidity antenatally or postnatally among RT patients, regardless if they delivered vaginally or by CD. However, steroids and immunosuppressant medications administered during pregnancy may have increased the risk of infection. Many studies in the literature identified a higher rate of
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infectious complications associated with steroids and immunosuppressant therapy. A study by Fernandez et al evaluated the impact of hypogammaglobulinemia in RT patients and suggested monitoring immunoglobulin levels to identify those at high risk of infection [20]. Low thresholds of intervention or administration of prophylactic antibiotics may have played a role in the prevention of chorioamnionitis, endometritis and wound infection post CD [21]. We could not determine whether prophylactic antibiotic treatment in RT patients differed from the controls. Furthermore, our study did not include data on immunoglobulin levels during pregnancy, an indicator for infection susceptibility. Although the women with RT were not found in our study to be at higher risk of developing urinary tract infections (UTI), a study by Fuchs and Mastrobattista did find that women with RT had an increased risk of UTIs as high as 40% [9,22]. Further information on the type and dose of drugs administered during pregnancy would help elucidate any potential association between medical treatment and risk of infection. Our study found an increased risk of PPH and blood transfusion in patients with a RT. The risk of developing hemorrhage in pregnant women with a RT was almost twice the risk compared to the general population. The actual pathophysiology of hemorrhage remains unclear and no prior studies in the literature have explored a potential association between PPH and RTs. One potential explanation is the higher rate of CDs among RT recipients which may in part contribute to the increased risk of PPH. An alternate explanation may be the fact that immunosuppressant medications have been shown to have a damaging effect on the vascular smooth muscle of arterioles [23,24]. While there are no specific studies to our knowledge that have evaluated the effects of these medications on the uterus, it is possible that these medications at least in part affect the uterine arterioles and their capacity to limit uterine bleeding following delivery. The first successful pregnancy in a post-transplant patient was accomplished without the administration of immunosuppressant medications. The safety of immunosuppressant drugs and their association with congenital anomalies remains a concern [25]. We observed a 5-fold increase in congenital malformations among RT patients. Earlier studies by Armenti et al reported a 3 to 5% risk of congenital anomalies among women who have undergone a RT, findings similar to the general population. No association was found between distinct patterns of malformation and in utero exposure to conventional immunosuppressants cyclosporine and tacrolimus [26]. Additional clinical studies were conducted by Armenti et al on the safety of mycophenolate following case reports of microtia and orofacial abnormalities associated with intrauterine exposure to the drug. A higher incidence of structural malformations was reported among RT recipients taking mycophenolate [27]. Although our study lacked information on the type and dosage of immunosuppressant drugs administered to RT patients, the increased risk of congenital malformations observed is concerning and should be discussed in prenatal counseling with parents. Our study found nearly 30% of RT recipients developed growth restriction. A study by Cruz Lemini et al. on 60 pregnancies in RT patients, reported a 4% incidence of IUGR [19]. We were unable to identify data on fetal growth
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abnormalities in the published registry data (the United Kingdom transplant registry data and the national transplant pregnancy registry (NTPR)). A significant number of births below 2500 g in RT patients were reported in the literature; however it is unclear whether this is due to prematurity or growth restriction [10,12]. Additional background information on RT patients included in our study would be helpful in explaining any existing association between IUGR and RTs. Anemia is common in patients with chronic renal failure, often persisting until the period following transplantation. A potential association between IUGR and maternal anemia could be a contributing factor to fetal growth restriction in RT patients [28,29]. Information on the underlying pathology of kidney failure in RT patients is useful. Renal transplantation, for example, does not reverse vasculopathy caused by advanced diabetes or systemic vasculitis. Pregnant RT patients with vasculopathy therefore continue to be at increased risk of IUGR, despite having a normal kidney function [30]. In subset analyses carried out in women with RT, diabetes was not found to have an independent effect on IUGR or IUFD (not in table). In our study, fetal mortalities were four times greater among women with a RT when compared to the controls. While the actual cause of IUFD is unknown, growth restriction and congenital anomalies can be major contributing factors. The UK transplant pregnancy registry previously published an IUFD incidence of 2% among RT recipients [12]. Deshpande and colleagues quoted 2.5% of RT patients experienced IUFD in their systematic review [10]. Similarly, we observed that 2.4% of fetuses died in utero among women with a RT. The majority of fetal deaths occurred among women with pre-existing hypertension. We cannot compare our findings with previous studies since growth restriction and congenital anomalies have not been previously studied. It is unclear whether congenital anomalies and growth restrictions are contributing factors to the increased rate of IUFD among transplanted patients. The scope of the data used in this study was limited to the quality of the data entered in the database. We acknowledge several limitations in our study. Further information on patient drug history would have allowed for comparison of the risk of congenital anomalies between cases and controls. The actual cause of fetal deaths is unknown, as it remains unclear whether the deaths were related to fetal anomalies or the consequence of growth restriction. Knowing the actual gestational age at delivery would be helpful in determining whether women with a RT have a greater risk of delivering extremely premature infants. Pregnancy in RT patients continues to be a challenge for obstetricians as it is associated with numerous maternal and fetal risks. To our knowledge this is the first study to explore an increased risk of PPH and blood transfusion among pregnant women who have previously received a RT. Further in-depth research is required to ensure proper management of possible obstetric complications associated with pregnancy in RT patients. Appropriate antenatal counseling is essential when preparing pregnant RT recipients for potential complications should any difficulties arise during such a special pregnancy.
J Matern Fetal Neonatal Med, 2015; 28(2): 162–167
Declaration of interest The authors report no conflicts of interest.
References 1. Ohler L, Coscia L, Armenti V. Milestones in transplantation. Progress Transplant [Biography Historical Article] 2008;18:63–4. 2. Davison JM. Dialysis, transplantation, and pregnancy. Am J Kidney Dis 1991;17:127–32. 3. Bailey LL. Organ transplantation: a paradigm of medical progress. Hastings Cent Rep 1990;20:24–8. 4. Miniero R, Tardivo I, Curtoni ES, et al. Outcome of pregnancy after organ transplantation: a retrospective survey in Italy. Transplant International 2005;17:724–9. 5. Al Duraihimh H, Ghamdi G, Moussa D, et al. Outcome of 234 pregnancies in 140 renal transplant recipients from five Middle Eastern Countries. Transplantation 2008;85:840–3. 6. Gutierrez MJ, Acebedo-Ribo M, Garcia-Donaire JA, et al. Pregnancy in renal transplant recipients. Transplantation Proceedings 2005;37:3721–2. 7. McKay DB, Josephson MA. Pregnancy in recipients of solid organs – effects on mother and child. N Engl J Med 2006;354:1281–93. 8. Gill JS, Zalunardo N, Rose C, Tonelli M. The pregnancy rate and live birth rate in kidney transplant recipients. Am J Transplant 2009;9:1541–9. 9. Mastrobattista JM, Gomez-Lobo V. Pregnancy after solid organ transplantation. Obstet Gynecol 2008;112:919–32. 10. Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes in kidney transplant recipients: a systematic review and metaanalysis. Am J Transplant 2011;11:2388–404. 11. Levidiotis V, Chang S, McDonald S. Pregnancy and maternal outcomes among kidney transplant recipients. J Am Soc Nephrol 2009;20:2433–40. 12. Sibanda N, Briggs JD, Davison JM, et al. Pregnancy after organ transplantation: a report from the UK Transplant pregnancy registry. Transplantation 2007;83:1301–7. 13. HCUP Overview. Healthcare Cost and Utilization Project (HCUP). February 2014. Agency for Healthcare Research and Quality, Rockville, MD. [updated 2014 Feb 11; cited 2013 July 10]. Available from: www.hcup-us.ahrq.gov/overview.jsp. 14. Berthelsen CL. Evaluation of coding data quality of the HCUP National Inpatient Sample. Top Health Inf Manage 2000;21:10–23. 15. Janjua HS, Hains DS, Mahan JD. Kidney transplantation in the United States: economic burden and recent trends analysis. Prog Transplant 2013;23:78–83. 16. Kenney PJ, Spirt BA, Leeson MD. Genitourinary anomalies: radiologic-anatomic correlations. RadioGraphics 1984;4:233–60. 17. Hua M, Odibo AO, Longman RE, et al. Congenital uterine anomalies and adverse pregnancy outcomes. Am J Obstet Gynecol 2011;205:558.e1–5. 18. Celik G, To¨z H, Ertilav M, et al. Biochemical parameters, renal function, and outcome of pregnancy in kidney transplant recipient. Transplant Proc 2011;43:2579–83. 19. Cruz Lemini MC, Ibarguengoitia Ochoa F, Villanueva Gonzalez MA. Perinatal outcome following renal transplantation. Int J Gynecol Obstet 2007;96:76–9. 20. Fernandez-Ruiz M, Lopez-Medrano F, Varela-Pena P, et al. Monitoring of immunoglobulin levels identifies kidney transplant recipients at high risk of infection. Am J Transplant 2012;12: 2763–73. 21. Francis C, Mumford M, Strand ML, et al. Timing of prophylactic antibiotic at cesarean section: a double-blinded, randomized trial. J Perinatol 2013;33:759–62. 22. Fuchs KM, Wu D, Ebcioglu Z. Pregnancy in renal transplant recipients. Sem Perinatol 2007;31:339–47. 23. Caramelo C, Alvarez-Arroyo MV, Yagu¨e S, et al. Cyclosporin A toxicity, and more: vascular endothelial growth factor (VEGF) steps forward. Nephrol Dial Transplant 2004;19:285–8. 24. Sharma A, Jain S, Gupta R, et al. Calcineurin inhibitor toxicity in renal allografts: morphologic clues from protocol biopsies. Indian J Pathol Microbiol 2010;53:651–7. 25. Armenti VT. Pregnancy after transplantation: milestones and assessments of risk. Am J Transplant 2011;11:2275–6.
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26. Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 2004; 103–14. 27. Sifontis NM, Coscia LA, Constantinescu S, et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006;82: 1698–702.
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28. Frasca GM, Balestra E, Gaffi G, et al. Kidney transplant: a mere stage of CKD?. G Ital Nefrol 2010;27:274–81. 29. Mason JB, Saldanha LS, Ramakrishnan U, et al. Opportunities for improving maternal nutrition and birth outcomes: synthesis of country experiences. Food Nutr Bull 2012;33(2 Suppl):104–37. 30. Mitchell RN. Learning from rejection: what transplantation teaches us about (other) vascular pathologies. J Autoimmun 2013;45:80–9.
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ORIGINAL ARTICLE
Obstetrical and neonatal outcomes in renal transplant recipients Kholoud Arab1, Lisa Oddy2, Valerie Patenaude2, and Haim Arie Abenhaim1,2 1
Department of Obstetrics and Gynecology, Jewish General Hospital, McGill University, Montreal, Canada and 2Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, Montreal, Quebec, Canada Abstract
Keywords
Objective: To measure the incidence and outcomes of pregnancies in renal transplant (RT) patients and to identify risk factors of adverse pregnancy outcomes. Methods: We conducted a population-based retrospective cohort study using the United States Nationwide Inpatient Sample from 2003–2010. The incidence of pregnancies in women with RT was measured and logistic regression analysis was used to estimate the adjusted effect of RT on maternal and fetal outcomes. Results: We identified 375 deliveries in patients with a RT among 7 094 300 births for an overall incidence of 5.3 cases per 100 000 births over 8 years. Maternal complications, including preeclampsia OR ¼ 9.87 (7.76, 12.55) and blood transfusion OR ¼ 2.29 (1.69, 3.12) were more common in women with RT as compared to in women without. RT pregnancies were also complicated by an increased risk of preterm birth OR ¼ 4.65 (3.72, 5.81), intrauterine fetal death OR ¼ 3.67 (1.89, 7.15) and fetal congenital anomalies OR ¼ 5.28 (2.81, 9.90). Among women with RT and pre-existing hypertension, the risk of intrauterine growth restriction (IUGR) was considerably increased from 4.3% to 21.8%, OR ¼ 3.79 (1.67, 8.62). Conclusion: Pregnancies in RT patients are associated with an increased risk of maternal and fetal morbidities. Among women with RT, pre-existing hypertension strongly increases the risk of IUGR.
Fetal outcomes, maternal outcomes, pregnancy, renal transplant, risk factors
Introduction The first successful organ transplant, described in the 1950s, was a renal transplant (RT) between two identical twins in Boston, United States [1]. The first successful pregnancy in a RT recipient was delivered by caesarean delivery (CD) in 1963 [2]. It is estimated that 1 in 50 women who have received an organ transplant will become pregnant [3,4]. The reported mean age of renal transplantation in women is 30.2 years, with a transplant-pregnancy interval of about 2 years [5,6]. Female patients with end stage renal disease experience decreased fertility as a result of amenorrhea. Fertility levels rise within a few months following a RT, due to restoration of the hypothalamic gonadal axis [6–8]. The reported overall post RT live birth rate ranges between 66.7%–73.5% [9–11]. Previous studies, mostly case series and few population-based studies, have found an increased risk of adverse pregnancy outcomes among RT patients [10,12]. The purpose of our study was to carry out a population-based
Address for correspondence: Haim Arie Abenhaim, Jewish General Hospital, Obstetrics & Gynecology, McGill University, Pav H, Room 325, 5790 Cote-Des-Neiges Road, Montreal, Quebec H3S 1Y9, Canada. Tel: +51 43408222 x5488. Fax: +51 43407941. E-mail: [email protected]
History Received 18 November 2013 Revised 6 March 2014 Accepted 26 March 2014 Published online 29 April 2014
cohort study to better understand the risks and outcomes of pregnant RT patients and their offspring.
Methods We carried out a population-based retrospective cohort study using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS), which includes approximately 8 million hospital stays each year in the United States [13]. The collected data represents 20% of in-patient admissions, covering approximately 1000 hospitals including specialty institutes in obstetrics and gynecology, public hospitals and academic centers. Several studies have assessed the quality of the available data by evaluating the database indicators [14]. While coding errors, which vary according to the method of data collection, can be identified within patient demographic groups, the quality of the database is considered appropriate in light of improvements that have been made following several adjustments over recent years [13]. Ethics approval for the use of this database was obtained by the Medical Research Ethics Department of the Jewish General Hospital, McGill University. The HCUP-NIS was chosen for its large sample size. We created a cohort that included 7 094 300 million births from 2003 to 2010. Changes occurred from 2003 onwards with respect to the sampling and weighting strategy used in the
Obstetrical and neonatal outcomes in renal transplants
DOI: 10.3109/14767058.2014.909804
NIS database. As a result we elected not to include data from 2002 and earlier to allow for consistency in our data analysis. We identified births using all discharges with a delivery code (65.x, 66.x or V27.x). We defined our exposure (renal transplant) using the ICD-9-CM (International Classification of Diseases 9) diagnosis code of (V42.0). The control group was defined as all deliveries not associated with the diagnosis of RT. We used the ICD-9-CM diagnosis and procedure codes to identify all deliveries associated with adverse pregnancy outcomes. The clinical outcomes were classified into maternal and fetal categories. Maternal outcomes were further sub classified into: antepartum (preeclampsia (PET), gestational diabetes (GDM), premature rupture of membrane (PROM), preterm birth, placental abruption and urinary tract infection (UTI)); intrapartum (caesarean delivery (CD), instrumental delivery, chorioamnionitis, anaesthesia complications, postpartum haemorrhage (PPH) and blood transfusion) and postpartum (postpartum endometritis, wound infection and thromboembolic events). The fetal outcomes included intrauterine growth restriction (IUGR), fetal congenital anomalies and intrauterine fetal death (IUFD). Our analysis was carried out in the following manner: first, the incidence of pregnancies complicated by RT was measured and descriptive statistics of baseline characteristics were carried out among women with and without a history of RT. Second, we conducted logistic regression analysis to estimate the effect of RT on maternal and fetal outcomes. Regression analyses adjusted for the following confounding variables: age, race, smoking, obesity, pre-existing hypertension and diabetes. A subset analysis among women with RT was carried out to evaluate the effect of pre-existing hypertension on IUGR and IUFD. The statistical software used for the analysis was SAS V9.2 (SAS Institute, Cary, NC). Statistical significance was defined as p50.05.
Results 375 cases of renal transplants were identified among 7 094 300 million births giving an overall incidence of 5.3 cases in 100 000 births over 8 years. The incidence varied and Figure 1. Incidence of pregnancy among renal transplant patients over 8 years. The incidence varied throughout the study period and there was no specific trend.
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no specific trend was noted throughout the study period (p ¼ 0.21) (Figure 1). When comparing baseline characteristics; diabetes, pre-existing hypertension and advanced maternal age (older than 35 years) were more common among patients with a RT than those without (Table 1). The adjusted effects of RT on maternal outcomes are listed in Table 2. Women with a RT were more likely to develop PET, preterm labor and PPH compared to those without a transplant. In addition, women with a history of RT were more likely to have CD and require blood transfusion. RT patients were not more likely to experience the following maternal morbidities; GDM, gestational hypertension, eclampsia, placental abruption or previa, intrapartum or postpartum infection, wound infection, thromboembolic events and labor anesthesia complications. No maternal deaths were recorded in this study. The effect of RT on fetuses and newborns is listed in Table 3. Prematurity, IUFD, fetal congenital anomalies and IUGR were all more common among births of women Table 1. Baseline characteristics of pregnant women with and without a renal transplant.
Characteristics Age 525 25–34 4¼35 Race White Black Hispanic Other Habits Smoking Alcohol Comorbidities Obesity Diabetes HTNa a
Renal transplant n ¼ 375 (%)
No renal transplant n ¼ 7 094 025 (%)
14.67 54.40 30.93
34.54 50.59 14.78
38.67 10.93 21.60 7.20
39.98 10.47 18.86 8.09
1.33 0.00
2.64 0.09
0.11 1.00
1.60 10.13 32.27
1.60 0.96 1.33
1.00 50.01 50.01
p Value 50.01
0.69
Pre-existing hypertension.
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Table 2. Effect of renal transplant on maternal outcomes, adjusted for age, race, smoking, obesity, pre-existing hypertension and diabetes.
Outcomes Antepartum complications Gestational hypertension Preeclampsia Eclampsia Gestational diabetes Premature rupture of membrane Chorioamnionitis Urinary tract infections Placental abruption Threatened preterm labor Intrapartum complications Caesarian delivery Anesthesia complications Instrumental delivery Postpartum complications Postpartum hemorrhage Blood transfusion Postpartum infections/pyrexia Wound complications VTE Maternal death Mental disorders
Renal transplant n ¼ 375 (%)
No renal transplant n ¼ 7 094 025 (%)
2.93 26.13 0.27 8.80 5.07 2.67 1.60 1.60 2.13
3.06 3.85 0.08 5.20 3.74 1.73 0.86 1.09 0.95
51.73 0.53 4.53
30.66 0.44 6.55
5.33 12.53 1.33 0.27 1.07 0.00 5.07
2.86 5.53 0.85 0.36 0.68 0.01 4.25
Adjusted OR (95% CI) 1.18 9.87 4.53 1.08 1.40 1.63 1.90 1.26 1.75
(0.64, (7.76, (0.64, (0.75, (0.88, (0.87, (0.85, (0.56, (0.87,
2.15) 12.55) 32.34) 1.56) 2.23) 3.05) 4.26) 2.82) 3.54)
Adjusted p value NS 50.001 NS NS NS NS NS NS NS
1.80 (1.47, 2.22) 1.16 (0.29, 4.66) 0.77 (0.47, 1.25)
50.001 NS NS
1.90 2.29 1.61 0.52 1.43
50.01 50.001 NS NS NS – NS
(1.21, (1.69, (0.67, (0.07, (0.53, – 1.02 (0.64,
2.99) 3.12) 3.90) 3.73) 3.83) 1.63)
VTE – Venous thromboembolism.
Table 3. Effect of renal transplant on fetal outcomes, adjusted for age, race, smoking, obesity, pre-existing hypertension and diabetes.
Outcomes Preterm birth spontaneous Intrauterine fetal death Congenital anomalies Intrauterine growth restriction
Renal transplant n ¼ 375 (%)
No renal transplant n ¼ 7 094 025 (%)
30.67 2.40 2.67 7.73
7.34 0.42 0.37 1.95
Adjusted OR (95% CI) 4.65 3.67 5.28 3.25
(3.72, (1.89, (2.81, (2.21,
5.81) 7.15) 9.90) 4.76)
Adjusted p value 50.001 50.001 50.001 50.001
Table 4. Effect of hypertension among renal transplant patients on fetal outcomes, adjusted for age, race, smoking, obesity, preexisting hypertension and diabetes.
Outcomes Intrauterine growth restriction Intrauterine fetal death
Hypertension n ¼ 121 (%)
No Hypertension n ¼ 254 (%)
Adjusted OR (95% CI)
Adjusted p value
21.8 4.1
4.3 1.6
3.79 (1.67, 8.62) 2.03 (0.55, 9.56)
50.01 NS
with RT. The effect of pre-existing hypertension among women with RT showed that risk of IUGR was considerably increased among women with pre-existing hypertension (Table 4).
Discussion Pregnancy in patients with a RT is considered rare in general obstetric practice. The existing literature suggests increased risks of obstetrical complications among RT recipients, however most of the studies are case series and few are population-based studies [2,4–6,9–12]. Studies published in transplant journals often do not address obstetrical issues surrounding pregnancy in RT recipients. We conducted a retrospective cohort study using a large population-based administrative database to measure the incidence of
pregnancy in RT patients and to evaluate common obstetrical outcomes. Our results suggest that RT births have been stable over the last several years however they continue to be associated with increased adverse maternal and fetal outcomes. Our exposure, RT, was assigned using the ICD-9-CM diagnosis code of V42.0. Numerous studies evaluating RT used V42.0, confirming the validity of this code. No alternative or supplementary coding for RT is available. Studies having used the HCUP-NIS database also used the same coding to identify patients with RT, including one recent study on the economic burden of RT in the United States [15]. To the best of our knowledge, this single ICD-9-CM code is a reliable and useful way to identify the cohort of RT patients in our study.
DOI: 10.3109/14767058.2014.909804
Our incidence measured at 5.3 cases per 100 000 births was calculated using the number of births and not pregnancies among RT patients. We set the cohort entry to be delivery rather than admissions in pregnancy to avoid an overrepresentation of renal failure given that these women are more likely to have multiple admissions in pregnancy but only one admission for delivery. The effect of renal transplantation on maternal and fetal outcomes was measured and an increased risk of maternal complications was found among RT patients, corroborating findings from previous studies in the literature. PET represents a major concern among patients with a RT. In a metaanalysis by Deshpande et al. the incidence of PET among pregnant RT patients was 27%. In our study, 26% of pregnant RT patients developed PET; however they were not more likely to develop eclampsia [10]. In addition, there was no increased risk of developing gestational hypertension among RT recipients. Many RTs are performed during childhood as a consequence of congenital renal abnormalities [16]. There is a known association between renal and genital malformations. Pregnant RT recipients may have concurrent uterine or cervical anomalies, potentially contributing to an increased risk of premature delivery [17]. Iatrogenic preterm delivery for maternal or fetal indications may contribute to the increased incidence of prematurity among RT recipients. Severe PET, graft rejection and severe growth restriction are major concerns among RT patients. Pregnant RT recipients need to be aware of possible adverse outcomes including premature delivery and prolonged neonatal intensive care unit (NICU) admission. We were unable to identify the actual risk of delivering prematurely however we identified an overall 30.6% increased risk of delivery before 37 weeks were completed among pregnant women with a RT. Celik et al. reported a 58% risk of prematurity among women with a RT, whereas Sibanda reported a 44% risk of premature delivery [12,18]. In a meta-analysis by Deshpande et al., there was a 45.6% risk of prematurity among RT recipients [10]. Additional data is required to differentiate late preterm cases and extreme prematurity in order to further facilitate the parental counseling process. In our study, 51% of women with RT gave birth by CD. This high rate of CD has previously been reported by Sibanda who measured the rate at 72% and in a meta-analysis by Deshpande et al. a reported 56.9 % of women with RT required CD [10,12]. Whether or not this was due to an increase in elective caesareans versus intrapartum is unknown. Most studies published in the literature did not report whether caesareans were elective or not. In a study by Cruz Lemini et al. on 75 RT pregnancies a reported 30% of CDs were performed electively [19]. It is possible that the increase is in part due to an advanced maternal age among women with RT as well as the increased risk of congenital anomalies and fetal growth abnormalities that is more common among women with a RT. We did not observe an increased risk of infectious morbidity antenatally or postnatally among RT patients, regardless if they delivered vaginally or by CD. However, steroids and immunosuppressant medications administered during pregnancy may have increased the risk of infection. Many studies in the literature identified a higher rate of
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infectious complications associated with steroids and immunosuppressant therapy. A study by Fernandez et al evaluated the impact of hypogammaglobulinemia in RT patients and suggested monitoring immunoglobulin levels to identify those at high risk of infection [20]. Low thresholds of intervention or administration of prophylactic antibiotics may have played a role in the prevention of chorioamnionitis, endometritis and wound infection post CD [21]. We could not determine whether prophylactic antibiotic treatment in RT patients differed from the controls. Furthermore, our study did not include data on immunoglobulin levels during pregnancy, an indicator for infection susceptibility. Although the women with RT were not found in our study to be at higher risk of developing urinary tract infections (UTI), a study by Fuchs and Mastrobattista did find that women with RT had an increased risk of UTIs as high as 40% [9,22]. Further information on the type and dose of drugs administered during pregnancy would help elucidate any potential association between medical treatment and risk of infection. Our study found an increased risk of PPH and blood transfusion in patients with a RT. The risk of developing hemorrhage in pregnant women with a RT was almost twice the risk compared to the general population. The actual pathophysiology of hemorrhage remains unclear and no prior studies in the literature have explored a potential association between PPH and RTs. One potential explanation is the higher rate of CDs among RT recipients which may in part contribute to the increased risk of PPH. An alternate explanation may be the fact that immunosuppressant medications have been shown to have a damaging effect on the vascular smooth muscle of arterioles [23,24]. While there are no specific studies to our knowledge that have evaluated the effects of these medications on the uterus, it is possible that these medications at least in part affect the uterine arterioles and their capacity to limit uterine bleeding following delivery. The first successful pregnancy in a post-transplant patient was accomplished without the administration of immunosuppressant medications. The safety of immunosuppressant drugs and their association with congenital anomalies remains a concern [25]. We observed a 5-fold increase in congenital malformations among RT patients. Earlier studies by Armenti et al reported a 3 to 5% risk of congenital anomalies among women who have undergone a RT, findings similar to the general population. No association was found between distinct patterns of malformation and in utero exposure to conventional immunosuppressants cyclosporine and tacrolimus [26]. Additional clinical studies were conducted by Armenti et al on the safety of mycophenolate following case reports of microtia and orofacial abnormalities associated with intrauterine exposure to the drug. A higher incidence of structural malformations was reported among RT recipients taking mycophenolate [27]. Although our study lacked information on the type and dosage of immunosuppressant drugs administered to RT patients, the increased risk of congenital malformations observed is concerning and should be discussed in prenatal counseling with parents. Our study found nearly 30% of RT recipients developed growth restriction. A study by Cruz Lemini et al. on 60 pregnancies in RT patients, reported a 4% incidence of IUGR [19]. We were unable to identify data on fetal growth
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abnormalities in the published registry data (the United Kingdom transplant registry data and the national transplant pregnancy registry (NTPR)). A significant number of births below 2500 g in RT patients were reported in the literature; however it is unclear whether this is due to prematurity or growth restriction [10,12]. Additional background information on RT patients included in our study would be helpful in explaining any existing association between IUGR and RTs. Anemia is common in patients with chronic renal failure, often persisting until the period following transplantation. A potential association between IUGR and maternal anemia could be a contributing factor to fetal growth restriction in RT patients [28,29]. Information on the underlying pathology of kidney failure in RT patients is useful. Renal transplantation, for example, does not reverse vasculopathy caused by advanced diabetes or systemic vasculitis. Pregnant RT patients with vasculopathy therefore continue to be at increased risk of IUGR, despite having a normal kidney function [30]. In subset analyses carried out in women with RT, diabetes was not found to have an independent effect on IUGR or IUFD (not in table). In our study, fetal mortalities were four times greater among women with a RT when compared to the controls. While the actual cause of IUFD is unknown, growth restriction and congenital anomalies can be major contributing factors. The UK transplant pregnancy registry previously published an IUFD incidence of 2% among RT recipients [12]. Deshpande and colleagues quoted 2.5% of RT patients experienced IUFD in their systematic review [10]. Similarly, we observed that 2.4% of fetuses died in utero among women with a RT. The majority of fetal deaths occurred among women with pre-existing hypertension. We cannot compare our findings with previous studies since growth restriction and congenital anomalies have not been previously studied. It is unclear whether congenital anomalies and growth restrictions are contributing factors to the increased rate of IUFD among transplanted patients. The scope of the data used in this study was limited to the quality of the data entered in the database. We acknowledge several limitations in our study. Further information on patient drug history would have allowed for comparison of the risk of congenital anomalies between cases and controls. The actual cause of fetal deaths is unknown, as it remains unclear whether the deaths were related to fetal anomalies or the consequence of growth restriction. Knowing the actual gestational age at delivery would be helpful in determining whether women with a RT have a greater risk of delivering extremely premature infants. Pregnancy in RT patients continues to be a challenge for obstetricians as it is associated with numerous maternal and fetal risks. To our knowledge this is the first study to explore an increased risk of PPH and blood transfusion among pregnant women who have previously received a RT. Further in-depth research is required to ensure proper management of possible obstetric complications associated with pregnancy in RT patients. Appropriate antenatal counseling is essential when preparing pregnant RT recipients for potential complications should any difficulties arise during such a special pregnancy.
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Declaration of interest The authors report no conflicts of interest.
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