Pregnancy, tacrolimus, and renal transplantation: survival of a 358-g baby

Simon Satchell, John Moppett, Michael Quinn and Anthony Nicholls

Renal Unit and Department of Paediatrics, Royal Devon and Exeter Hospital, Barrack Road, Exeter, UK

Sir,

One in 50 female renal transplant recipients of child-bearing age becomes pregnant. However, there are only a few reports of pregnancies in transplant patients taking tacrolimus. We report such a pregnancy marked by severe intra-uterine growth retardation (IUGR) and the delivery at 28 weeks gestation of an infant weighing only 358 g but surviving at 15 months of age.

Case.

A 26-year-old woman received a cadaveric renal transplant 2 years after commencing haemodialysis. Early rejection was treated with steroids and antithymocyte globulin and immunosuppression was maintained with prednisolone, cyclosporin, and azathioprine. The best serum creatinine of 155 µmol/l was reached after 4 months. Three years after transplantation, borderline cellular rejection was treated with pulsed prednisolone. After 5 years cyclosporin was replaced with tacrolimus (0.12 mg/kg/day) because the serum creatinine had risen to 255 µmol/l and a further biopsy showed ongoing cellular rejection. At this time the patient became pregnant (despite medical advice against this) when her serum creatinine was 282 µmol/l. Her last menstrual period began 13 days before starting tacrolimus. During pregnancy, tacrolimus trough blood levels were 8–12 ng/ml. The maternal creatinine remained stable apart from a transient rise following delivery and was 284 µmol/l 2 weeks after delivery, but deteriorated to 393 µmol/l 12 months later. However there was marked IUGR and a Caesarian section (CS) was performed at 28 weeks.

The female infant weighed only 358 g and required respiratory support. She was slow to wean from ventilation, developed bronchopulmonary dysplasia, and still required overnight oxygen when discharged, aged 6 months. Other problems included neonatal hepatitis, coagulopathy, nephrogenic diabetes insipidus, and excessive urinary salt loss. Metabolic bone disease resulted in several long bone and rib fractures. She weighed only 2.11 kg (3rd centile 4.35 kg) at discharge.

Comment.

This case is exceptional in the maintenance of a pregnancy in a patient with a poorly functioning renal allograft and treated with tacrolimus and also in the survival of the extremely low-birth-weight infant. We discuss the influence of renal failure and drug treatments on the pregnancy and the resulting infant. In patients with renal disease but near-normal renal function, pregnancy is usually uncomplicated provided blood pressure remains well controlled. However, in patients with severe renal failure (creatinine >230 µmol/l) only 2/3 of pregnancies succeed and there is a very high incidence of IUGR and preterm delivery. In renal transplant recipients, 93% of gestations that continue beyond the 20th week end successfully, but the incidence of IUGR (40%) and preterm delivery (50%) is high [1].

Experience of pregnancy in renal transplant patients treated with tacrolimus is limited to a few cases. One woman with a serum creatinine at conception of 124 µmol/l underwent a CS at 33.4 weeks because of IUGR and the infant weighed 1312 g [2]. Another report describes two pregnancies with maternal creatinines at conception of 140 and 120 µmol/l. Healthy infants weighing 3410 and 2400 g were delivered by CS at 38 and 36 weeks respectively [3]. In a further case the initial serum creatinine was 118 µmol/l and fetal growth was normal but a CS was performed at 31 weeks because of pre-eclampsia. The infant weighed 1140 g [4]. There is wider experience with tacrolimus in pregnancy in liver transplant recipients in whom preterm deliveries are common, but prenatal growth for gestational age and postnatal infant growth are normal [5].

Survival of a 358-g neonate is very unusual. This weight is on 3rd centile for a 23-week gestation fetus and well below that expected at 28 weeks gestation (3rd centile 800 g, 50th centile 1100 g). Survival at 28 weeks gestation is approximately 80%, but decreases exponentially with increasing growth retardation. Predicted survival with a weight less than 500 g is less than 2%. Neonatal hepatitis has a variety of causes but the early onset in this case, the negative results of investigations, and the spontaneous recovery suggest that hepatotoxic drugs may have been involved. Renal solute loss is common in premature neonates and is probably due to nephron immaturity, which also leads to renal unresponsiveness to vasopressin, and diabetes insipidus. Metabolic bone disease of prematurity is multi-factorial in nature, but again renal loss of phosphate in particular plays a role. Poor weight gain is a recognized sequelae of IUGR, compounded here by malabsorption secondary to neonatal hepatitis, renal salt wasting, and several episodes of sepsis.

The contribution of tacrolimus toxicity to the complications seen in this case cannot be precisely gauged. However, as tacrolimus crosses the placenta the similarity of these complications to adverse effects seen in adults should be noted. In adults, tacrolimus may cause a rise in plasma creatinine and hypophosphataemia, occasionally causes tubular necrosis and abnormal liver function tests and rarely causes osteoporosis and coagulopathy. However, infants born to liver transplant recipients taking tacrolimus do not generally experience these adverse effects [5].

In summary therefore it seems likely that the IUGR in this case can be attributed to a poorly functioning maternal renal allograft requiring immunosuppressive therapy rather than to a specific effect of tacrolimus. The possibility remains that some of the post-natal complications, whilst mostly due to extremely low birth weight, were exacerbated by prior maternal administration of tacrolimus.

References

  1. Davison JM. Pregnancy in renal allograft recipients: problems, prognosis and practicalities. Baillieres Clin Obstet Gynaecol1994; 8: 501–525[ISI][Medline]
  2. Yoshimura N, Oka T, Fujiwara Y, Ohmori Y, Yasumura T, Honjo H. A case report of pregnancy in renal transplant recipient treated with FK506 (tacrolimus). Transplantation1996; 61: 1552–1553[ISI][Medline]
  3. Midtvedt K, Hartmann A, Brekke IB, Lyngdal PT, Bentdal Ø, Haugen G. Successful pregnancies in a combined pancreas and renal allograft recipient and in a renal graft recipient on tacrolimus treatment. Nephrol Dial Transplant1997; 12: 2764–2765[Free Full Text]
  4. Resch B, Mache CJ, Windhager T, Holzer H, Leitner G, Muller W. FK 506 and successful pregnancy in a patient after renal transplantation. Transplant Proc1998; 30: 163–164[ISI][Medline]
  5. Jain A, Venkataramanan R, Fung JJ et al. Pregnancy after liver transplantation under tacrolimus. Transplantation1997; 64: 559–565[ISI][Medline]




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