Pregnancy in patients with chronic renal disease ROBERT A. BEAR, MD, FRCP[C], FACP
Pregnancy is not invariably contraindicated in patients with preexisting renal disease. Clinical data now exist that permit the clinician to distinguish such patients who are likely to experience difficulty during pregnancy from those in whom pregnancy can be undertaken with high expectation of success. Patients suffering from systemic lupus erythematosus, active or inactive, with or without lupus nephritis, should avoid pregnancy. Patients with other forms of chronic renal disease in whom the serum creatinine concentration prior to pregnancy is less than 1.5 mg/dL are not exposed to increased maternal or fetal risk. On the other hand, patients with serum creatinine values exceeding 1.6 mg/dL experience a high incidence of maternal and fetal complications and should avoid pregnancy. The life expectancy of recipients of a renal transplant is uncertain, and these patients should receive counselling as to the advisability of undertaking pregnancy. The maternal risk in such patients is not inordinately high, but the fetal risk is considerable. La grossesse n'est pas invariablement contreindique chez les patients souffrant de maladie renale preexistante. Des donnees cliniques existent maintenant qui permettent au clinicien de distinguer les patientes susceptibles de rencontrer des difficult6s durant Ia grossesse de celles chez qui une grossesse peut 6tre entreprise avec une forte probabilit6 de succes. Les patientes atteintes de lupus erythe. mateux dissemin6, actif ou inactif, avec ou sans nephrite lupeuse, devraient eviter Ia grossesse. Les patientes presentant d'autres formes de maladie renale chronique et chez qui les concentrations s6riques en cr6atinine avant Ia grossesse sont inferieure . 1.5 mg/dL ne sont pas expos6es a un risque maternel ou foetal augmente. D'autre part, les patientes ayant une cr6atinin6mie depassant 1.6 mg/dL ont une haute frequence de complications maternelles et foetales et devraient eviter Ia grossesse. Lesperance de vie des greff6es du rein est Incertaine, et ces patientes devraient itre orientees From the division of nephrology, department of medicine, St. Michael's Hospital and the University of Toronto, Toronto Reprint requests to: Dr. Robert A. Bear Division of nephrology, Department of medicine, St. Michael's Hospital, 30 Bond St., Toronto, Ont. M5B 1W8
sur lopportunite dentreprendre une grossesse. Le risque maternel chez ces patientes nest pas excessivement haut, mais le risque foetal est considerable. The concept is widespread that pregnancy in a patient with pre-existing renal disease will be accompanied by increased maternal and fetal risk. This concept is not universally true. Clinical data are now available that permit the clinician to separate those patients with existing renal disease who are likely to encounter difficulties from those in whom pregnancy can be undertaken with high expectation of success. In this review I summarize these clinical data with respect to pregnancy in patients with systemic lupus erythematosus (SLE) and other renal diseases and in recipients of renal transplants. Pregnancy associated with essential hypertension is reviewed in a forthcoming issue of the Journal.1
Systemic lupus erythematosus Since subclinical or symptomatic renal disease complicates SLE in such a high percentage of cases, a discussion of pregnancy in patients with SLE is appropriate. In my view patients with SLE, active or inactive and with or without clinically evident lupus nephritis, should never become pregnant. An increased rate of relapse probably is associated with SLE during pregnancy,2 and the frequency of spontaneous abortion, fetal death and prematurity is high.3 Furthermore, there is an extremely high rate of exacerbation of SLE post partum.2'47 Patients with lupus nephritis, active or in remission, do even less well during pregnancy and in the postpartum period; relapses of systemic and renal lupus erythematosus are frequent and are difficult to control, and resultant postpartum maternal mortality rates of 30% to 85% have been reported in several small series.24'8'9 The cause of reactivation of SLE in the puerperium is not clear but may be related to sudden withdrawal of the immunosuppression of pregnancy If a woman with SLE does become pregnant, therapeutic abortion should not be performed because relapse following this procedure is frequent and 25% of patients die.6 In such patients, anecdotal data support the prescription of prednisone and azathioprine during pregnancy and in the postpartum period.7-10 ,, 5
Other renal disorders Women with renal disorders other than SLE, such as chronic glomerulonephritis with or without nephrotic syndrome, chronic interstitial nephritis, polycystic kidney disease and diabetic glomerulosclerosis can be considered collectively with respect to fetal and maternal risks during pregnancy, since the outcome in such cases- is not determined by the nature of the kidney disease but by the degree to which renal function has been lost prior to pregnancy. This concept has been appreciated for many years, but considerable confusion has existed regarding both the degree of impairment of renal function (as determined by the degree of elevation in the serum creatinine value) beyond which pregnancy becomes inadvisable and the effect of pregnancy on the natural history of the chronic renal disorder. In women with a history of healed idiopathic nephrotic syndrome, relapse during pregnancy does not occur, nor are such pregnancies marked by an increased risk of other fetal or maternal complications." Women with a history of acute glomerulonephritis without active glomerular disease at the time of conception also tolerate pregnancy well,'2 although such patients may be predisposed to premature delivery and pre-eclampsia for up to 3 years after an episode of acute glomerulonephritis." Since 1962 five detailed studies have considered the problem of pregnancy in patients with pre-existing active renal diseases.'2-'6 Kaplan, Smith and Tillman" reported the results of 30 uninterrupted pregnancies in patients with glomerulonephritis. Unfortunately, the details of renal function were scanty. In patients with proteinuria alone, the fetal and maternal results of pregnancy were normal; 70% of patients with proteinuria and hypertension had pre-eclampsia and there was an increased frequency of prematurity and fetal mortality; three patients with proteinuria, hypertension and azotemia suffered spontaneous abortion. Mackay's study'4 of pregnant patients with various underlying renal diseases observed between 1951 and 1961 was limited in value by the lack of documentation of maternal renal function and because effective antihypertensive therapy had not yet been introduced. Patients were divided into four groups: those with proteinuria and
CMA JOURNAL/MARCH 18, 1978/VOL. 118 663
normal renal function, those with abnormal renal function and blood pressure less than 175/110 mm Hg, those with abnormal renal function and blood pressure greater than 175/110 mm Hg and those with abnormal renal function and chronic renal infection. Basically, this study confirmed the results of Kaplan and colleagues'12 survey - that patients with proteinuria alone experienced relatively uneventful pregnancies with good fetal survival, while patients with azotemia and hypertension experienced pregnancies marked by accelerated hypertension, by excessive fetal and perinatal mortality and by apparent deterioration in maternal renal function. In 1973, Fairley, Whitworth and Kincaid-Smith15 updated their experience in managing pregnant patients with underlying glomerulonephritis. Analysis of their data is difficult because of the brevity of the presentation, the lack of control biopsy data, their failure to document accurately maternal renal function and its variation, the frequent performance of therapeutic abortion without any definite indication and the absence of patient follow-up data. They present data demonstrating apparent progression in the histologic appearance of renal lesions despite unchanged maternal serum creatinine clearance values, and they state that "the course of pregnancy is not predictable in the individual patient, but the serious progression that may accompany even the mildest lesions makes glomerulonephritis a justifiable medical indication for termination of pregnancy". Despite these conclusions, review of the published data seems to support the concept that patients with mild renal disease tolerate pregnancy without difficulty, while patients with serious impairment of renal function experience complications. This paper does, however, include the largest series of published observations on pregnancy in patients with membranoproliferative glomerulonephritis; it is of interest that a number of these patients did poorly during pregnancy. A more definitive statement regarding the risks of pregnancy in patients with this disorder awaits publication of further clinical studies. Although the studies outlined above established a loose correlation between the degree of severity of the underlying kidney disease and the maternal and fetal prognosis of pregnancy, the accumulated data were not sufficient to permit adequate counselling of patients with renal disease who wanted to become pregnant, or to aid in the precise clinical management of such patients after the onset of gestation. In 1974 Strauch and Hayslett16 reported
the results of 41 pregnancies in 25 patients with renal disease. Excluding patients with SLE, there were 26 uninterrupted pregnancies in 14 patients with various pre-existing glomerular disorders. Pregestational serum creatinine values were available in 15 patients; among those with values of 0.7 to 1.3 mg/dL there were 11 uninterrupted pregnancies, all of which resulted in full-term uncomplicated deliveries without apparent untoward effect upon maternal renal function. Four uninterrupted pregnancies occurred in patients with pregestational serum creatinine values of 1.7 to 2.3 mg/dL; three patients experienced hypertension and all four had moderate to severe edema. One spontaneous abortion occurred at 4 months and one premature delivery at 28 weeks, and two pregnancies progressed to term. Adequate follow-up data were available on only one patient, in whom uremia developed rapidly. These data correlate closely with my previous findings17 in 36 pregnancies in 29 patients with a variety of pre-existing renal diseases in whom serum creatinine values before pregnancy or at first evaluation were less than 1.5 mg/dL. Hypertension developed during pregnancy only if it was noted before conception, and it was always manageable. There was a slight increase in the frequency of cesarean section but none in the frequency of fetal abnormality, prematurity or fetal death. Follow-up data on 24 of the 29 patients from 6 to 84 months post partum revealed that in no instance did pregnancy have an untoward effect on maternal renal function. On the other hand, pregnancy in eight patients with serum creatinine values of 1.7 to 4.8 mg/dL was complicated in seven. The rate of fetal survival was diminished, the rates of fetal abnormality, prematurity and cesarean section were high, and typically pregnancy was associated with severe, poorly controlled hypertension, increased proteinuria and further loss of maternal kidney function. During the follow-up period renal failure developed in three patients, two of whom required dialysis; one died of cardiorenal failure. The best available data suggest, therefore, that in patients with approximately 50% loss of renal function (i.e., those in whom the serum creatinine value exceeds 1.6 mg/dL), there is a striking increase in the frequency of maternal and fetal complications. There is little information regarding the optimal management of these patients should pregnancy occur, specifically with respect to the role of therapeutic abortion in preserving maternal renal function. Occasionally, pregnancies in patients with progressive renal failure have been maintained successfully with
664 CMA JOURNAL/MARCH 18, 1978/VOL. 118
frequent use of hemodialysis therapy,18 and occasionally patients with endstage renal disease receiving long-term therapy with hemodialysis have experienced uncomplicated pregnancies.19 Renal transplantation The maternal and fetal prognosis of pregnancy in renal transplant recipients has been reviewed elsewhere.20'21 Renal transplant recipients have a decreased life expectancy, and this fact raises the philosophical question of whether pregnancy should be undertaken if the mother has little likelihood of being able to fulfil her full parental obligations. Although renal transplant recipients usually tolerate pregnancy well, hypertension and deterioration of renal function have been noted,22 and dystocia and even rupture of the uterus may occur.23 The frequency of spontaneous abortion is not increased; however, the frequency of fetal abnormalities is increased, and neonatal adrenal suppression and sepsis have been noted. In summary, patients with SLE, active or inactive, with or without lupus nephritis, should avoid pregnancy. Patients with other chronic renal diseases in whom the serum creatinine values before conception are less than 1.5 mg/ dL can contemplate successful pregnancy without increased maternal or fetal risk, while patients with serum creatinine values exceeding 1.6 mg/dL have a high frequency of maternal and fetal complications and should avoid pregnancy. The life expectancy of renal transplant recipients is uncertain, and these patients should receive counselling as to the advisability of undertaking pregnancy. The maternal risk in such patients is not inordinately high, but the fetal risk is considerable. References 1. BEAR RA, ERENRICH N: Essential hypertension and pregnancy. Can Med Assoc J (in press) 2. GARSENSTEIN M, POLLAK yE, KARK RM: Systemic lupus erythematosus and pregnancy. N Engi J Med 267: 165, 1962 3. Esms D, LARSON DL: Systemic lupus erythematosus and pregnancy. Clin Obstet Gynecol 8: 307, 1965 4. MURRAY RA: Lupus erythematosus in pregnancy. I Obstet Gynaecol Br Emp 65: 401. 1950 5. FRIEDMAN EA, RursoEIu'oIw JQ: Pregnancy and lupus erythematosus. Obstet Gynecol 8: 601, 1956 6. DONALDSON LB, DE ALVAREZ RR: Further observations on lupus erythematosus associated with pregnancy. Am I Obstet Gynecol 83: 1461. 1962 7. Dusois EL (ed): Systemic lupus erythematosus in pregnancy, in Lupus Erythematosus, New York, McGraw, 1966, pp 129-276 8. BEAR RA: Pregnancy and lupus nephritis. A detailed report of six cases with a review of the literature. Obstet Gynecol 47: 715, 1976 9. SHARON E, JONES J, DIAMOND H, et al: Pregnancy and azathioprine in systemic lupus erythematosus. Am I Obstet Gynecol 118: 25, 1974 10. McGEE CD, MAicowsxu EL: Systemic lupus erythematosus in pregnancy. Am I Obstet Gynecol 107: 1008, 1970 11. MARKER SP, HEYMANN w: Pregnancy in patients who have had the idiopathic nephrotic syndrome in childhood. I Pediatr 81: 1140, 1972
12. KAPLAN
AL,
SMrrH
JP,
TILLMAN
MB:
Healed acute and chronic nephritis in pregnancy. Am J Obstet Gynecol 83: 1519, 1962 13. RAURAMO L, KASANEN A, ELFYING K, et al:
Fertility, pregnancies and deliveries in women with history of nephritis or pyelQnephritis. Acta Obstet Gynecol Scand 41: 357, 1962 14. MACKAY EV: Pregnancy and renal disease. A ten-year survey. Aust NZ I Obstet Gynaecol 3: 21, 1963 15. FAIRLEY KF, WHITWOETH JA, KINCAID-SMITH
P: Glomerulonephritis and pregnancy, in Glomerulonephritis: Morphology, Natural History, and Treatment, KINcAID-SMIm P,
MATHEW TH, Bacscn L (eds), New York, Wiley, 1973, pp 997-1012 16. STRAUCH BS, HAYSLETT JP: Kidney disease and pregnancy. Br Med J 4: 578, 1974 17. BEAR RA: Pregnancy in patients with renal disease. A study of 44 cases. Obstet Gynecol 48: 13, 1976 18. HERWIG KR, MERRILL JP, JACKSON RL, et al:
Chronic renal disease and pregnancy. Am J Obstet Gynecol 92: 1117, 1965 19. SCHEHINER GE: Dialysis and pregnancy (E). JAMA 235: 1725, 1976 20. TAGATZ GE, SIMMONS RL: Pregnancy after
renal transplantation (E). Ann intern Med 82: 113, 1975 21. PENN I, MAKowSKI E, DROEGEMUELLER N, Ct al: Parenthood in renal homograft recipients. JAMA 216: 1755, 1971 22. CAPLAN RM, DOSSETOR JB, MAUGHAN GB:
Pregnancy following cadaver kidney homotransplantation. Am I Obstet Gynecol 106: 644, 1970
23. MERRILL LK, BOARD JA, tions of pregnancy after including a report of rupture. Obstet Gynecol
LEE HM: Complicarenal transplantation spontaneous uterine 41: 270, 1973
Alpha1*antitrypsin phenotypes and lung function in a moderately polluted northern Ontario community D.N. OsTRow, MD, FACCP, FRCP[C]; J. MANFREDA, MD; K.S. TSE, MD, FRCP[C]; T. DORMAN,* MD, FRCP[c]; R.M. CHERNIACK, MD, FCCP, FACP, FRCP[C]
To determine whether persons with intermediate value c&1-antitrypsin phenotypes living in a polluted environment manifest significant abnormalities in lung function, a study was undertaken of an age-, sex- and smoking-stratified sample of 391 persons from the town of Fort Frances, Ont., which has elevated values of total dustfall, suspended particulates and hydrogen sulfide. Indices of pulmonary function were derived from the maximum expiratory flow and the single breath expiratory nitrogen washout curves. The percentage frequency of the M, MS and MZ phenotypes was 91.7, 7.3 and 0.8, respectively. There was no significant difference between the M and MS groups as indicated by the nitrogen washout curve and maximum expiratory flow curve. There was no significant difference between the three MZ subjects and the M group. In both M and MS groups smokers displayed evidence of airflow obstruction when compared with nonsmokers. It would appear that, when compared with M subjects, persons with the MS phenotype living in a moderately polluted area show no changes in indicators of pulmonary function, including tests of early airway disease, that cannot be attributed to their smoking habit. Afin de determiner si les personnes dont les ph6notypes determinent des taux interm6diaires de cz1-antitrypsine et qui vivent dans un environnement pollu6 manifestent des anomalies From the departments of medicine and immunology, University of Manitoba, Winnipeg From Fort Frances Clinic, Fort Frances. Ont. Reprint requests to: Dr. David Ostrow, Faculty of medicine, University of Manitoba, Rm. 5-204, 750 Bannatyne Ave., Winnipeg, Man. R3E 0W3
pulmonaires significatives, une 6tude a ete entreprise chez un echantillon stratifie pour l'ige, le sexe et l'habitude de fumer de 391 personnes de Fort Frances, Ontario, une municipalite ayant des taux elev6s de poussiere, de particules en suspension et de sulfure d'hydrogane. Les indices pulmonaires ont et6 obtenus a partir du debit expiratoire maximum et des courbes d'.limination de lazote a l'expiration simple. Les pourcentages des phenotypes M, MS et MZ ont ete de 91.7, 7.3 et 0.8, respectivement. Dl n'y a pas eu de difference significative entre Des groupes M et MS, tel qu'indique par Ia courbe d'elimination de I'azote et Ia courbe du debit expiratoire maximum. Dl n'y avait pas de difference significative entre Des trois sujets de ph6notype MZ et le groupe M. Dans Des deux groupes M et MS, Des fumeurs ont manifest6 des signes d'obstruction respiratoire, comparativement aux nonfumeurs. ID semble donc que, en comparaison avec Des sujets de ph6notype M, Des personnes de ph6notype MS vivant dans une region moder6ment polluee ne presentent aucun changement des indices de Ia fonction pulmonaire, y compris ceux pour Des maladies des voies respiratoires & Deur d6but qui ne peuvent itre attribu6es a l'habitude de fumer. Alphai-antitrypsin (AAT) is a glycoprotein that makes up over 90% of the serum ai-globulins. It is an acutephase reactant protein because its concentration in the serum increases considerably in various physiologic and pathologic conditions such as pregnancy, the use of oral contraceptives, infections and others. Functionally, it is capable of inhibiting a number of
enzymes including trypsin, chymotrypsin, plasmin, elastase, kallikrein and leukocytic and bacterial proteases. The serum concentration of AAT is genetically determined by a pair of autosomal genes and the genetics of the AAT system is controlled by autosomal codominant inheritance. On the basis of differences in electrophoretic mobility with appropriate techniques, 24 variants of AAT have been identified. An alphabetical letter is assigned to each of the variants and the M variant is the most common in the population. Letters early in the alphabet indicate those AAT variants with fast electrophoretic mobility toward the anode and, conversely, the Z variant has the slowest electrophoretic mobility. The majority of the population (more than 90%) have the AAT phenotype M (MM) and have a normal value of serum AAT of over 200 mg/dL. In 1963 Laurell and Eriksson' first observed the association between AAT deficiency and the early-onset, panlobular type of emphysema. Although it is now well established that individuals with the AAT phenotype ZZ, who have very low values of serum AAT, are at high risk of having chronic airflow obstruction and pulmonary emphysema, the risk to persons with intermediate levels of AAT (e.g., phenotypes MZ and MS) remains controversial. It has been demonstrated that the lung elastic recoil is lower than expected2 in older relatives of patients with severe AAT deficiency and that the rate of deterioration of arterial oxygen tension with age is increased.3 In addition, the proportion of MZ subjects is less in the general population than in patients attending clinics for persons with chronic obstructive pulmonary disease, but no apparent
CMA JOURNAL/MARCH 18, 1978/VOL. 118 669
Pregnancy is not invariably contraindicated in patients with preexisting renal disease. Clinical data now exist that permit the clinician to distinguish such patients who are likely to experience difficulty during pregnancy from those in whom pregnancy can be undertaken with high expectation of success. Patients suffering from systemic lupus erythematosus, active or inactive, with or without lupus nephritis, should avoid pregnancy. Patients with other forms of chronic renal disease in whom the serum creatinine concentration prior to pregnancy is less than 1.5 mg/dL are not exposed to increased maternal or fetal risk. On the other hand, patients with serum creatinine values exceeding 1.6 mg/dL experience a high incidence of maternal and fetal complications and should avoid pregnancy. The life expectancy of recipients of a renal transplant is uncertain, and these patients should receive counselling as to the advisability of undertaking pregnancy. The maternal risk in such patients is not inordinately high, but the fetal risk is considerable. La grossesse n'est pas invariablement contreindique chez les patients souffrant de maladie renale preexistante. Des donnees cliniques existent maintenant qui permettent au clinicien de distinguer les patientes susceptibles de rencontrer des difficult6s durant Ia grossesse de celles chez qui une grossesse peut 6tre entreprise avec une forte probabilit6 de succes. Les patientes atteintes de lupus erythe. mateux dissemin6, actif ou inactif, avec ou sans nephrite lupeuse, devraient eviter Ia grossesse. Les patientes presentant d'autres formes de maladie renale chronique et chez qui les concentrations s6riques en cr6atinine avant Ia grossesse sont inferieure . 1.5 mg/dL ne sont pas expos6es a un risque maternel ou foetal augmente. D'autre part, les patientes ayant une cr6atinin6mie depassant 1.6 mg/dL ont une haute frequence de complications maternelles et foetales et devraient eviter Ia grossesse. Lesperance de vie des greff6es du rein est Incertaine, et ces patientes devraient itre orientees From the division of nephrology, department of medicine, St. Michael's Hospital and the University of Toronto, Toronto Reprint requests to: Dr. Robert A. Bear Division of nephrology, Department of medicine, St. Michael's Hospital, 30 Bond St., Toronto, Ont. M5B 1W8
sur lopportunite dentreprendre une grossesse. Le risque maternel chez ces patientes nest pas excessivement haut, mais le risque foetal est considerable. The concept is widespread that pregnancy in a patient with pre-existing renal disease will be accompanied by increased maternal and fetal risk. This concept is not universally true. Clinical data are now available that permit the clinician to separate those patients with existing renal disease who are likely to encounter difficulties from those in whom pregnancy can be undertaken with high expectation of success. In this review I summarize these clinical data with respect to pregnancy in patients with systemic lupus erythematosus (SLE) and other renal diseases and in recipients of renal transplants. Pregnancy associated with essential hypertension is reviewed in a forthcoming issue of the Journal.1
Systemic lupus erythematosus Since subclinical or symptomatic renal disease complicates SLE in such a high percentage of cases, a discussion of pregnancy in patients with SLE is appropriate. In my view patients with SLE, active or inactive and with or without clinically evident lupus nephritis, should never become pregnant. An increased rate of relapse probably is associated with SLE during pregnancy,2 and the frequency of spontaneous abortion, fetal death and prematurity is high.3 Furthermore, there is an extremely high rate of exacerbation of SLE post partum.2'47 Patients with lupus nephritis, active or in remission, do even less well during pregnancy and in the postpartum period; relapses of systemic and renal lupus erythematosus are frequent and are difficult to control, and resultant postpartum maternal mortality rates of 30% to 85% have been reported in several small series.24'8'9 The cause of reactivation of SLE in the puerperium is not clear but may be related to sudden withdrawal of the immunosuppression of pregnancy If a woman with SLE does become pregnant, therapeutic abortion should not be performed because relapse following this procedure is frequent and 25% of patients die.6 In such patients, anecdotal data support the prescription of prednisone and azathioprine during pregnancy and in the postpartum period.7-10 ,, 5
Other renal disorders Women with renal disorders other than SLE, such as chronic glomerulonephritis with or without nephrotic syndrome, chronic interstitial nephritis, polycystic kidney disease and diabetic glomerulosclerosis can be considered collectively with respect to fetal and maternal risks during pregnancy, since the outcome in such cases- is not determined by the nature of the kidney disease but by the degree to which renal function has been lost prior to pregnancy. This concept has been appreciated for many years, but considerable confusion has existed regarding both the degree of impairment of renal function (as determined by the degree of elevation in the serum creatinine value) beyond which pregnancy becomes inadvisable and the effect of pregnancy on the natural history of the chronic renal disorder. In women with a history of healed idiopathic nephrotic syndrome, relapse during pregnancy does not occur, nor are such pregnancies marked by an increased risk of other fetal or maternal complications." Women with a history of acute glomerulonephritis without active glomerular disease at the time of conception also tolerate pregnancy well,'2 although such patients may be predisposed to premature delivery and pre-eclampsia for up to 3 years after an episode of acute glomerulonephritis." Since 1962 five detailed studies have considered the problem of pregnancy in patients with pre-existing active renal diseases.'2-'6 Kaplan, Smith and Tillman" reported the results of 30 uninterrupted pregnancies in patients with glomerulonephritis. Unfortunately, the details of renal function were scanty. In patients with proteinuria alone, the fetal and maternal results of pregnancy were normal; 70% of patients with proteinuria and hypertension had pre-eclampsia and there was an increased frequency of prematurity and fetal mortality; three patients with proteinuria, hypertension and azotemia suffered spontaneous abortion. Mackay's study'4 of pregnant patients with various underlying renal diseases observed between 1951 and 1961 was limited in value by the lack of documentation of maternal renal function and because effective antihypertensive therapy had not yet been introduced. Patients were divided into four groups: those with proteinuria and
CMA JOURNAL/MARCH 18, 1978/VOL. 118 663
normal renal function, those with abnormal renal function and blood pressure less than 175/110 mm Hg, those with abnormal renal function and blood pressure greater than 175/110 mm Hg and those with abnormal renal function and chronic renal infection. Basically, this study confirmed the results of Kaplan and colleagues'12 survey - that patients with proteinuria alone experienced relatively uneventful pregnancies with good fetal survival, while patients with azotemia and hypertension experienced pregnancies marked by accelerated hypertension, by excessive fetal and perinatal mortality and by apparent deterioration in maternal renal function. In 1973, Fairley, Whitworth and Kincaid-Smith15 updated their experience in managing pregnant patients with underlying glomerulonephritis. Analysis of their data is difficult because of the brevity of the presentation, the lack of control biopsy data, their failure to document accurately maternal renal function and its variation, the frequent performance of therapeutic abortion without any definite indication and the absence of patient follow-up data. They present data demonstrating apparent progression in the histologic appearance of renal lesions despite unchanged maternal serum creatinine clearance values, and they state that "the course of pregnancy is not predictable in the individual patient, but the serious progression that may accompany even the mildest lesions makes glomerulonephritis a justifiable medical indication for termination of pregnancy". Despite these conclusions, review of the published data seems to support the concept that patients with mild renal disease tolerate pregnancy without difficulty, while patients with serious impairment of renal function experience complications. This paper does, however, include the largest series of published observations on pregnancy in patients with membranoproliferative glomerulonephritis; it is of interest that a number of these patients did poorly during pregnancy. A more definitive statement regarding the risks of pregnancy in patients with this disorder awaits publication of further clinical studies. Although the studies outlined above established a loose correlation between the degree of severity of the underlying kidney disease and the maternal and fetal prognosis of pregnancy, the accumulated data were not sufficient to permit adequate counselling of patients with renal disease who wanted to become pregnant, or to aid in the precise clinical management of such patients after the onset of gestation. In 1974 Strauch and Hayslett16 reported
the results of 41 pregnancies in 25 patients with renal disease. Excluding patients with SLE, there were 26 uninterrupted pregnancies in 14 patients with various pre-existing glomerular disorders. Pregestational serum creatinine values were available in 15 patients; among those with values of 0.7 to 1.3 mg/dL there were 11 uninterrupted pregnancies, all of which resulted in full-term uncomplicated deliveries without apparent untoward effect upon maternal renal function. Four uninterrupted pregnancies occurred in patients with pregestational serum creatinine values of 1.7 to 2.3 mg/dL; three patients experienced hypertension and all four had moderate to severe edema. One spontaneous abortion occurred at 4 months and one premature delivery at 28 weeks, and two pregnancies progressed to term. Adequate follow-up data were available on only one patient, in whom uremia developed rapidly. These data correlate closely with my previous findings17 in 36 pregnancies in 29 patients with a variety of pre-existing renal diseases in whom serum creatinine values before pregnancy or at first evaluation were less than 1.5 mg/dL. Hypertension developed during pregnancy only if it was noted before conception, and it was always manageable. There was a slight increase in the frequency of cesarean section but none in the frequency of fetal abnormality, prematurity or fetal death. Follow-up data on 24 of the 29 patients from 6 to 84 months post partum revealed that in no instance did pregnancy have an untoward effect on maternal renal function. On the other hand, pregnancy in eight patients with serum creatinine values of 1.7 to 4.8 mg/dL was complicated in seven. The rate of fetal survival was diminished, the rates of fetal abnormality, prematurity and cesarean section were high, and typically pregnancy was associated with severe, poorly controlled hypertension, increased proteinuria and further loss of maternal kidney function. During the follow-up period renal failure developed in three patients, two of whom required dialysis; one died of cardiorenal failure. The best available data suggest, therefore, that in patients with approximately 50% loss of renal function (i.e., those in whom the serum creatinine value exceeds 1.6 mg/dL), there is a striking increase in the frequency of maternal and fetal complications. There is little information regarding the optimal management of these patients should pregnancy occur, specifically with respect to the role of therapeutic abortion in preserving maternal renal function. Occasionally, pregnancies in patients with progressive renal failure have been maintained successfully with
664 CMA JOURNAL/MARCH 18, 1978/VOL. 118
frequent use of hemodialysis therapy,18 and occasionally patients with endstage renal disease receiving long-term therapy with hemodialysis have experienced uncomplicated pregnancies.19 Renal transplantation The maternal and fetal prognosis of pregnancy in renal transplant recipients has been reviewed elsewhere.20'21 Renal transplant recipients have a decreased life expectancy, and this fact raises the philosophical question of whether pregnancy should be undertaken if the mother has little likelihood of being able to fulfil her full parental obligations. Although renal transplant recipients usually tolerate pregnancy well, hypertension and deterioration of renal function have been noted,22 and dystocia and even rupture of the uterus may occur.23 The frequency of spontaneous abortion is not increased; however, the frequency of fetal abnormalities is increased, and neonatal adrenal suppression and sepsis have been noted. In summary, patients with SLE, active or inactive, with or without lupus nephritis, should avoid pregnancy. Patients with other chronic renal diseases in whom the serum creatinine values before conception are less than 1.5 mg/ dL can contemplate successful pregnancy without increased maternal or fetal risk, while patients with serum creatinine values exceeding 1.6 mg/dL have a high frequency of maternal and fetal complications and should avoid pregnancy. The life expectancy of renal transplant recipients is uncertain, and these patients should receive counselling as to the advisability of undertaking pregnancy. The maternal risk in such patients is not inordinately high, but the fetal risk is considerable. References 1. BEAR RA, ERENRICH N: Essential hypertension and pregnancy. Can Med Assoc J (in press) 2. GARSENSTEIN M, POLLAK yE, KARK RM: Systemic lupus erythematosus and pregnancy. N Engi J Med 267: 165, 1962 3. Esms D, LARSON DL: Systemic lupus erythematosus and pregnancy. Clin Obstet Gynecol 8: 307, 1965 4. MURRAY RA: Lupus erythematosus in pregnancy. I Obstet Gynaecol Br Emp 65: 401. 1950 5. FRIEDMAN EA, RursoEIu'oIw JQ: Pregnancy and lupus erythematosus. Obstet Gynecol 8: 601, 1956 6. DONALDSON LB, DE ALVAREZ RR: Further observations on lupus erythematosus associated with pregnancy. Am I Obstet Gynecol 83: 1461. 1962 7. Dusois EL (ed): Systemic lupus erythematosus in pregnancy, in Lupus Erythematosus, New York, McGraw, 1966, pp 129-276 8. BEAR RA: Pregnancy and lupus nephritis. A detailed report of six cases with a review of the literature. Obstet Gynecol 47: 715, 1976 9. SHARON E, JONES J, DIAMOND H, et al: Pregnancy and azathioprine in systemic lupus erythematosus. Am I Obstet Gynecol 118: 25, 1974 10. McGEE CD, MAicowsxu EL: Systemic lupus erythematosus in pregnancy. Am I Obstet Gynecol 107: 1008, 1970 11. MARKER SP, HEYMANN w: Pregnancy in patients who have had the idiopathic nephrotic syndrome in childhood. I Pediatr 81: 1140, 1972
12. KAPLAN
AL,
SMrrH
JP,
TILLMAN
MB:
Healed acute and chronic nephritis in pregnancy. Am J Obstet Gynecol 83: 1519, 1962 13. RAURAMO L, KASANEN A, ELFYING K, et al:
Fertility, pregnancies and deliveries in women with history of nephritis or pyelQnephritis. Acta Obstet Gynecol Scand 41: 357, 1962 14. MACKAY EV: Pregnancy and renal disease. A ten-year survey. Aust NZ I Obstet Gynaecol 3: 21, 1963 15. FAIRLEY KF, WHITWOETH JA, KINCAID-SMITH
P: Glomerulonephritis and pregnancy, in Glomerulonephritis: Morphology, Natural History, and Treatment, KINcAID-SMIm P,
MATHEW TH, Bacscn L (eds), New York, Wiley, 1973, pp 997-1012 16. STRAUCH BS, HAYSLETT JP: Kidney disease and pregnancy. Br Med J 4: 578, 1974 17. BEAR RA: Pregnancy in patients with renal disease. A study of 44 cases. Obstet Gynecol 48: 13, 1976 18. HERWIG KR, MERRILL JP, JACKSON RL, et al:
Chronic renal disease and pregnancy. Am J Obstet Gynecol 92: 1117, 1965 19. SCHEHINER GE: Dialysis and pregnancy (E). JAMA 235: 1725, 1976 20. TAGATZ GE, SIMMONS RL: Pregnancy after
renal transplantation (E). Ann intern Med 82: 113, 1975 21. PENN I, MAKowSKI E, DROEGEMUELLER N, Ct al: Parenthood in renal homograft recipients. JAMA 216: 1755, 1971 22. CAPLAN RM, DOSSETOR JB, MAUGHAN GB:
Pregnancy following cadaver kidney homotransplantation. Am I Obstet Gynecol 106: 644, 1970
23. MERRILL LK, BOARD JA, tions of pregnancy after including a report of rupture. Obstet Gynecol
LEE HM: Complicarenal transplantation spontaneous uterine 41: 270, 1973
Alpha1*antitrypsin phenotypes and lung function in a moderately polluted northern Ontario community D.N. OsTRow, MD, FACCP, FRCP[C]; J. MANFREDA, MD; K.S. TSE, MD, FRCP[C]; T. DORMAN,* MD, FRCP[c]; R.M. CHERNIACK, MD, FCCP, FACP, FRCP[C]
To determine whether persons with intermediate value c&1-antitrypsin phenotypes living in a polluted environment manifest significant abnormalities in lung function, a study was undertaken of an age-, sex- and smoking-stratified sample of 391 persons from the town of Fort Frances, Ont., which has elevated values of total dustfall, suspended particulates and hydrogen sulfide. Indices of pulmonary function were derived from the maximum expiratory flow and the single breath expiratory nitrogen washout curves. The percentage frequency of the M, MS and MZ phenotypes was 91.7, 7.3 and 0.8, respectively. There was no significant difference between the M and MS groups as indicated by the nitrogen washout curve and maximum expiratory flow curve. There was no significant difference between the three MZ subjects and the M group. In both M and MS groups smokers displayed evidence of airflow obstruction when compared with nonsmokers. It would appear that, when compared with M subjects, persons with the MS phenotype living in a moderately polluted area show no changes in indicators of pulmonary function, including tests of early airway disease, that cannot be attributed to their smoking habit. Afin de determiner si les personnes dont les ph6notypes determinent des taux interm6diaires de cz1-antitrypsine et qui vivent dans un environnement pollu6 manifestent des anomalies From the departments of medicine and immunology, University of Manitoba, Winnipeg From Fort Frances Clinic, Fort Frances. Ont. Reprint requests to: Dr. David Ostrow, Faculty of medicine, University of Manitoba, Rm. 5-204, 750 Bannatyne Ave., Winnipeg, Man. R3E 0W3
pulmonaires significatives, une 6tude a ete entreprise chez un echantillon stratifie pour l'ige, le sexe et l'habitude de fumer de 391 personnes de Fort Frances, Ontario, une municipalite ayant des taux elev6s de poussiere, de particules en suspension et de sulfure d'hydrogane. Les indices pulmonaires ont et6 obtenus a partir du debit expiratoire maximum et des courbes d'.limination de lazote a l'expiration simple. Les pourcentages des phenotypes M, MS et MZ ont ete de 91.7, 7.3 et 0.8, respectivement. Dl n'y a pas eu de difference significative entre Des groupes M et MS, tel qu'indique par Ia courbe d'elimination de I'azote et Ia courbe du debit expiratoire maximum. Dl n'y avait pas de difference significative entre Des trois sujets de ph6notype MZ et le groupe M. Dans Des deux groupes M et MS, Des fumeurs ont manifest6 des signes d'obstruction respiratoire, comparativement aux nonfumeurs. ID semble donc que, en comparaison avec Des sujets de ph6notype M, Des personnes de ph6notype MS vivant dans une region moder6ment polluee ne presentent aucun changement des indices de Ia fonction pulmonaire, y compris ceux pour Des maladies des voies respiratoires & Deur d6but qui ne peuvent itre attribu6es a l'habitude de fumer. Alphai-antitrypsin (AAT) is a glycoprotein that makes up over 90% of the serum ai-globulins. It is an acutephase reactant protein because its concentration in the serum increases considerably in various physiologic and pathologic conditions such as pregnancy, the use of oral contraceptives, infections and others. Functionally, it is capable of inhibiting a number of
enzymes including trypsin, chymotrypsin, plasmin, elastase, kallikrein and leukocytic and bacterial proteases. The serum concentration of AAT is genetically determined by a pair of autosomal genes and the genetics of the AAT system is controlled by autosomal codominant inheritance. On the basis of differences in electrophoretic mobility with appropriate techniques, 24 variants of AAT have been identified. An alphabetical letter is assigned to each of the variants and the M variant is the most common in the population. Letters early in the alphabet indicate those AAT variants with fast electrophoretic mobility toward the anode and, conversely, the Z variant has the slowest electrophoretic mobility. The majority of the population (more than 90%) have the AAT phenotype M (MM) and have a normal value of serum AAT of over 200 mg/dL. In 1963 Laurell and Eriksson' first observed the association between AAT deficiency and the early-onset, panlobular type of emphysema. Although it is now well established that individuals with the AAT phenotype ZZ, who have very low values of serum AAT, are at high risk of having chronic airflow obstruction and pulmonary emphysema, the risk to persons with intermediate levels of AAT (e.g., phenotypes MZ and MS) remains controversial. It has been demonstrated that the lung elastic recoil is lower than expected2 in older relatives of patients with severe AAT deficiency and that the rate of deterioration of arterial oxygen tension with age is increased.3 In addition, the proportion of MZ subjects is less in the general population than in patients attending clinics for persons with chronic obstructive pulmonary disease, but no apparent
CMA JOURNAL/MARCH 18, 1978/VOL. 118 669
