A number of single-center studies have described fetal and maternal complications in pregnancies after renal transplantation. The fetal complications reported include preterm delivery and low birth weight. With regard to maternal complications, there is uncertainty about the relationship between hypertension and pregnancy outcome and about whether pregnancy adversely affects long-term renal transplant function. After cardiothoracic and liver transplants, the number of recorded pregnancies is small and the information available is limited.
There are published reports from two registry studies. The first is from the European Dialysis and Transplant Association Registry and contains data on more than 400 pregnancies in renal transplant recipients (1). However, most of the data in this study were collected in the 1980s, do not represent current practice such as immunosuppressive protocols, and very few items of information are available for each pregnancy. Data also are available from the United States National Transplantation Pregnancy Registry (NTPR) based in Philadelphia (2–4), which collates information from patients who either self-report or are identified by doctors and/or transplant coordinators.
The United Kingdom (U.K.) Transplant Pregnancy Registry, which was established in 1997 to obtain detailed information on maternal and fetal outcomes of pregnancies in organ transplant recipients in the United Kingdom (5), has published preliminary results on outcomes for kidney transplant recipients (6).
SUBJECTS AND METHODS
In 1997 all kidney, liver, and cardiothoracic organ transplant follow-up units in the United Kingdom were asked to identify female transplant recipients with a recent pregnancy. This question was repeated annually for the next 3 years and with some retrospective collection, a data set extending from 1994 to 2001 was obtained. Data were received from 56 of the 63 units that had identified female renal transplant patients with a recent pregnancy. Data also were received from six cardiothoracic and four liver transplant units in the United Kingdom and one liver unit in the Republic of Ireland, and the 50 obstetric units associated with the transplant follow-up units.
For all pregnancies, the data collected included serum creatinine (SCr), systolic and diastolic blood pressure, urine protein, and hemoglobin, each recorded within 3 months before pregnancy, during the second and third trimesters, and 3 to 6 months after delivery. Long-term postpregnancy SCr data were obtained from transplant follow-up information reported annually to the UKT database. In addition, information was collected on episodes of renal dysfunction during pregnancy and their cause, transplant biopsy and resulting diagnosis (if performed during pregnancy), immunosuppressive drug regimens, use of antihypertensive drugs, and past obstetric history. An episode of renal dysfunction was defined as an increase in SCr of 20% or more. Data also were collected on pregnancies that failed to attain 24 weeks’ gestation, including the cause, if known, and the gestational age. For pregnancies that reached 24 weeks or more, details of the delivery, including the type of labor (spontaneous, induced or elective caesarean section), any complications before or during labor and delivery, in addition to the type of anesthetic, were collected. For the infant, the information requested included birth weight, gender, gestation, major complications, and (if the baby died), time and cause of death.
We used logistic regression to study the effect of several factors on three outcomes: success of pregnancy, risk of preterm delivery, and low birth weight. A successful pregnancy was defined as one that resulted in a live birth, a preterm delivery was defined as one with a gestation of between 24 and 37 weeks, low birth weight was defined as <2500 g and very low birth weight as <1500 g. The factors considered included SCr, blood pressure, presence of drug-treated hypertension (DHTN), renal dysfunction, maternal age at delivery, and time from transplant to delivery. A SCr of >150 μmol/L was regarded as being considerably elevated. Although the choice of a 150 μmol/L threshold is arbitrary, a previous study of pregnancy in renal allograft recipients used this number (7) and it represents substantial impairment of renal function.
Stepwise regression was used to identify factors that had a statistically significant association with the outcome. To take missing data into account, important factors for each outcome were selected using two types of data sets and the results compared. In the first data set, a “Missing” category was created for each of the factors that had data missing, with continuous variables grouped into clinically relevant categories so that none of the observations were excluded and the entire cohort was used. The model obtained using the entire cohort was compared to that found from a complete case analysis, that is, an analysis including only those pregnancies with complete data for the factors considered for a given outcome.
To examine the effect of pregnancy on subsequent renal allograft function, we used the nonparametric Mann–Whitney test to analyze median SCr levels separately for patients with SCr ≤150 μmol/L and those with SCr >150 μmol/L before pregnancy. We also performed a matched case-control study in which each of the 176 patients in our cohort was matched to a female renal allograft recipient on the UKT database with no reported pregnancy episodes. Matching was based on age at transplant, date of transplant, graft number, donor type, donor-recipient tissue match and SCr level at similar posttransplant times. Kaplan-Meier survival curves were used to estimate postpregnancy graft survival, in which patient death with a functioning graft was counted as graft failure.
As there were few pregnancies in cardiothoracic, liver, and multiorgan transplant recipients, only brief summaries of the outcomes of these pregnancies are given. Results of a detailed analysis of pregnancy outcomes in kidney transplant recipients are presented.
Pregnancies in Cardiothoracic Transplant Recipients
A total of 18 pregnancies were reported in 11 heart, one double lung, and five heart-lung block transplant recipients. Two pregnancies were reported in one heart transplant recipient (Table 1)(8). There were 15 (83%) live births, two early fetal losses as the result of miscarriage (one) and ectopic pregnancy (one), whereas the remaining pregnancy ended in a stillbirth. Among the live births for which data were reported, preterm delivery occurred in two of six and low birth weight in 8 of 10.
Pregnancies in Liver Transplant Recipients
A total of 18 pregnancies were reported in 16 liver transplant recipients, two of whom had two pregnancies each. Outcomes were reported for 16 of the 18 pregnancies (Table 1). There were 11 live births (69%), with early fetal loss in the remaining five as the result of miscarriage (two), therapeutic termination (two), and ectopic pregnancy (one). Among the live births for which data were reported, preterm delivery occurred in four of eight and low birth weight in four of seven.
Pregnancies in Multiorgan Transplant Recipients
Four pregnancies were reported in multiorgan recipients; one liver and kidney recipient and three kidney-pancreas recipients. Live births occurred in two kidney–pancreas recipients whereas the outcome was not reported in the other two recipients.
Pregnancies in Kidney Transplant Recipients
A total of 193 pregnancies were reported in 176 kidney transplant recipients, 17 of whom had two pregnancies each. Outcomes were reported for 188 (97%) of the pregnancies (Table 1) and of these, 149 (79%) resulted in a live birth, three in a stillbirth, and the remaining 36 ended before 24 weeks as a consequence of miscarriage in 21 (11%), therapeutic termination in 11 (6%), intrauterine fetal death in three (2%), and ectopic pregnancy in one (<1%). There were no neonatal deaths, but one infant died within 3 months of delivery from an unreported cause.
The type of labor was reported for 121 of the 149 live births (Table 1). In 14 (12%) labor was spontaneous, it was induced in 29 (24%), and an elective caesarean was performed in the remaining 78 (64%). Of the 107 pregnancies in which labor was induced or an elective caesarean was performed, the reason was reported for 90. In some cases, more than one reason was reported. The main reasons given were hypertension or preeclampsia in 32 (36%), deteriorating renal function in 22 (24%), intrauterine growth retardation in 18 (20%), and fetal distress in 10 (11%). The mode of delivery is shown in Table 1. Normal vaginal delivery occurred in 25 (21%), delivery was instrumental in nine (7%), and the overall caesarean section rate was 72% (87 pregnancies). Thus, 78 (90%) of the caesarean sections were elective while the remaining nine (10%) were undertaken after the onset of labor.
Maternal Antihypertensive Therapy
Antihypertensive therapy before and during pregnancy was reported for 128 of the 193 pregnancies (Table 2). Of the 88 (69%) pregnancies in which the patient was on therapy prepregnancy, therapy stopped during pregnancy in one. In an additional 10 (8%) pregnancies, therapy commenced during pregnancy.
Maternal Demographic Data
The mean age at the time of transplant was 25 years (range, 7–39 years) and was 30 years (range, 20–43 years) at the end of pregnancy. The mean interval from transplant to end of pregnancy was 6 years (range, 3 months–19 years). Of the 176 recipients, 141 (80%) had received a kidney from a cadaveric heartbeating donor, 34 (19%) from a live donor, and one (1%) from a cadaveric nonheartbeating donor. The transplant recipients included in this study received their transplants between 1977 and 1999. During that time, 13% of kidney transplants in female patients aged between 7 and 39 years were from living related donors. Thus, there was a proportionately greater (P=0.01) number of live donor transplants among patients with pregnancies compared with the general female transplant recipient population. There was, however, no statistically significant difference between the proportion of successful pregnancies in cadaveric and live donor transplant recipients. The graft was a first in 144 (82%) of the patients, a second in 29 (16%), and a third in three (2%) of the patients.
Factors That Influenced Pregnancy Outcome in Renal Transplant Recipients
Success of Pregnancy
A successful pregnancy was defined as one that resulted in a live birth. A pregnancy was classed as unsuccessful if it resulted in a miscarriage, an ectopic pregnancy, intrauterine fetal death, or stillbirth. Therapeutic terminations were excluded from this analysis because these pregnancies were not allowed to run their course. When the entire cohort was used, there was suggestive evidence of an association of prepregnancy systolic blood pressure (P=0.08) with the risk of an unsuccessful pregnancy. In the complete case analysis, prepregnancy SCr (P=0.03) and systolic blood pressure (P=0.03) were found to be statistically significant (R2=14.9%, Table 3).
Of the 149 live births, gestational age was reported in 121 and of these, 61 (50%) were preterm (<37 weeks) as shown in Table 1. Of the 121, the type of labor was reported in 112 and 57 (51%) of these were preterm. Of the preterm deliveries, 47 of the 57 (83%) were by elective caesarean section, labor was induced in seven (12%) and in only three (5%) was it spontaneous, compared with 26 (47%), 20 (36%) and 9 (16%) respectively, among the 55 pregnancies that were delivered after 37 weeks (Fig. 1a). The differences in the rates of the labor types between the preterm and full term deliveries were statistically significant (P<0.001).
Of the 47 preterm deliveries by elective caesarean, the main reasons reported were hypertension or preeclampsia in 18 (44%), deteriorating renal function in 14 (34%), intrauterine growth retardation in 11 (27%), and fetal distress in eight (20%). For some patients more than one reason was given.
The model obtained using the entire cohort (R2= 28.7%, Table 3) shows that compared with patients with prepregnancy SCr ≤150μmol/L, those with a prepregnancy SCr >150 μmol/L were associated with a greater risk of preterm delivery (P=0.007). Also, the risk of preterm delivery was greater for those patients in whom DHTN was present during pregnancy compared with those in whom it was absent (P<0.001). The complete case analysis yielded a model with the same factors as those listed in Table 3.
Low Birth Weight
Infants with a lower gestational age tend to have a lower birth weight. Therefore, gestational age is a confounding variable that must be adjusted for in modeling the risk of low birth weight. There were 101 infants for whom both the birth weight and gestational age were reported. Of these, 53 (52%) had a low birth weight (<2500 g) and 25 (22%) had a very low birth weight (<1500 g). Forty-four (82%) of the 53 infants with a low birth weight were delivered preterm, compared with 9 (17%) of the infants with a birth weight >2500 g (Fig. 1b). When gestational age was adjusted for, no significant association was found between birth weight and any of the other factors, including presence of DHTN before or during pregnancy, SCr level, and renal dysfunction. Presence of DHTN before (P=0.09) and during (P=0.02) pregnancy was the only other factor that, individually, had a statistically significant effect on the risk of a low birth weight. When gestational age was adjusted for, however, the association between DHTN and low birth weight ceased to be significant.
Effect of Pregnancy on Renal Allograft Function
For 109 of all 193 pregnancies, maternal SCr was reported before pregnancy, during the second and third trimesters and between 3 and 6 months after pregnancy (Table 2). The median SCr decreased from the prepregnancy level of 125 μmol/L to 110 μmol/L in the second trimester and then increased marginally to 112 μmol/L in the third trimester with, finally, a median level of 130 μmol/L at 3 to 6 months postpartum. Of the 109 pregnancies, 29 (27%) had a SCr >150 μmol/L before pregnancy and 41 (38%) after pregnancy. The initial decline in SCr from prepregnancy to the second trimester (median, 12 μmol/L, P<0.0001) and the increase from prepregnancy to the postpartum period (median, 7 μmol/L, P<0.0001) were both statistically significant. Graft dysfunction developed in 30 (20%) of the 150 pregnancies for which this information was reported (Table 2).
We investigated the association between prepregnancy and postpartum SCr levels. The patients were divided into two groups depending on whether their prepregnancy SCr level was ≤150 μmol/L (n=80) or >150 μmol/L (n=29). Figure 2 shows the median, 25th, and 75th percentiles for prepregnancy, second and third trimester, and postpartum SCr levels for the two groups. The changes seen, in which the SCr level drops during the early part of the pregnancy and rises towards the baseline level during the third trimester, follow the trend expected for nontransplant pregnancies. However, for patients with prepregnancy SCr >150 μmol/L, the postpartum SCr level tended to be higher (P=0.04) than their baseline level compared with patients with prepregnancy SCr ≤150 μmol/L.
A Kaplan–Meier survival curve (Fig. 3) was used to compare the postpregnancy renal allograft survival of patients with and without DHTN during pregnancy. The results suggest that the presence of DHTN during pregnancy may be associated with poorer postpregnancy graft survival.
In the matched case–control study, graft survival beyond pregnancy was known for 139 of the 176 patients in our cohort. Two-year postpregnancy graft survival was 94% for patients in our cohort and was 93% among the matched group. There was no significant difference in survival rates between the two groups during the 2-year follow-up period (P=0.7)
Prepregnancy Immunosuppressive Drug Therapy in Renal Transplant Recipients
There were no significant associations between the prepregnancy immunosuppressive regimen and prepregnancy SCr, presence of DHTN prepregnancy, and the risk of a preterm delivery or low birth weight (data not shown).
There is substantial literature on pregnancy in renal allograft recipients, mainly from single center studies with small patient numbers. The U.K. Transplant Pregnancy Registry provides an opportunity for statistical analyses of more comprehensive data from patients distributed throughout the United Kingdom, mainly aiming to assess the effect of prepregnancy factors on pregnancy outcome and the effect of pregnancy on subsequent renal function and graft survival to allow better counseling of female transplant recipients.
Among renal allograft recipients of childbearing age, the likelihood of a pregnancy being successful is high. The U.K. Registry data showed a live birth rate of 79% and a similar figure of 76% was reported by the NTPR in the United States (4). However, a substantial proportion of maternal and fetal complications occur and it is important to know the incidence of these and the main predisposing factors in order to provide good quality counseling and patient care.
With regard to pregnancy outcomes, the problems of preterm delivery and low birth weight of the fetus are well recognized. Our Registry data showed a very high incidence of preterm delivery (50%), similar to that of 53% recorded by the NTPR (4), both in contrast to a figure of 7% for the general U.K. population (9). Our logistic regression modeling results (Table 3) suggest that a patient with SCr >150 μmol/L, especially in the presence of hypertension, should be counseled about the likelihood of preterm delivery and its associated drawbacks and complications. Although the choice of 150 μmol/L is arbitrary, a previous study of pregnancy in renal allograft recipients used this figure (7) and a level of SCr in excess of 150 μmol/L indicates that renal function is less than half of normal and therefore substantially impaired.
With regard to low birth weight, our analysis has failed to find any additional predisposing factors, but rather that it is an almost inevitable consequence of preterm delivery. In a previous study of the factors influencing birth weight in Cyclosporin (CsA)-treated female renal allograft recipients, a number of factors, including a prepregnancy SCr >1.5 mg/dL (approximately 130 μmol/L) and hypertension, were found to have a significant effect on the risk of low birth weight (10). However, failure to adjust for gestational age may mean that the effect of these variables on birth weight was overestimated. In addition to its association with low birth weight, preterm delivery is unlikely to be spontaneous. The U.K. Registry data showed a spontaneous delivery rate of 5% among preterm deliveries and, by contrast, a preterm elective caesarean delivery rate of 83%. The most frequent indications for elective caesarean among preterm deliveries were hypertension/preeclampsia and deteriorating renal function.
One of the anxieties about pregnancy in the organ allograft recipient is the potential adverse effect of maternal immunosuppression on the fetus (11, 12). Among pregnancies that ended in a live birth, we found no evidence of an association between the three main prepregnancy immunosuppressive therapies prescribed for patients in the Registry, namely azathioprine (Aza), CsA, and combined Aza/CsA (all combined with prednisolone) and the occurrence of preterm delivery or low birth weight. In an NTPR study, however, CsA-based therapy was found to be associated with a greater frequency of low birth weight infants when compared with the offspring of mothers receiving Aza and/or prednisolone without a calcineurin inhibitor (13). In addition, a meta-analysis has shown a nonsignificant trend to a greater-than-normal frequency of major malformations in the offspring of CsA-treated organ transplant recipients (14), but there has not been confirmation of this finding as yet from other studies. Finally, immunosuppression of the fetus is clearly a possible adverse effect and tests showing a depressed immune response have been described in infants born to renal allograft recipients, with some of the abnormalities persisting at one year but without any apparent accompanying morbidity (15).
Early fetal loss by miscarriage was reported in 11% of pregnancies in the Registry, and the most recent figure reported from the NTPR is 14% (4). Miscarriage is potentially underreported in the two registries and miscarriage rates could be greater that those quoted. Miscarriage would therefore seem to be more common in renal allograft recipients, as figures of 8% to 9% (16) are often quoted for the general population. The incidence figures for ectopic pregnancy, intrauterine fetal death and stillbirth in our Registry are each 2% or less, but the total number of patients in the Registry is too small to say whether these categories of fetal loss are more common than in the general population.
Although information relating to the likelihood of giving birth to a healthy baby is important to the patient with a renal allograft, so too is knowledge about the possible effect of pregnancy on long term graft function. Few reported studies have compared renal function and graft survival after pregnancy with that of a control group. In three studies, no long-term adverse effect of pregnancy was observed on subsequent renal function or graft survival (17–19) whereas in a fourth, higher postpartum SCr levels and greater long term graft loss were found in the pregnancy group (20). Thus, the evidence to date—in small studies—has been conflicting. This U.K. Registry analysis of graft survival contains 139 patients and the same number of matched control subjects. This study showed virtually identical graft survival at 2 years postpregnancy as in the controls and therefore provides more evidence of lack of an adverse effect of pregnancy on renal allograft survival. However, graft loss is a crude index of damage to the graft. The finding in our study of a tendency for higher prepregnancy SCr levels to fail to return to the baseline postpartum is of concern. It could indicate that pregnancy may have a harmful effect on renal function when substantial renal dysfunction existed before the pregnancy, a finding supported by expert consensus (21).
Our study emphasizes that hypertension is very common in renal allograft recipients, as 69% of those in the Registry were receiving antihypertensive therapy before pregnancy, with an increase to 76% during pregnancy. The association of hypertension with the success rate of pregnancy and preterm delivery has already been discussed. In addition, our study has suggested that the combination of hypertension and pregnancy could have an adverse effect on subsequent renal function. It could be that any risk of persistent renal damage developing after pregnancy is confined to those renal allograft recipients who have substantially impaired renal function prior to the pregnancy and/or hypertension severe enough to require drug therapy. Further investigation of this possibility would be worthwhile.
In the group of cardiothoracic recipients, live births were reported in 83% of the 18 pregnancies, an encouraging outcome. The NTPR has reported live births in 69% of heart and 53% of lung recipients (4) so that the outcome in the United Kingdom would seem to compare very favorably. However, therapeutic termination was performed in 9% of the heart and 33% of the lung recipients among the NTPR patients, higher than among those in the U.K. Registry, which may partially explain the apparently greater success rate of pregnancy in the U.K. patients. Among liver transplant recipients, live births were reported in 69% of 16 pregnancies, similar to the 73% reported by the NTPR. As with kidney transplant recipients, our analysis has shown preterm delivery to be common among cardiothoracic and liver transplant recipients.
In conclusion, this analysis of data from the U.K. Transplant Pregnancy Registry is encouraging in that it reports that pregnancy ended with a live birth in a large majority of patients, especially in those with kidney and cardiothoracic transplants. In kidney transplant recipients, preterm delivery occurred in half of the patients and in this group, delivery was by elective caesarean in 83%, with very few having spontaneous delivery. The increased risks to the baby associated with preterm delivery indicate the need not only for close antenatal supervision but also for prepregnancy counseling. The mother needs to be made aware of the likelihood of preterm delivery and that, in addition, where hypertension is present (especially if poorly controlled), and/or renal function is poor, the prospects of a live birth are considerably reduced. There is no cut-off value of SCr greater than which one would advise against pregnancy, but this course of action needs to be discussed fully when levels are above 150 μmol/L. Finally, another very important question is whether long term graft survival and the level of renal function of the mother can be adversely affected by pregnancy. Although our case–control study provides reassurance on this point, our data suggest the existence of an adverse effect of hypertension and/or poor prepregnancy renal function on the allograft.
The authors would like to thank Professor C.W.G. Redman from John Radcliffe Hospital in Oxford, United Kingdom, for his valuable input in setting up the U.K. Transplant Pregnancy Registry.
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