Table of Contents

Original investigation

J NEPHROL 2002; 15: 626-632

Pregnancy after renal transplantation in Italian patients: Focus on fetal outcome

Roberto Miniero¹, Irene Tardivo², Emilio Sergio Curtoni³, Giuseppe Paolo Segoloni⁴, Ennio La Rocca⁵, Antonio Nino⁶, Paola Todeschini⁷, Carla Tregnaghi⁸, Alberto Rosati⁹, Paola Zanelli¹⁰, Anna Maria Dall'Omo¹¹ - ^1,2 Department of Pediatrics, S. Luigi Hospital, Orbassano; ^3,11 Transplant Immunology Service, S. Giovanni Battista Hospital, Torino; ⁴ Department of Nephrology and Dialysis, S. Giovanni Battista Hospital, Torino; ⁵ I^st Division of Medicine, S. Raffaele Scientific Institute, Milano; ⁶ Department of General Surgery, Annunziata Hospital, Cosenza; ⁷Department of Nephrology and Dialysis, S. Orsola Policlinic, Bologna; ⁸ Division of Nephrology and Transplants, S. Chiara Hospital, Pisa; ⁹ Unit of General Surgery and Organ Transplant, Careggi Hospital, Firenze; ¹⁰ Department of Clinical Medicine and Nephrology, Maggiore Hospital, Parma - Italy

ABSTRACT: Background. In the last few years advances in surgical techniques and immunosuppression have improved not only survival, but also quality of life in organ transplanted patients. Hence, the number of women of child-bearing age who decide to have a child ­ which means resuming a normal life ­ has increased. This multicenter retrospective study describes pregnancies after kidney transplantation and is the first such survey in Italy.
Methods. We analyzed the outcomes from 56 pregnancies in 42 kidney transplant recipients from data collected in questionnaires, hospital records, and phone interviews. All recipients were maintained on cyclosporine (CsA), azathioprine (AZA), corticosteroids or tacrolimus (FK506) before and during pregnancy.
Results. The average time from transplantation to childbirth was 62 months (range 12 to 180). Complications arose during pregnancy in 16 out of 36 term pregnancies (44.4%). Four transplant rejections (11.8%) were documented, two of them irreversible. Thirty-six infants were born, and 20 abortions reported (35.7%). Of these 36 babies, 16 (44.4%) were born at term, and 20 (55.6%) before term. Thirty-three Cesarean sections were performed (91.7%). Among the 20 pre-term babies, 11 can be grouped as follows: 5 low-birth-weight (LBW) (13.9%), 4 very low-birth-weight (VLBW) (8.3%) and 2 extremely very low-birth-weight (EVLBW) (5.6%). The children were followed up for periods ranging from 2 months to 13 years.
Conclusions. In kidney transplant recipients who became pregnant the incidence of spontaneous abortion and pre-term delivery was increased. Newborns delivered to these patients had low birth weight, but no congenital defects were noted and their development was normal.

Key words: Kidney transplant, Pregnancy, Newborn

Introduction

In the last few years advances in surgical techniques and immunosuppression have improved not only survival, but also quality of life in organ transplanted patients (1). Hence, the number of women of childbearing age who decide to have a child ­ which means resuming a normal life ­ has increased (2, 3). In the majority of studies dealing with pregnancies following kidney transplantation (4, 5), the most pressing questions concern the use of immunosuppressive drugs and the effects they may have on the fetus, the course of pregnancy, and childbirth (6, 7). Pre-term births and intra-uterine growth retardation (IUGR) are frequent. According to some studies, the rate of miscarriage is higher than for the general population. Several studies have reported fetal malformations, including labiopalatoschisis and even heart defects (8-22). Furthermore, the effects of immunosuppressive therapy on the immune system of the developing fetus are still unclear (22-24).

Subjects and methods

We sent a questionnaire to all the AIRT (Inter-regional association for organ transplantation) kidney transplant centers and to other Italian transplant centers to find out about pregnancy outcomes after renal transplantation (complications, miscarriages, stillborns, therapeutic abortions and live births) and obtain data on pregnancies at term and spontaneous or therapeutic abortions before transplantation. We collected and retrospectively analyzed data from the questionnaires, from hospital records and phone interviews and collected information on the mother's follow-up as a function of transplant rejection risk, interval from transplantation to pregnancy and drugs received during pregnancy.
The infants' general health and follow-up were examined closely; the data were collected by phone interview from the mother and/or pediatricians. The mode of delivery (natural childbirth or Cesarean section), the baby's weight, length, head circumference, Apgar score and labor values were all evaluated.
We classified infants according to gestational age, by which they are defined as pre-term, term and post-term, and weight, dividing them into appropriate, small for date or large for date (or macrosomal).
According to gestational age, pre-term infants were grouped as low-birth-weight (LBW), very low-birth-weight (VLBW), and extremely very low-birth-weight (EVLBW) (25). The first group includes moderately premature babies delivered between gestational weeks 32 and 37, weighing between 1500 and 2500 g; VLBW are greatly premature infants delivered between weeks 29 and 32 and weighing 1000-1500 g at birth; EVLBW, very greatly premature babies, were born between weeks 22 and 28,  weighing between 500 and 1000 g.
We also inquired about growth, vaccinations and any allergic reactions, laboratory tests, and the last measured height and weight.

Results

Five of the nine AIRT kidney transplant centers sent us their data, two centers had not had any pregnancies after transplantation and two did not agree to reply. Data were also obtained from the centers in Milan (San Raffaele Hospital) and Cosenza. Our study includes 56 pregnancies, in 42 patients between December 1987 and January 2001.
Thirty-six pregnancies were at term and 20 abortions were recorded (Tab. I). The average time from transplantation to childbirth was 62 months (range 12 - 180 months).
All patients received immunosuppressive therapy during pregnancy, which consisted of cyclosporine (CsA), azathioprine (A-A), steroids or tacrolimus (FK506) (Tab. II).
At the time of transplant, the mothers' average age was 26.2 years (range 15.3-38.3 years); the average age at delivery was 31.4 years (range 23.11-37.2 years). None of the patients had had a pregnancy before transplantation.

TABLE I - OUTCOME OF PREGNANCIES

TABLE II - IMMUNOSUPPRESSIVE THERAPY DURING PREGNANCY

Complications of pregnancy

Complications were observed in 16 of the 36 term pregnancies (44.4%); hypertension was the most frequent, in 10 pregnancies at term (27.7%). Other complications were: threatened abortion, altered liver and kidney functions, anemia, reduced platelet count, hyperparathyroidism, hypercalcemia, hypercalcinuria, gravidic cholestasis, increased CsA blood levels leading to temporary interruption of the treatment, CsA-induced kidney toxicity and corticosteroid-induced bilateral necrosis of the femur head (Fig. 1).
Therapeutic abortions were caused by the malfunctioning of the transplanted organs and by uncontrollable blood pressure fluctuations. Four patients decided to terminate pregnancy, and there were eight miscarriages.

Fig. 1 - Complications during term pregnancies.

Maternal follow-up after delivery

Four transplant rejections (11.8%) were observed, two of these irreversible. These two patients are still being dialyzed, awaiting a new transplant. Another patient had post-partum hypertension, and was still on anti-hypertensive therapy at the time of interview. Epstein Barr virus encephalitis was observed early post-partum in one case, with full recovery.

Infants (Tab. III)

Thirty-six newborns were registered; four women had two pregnancies at term. Of these 36 babies, 16 (44.4%) were born at term, and 20 (55.6%) before term. The overall mean gestational age was 34.9 weeks (median 31 weeks), with a range of 22 to 40 weeks.
The average gestational age was 38.4 weeks (median 39 weeks) for the infants delivered at term and 33.55 weeks (median 29.5 weeks) for those delivered pre-term.
The mean birth weight was 2474 g (median 2575 g), (Tab. III).
The mean length was 45.1 cm (median 44 cm), with a range from 36 to 52 cm. The mean head circumference was 33.6 cm, median 33.5 cm and range 31 - 36 cm. The Apgar score ranged between 6/10 and 10/10.
Complications were observed in nine cases. One case had hypoglycemia, hypothermia and bradycardia (the mother was taking ß-blockers). One child delivered after only six months of gestation died from respiratory distress syndrome (Tab. III).
The 20 pre-term babies of our study can be divided as follows: 5 LBW (25% of pre-term deliveries) 3 VLBW (15% of the pre-term population) and 2 EVLBW (10% of the pre-term babies) (Tab. III).
Thirty-three Cesarean sections were performed; only three childbirths were delivered vaginally (Tab. IV).
Of the 16 babies delivered at term, one was classified as "small for date" (6.25% of the term babies, 2.8% of the total). Following an IUGR diagnosis, one baby had to be delivered by Cesarean section at week 39 of pregnancy. His weight was 2650 g, so he cannot be included in the small-for-date group (weight ¾ 2500 g): this case is reported separately since it is below the 10th percentile.
The remaining infants (10 pre-term and 15 term babies) are regarded as appropriate for gestational age (Tab. V and Fig. 2).

TABLE III - OUTCOME OF 36 PREGNANCIES AND NEONATAL COMPLICATIONS

TABLE IV - DELIVERY

TABLE V - CLASSIFICATION OF THE 36 NEWBORNS

* deceased intrauterine growth retardation (IUGR)<-> <10°.

Fig. 2 - Classification of the 36 newborns.

Infant follow-up

No baby was breast-fed because immunosuppressive drugs are secreted in mother's milk. The median follow-up of the children was 7 years (range 2 months - 13 years). They were all vaccinated with no side effects. Their development was uneventful and the pathological conditions they presented at birth resolved completely.

Discussion

The first pregnancy after organ transplantation was described in 1963 in a woman who had received a kidney allograft (4). Now, pregnancy is a realistic possibility after solid organ transplantation and it has been estimated that one in 50 women of childbearing age will become pregnant after organ transplantation (1). Women of childbearing age should be counselled about the possibility and risks of pregnancy after kidney transplantation. Women who are not rubella immune should receive the vaccine before transplantation, because live virus vaccines are contraindicated after a transplant. Women are usually advised to wait at least one year after living related donor transplantation and two years after a cadaver transplantation. However, waiting five or more years may result in impaired renal function post-partum that fails to recover, because of gradual deterioration secondary to chronic rejection.
Contraceptive counselling should begin immediately after transplantation, because ovulatory cycles may begin within 1-2 months of transplantation in women with well functioning grafts. Low dose estrogen-progesterone oral contraceptive preparations are recommended. The risk of infection from intrauterine devices is increased in immunocompromised patients. The efficacy of IUDs may be reduced because of the inflammatory properties of immunosuppressive agents (34). Criteria that should be ideally met before conception are shown in Table VI.
Women with mild to moderate hypertension should be watched closely, warned about signs of early pre-eclampsia and delivered at 37 weeks of gestation (34).
The most common bacterial infections are of the urinary tract, that occur in up to 40% of pregnant transplant recipients. They are particularly common in patients who developed end-stage renal disease due to pyelonephritis. These women should have monthly screening urine cultures if asymptomatic bacteriuria is present; they should be treated for two weeks and may be given suppressive doses of antibiotics for the rest of the pregnancy. Penicillins that do not interact with the eukaryote metabolism are the preferred antibiotics. Cytomegalovirus remains the most frequent cause of viral infection post-transplantation; herpes simplex virus infection before 20 weeks of gestation is associated with an increased rate of abortion. An infant born to an HBSAg-positive mother should be given hepatitis B immunoglobulin within 12 h of birth and HBV vaccine at another side within 48 h, followed by a booster injection at one and six months. The combination of immunoglobulin and vaccine offers protection for more than 90% of infants (34).
The main topics in the debate on post-organ transplantation pregnancy are the course of the pregnancy, the function and survival of the transplanted organ, and the effects of immunosuppressive agents on the developing fetus, including the long-term outcome of the infant (9,26).
Studies of patients after kidney, liver or heart transplants showed live-births between 69% and 74%. In our study, the percentage of pregnancies at term was comparable (64.3%).
The most frequent complications include hypertension and maternal infections, pre-term delivery and low birth weight of the newborn (8, 9, 27). In accordance with these observations, we found that prematurity was common (55.6% of pregnancies) and much more frequent than in the non-transplant population, where the overall incidence of prematurity is only about 11% (17,28-30). In the general population small-for-date newborns amount to 5%, whereas in our series they amounted to 10%. In the general population, 5% of premature infants are LBW, 1% is VLBW and 0.25% is EVLBW. In our series 55.6% of the babies were born before term; 25% were classified as LBW, 15% as VLBW and 10% as EVLBW.
Published guidelines include the recommendations that women who have received a kidney transplant must have stable graft function and must be on maintenance immunosuppression before considering pregnancy, in order to minimize risks (4, 10) (Tab. VI). Most pregnancies in patients with normal, stable organ function had no effect on graft function or survival, whereas deteriorated graft function involves a significant risk of graft loss within two years of delivery (10, 17). In some reports, the incidence of acute rejection during or within three months of pregnancy ranges between 9 and 14.5%. In our series, rejection occurred in four kidney recipients, and was definitive in two (5.9%). This finding is in accord with previous data showing that the incidence of clinically diagnosed rejection of renal allografts is not influenced by pregnancy (12, 29). We presume that all the centers participating in our study carefully verified the mother's clinical and biological parameters in order to allow pregnancy.
We found that spontaneous abortion (16%) was more frequent than expected (10%) in the Italian population (32). An increased abortion rate has also been reported by other authors (2,3,12,16,33).
Cesarean section was required in 91.7%, compared to 23% in the general population (29). It should not be overlooked that after kidney transplantation natural childbirth may be unadvisable because of the position of the organ. The rate of Cesarean section after transplant reported in other series is lower than in our series, but always much higher than in the general population. It is difficult to explain this difference, which may be a consequence of obstetric center guidelines. It is certainly partly due to the need to plan the baby's birth, and to whether there are any maternal (e.g. hypertension or bilateral necrosis of the head of the femur) or fetal intrauterine growth retardation (IUGR) complications.
As reported in the literature, subsequent pregnancies, which occurred in four patients in our series, do not seem to increase the risk of complications or transplant rejection (9).
Fetal malformations have been reported, consequent to immunosuppressive therapy (8-22). We observed no fetal malformations and perinatal complications were mild, except for one death due to adult respiratory distress syndrome (ARDS).
Offspring of patients receiving CsA may suffer from an increased incidence of autoimmune diseases (14, 23). We observed no congenital malformations or autoimmune diseases. However, the observation period in most cases was too short to fully assess the real risk and to draw firm conclusions. Long-term immunological monitoring of children born to allograft recipients is mandatory.
In organ recipients an interval of 1-2 years between transplant and conception is recommended, although some successful cases have been reported after a shorter time. In our study group, the mean interval between transplantation and pregnancy was mostly longer than two years (62 months, though in one case the interval was only a year).
Our study confirms that organ-transplanted patients can carry through a pregnancy and give birth to healthy infants as long as they are closely followed throughout pregnancy (8, 9,17,27,28,30). These pregnancies are at high risk and call for a multidisciplinary approach. Talking to the doctor before deciding to have a baby is vital: this is the best time to clarify the pregnancy-related risks for both the infant and the mother, even from the point of view of her life expectancy. The possibility of the fetus being transmitted the same disease that made the transplant necessary for the mother has also to be taken into account.
The findings of this survey may serve as a basis for future monitoring protocols of mothers during pregnancy or specific studies about children. The results might answer some scientific questions and could have a major social, educational and emotional impact on patients who have already been, or are going to be, transplanted and ­ last but not least ­ on their families, as many transplanted patients are still children.

TABLE VI - CRITERIA FOR TRANSPLANT RECIPIENTS CONTEMPLATING PREGNANCY

Address for correspondence: Prof. Roberto Miniero, M.D. - Università di Torino Ospedale San Luigi Dept. Pediatria 10043 Orbassano (Torino) Italy roberto.miniero@unito.it

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Received: April 02, 2002 Revised: September 13, 2002 Accepted: October 07, 2002

Copyright (c) 2002 Italian Society of Nephrology

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