Effect of pregnancy on the long-term function of renal allografts: An update

Effect of Pregnancy on the Long-Term Function of Renal Allografts: An Update S.N. Sturgiss, MD, MRCOG, and J.M. Davison, MD, FRCOG 0 In 1992 we published a case-controlled study of posttransplant follow-up in 36 renal allograft recipients (Am J Kidney Dis i&167-172,1992). Eighteen of these patients became pregnant and comprise the index group; the 16 patients who did not become pregnant were considered controls. By the end of the follow-up period, plasma creatinine in the index group and controls had increased by 19% and 6%, respectively. Graft loss or chronic rejection occurred in one patiint in the index group and in two in the control group. As there were no significant differences between the two groups, we concluded that pregnancy was unlikely to have a major effect on longterm graft function and/or survival. Subsequently, a case control study of Finnish women demonstrated graft survival favoring women who never conceived versus those who did (6g% Y lOO%, respectively; P < 0.006) and thus prompted us to extend our posttransplant follow-up by a further 3 years. Data are currently available for 17 index subjects and 17 controls and during the entire follow-up period, graft losses have occurred in one index subject and in four controls. Plasma creatinine at the end of the follow-up period (1.40 ? 0.52 mg/dL and 1.64 2 0.95 mg/dL, respectively) had increased from 3 years earlier by 11% and 7%, respectively, increments across time that were not significant. Although the increase in plasma creatinine was greater in the index subjects compared with the controls, there were no significant differences between the two groups. While our data do not exclude a minor deleterious effect of pregnancy on long-term graft function, we believe that female allograft recipients can be reassured that pregnancy is unlikely to substantially after long-term graft function. 0 19525 by the National

Kidney

INDEK WORDS: Pregnancy;

Foundation,

pregnancy

Inc.

complications;

renal allograft

I

N 1992 we reported a case-controlled study of posttransplant follow-up for a mean of 12 years’ duration (range, 4 to 23 years) in 36 renal allograft recipients.’ Eighteen of these patient became pregnant and comprise the index group. The 18 patients who did not become pregnant were considered controls (matched for underlying disease and renal function). By the end of the follow-up period (in early 1991), plasma creatinine (mean ? SD) in the index group (1.26 + 0.83 mg/dL) and in the controls (1.44 it 0.59 mg/dL) had increased by 19% and 8%, respectively, and glomerular filtration rate (inulin clearance) in the index group (58 + 29 rnL/min) and controls (56 ? 32 mL/min) had decreased almost reciprocally, by 18% and 7%, respectively. Graft loss or chronic rejection occurred in one patient in the index group and in two patients in the From the Department of Obstetrics and Gynaecology, Royal Victoria Infirmary, and the Departments of Medicine and Surgery, Royal Victoria Injirmary and Freeman Road Hospital, University of Newcastle-upon-Tyne, UK. Received February 15, 1995; accepted in revised form March 3, 1995. Address reprint requests to S.N. Sturgiss, MD, MRCOG, Department of Obstetrics and Gynaecology, Leazes Wing (4th Floor), Royal Victoria Infirmary, Newcastle-upon-Tyne, UK NEI 4LP. 0 1995 by the National Kidney Foundation, Inc. 0272-6386/95/2601-0.00/O

54

American

Journal

recipients.

control group. There was one death in the index group 9 years after the second of two successful pregnancies. Although there were no significant differences between the two groups, the decrement in renal function in the index subjects was greater than in the controls. We therefore acknowledged that pregnancy might have a minor effect on long-term graft function and/or survival, but that further evaluation would require a larger multicenter study or more sensitive markers of renal function. Overall, the results were encouraging for transplant recipients wishing to conceive, endorsing conclusions from earlier but smaller and more limited studies.2,3 It also has been pointed out that the women described in our earlier report were at “high risk” in that several were hypertensive and/or had prepregnancy plasma creatinine levels above 1.5 mg/dL and two were diabetic. The relatively favorable long-term outcome in these women, therefore, was even more encouraging.4 To our surprise, the investigators of a recent study5 came to a strikingly different conclusion. Indeed, the title of the report (“Impaired Renal Function After Pregnancy in Renal Transplant Recipients”) was cause for concern. Salmela et al analyzed long-term outcome in 66 renal allograft recipients, 22 of whom had become pregnant and 44 controls, matched for underlying

of Kidney

Diseases,

Vol 26, No 1 (July),

1995:

pp 54-56

PREGNANCY

IN RENAL ALLOGRAFT

RECIPIENTS

graft function, who had not. Plasma creatinine levels 3 months and 1 year after delivery (1.82 + 0.68 mg/dL and 1.97 + 0.74 mg/dL, respectively; mean IfI SEM) were significantly greater than at corresponding posttransplantation intervals in the controls (1.17 ? 0.11 mg/dL and 1.26 + 0.23 mg/dL, respectively). Moreover, the loyear graft survival rate was 69% in the patients who had become pregnant compared with 100% in the control subjects. In the introduction to their report, Salmela et al stated, “Studies on the long-term effect of pregnancy on renal function and graft survival are missing,” which is puzzling, bearing in mind previous publications,*.” including our own.’ Then there was a lost opportunity to discuss their findings in relation to the more favorable data, a comparison that would have been revealing. Nevertheless, their data do require scrutiny. It is unlikely that the increment in plasma creatinine represents increased protein intake in these women rather than a change in endogenous clearance because inulin clearance results have endorsed creatinine data,‘.6 even taking into account the special situation of a single kidney, let alone gestational hyperfiltration.’ As for the worrisome life table analysis, it has been pointed out previously that the statistical significance derives from a highly unusual outcome, namely, that in 10 years there were no graft failures in the controls, which is certainly contrary to the experience of most transplant centers, even allowing for the fact that renal function in allograft recipients who conceive generally is better than for transplant recipients as a whole.’ Of interest, the mean gestational age attained in the pregnancies was on average 2 weeks more than that in other series (reviewed in ref 9) which could perhaps be permanently detrimental to some allografts given that many gravidas have a 15% to 20% decrement in renal function, albeit transient, during the third trimester.6.9 To ensure that our optimism was not misguided we have updated our 1992 publication, extending posttransplant follow-up by 3 years. Data are currently available for 17 index subjects and 17 controls. Over the entire follow-up period, graft losses have occurred in one index subject and in four controls. One index subject has died (15 years after transplantation, at a time when

55 2.60 2.40 2.20 2 2.00 p 1.60

“ . “ ”

Prepregnant

Fig index bars) years

Follcw-up: 12 years

1. Plasma creatinine (mg/dL) subjects (light bars) and control before pregnancy and during and 15 years.

Follow-up: 15 years

(mean t subjects follow-up

SD) in (dark at 12

graft function was satisfactory) and three control subjects have died following three of the four graft losses in the group. Data for the remaining 15 index and 13 control subjects are shown in Fig 1. Although the number of patients has decreased, tracking the remaining individuals has produced trends that are similar to those of the original study. Compared with 3 years earlier, plasma creatinine at the end of follow-up in the index subjects and controls (1.40 + 0.52 mg/ dL and 1.54 & 0.95 mg/dL, respectively) had increased by 11% and 7%, respectively (Fig 1). These increments across time were not significant. Although the increase in plasma creatinine was greater in the index subjects compared with the controls, there were no significant differences between the two groups. (Complete inulin clearance data unfortunately are not available.) Although we acknowledge that our data do not exclude a minor deleterious effect of pregnancy on long-term graft function, we believe that female allograft recipients can be reassured that pregnancy is unlikely to substantially alter longterm graft function. ADDENDUM Since this article was accepted for publication, two studies have been published that counter the view of Salmella et al5 and endorse the reassurance that pregnancy is not detrimental to long-term graft function.“.”

ACKNOWLEDGMENT The work would not have been possible without the help and support of the Renal Transplant Team at the Royal Victo-

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STURGISS

ria Infirmary and Freeman Hospital, Newcastle-upon-Tyne. We are indebted to Professor R. Wilkinson, Drs R.W. Elliott, T.H.J. Goodship, T.W.J. Lennard, G. Proud, J.S. Tapson, R.M.R. Taylor, and M.K. Ward, and the late P.J. Dewar.

REFERENCES 1. Sturgiss SN, Davison JM: Effect of pregnancy on longterm function of renal allografts. Am J Kidney Dis 19:167172, 1992 2. Whetham

JCG, Cardella C, Harding M: Effect of pregnancy on graft function and graft survival in renal cadaver transplant patients. Am J Obstet Gynecol 145: 193-197, 1983 3. EDTA: Combined report on regular dialysis and transplantation in Europe, XIX, 1988. Nephrol Dial Transplant 4:31-40, 1989 4. Lindheimer MD, Katz AI: Pregnancy in the renal transplant patient. Am J Kidney Dis 19:173-176, 1992 5. Salmela KT, Kyllonen LEJ, Holmberg C, Gronhagen-

AND

DAVISON

Riska C: Impaired renal function after pregnancy in renal transplant recipients. Transplantation 56: 1372- 1375, 1993 6. Davison JM: The effect of pregnancy on kidney function in renal allografts. Kidney Int 27:74-79, 1985 7. Baylis C: Glomerular filtration and volume regulation in gravid animal models. Baillieres Clin Obstet Gynaecol 8:235-264, 1994 8. Lindheimer

MD, Katz AT: Pregnancy in women receiving renal replacement therapy. Kidney Curr Surv World Literature 3:135-137, 1994 9. Davison JM: Pregnancy in renal allograft recipients: Problems, prognosis and practicalities. Baillieres Clin Obstet Gynaecol 8:501-525, 1994 10. Saber LTS, Duarte G, Costa JAC, Cologna AI, Garcia TMP, Ferray AS: Pregnancy and kidney transplantation: Experience in a developing country. Am J Kidney Dis 25465-470, 1995

11. First MR, Combs CA, Weiskittel P, Miodovnik M: Lack of effect of pregnancy on renal allograft survival or function. Nephrology 59:472-476, 1995