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Glomerulonephritis in Pregnancy
GLOMERULONEPHRITIS IN PREGNANCY ELIZABETH
M USSEY
PREGNANCY for a woman who has chronic glomerulonephritis is a potential hazard which, on the one hand, can eventuate in fetal and perhaps maternal death and, on the other hand, can be marked by a relatively smooth course without exacerbation of the prior renal disease. Management of such pregnancies will call on the widest knowledge and most discriminating judgment of the obstetrician, who must attempt to predict the probable outcome on the basis of laboratory and clinical findings evaluated against his experience and that of others. Unfortunately the value of the recorded experiences of others is diminished by several factors: the relative rarity of acute and chronic glomerulonephritis in pregnant women; the confusing terminology employed for the most part in obstetric literature prior to 1940, and the difficulty at times in the clinical distinction of chronic glomerulonephritis from either essential hypertension or preeclampsia. As long ago as 1839 Rayer is said to have differentiated the renal disorder occurring late in pregnancy from that which antedated the pregnancy and became manifest early in gestation. Yet, a clear delineation of the toxemias of pregnancy was agreed on only as recently as 1939 when The American Committee on Maternal Welfare23 separated hypertension peculiar to pregnancy (preeclampsia) from hypertension independent of, or antedating, pregnancy (essential hypertension and hypertension associated with pre-existing renal disease). Throughout the third and fourth decades of this century a considerable literature accumulated under the general title of "Chronic Nephritis in Pregnancy" and numerous cases were reported in detail. A glance at such reports rapidly leads to the realization :that the patient having so-called chronic nephritis usually had either preeclampsia or essential hypertension and rarely exhibited the features of chronic glomerulonephritis. In 1926, Stander and Peckham33 proposed a classification of the toxemias of pregnancy consisting of five types: eclampsia, preeclampsia, chronic nephritis, eclampsia superimposed 'on chronic nephritis, and the low reserve kidney. Although hypertensive vascular disease was not recognized by Stander and Peckham and the concept of the low reserve kidney has not withstood critical analysis, nonetheless the grouping was widely accepted 1051
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and served a useful purpose in pointing out the poorly recognized fact that toxemia of pregnancy was not one syndrome but several, varying in etiology but merging to become indistinguishable clinically at times. However, all patients manifesting hypertension in the course of their pregnancy failed to drop neatly into one of these pigeon holes and contrary points of view began to make their appearance. Herrick and Tillman 19 were among those who emphasized that "the toxemias may not be isolated, idiopathic states but ... are possibly related to certain common general medical conditions .... In most obstetric clinics a woman with high blood pressure is classified as having nephritis. Primary vascular disease is still unrecognized." Later Herrick 18 pointed out that the failure of many obstetric writers to "differentiate nephritis and vascular disease ... has given rise to needless argument and a confusion which lessens the value of much of the older writing upon the subject." In attempting to emphasize the role of renal and hypertensive disease in the production of toxemias of pregnancy, Herrick, however, leaned far to the opposite side and held that at least a majority of the instances of toxemia contain "a thread of one of these two conditions." Thus, all of his 594 cases of toxemia could be placed into one of the two groups: in the first, and smaller, it was "associated with a latent or manifest primary glomerulonephritis, and in the second, and larger, with hypertensive cardiovascular disease." A compromise among the divergent views was finally effected by the Committee for Classification of the Toxemias whose classification 23 is, in brief, as follows: Group A. Disease independent of pregnancy 1. Hypertensive or arterial vascular disease, benign and malignant. 2. Renal disease, ineluding glomerulonephritis, pyelonephritis, and other forms of severe renal disease, including nephrosis, polycystic kidneys and others. Group B. Disease not independent of pregnancy 1. Preeelampsia, mild and severe 2. Eclampsia Group C. Unelassified (unknown)
The most recent classification of the toxemias is one proposed by Eastman, Titus, McCormick, and Greenhill. 16 In it primary renal disease is excluded completely and the remaining conditions are separated into two groups: A. Acute toxemias 1. Preeclampsia 2. Eclampsia
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B. Chronic hypertensive vascular disease (essential hypertension) 1. vVithout superimposed acute toxemia 2. With superimposed acute toxemia
Onc might take issue with the omission of chronic glomerulonephritis from this tabulation. Essential hypertension is no more a true toxemia of pregnancy than is chronic glomerulonephritis, and, although the latter occurs more rarely, it too must be considered in the differential diagnosis in the pregnant patient with hypertension. INCIDENCE
Glomerulonephritis is rarely complicated by pregnancy. Dieckmann 8 reported 12 cases of primary renal disease in pregnancy, collected over a period of twelve years during which time more than 22,000 patients were delivered. Three of the 12 patients had acute glomerulonephritis; 2, the nephrotic form of glomerulonephritis; 4, recurrent acute glomerulonephritis; and 3, lipoid nephrosis. He stated that Wegner had found 6 cases of chronic glomerulonephritis in 10,596 deliveries, an incidence of 0.056 per cent. Eastman reported encountering 641 cases of "chronic nephritis" (probably including nephrosclerosis) and 2 cases of acute nephritis during a ten-year period during which there were 16,150 admissions and 10,965 deliveries. Dieckmann 9 further stated that primary renal disease including glomerulonephritis, pyelonephritis, nephrosis and other rare conditions makes up less than 2 per eent of the so-called toxemias of pregnancy. Kuder and Stander published their incidence of toxemia of pregnancy as 14.067 per cent, of which 21.47 per cent of patients had chronic nephritis; most of these, they stated, undoubtedly suffered from nephrosclerosis. According to Herrick chronic nephritis constitutes 5 to 10 per cent of all cases of late toxemia. Dodds and Browne observed 17 nephritic patients in 21 pregnancies, an incidence of 1 to 1,100 deliveries (0.09 per cent). Browne more recently stated that 5 per cent of all patients who have hypertension in pregnancy have chronic nephritis. Irving found chronic nephritis present in 13 (1.1 per cent) of 1,182 patients with hypertension and albuminuria in pregnancy. Miller has found 4 cases of acute glomerulonephritis and 89 cases of chronic glomerulonephritis, an incidence of 3 cases per thousand patients delivered (0.3 per cent). He stated that this figure is higher than it should be because of the erroneous grouping of all the nephropathies under the term "chronic nephritis." Wellen found 4 cases of chronic glomerulonephritis in 272 cases of "toxemia" which occurred among 7,897 deliveries. Dexter and Weiss failed to find any cases of glomerulonephritis among 80 pregnant patients with blood pressures in excess of 140 mm. of mercury systolic and 90 mm. diastolic.
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It is apparent that the true incidence of chronic glomerulonephritis is unknown, individual statistics reflecting the current classification of the toxemias. It is equally apparent that no report represents a large series of cases, and that the experience of any individual obstetrician with the disease is limited. Indeed, Bell's seriesl of 55 pregnancies in 20 patients who had chronic glomerulonephritis is the largest reported, and these studies of course represent postmortem analyses only. The suggestion has been advanced that the paucity of cases of chronic glomerulonephritis complicated by pregnancy might be related to decreased fertility though data bearing on this point is lacking. AGE AND PARITY
Chronic glomerulonephritis is for the most part a disease of young people. In the series of Dodds and Browne, 11 of the 17 patients were less than 25 years of age. Nine were primigravidas and 8 were multigravidas. Of the latter, 5 were para 1, 2 were para 2, and 1 was para 3. Gareis reported 10 patients, 7 of whom were less than 21 years of age; 1 each was age 23,28 and 38 years. Dieckmann 8 stated that glomerulonephritis in pregnancy is characteristically a disease of the young primigravida. All of his patients except 1 were less than 27 years of age. HISTORY
The history, of course, will frequently reveal the presence of antecedent "renal disease. Dodds and Browne found such a history in 11 of their patients, in all of whom reliable medical records were obtainable. Two patients of the remaining 6 had had scarlet fever and 1 had had frequent"'episodes of sore throat.:Only 4 of the 10 patients whose cases were reported by Gareis had no relevant history to suggest the prior onset of nephropathy. SIGNS AND SYMPTOMS
Symptoms presented by the pregnant patient who suffers from glomerulonephritis vary with the phase and severity of the disease and are not different from those of nonpregnant individuals who have this disease. Headache is the most frequent complaint; lassitude, dizzy spells, nausea, vomiting, anorexia and visual disturbances are likely to occur only when patients have advanced renal involvement.H. 18. 21. 29 Albuminuria. Indeed, the paucity of symptoms even when renal function is fairly inadequate could well lead to overlooking the disease entirely were it not for the almost constant albuminuria which is
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discoverable at the time of the first prenatal visit. Such a finding should lead the obstetrician to suspect renal disease although urinary albumin may be present as a result of cystitis, pyelitis, nephrosclerosis or other renal pathologic lesions or even because of contamination of the specimen with vaginal secretions. Although the degree of albuminuria may be slight, the finding tends to be persistent. However, Theobald and Goodall have pointed out the fact that temporary absence of protein in the urine can occur during the first half of pregnancy, in cases of chronic glomerulonephritis. Hematuria. This is a constant finding in acute glomerulonephritis, and hyaline or granular casts are usually seen. Erythrocytes and casts mayor may not be observed in the urine of patients who have chronic glomerulonephritis but are generally found at some time in the course of a pregnancy superimposed on the chronic glomerulonephritis. s . 10. 18 Although the Addis count of urinary sediment has not been widely used, Dieckmann s . 9 has found it a useful tool for establishing a diagnosis of acute glomerulonephritis in pregnancy. Both preeclampsia and acute glomerulonephritis may cause the appearance of proteinuria, edema, hypertension, and formed elements in the urine and, more l'arely, of nitrogen retention. Although the urine of normal pregnant women may occasionally show an increase in the Addis count,12 the continued finding of erythrocytes is probably significant. In the urine of 41 of 100 women with abnormal sediment, 8 erythrocytes persisted for a week or longer. Only 8 of these were given a diagnosis of "acute or recurrent acute glomerulonephritis"; the remainder were thought to have toxemia of pregnancy. In mild preeclampsia, the Addis count shows little change from that in normal pregnant women, but it is abnormal in patients with either severe preeclampsia or acute or chronic glomerulonephritis. Hypertension. Elevation of the blood pressure mayor may not be observed, its occurrence being an indication of the degree and duration of renal damage. A sudden increase of blood pressure, especially in the latter half of gestation, is suggestive of the appearance of preeclampsia superimposed on chronic glomerulonephritis. That the blood pressure is subject to wide fluctuations and can return to normal in previously hypertensive individuals with primary renal disease is pointed out by Theobald, Goodall and Browne. However, the experienee of the majority of observers 9 • 10. 32 appears to be that hypertension, if present, usually is maintained or exaggerated as pregnancy progresses. Edema. Edema is not a constant finding, tending to appear after the twentieth week of pregnancy10 or to be present in patients manifesting a nephrotic type of glomerulo;nephritis. Its occurrence early
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in pregnancy suggests the existenee of hypoproteinemia while during the third trimester edema may be the initial sign of the development of preeclampsia. Retinal Changes. Retinal changes are more commonly seen in cases of chronic glomerulonephritis than in cases of acute glomerulonephritis.13 In both groups of cases, ocular abnormalities are roughly parallel in degree to the severity and duration of the disease. Thus, the majority of cases of acute glomerulonephritis show only minimal changes in the retina, consisting of blurring of the disk and slight arteriolar narrowing, but the picture of hypertensive retinopathy may Occur in individuals who are severely ill. Patients who appear to have recovered completely from acute glomerulonephritis manifest no ocular lesions, and even those in whom chronic renal disease persists may show no retinal abnormalities for a protracted period. Retinal lesions appear to develop in response to prolonged arterial hypertension and may be found in the absence of renal insufficiency. In most cases in which retinal lesions are found, renal insufficiency ultimately develops if it was not present before the retinal changes appeared. The occurrence of marked vascular sclerosis, of hem orrh ages and of cotton-wool exudates indicates a poor prognosis. The retinal findings in pregnant women who have chronic glomerulonephritis are not at variance with the findings in nonpregnant individuals who have it. Abnormal retinal changes were noted by Dieckmann 9 in 67 per cent of patients having chronic glomerulonephritis. Dodds and Browne found "albuminuric retinitis" in only 2 of 17 cases of chronic glomerulonephritis; both these patients had marked renal involvement. In all of the 10 cases reported by Gareis narrowing of the arterioles and an increased light streak were found and in 1 case retinopathy was noted. Hallum, who has examined 2,500 women suffering from hypertension associated with pregnancy, stated that he has not seen any patient whose hypertension was known to be due to acute glomerulonephritis. In cases of pre-existing renal disease, the retinal changes were only those to be expected from the degree of generalized vascular disease which had resulted from the previous nephritis: that is, varying degrees of arteriovenous "nicking," asymmetrical arteriolar constrictions and increased light reflex. The appearance of localized or generalized spasm indicated the existence of superimposed preeclamptic toxemia. More extensive description of the retinal lesions associated with glomerulonephritis is to be found elsewhere in this volume. 20 Changes in Blood. No characteristic alterations of cellular elements or chemical constitutents of the blood have been noted other than those which are common in acute and chronic glomerulonephritis
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without associated pregnancy. Severe degrees of anemia, usually normocytic, oocur and usually, although not always, reflect the amount of impairment of renal function. 13 When renal insufficiency develops, the values for urea nitrogen and uric acid in the blood may rise, but they do not appear to be altered by pregnancy per se. With the superimposition of severe preeclampsia, there is frequently an elevation of the levels of uric acid and sulfates in the blood out of proportion to that of the blood urea, possibly because of hepatic damage. 9 In patients who have marked albuminuria, the plasma proteins may be depleted below the normal and there may be reversal of the albumin-globulin ratio. In general, however, values for various constituents of the blood are not changed by an otherwise uncomplicated pregnancy in the woman who has glomerulonephritis. Changes in Renal Function. Impairment of renal function may not appear for many months or years after the onset of chronic glomerulonephritis,!a and in many cases the diagnosis may rest only on the consistent finding of variable amounts of urinary albumin I , 10 while the specific gravity of the urine remains high and the exeretion of dyes and other substances is within normal limits. In normal pregnant women the urea clearance has been found to range between 60 and U8 per cent of normal; a third of the valuefl for 19 patients fell between 60 and 80 per cent of normal,l2 Chesley found the average urea elearance for 80 normal pregnant women to be U9 per eent, with a range of from 45 to 175 per cent. He also found the uric acid elearance to average 112 per cent, with a range of from 45 to 215 per cent. In 5 cases the uric acid clearance was less than 70 per cent of normal, and in 4 the urea clearance was less than 70 per cent. Dieckmann 7 was of the opinion that no value for urea clearance in excess of 50 per cent of normal can be considered indicative of decreased renal function during pregnancy. Welsh, Wellen and Taylor have measured the filtration rate, effeetive renal blood flow, tubular excretory mass and phenol red clearance of women during normal pregnancies and found no variation from the results obtained for nonpregnant women. Apparently there are few reports of measurements of renal excretory capacity in pregnant women suffering from chronic glomerulonephritis. Gar~is stated that, of his 10 patients, 4 excreted less than 60 per cent of the phenolsulfonphthalein injected, 6 had less than 50 per cent of normal urea elearance, and all but 2 failed to form urine with a specific gravity greater than 1.010. The first reported complete clearance studies on pregnant women with chronic glomerulonephritis were those of Wellen, Welsh and
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Taylor. They investigated 2 patients whose urea clearance values before conception were known to be one half and two thirds of normal, respectively. Both were found during pregnancy to have abnormally low values for glomerular filtration, effective renal blood flow and tubular excretory mass. In summary, it may be said that laboratory study of the urine, blood and renal function of pregnant patients who have chronic glomerulonephritis does not show results differing in any respect from those obtained for nonpregnant patients who have the same disease. Any abnormalities exhibited by such patients in the course of pregnancy are a reflection of their primary renal disease and not of the superimposed gestation. DIFFERENTIAL DIAGNOSIS
Acute glomerulonephritis must be distinguished from preeclamptic toxemia and from other disease of the urinary tract which may produce hematuria, pyuria or proteinuria. As a rule preeclampsia does not appear prior to the last trimester of pregnancy and acute glomerulonephritis occurs more commonly in the first half of pregnancy. Further, the extreme rarity of acute glomerulonephritis during gestation favors a diagnosis of preeclampsia when a confusing clinical picture exists. Dieckmann 8 has pointed out that absolute distinction between the two conditions is dependent on the duration of hematuria, persistence of which for more than one week he considered to be evidence of acute glomerulonephritis. He stated further that the edema associated with preeclampsia tends to be more dependent than does that in patients with acute glomerulonephritis and usually subsides more rapidly after delivery. Ordinarily proteinuria is more marked in acute nephritis and does not disappear after delivery as in preeclampsia and eclampsia. Peters and Miller have also noted the marked similarity between acute glomerulonephritis and preeclampsia, and the latter is of the opinion that only postpartum follow-up or postmortem examination will prevent errors in diagnosis. A correct diagnosis of chronic glomerulonephritis may be impossible to make in the course of an individual pregnancy or, in some instances, even during life. One suspects the presence of primary renal disease in the patient who shows albuminuria out of proportion to or without elevation of blood pressure, whose urine from time to time contains casts or erythrocytes, and whose blood studies may show anemia or hypoproteinemia. A history of antecedent acute or chronic renal disease and especially prior medical records of such episodes are invaluable. However, as Miller has pointed out, a patient "may make a complete recovery from an acute nephritis and
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develop eclamptic toxemia in a subsequent pregnancy, and ... occasionally a patient with chronic Bright's disease may have no subjective symptoms." When the patient initially presents herself in the second or third trimesters of pregnancy and examination reveals the triad of hypertension, edema and albuminuria, distinction between chronic glomerulonephritis and preeclampsia or essential hypertension cannot always be made. When serious disease due to anyone of the three conditions is present, clinical and laboratory findings may be the same. Edema tends to be more pronounced in preeclamptic toxemia, and albuminuria is more likely to be minimal or absent in cases of essential hypertension than in those of chronic glomerulonephritis. The eye grounds of patients who have preeclampsia and eclampsia commonly show spastic localized and generalized constrictions in contrast to the increased light reflex and arteriovenous compression of essential hypertension or chronic glomerulonpehritis of long standing. Chesley has recently claimed that renal function tests can be used to distinguish the three conditions. In 113 cases of preeclamptic toxemia, he found an average uric acid clearance of 52 per cent with an essentially normal urea clearance of 95 per cent. In 33 cases of uncomplicated hypertensive disease, the clearance values were approximately those obtained for normal persons. However, in 3 cases of renal disease, both the clearances were almost equally decreased, and there was a tendency for severe renal involvement to result in greater depression of the urea than of the uric acid clearance. CLINICAL COURSE OF SIMULTANEOUS PREGNANCY AND GLOMERULONEPHRITIS
The experiences of various obstetricians who have observed simultaneous pregnancy and glomerulonephritis, acute or chronic, have been farfrom uniform, and the resultant points of view are correspondingly divergent. Unfortunately, the reported series of cases on which conclusions are based are too small to have statistical validity, and data are usually insufficient to permit proper evaluation of the clinical status of the individual patients. Dieckmann 8 has surveyed the outcome of 13 pregnancies in 12 patients who had acute recurrent or acute glomerulonephritis or lipoid nephrosis. Only 3 of these pregnancies went to spontaneous delivery at term. One patient underwent cesarean section and sterilization at thirty -seven weeks of gestation. Three pregnancies terminated in spontaneous abortions at thirteen, eighteen, and twenty-three weeks. The remaining 6 pregnancies were interrupted between the tenth and eighteenth weeks of pregnancy, and 4 of these patients
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were sterilized. The outcome of pregnancy is not given m other references to acute glomerulonephritis in pregnancy. Among patients who have chronic glomerulonephritis the outlook is by no means uniformly unfavorable. Goodall detailed his experiences with a nulligravida, 28 years of age, who exhibited severe albuminuria and elevation of blood pressure to 170 systolic and 90 diastolic. She was given a poor prognosis in regard to childbearing but nonetheless she married and subsequently became pregnant. At ten weeks of gestation, she was found to have further elevation of blood pressure to 190/105, together with a large amount of albumin and a few hyaline and granular casts in the urine. Therapeutic abortion was advised but refused. Surprisingly, she showed gradual improvement: the blood pressure decreased to 110/70 at four and onehalf months of gestation and remained at that level until term, when she had a normal delivery and a living baby. Within the next six months, the blood pressure was never greater than 120/80, and the urine contained no casts and only an occasional trace of albumin. Goodall alluded to 4 "other cases of a similar nature" hut did not report them in detail. Reid and Teel described the course of pregnancy in 15 patients who had chronic glomerulonephritis antedating gestation. In 11 cases, fairly adequate medical records were available during and since the known occurrence of acute or subacute glomerulonephritis from one to sixteen years previously. In 7 cases albuminuria increased during pregnancy, and in 8 the blood pressure rose. Severe preeclampsia developed in 1 case and cesarean section was performed. In 1 case pregnancy terminated spontaneously during the sixth month with delivery of a macerated, nonviable fetus. In 7 cases labor was induced during the last six weeks of gestation. All of the mothers and 14 of the infants survived. Admittedly, most of these patients "did not show renal insufficiency at the onset of pregnancy." The authors stated that, although they were surprised at the generally favorable results obtained, one should be cautious about minimizing the potential hazards of chronic glomerulonephritis complicating pregnancy. Dodds and Browne reported that 8 of their 17 patients had an exacerbation of their symptoms during gestation and 9 went through pregnancy without any sign of deterioration of their renal status. Of the 8 who became worse, 6 died within the follow-up period of six months to twelve years. The other two had uremia, extreme hypertension and albuminuric retinitis within six years and two years, respectively, of the observed pregnancy.
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M ussey and Keith gave an account of pregnancy in a primigravid patient who had glomerulonephritis of twenty-one years' duration. There was no appreciable alteration in the signs and symptoms of renal di~ease until the appearance at the thirty-eighth week of pregnancy of increased hypertension and albuminuria. Termination of the pregnancy was successfully accomplished by cesarean section. They were of the opinion that, because of the potential hazards to both the fetus and the mother, a second pregnancy should not be undertaken or should be interrupted if it occurred. Subsequent to their report, the patient did become pregnant and submitted to therapeutic abortion during the first trimester. Dieckmann 9 has stated that it is unusual for a patient who has chronic glomerulonephritis to carry her pregnancy to term, the usual outcome being abortion or premature delivery. In none of the 4 cases reported by Wellen did pregnancy remain uncomplicated. In 3 cases superimposed toxemia of pregnancy developed and in 2 eases stillborn babies were delivered in spite of cesarean section. The fourth patient suffered her initial attack of glomerulonephritis at the onset of her pregnancy, which was terminated therapeutically at the third month. Four specific questions with regard to simultaneous pregnancy and chronic glomerulonephritis should be considered: 1. Does the presence of preexisting nephritis alter the course or increase the risk of gestation? 2. Does the occurrence of a pregnancy have a detectable effect on the previous renal damage? 3. What is the prognosis for the fetus? 4. Is the subsequent course of the renal disease altered by the occurrence of pregnancy? Effect of Nephritis on Pregnancy. Probably renal disease results in increased susceptibility to development of preeclampsia or eclampsia. 4 • 6 Of Wellen's 3 patients suffering from chronic glomerulonephritis, all showed evidence of superimposed toxemia, and the 2 multiparas had had similar episodes in all previous pregnancies. Nearly half of the patients whose cases were reported by Dodds and Browne exhibited an exaggeration of already present abnormal findings which might have represented preeclampsia, although the data are insufficient to permit definite conclusions. Bell reported postmortem analysis of the histories of 20 women who had chronic glomerulonephritis. These women had had 55 pregnancies, which resulted in 17 spontaneous and 6 induced abortions during the first trimester, 2 premature labors (1 spontaneous and 1 induced), 2 stillbirths, and 10 instances of preeclampsia or eclampsia which resulted in living babies at birth. Only 18 pregnancies proceeded normally. However, in the series
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published by Reid and Teel, preeclampsia appeared in only lout of the 15 cases. Effect of Pregnancy on Nephritis. Data are not available to determine with finality whether pregnancy per se has an effect on the glomerulonephri-tic kidney, and opinions in this regard are conflicting. Miller spoke of the added burden imposed by pregnancy on the already damaged kidney and stated that progressive deterioration is the exception rather than the rule as pregnancy advances. With each successive pregnancy the aggravation of symptoms appears earlier and is more pronounced. Termination of gestation appears to be of at least temporary benefit. Bell likewise referred to the additional load thrown on the kidneys by pregnancy, and Fishberg agreed that an adverse effect is usually exerted on glomerulonephritis by a coincident pregnancy. He failed, however, to find an adequate explanation for the mechanism of the progressive renal impairment so often noted. Few cases, he concluded, manifest a so-called lighting-up of the glomerulonephritic process, and he inclined toward the belief that "the addition of pressure on the ureters and renal veins will, more readily than in individuals starting with healthy kidneys, impair renal function and, through the intermediacy of lessened renal blood flow, elevate the blood pressure." On the other hand, Theobald stated that "a woman with chronic glomerulonephritis may pass through pregnancy without further damaging her kidneys providing that the condition has not progressed sufficiently far to embarrass her general health and that certain tests for renal efficiency prove satisfactory." The 2 patients studied by Wellen and associates gave no evidence of significant progression of the renal lesions during gestation or for twenty-eight and sixteen months postpartum. Evaluation of these patients was made by rather complete clearance studies which demonstrated a probably slight diminution of all functions measured but no abrupt decrease which could be attributed to the pregnancy. There is no conclusive evidence that normal pregnancy actually throws a greater load on normal kidneys. Dieckmann 7 has found lowered concentration of urea in the blood and, during the last half of normal pregnancy, a decrease in urea clearance by individual patients. There is delayed or decreased elimination of water by the kidneys and a decrease in the chloride and urea content of urine. Chesley demonstrated wide variations in uric acid and urea clearance in nonhypertensive pregnancy but the mean values were more than 100 per cent of normal. Numerous reports 5 are available of pregnancy occurring after nephrectomy, with the remaining kidney, if normal, capable of maintaining adequate excretory function. Herrick, how-
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ever, pointed out that any organ may function satisfactorily until its factor of safety is abolished. In the kidney damaged by chronic glomerulonephritis what reserve remains may be absorbed by pregnancy, the demands of which, in his opinion, vary directly with the age and size of the fetus. Although the earlier literature frequently contained statements suggesting that pregnancy may predispose to the subsequent appearance of "nephritis" or that preeclampsia and eclampsia are a common cause of "chronic nephritis," it is now generally agreed that normal pregnancy cannot result in the appearance of renal damage and that residual damage from specific toxemia, when it occurs, is vascuiar rather than glomerular.l' 3 Prognosis for the Fetus. It has been rather generally coneeded that fetal loss is significantly increased by the presence of glomerulonephritis in pregnancy. As previously noted, Dieckmann9 stated that such pregnancies rarely continue to term but commonly terminate spontaneously after from twelve to twenty-six weeks. In Miller's opinion fetal salvage of more than 33 per cent eannot be anticipated. The survival in Do~lds and Browne's series was 62 per cent; in that of Bell, about 50 per cent; in that of Reid and Teel, 93.3 per cent. Herrick stated that the later months of pregnancy bring the greatest load on the kidneys and offer the greatest hazard to the fetus, which is likely to die in utero or be expelled prematurely. Although Dieckmann 9 considered that vascular damage to the placenta is the explanation of the increase in fetal death, Herrick did not agree that the evidence is conclusive that such damage occurs or is significant. Ultimate Prognosis. Most authors lo • 13, 18,29 express the opinion that pregnancy in a patient who has chronic glomerulonephritis not only is accompanied by gradual increase in renal damage but that renal function subsequent to the period of gestation is found to be in an even more precarious state than it was prior to pregnancy. Further, the occurrence of another pregnancy eauses earlier appearance and more severe manifestations of renal breakdown. 18 1t is true that some patients whose renal damage is mild appear to tolerate pregnancy well and may be found subsequently to have little or no evidence of their glomerulonephritis.l3 • 29 Reid and Teel found 11 of their 15 patients to be in no worse condition six months to five years after pregnancy, and Dodds and Browne made the same observation in 9 out of 17 patients. The latter stated that they were unable to ascertain that the worsened renal status in the other patients was induced solely by the pregnancy rather than by the usual downhill course of the glomerulonephritis itself. Mortality statistics are of little help in elucidating the problem
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because of the lack of uniform terminology to which allusion wafl previously made. Thus, Stander and Peckham~4 have stated that more than 40 per cent of patients die within ten years following recognition of nephritis during pregnancy, and Paxson found that 3.25 per cent of 1,349 puerperal deaths in Philadelphia in the years 1931 through 1938 were attributable to chronic nephritis. Yet it is fairly certain that the term "chronic nephritis" has been loosely used to include renal disease of arteriosclerotic origin as well as glomerulonephritis. Apparently no figures are available to support 01' refute the assertion that occurrence of a pregnancy reduces the already lessened life expectancy of the woman suffering from chronic glomerulonephritifl. Theobald on the other hand assembled mortality rates for England and Wales since vital statistics had been collected and found the death rates for chronic nephritis to be higher in men than in women. During the same period (1911 to 1922) the mortality rates for chronic nephritis were approximately equal in married and single women up to the age of 55 years. He interpreted his findings as indicating no causal relation between pregnancy and chronic nephritis. The problem with regard to acute glomerulol}ephritis is no more elearly illuminated, owing to the rarity of the disease. It is generally agreed that complete recovery from an attack of acute glomerulonephritis is compatible with a normal rather than an increased riflk during a subsequent pregnancy.8, 13 There ifl no evidence that such women are prediflposed to the development of toxemia of pregnancy or to a recurrence of acute glomerulonephritis. MANAGEMENT
Treatment of glomerulonephritis (discussed elsewhere in this volume)27 of the pregnant woman does not differ from that advised for the nonpregnant patient except that more elose and frequent observation is essential. A balanced diet, especially for replacement of protein, adequate rest and avoidance of infection are basic measureH. Careful elinical and laboratory evaluation should be performed as early as possible and repeated often enough to detect promptly the adverse Higns of renal decompensation or preeclampHia. Hospitalization is imperative in many cases. The fundamental question which is raised when a gravid patient is found to have evidence of chronic glomerulonephritis concerns the advisability of terminating the pregnancy. Peckham stated that, generally speaking, a diagnosis of chronic nephritis is sufficient indication to consider emptying the uterus although the situation should be thoroughly discussed and the preference of the patient and her husband should be respected if possible. Dodds and Browne agreed
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but pointed out from their experienee that patients with mild chronic nephritis may weather a pregnancy without mishap. In their opinion elevation of the blood urea to more than 40 mg. per 100 cc., albuminuric retinitis, edema and much albuminuria indicate a prognosis so had for both mother and infant that the pregnancy should not be allowed to continue. Miller likewise was of the opinion that a diagnosis of chronic nephritis is justification for interruption of pregnancy particularly in the multipara whose obstetrical future is "practically hopeless." For the primigravid patient one might be more lenient since this pregnancy might represent her only chance for a living child. Evidence of progressive renal insufficiency or the appearance of signs and symptoms of preeclampsia are forewarnings of the possibility of fetal death and warrant prompt intervention. There is, however, no indicator to reveal the answer to the question of whether waiting for fetal viability will mean a delay that only results in intra-uterine death of the infant. If continued rest in bed in a hospital does not reverse a rising blood pressure and increasing albuminuria or if there is progression of retinal changes, interruption of the pregnancy, regardless of its duration, is justified. Detailed discussion of the methods of emptying the uterus is not pertinent to the subject. In brief, the following accepted procedures may be considered. Prior to the fourth month of pregnancy, dilatation and curettage is indicated. During the middle trimester, hysterotomy is usually the operation of choice. When viability of the fetus has been attained and the cervix is properly effaced, induction of labor with pitocin or amniotomy or both is the most conservative means available. There are, however, cases in which cesarean section may appropriately be employed in spite of the added hazard of abdominal delivery. The indication for performance of a cesarean section is urgency of termination of pregnancy in the patient who has an "unripe" cervix and, usually, has had no prior vaginal delivery. Prevention of future pregnancies is advisable for most patients who have chronic glomerulonephritis and is imperative in those patients manifesting any degree of renal insufficiency or progressive impairment of function. If the contraindication to pregnancy is absolute, one should rarely rely on measures which are only relatively effective, such asyaginal medicaments and diaphragms. Ultimately, therefore, the patient and her husband will be confronted with the question of sterilization if personal beliefs do not forbid contemplation of such a procedure. Bilateral tubal ligation or excision can be done at the time of cesarean section but the abdominal route of delivery should not be
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elected solely for this purpose. It is preferable to deliver the baby vaginally and to perform salpingectomy either in the immediate puerperium through a small midline abdominal incision or after an interval of six to twelve weeks through the vaginal or abdominal approach. Vasectomy in the male is sometimes advised, but such a procedure hardly seems justified when the reason for avoidance of pregnancy lies in the female partner for whom the prognosis as to future life and health must be considered guarded at best. SUMMARY
The pertinent literature relative to acute and chronic glomerulonephritis in pregnancy has been reviewed. Patients who have renal damage of mild degree may tolerate pregnancy well although they possibly tend to be more susceptible to the development of preeclampsia. Patients who have marked renal involvement may be expected to exhibit increasing hypertension, albuminuria and pathologic changes in the retina which at any time may necessitate interruption of pregnancy. The prognosis for ultimate survival of the fetus is reduced by the presence of severe chronic glomerulonephritis. REFERENCES 1. Bell, E. T.: Renal Diseases. Philadelphia, Lea & Febiger, 1946,434 pp. 2. Browne, F. J.: Chronic Hypertension and Pregnancy. Brit. M. J. 2:283287 (Aug. 23) 1947. 3. Browne, F. J. and Dodds, Gladys H.: The Remote Prognosis of the Toxaemias of Pregnancy; Based on a Follow-up Study of 400 Patients in 589 Pregnancies for Periods Varying From 6 Months to 12 Years. J. Obst. & Gynaec. Brit. Emp. 46:443-461 (June) 1939. 4. Chesley, L. C.: Simultaneous Renal Clearances of Urea and Uric Acid in the Differential Diagnosis of the Late Toxemias. Am. J. Obst. & Gynec. 59:960-969 (May) 1950. 5. Crabtree, E. G. Urological Diseases of Pregnancy. Boston, Little, Brown and Company, 1942, 472 pp. 6. Dexter, Lewis and Weiss, Soma: Preeclamptic and Eclamptic Toxemia of Pregnancy. Boston, Little, Brown and Company, 1941, 415 pp. 7. Dieckmann, W. J.: Renal Function in the Toxemias of Pregnancy. Am. J. Obst. & Gynec. 29:472-488 (Apr.) 1935. 8. Dieckmann, W. J.: Acute Nephritis and Pregnancy. Am. J. Obst. & Gynec. 32:227-240 (Aug.) 1936. 9. Dieckmann, W. J.: The Toxemias of Pregnancy. St. Louis, The C. V. Mosby Company, 1941, 521 pp. 10. Dodds, Gladys H. and Browne, F. J.: Chronic Nephritis in Pregnancy. Proc. Roy. Soc. Med. 33 (pt. 2) :737-740 (Sept.) 1940. 11. Eastman, N.: Quoted by Dieckmann, W. J.B 12. Elden, C. A. and Cooney, J. W.: The Addis Sediment Count and Blood Urea Clearance Test in Normal Pregnant Women. J. Clin. Investigation. 14:889-891 (N ov.) 1935.
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13. Fishberg, A. M.: Hypertension and Nephritis. Ed. 4, Philadelphia, Lea & Febiger, 1939, 779 pp. 14. Gareis, L. C.: Chronic Nephritis in Pregnancy With Special Reference to the Diagnosis. Bull. School Med. Univ. Maryland. 33:18-25 (July) 1948. 15. Goodall, J. R.: Nephritis and Pregnancy. Am. J. Obst. & Gynec. 26:556569 (Oct.) 1933. 16. Greenhill, J. P.: Toxemia [Editors Note.] In: The 1950 Year Book of Obstetrics and Gynecology. Chicago, The Year Book Publishers, 1950, pp. 109-110. 17. Hallum, A. V.: Retinal Arterioles in the Hypertensions of Pregnancy. Tr. Am. Ophth. Soc. 43:585-607, 1945. 18. Herrick, W. W.: The Vascular and Renal Complications of Pregnancy. Bull. New York Acad. Med. 14:429-446 (July) 1938. 19. Herrick, W. W. and Tillman, A. J. B.: Toxemia of Pregnancy: Its Relation to Cardiovascular and Renal Disease; Clinical and Necropsy Observations With a Long Follow-up. Arch. Int. Med. 55:643-664 (Apr.) 1935. 20. Hollenhorst, R. W.: The Ophthalmologic Aspects of Chronic Renal Disease. M. CLIN. NORTH AMERICA. (This Issue.) 21. Irving, F. C.: A Study of Consecutive Cases of Hypertension and Albuminuria in Pregnancy. Pennsylvania M. J. 44:557-562 (Feb.) 1941. 22. Keith, N. M.: Discussion. Proc. Staff Meet., Mayo Clin. 24:145-148 (Mar. 16) 1949. 23. Kellogg, F. S. and Reed, D. E.: The Classification of Hypertension and Albuminuria in Pregnancy. In: Proceedings of the American Congress on Obstetrics and Gynecology, Cleveland, Ohio, September 11-15, 1939. Evanston, Illinois, The Mumm Print Shop, Inc., 1941, pp. 165172. 24. Kuder, K. and Stander, H. J.: Nephritis and Pregnancy. New York State J. Med. 34:5-9 (Jan. 1) 1934. 25. Miller, Douglas: Observations on Eclamptic Toxaemia and on Essential Hypertension and Chronic Nephritis in Pregnancy. Edinburgh M. J. 49:209-233 (Apr.) 1942. 26. Mussey, M. E.: Chronic Glomerulonephritis Complicating Pregnancy. Proc. Staff Meet., Mayo Clin. 24:145-148 (Mar. 16) 1949. 27. Odel, H. M. and Daugherty, G. W.: M. CUN. NORTH AMERICA. (This issue.) 28. Paxson, N. F.: Chronic Nephritis and Pregnancy Fatalities in Philadelphia. Am. J. Obst. & Gynec. 40:995-1001 (Dec.) 1940. 29. Peckham, C. H.: Chronic Nephritis Complicating Pregnancy. Am. J. Surg. 35:325-330 (Feb.) 1937. 30. Peters, J. P.: The Nature of the Toxemias of Pregnancy. J.A.M.A.110:329331 (Jan. 29) 1938. 31. Rayer: Quoted by Fishberg, A. M.13 32. Reid, D. E. and Teel, H. M.: Nonconvulsive Pregnancy Toxemias: Their . Relationship to Chronic Vascular and Renal Disease. Am ..J. Obst. & Gynec. 37:886-896 (May) 1939. 33. Stander, H. J. and Peckham, C. H.: A Classification of the Toxemias of the Latter Half of Pregnancy. Am. J. Obst. & Gynec. 11 :583-602 (May) 1926. 34. Stander, H. J. and Peckham, C. H.: Prognosis in Nephritis Complicating Pregnancy. Am. J. Obst. & Gynec. 22:626-636 (Oct.) 1931.
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35. Theobald, G. W.: Further Observations on the Relation of Pregnancy to Hypertension and Chronic Nephritis. J. Obst. & Gynaec. Brit. Emp. 43:1037-1052 (Dec.) 1936. 36. Wegner, Carl: Quoted by Dieckmann, W. J.8 37. Wellen, Irwin: Specific "Toxemia," Essential Hypertension, and Glomerulonephritis Associated With Pregnancy. Am. J. Obst. & Gynec. 3.9:1624 (Jan.) 1940. 38. Wellen, Irwin, Welsh, Catherine A. and Taylor, H. C., Jr.: The Effect of Pregnancy on Renal Function in Women With Pre-existing Essential Hypertension and With Chronic Diffuse Glomerulonephritis ..1. Clin. Investigation. 23:742-749 (Sept.) 1944. 3!l. Welsh, Catherine A., Wellen, Irwin and Taylor, H. C., Jr.: The Filtration Rate, Effective Renal Blood Flow, Tubular l';xcretory Mass and Phenol Red Clearance in Normal Pregnancy. J. Clin. Invest.igation. 21 :57-61 (Jan.) 1942.
M USSEY
PREGNANCY for a woman who has chronic glomerulonephritis is a potential hazard which, on the one hand, can eventuate in fetal and perhaps maternal death and, on the other hand, can be marked by a relatively smooth course without exacerbation of the prior renal disease. Management of such pregnancies will call on the widest knowledge and most discriminating judgment of the obstetrician, who must attempt to predict the probable outcome on the basis of laboratory and clinical findings evaluated against his experience and that of others. Unfortunately the value of the recorded experiences of others is diminished by several factors: the relative rarity of acute and chronic glomerulonephritis in pregnant women; the confusing terminology employed for the most part in obstetric literature prior to 1940, and the difficulty at times in the clinical distinction of chronic glomerulonephritis from either essential hypertension or preeclampsia. As long ago as 1839 Rayer is said to have differentiated the renal disorder occurring late in pregnancy from that which antedated the pregnancy and became manifest early in gestation. Yet, a clear delineation of the toxemias of pregnancy was agreed on only as recently as 1939 when The American Committee on Maternal Welfare23 separated hypertension peculiar to pregnancy (preeclampsia) from hypertension independent of, or antedating, pregnancy (essential hypertension and hypertension associated with pre-existing renal disease). Throughout the third and fourth decades of this century a considerable literature accumulated under the general title of "Chronic Nephritis in Pregnancy" and numerous cases were reported in detail. A glance at such reports rapidly leads to the realization :that the patient having so-called chronic nephritis usually had either preeclampsia or essential hypertension and rarely exhibited the features of chronic glomerulonephritis. In 1926, Stander and Peckham33 proposed a classification of the toxemias of pregnancy consisting of five types: eclampsia, preeclampsia, chronic nephritis, eclampsia superimposed 'on chronic nephritis, and the low reserve kidney. Although hypertensive vascular disease was not recognized by Stander and Peckham and the concept of the low reserve kidney has not withstood critical analysis, nonetheless the grouping was widely accepted 1051
1052
ELIZABF~'l'H
-
MUSSEY
and served a useful purpose in pointing out the poorly recognized fact that toxemia of pregnancy was not one syndrome but several, varying in etiology but merging to become indistinguishable clinically at times. However, all patients manifesting hypertension in the course of their pregnancy failed to drop neatly into one of these pigeon holes and contrary points of view began to make their appearance. Herrick and Tillman 19 were among those who emphasized that "the toxemias may not be isolated, idiopathic states but ... are possibly related to certain common general medical conditions .... In most obstetric clinics a woman with high blood pressure is classified as having nephritis. Primary vascular disease is still unrecognized." Later Herrick 18 pointed out that the failure of many obstetric writers to "differentiate nephritis and vascular disease ... has given rise to needless argument and a confusion which lessens the value of much of the older writing upon the subject." In attempting to emphasize the role of renal and hypertensive disease in the production of toxemias of pregnancy, Herrick, however, leaned far to the opposite side and held that at least a majority of the instances of toxemia contain "a thread of one of these two conditions." Thus, all of his 594 cases of toxemia could be placed into one of the two groups: in the first, and smaller, it was "associated with a latent or manifest primary glomerulonephritis, and in the second, and larger, with hypertensive cardiovascular disease." A compromise among the divergent views was finally effected by the Committee for Classification of the Toxemias whose classification 23 is, in brief, as follows: Group A. Disease independent of pregnancy 1. Hypertensive or arterial vascular disease, benign and malignant. 2. Renal disease, ineluding glomerulonephritis, pyelonephritis, and other forms of severe renal disease, including nephrosis, polycystic kidneys and others. Group B. Disease not independent of pregnancy 1. Preeelampsia, mild and severe 2. Eclampsia Group C. Unelassified (unknown)
The most recent classification of the toxemias is one proposed by Eastman, Titus, McCormick, and Greenhill. 16 In it primary renal disease is excluded completely and the remaining conditions are separated into two groups: A. Acute toxemias 1. Preeclampsia 2. Eclampsia
GJ~OMERULONEPHRITIS
IN PREGNANCY
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B. Chronic hypertensive vascular disease (essential hypertension) 1. vVithout superimposed acute toxemia 2. With superimposed acute toxemia
Onc might take issue with the omission of chronic glomerulonephritis from this tabulation. Essential hypertension is no more a true toxemia of pregnancy than is chronic glomerulonephritis, and, although the latter occurs more rarely, it too must be considered in the differential diagnosis in the pregnant patient with hypertension. INCIDENCE
Glomerulonephritis is rarely complicated by pregnancy. Dieckmann 8 reported 12 cases of primary renal disease in pregnancy, collected over a period of twelve years during which time more than 22,000 patients were delivered. Three of the 12 patients had acute glomerulonephritis; 2, the nephrotic form of glomerulonephritis; 4, recurrent acute glomerulonephritis; and 3, lipoid nephrosis. He stated that Wegner had found 6 cases of chronic glomerulonephritis in 10,596 deliveries, an incidence of 0.056 per cent. Eastman reported encountering 641 cases of "chronic nephritis" (probably including nephrosclerosis) and 2 cases of acute nephritis during a ten-year period during which there were 16,150 admissions and 10,965 deliveries. Dieckmann 9 further stated that primary renal disease including glomerulonephritis, pyelonephritis, nephrosis and other rare conditions makes up less than 2 per eent of the so-called toxemias of pregnancy. Kuder and Stander published their incidence of toxemia of pregnancy as 14.067 per cent, of which 21.47 per cent of patients had chronic nephritis; most of these, they stated, undoubtedly suffered from nephrosclerosis. According to Herrick chronic nephritis constitutes 5 to 10 per cent of all cases of late toxemia. Dodds and Browne observed 17 nephritic patients in 21 pregnancies, an incidence of 1 to 1,100 deliveries (0.09 per cent). Browne more recently stated that 5 per cent of all patients who have hypertension in pregnancy have chronic nephritis. Irving found chronic nephritis present in 13 (1.1 per cent) of 1,182 patients with hypertension and albuminuria in pregnancy. Miller has found 4 cases of acute glomerulonephritis and 89 cases of chronic glomerulonephritis, an incidence of 3 cases per thousand patients delivered (0.3 per cent). He stated that this figure is higher than it should be because of the erroneous grouping of all the nephropathies under the term "chronic nephritis." Wellen found 4 cases of chronic glomerulonephritis in 272 cases of "toxemia" which occurred among 7,897 deliveries. Dexter and Weiss failed to find any cases of glomerulonephritis among 80 pregnant patients with blood pressures in excess of 140 mm. of mercury systolic and 90 mm. diastolic.
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It is apparent that the true incidence of chronic glomerulonephritis is unknown, individual statistics reflecting the current classification of the toxemias. It is equally apparent that no report represents a large series of cases, and that the experience of any individual obstetrician with the disease is limited. Indeed, Bell's seriesl of 55 pregnancies in 20 patients who had chronic glomerulonephritis is the largest reported, and these studies of course represent postmortem analyses only. The suggestion has been advanced that the paucity of cases of chronic glomerulonephritis complicated by pregnancy might be related to decreased fertility though data bearing on this point is lacking. AGE AND PARITY
Chronic glomerulonephritis is for the most part a disease of young people. In the series of Dodds and Browne, 11 of the 17 patients were less than 25 years of age. Nine were primigravidas and 8 were multigravidas. Of the latter, 5 were para 1, 2 were para 2, and 1 was para 3. Gareis reported 10 patients, 7 of whom were less than 21 years of age; 1 each was age 23,28 and 38 years. Dieckmann 8 stated that glomerulonephritis in pregnancy is characteristically a disease of the young primigravida. All of his patients except 1 were less than 27 years of age. HISTORY
The history, of course, will frequently reveal the presence of antecedent "renal disease. Dodds and Browne found such a history in 11 of their patients, in all of whom reliable medical records were obtainable. Two patients of the remaining 6 had had scarlet fever and 1 had had frequent"'episodes of sore throat.:Only 4 of the 10 patients whose cases were reported by Gareis had no relevant history to suggest the prior onset of nephropathy. SIGNS AND SYMPTOMS
Symptoms presented by the pregnant patient who suffers from glomerulonephritis vary with the phase and severity of the disease and are not different from those of nonpregnant individuals who have this disease. Headache is the most frequent complaint; lassitude, dizzy spells, nausea, vomiting, anorexia and visual disturbances are likely to occur only when patients have advanced renal involvement.H. 18. 21. 29 Albuminuria. Indeed, the paucity of symptoms even when renal function is fairly inadequate could well lead to overlooking the disease entirely were it not for the almost constant albuminuria which is
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discoverable at the time of the first prenatal visit. Such a finding should lead the obstetrician to suspect renal disease although urinary albumin may be present as a result of cystitis, pyelitis, nephrosclerosis or other renal pathologic lesions or even because of contamination of the specimen with vaginal secretions. Although the degree of albuminuria may be slight, the finding tends to be persistent. However, Theobald and Goodall have pointed out the fact that temporary absence of protein in the urine can occur during the first half of pregnancy, in cases of chronic glomerulonephritis. Hematuria. This is a constant finding in acute glomerulonephritis, and hyaline or granular casts are usually seen. Erythrocytes and casts mayor may not be observed in the urine of patients who have chronic glomerulonephritis but are generally found at some time in the course of a pregnancy superimposed on the chronic glomerulonephritis. s . 10. 18 Although the Addis count of urinary sediment has not been widely used, Dieckmann s . 9 has found it a useful tool for establishing a diagnosis of acute glomerulonephritis in pregnancy. Both preeclampsia and acute glomerulonephritis may cause the appearance of proteinuria, edema, hypertension, and formed elements in the urine and, more l'arely, of nitrogen retention. Although the urine of normal pregnant women may occasionally show an increase in the Addis count,12 the continued finding of erythrocytes is probably significant. In the urine of 41 of 100 women with abnormal sediment, 8 erythrocytes persisted for a week or longer. Only 8 of these were given a diagnosis of "acute or recurrent acute glomerulonephritis"; the remainder were thought to have toxemia of pregnancy. In mild preeclampsia, the Addis count shows little change from that in normal pregnant women, but it is abnormal in patients with either severe preeclampsia or acute or chronic glomerulonephritis. Hypertension. Elevation of the blood pressure mayor may not be observed, its occurrence being an indication of the degree and duration of renal damage. A sudden increase of blood pressure, especially in the latter half of gestation, is suggestive of the appearance of preeclampsia superimposed on chronic glomerulonephritis. That the blood pressure is subject to wide fluctuations and can return to normal in previously hypertensive individuals with primary renal disease is pointed out by Theobald, Goodall and Browne. However, the experienee of the majority of observers 9 • 10. 32 appears to be that hypertension, if present, usually is maintained or exaggerated as pregnancy progresses. Edema. Edema is not a constant finding, tending to appear after the twentieth week of pregnancy10 or to be present in patients manifesting a nephrotic type of glomerulo;nephritis. Its occurrence early
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ELIZABE'l'H MUSSEY
in pregnancy suggests the existenee of hypoproteinemia while during the third trimester edema may be the initial sign of the development of preeclampsia. Retinal Changes. Retinal changes are more commonly seen in cases of chronic glomerulonephritis than in cases of acute glomerulonephritis.13 In both groups of cases, ocular abnormalities are roughly parallel in degree to the severity and duration of the disease. Thus, the majority of cases of acute glomerulonephritis show only minimal changes in the retina, consisting of blurring of the disk and slight arteriolar narrowing, but the picture of hypertensive retinopathy may Occur in individuals who are severely ill. Patients who appear to have recovered completely from acute glomerulonephritis manifest no ocular lesions, and even those in whom chronic renal disease persists may show no retinal abnormalities for a protracted period. Retinal lesions appear to develop in response to prolonged arterial hypertension and may be found in the absence of renal insufficiency. In most cases in which retinal lesions are found, renal insufficiency ultimately develops if it was not present before the retinal changes appeared. The occurrence of marked vascular sclerosis, of hem orrh ages and of cotton-wool exudates indicates a poor prognosis. The retinal findings in pregnant women who have chronic glomerulonephritis are not at variance with the findings in nonpregnant individuals who have it. Abnormal retinal changes were noted by Dieckmann 9 in 67 per cent of patients having chronic glomerulonephritis. Dodds and Browne found "albuminuric retinitis" in only 2 of 17 cases of chronic glomerulonephritis; both these patients had marked renal involvement. In all of the 10 cases reported by Gareis narrowing of the arterioles and an increased light streak were found and in 1 case retinopathy was noted. Hallum, who has examined 2,500 women suffering from hypertension associated with pregnancy, stated that he has not seen any patient whose hypertension was known to be due to acute glomerulonephritis. In cases of pre-existing renal disease, the retinal changes were only those to be expected from the degree of generalized vascular disease which had resulted from the previous nephritis: that is, varying degrees of arteriovenous "nicking," asymmetrical arteriolar constrictions and increased light reflex. The appearance of localized or generalized spasm indicated the existence of superimposed preeclamptic toxemia. More extensive description of the retinal lesions associated with glomerulonephritis is to be found elsewhere in this volume. 20 Changes in Blood. No characteristic alterations of cellular elements or chemical constitutents of the blood have been noted other than those which are common in acute and chronic glomerulonephritis
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PREG~ANCY
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without associated pregnancy. Severe degrees of anemia, usually normocytic, oocur and usually, although not always, reflect the amount of impairment of renal function. 13 When renal insufficiency develops, the values for urea nitrogen and uric acid in the blood may rise, but they do not appear to be altered by pregnancy per se. With the superimposition of severe preeclampsia, there is frequently an elevation of the levels of uric acid and sulfates in the blood out of proportion to that of the blood urea, possibly because of hepatic damage. 9 In patients who have marked albuminuria, the plasma proteins may be depleted below the normal and there may be reversal of the albumin-globulin ratio. In general, however, values for various constituents of the blood are not changed by an otherwise uncomplicated pregnancy in the woman who has glomerulonephritis. Changes in Renal Function. Impairment of renal function may not appear for many months or years after the onset of chronic glomerulonephritis,!a and in many cases the diagnosis may rest only on the consistent finding of variable amounts of urinary albumin I , 10 while the specific gravity of the urine remains high and the exeretion of dyes and other substances is within normal limits. In normal pregnant women the urea clearance has been found to range between 60 and U8 per cent of normal; a third of the valuefl for 19 patients fell between 60 and 80 per cent of normal,l2 Chesley found the average urea elearance for 80 normal pregnant women to be U9 per eent, with a range of from 45 to 175 per cent. He also found the uric acid elearance to average 112 per cent, with a range of from 45 to 215 per cent. In 5 cases the uric acid clearance was less than 70 per cent of normal, and in 4 the urea clearance was less than 70 per cent. Dieckmann 7 was of the opinion that no value for urea clearance in excess of 50 per cent of normal can be considered indicative of decreased renal function during pregnancy. Welsh, Wellen and Taylor have measured the filtration rate, effeetive renal blood flow, tubular excretory mass and phenol red clearance of women during normal pregnancies and found no variation from the results obtained for nonpregnant women. Apparently there are few reports of measurements of renal excretory capacity in pregnant women suffering from chronic glomerulonephritis. Gar~is stated that, of his 10 patients, 4 excreted less than 60 per cent of the phenolsulfonphthalein injected, 6 had less than 50 per cent of normal urea elearance, and all but 2 failed to form urine with a specific gravity greater than 1.010. The first reported complete clearance studies on pregnant women with chronic glomerulonephritis were those of Wellen, Welsh and
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ELIZABETH MUSSEY
Taylor. They investigated 2 patients whose urea clearance values before conception were known to be one half and two thirds of normal, respectively. Both were found during pregnancy to have abnormally low values for glomerular filtration, effective renal blood flow and tubular excretory mass. In summary, it may be said that laboratory study of the urine, blood and renal function of pregnant patients who have chronic glomerulonephritis does not show results differing in any respect from those obtained for nonpregnant patients who have the same disease. Any abnormalities exhibited by such patients in the course of pregnancy are a reflection of their primary renal disease and not of the superimposed gestation. DIFFERENTIAL DIAGNOSIS
Acute glomerulonephritis must be distinguished from preeclamptic toxemia and from other disease of the urinary tract which may produce hematuria, pyuria or proteinuria. As a rule preeclampsia does not appear prior to the last trimester of pregnancy and acute glomerulonephritis occurs more commonly in the first half of pregnancy. Further, the extreme rarity of acute glomerulonephritis during gestation favors a diagnosis of preeclampsia when a confusing clinical picture exists. Dieckmann 8 has pointed out that absolute distinction between the two conditions is dependent on the duration of hematuria, persistence of which for more than one week he considered to be evidence of acute glomerulonephritis. He stated further that the edema associated with preeclampsia tends to be more dependent than does that in patients with acute glomerulonephritis and usually subsides more rapidly after delivery. Ordinarily proteinuria is more marked in acute nephritis and does not disappear after delivery as in preeclampsia and eclampsia. Peters and Miller have also noted the marked similarity between acute glomerulonephritis and preeclampsia, and the latter is of the opinion that only postpartum follow-up or postmortem examination will prevent errors in diagnosis. A correct diagnosis of chronic glomerulonephritis may be impossible to make in the course of an individual pregnancy or, in some instances, even during life. One suspects the presence of primary renal disease in the patient who shows albuminuria out of proportion to or without elevation of blood pressure, whose urine from time to time contains casts or erythrocytes, and whose blood studies may show anemia or hypoproteinemia. A history of antecedent acute or chronic renal disease and especially prior medical records of such episodes are invaluable. However, as Miller has pointed out, a patient "may make a complete recovery from an acute nephritis and
GLOMERULONEPHRITIS IN PREGNANCY
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develop eclamptic toxemia in a subsequent pregnancy, and ... occasionally a patient with chronic Bright's disease may have no subjective symptoms." When the patient initially presents herself in the second or third trimesters of pregnancy and examination reveals the triad of hypertension, edema and albuminuria, distinction between chronic glomerulonephritis and preeclampsia or essential hypertension cannot always be made. When serious disease due to anyone of the three conditions is present, clinical and laboratory findings may be the same. Edema tends to be more pronounced in preeclamptic toxemia, and albuminuria is more likely to be minimal or absent in cases of essential hypertension than in those of chronic glomerulonephritis. The eye grounds of patients who have preeclampsia and eclampsia commonly show spastic localized and generalized constrictions in contrast to the increased light reflex and arteriovenous compression of essential hypertension or chronic glomerulonpehritis of long standing. Chesley has recently claimed that renal function tests can be used to distinguish the three conditions. In 113 cases of preeclamptic toxemia, he found an average uric acid clearance of 52 per cent with an essentially normal urea clearance of 95 per cent. In 33 cases of uncomplicated hypertensive disease, the clearance values were approximately those obtained for normal persons. However, in 3 cases of renal disease, both the clearances were almost equally decreased, and there was a tendency for severe renal involvement to result in greater depression of the urea than of the uric acid clearance. CLINICAL COURSE OF SIMULTANEOUS PREGNANCY AND GLOMERULONEPHRITIS
The experiences of various obstetricians who have observed simultaneous pregnancy and glomerulonephritis, acute or chronic, have been farfrom uniform, and the resultant points of view are correspondingly divergent. Unfortunately, the reported series of cases on which conclusions are based are too small to have statistical validity, and data are usually insufficient to permit proper evaluation of the clinical status of the individual patients. Dieckmann 8 has surveyed the outcome of 13 pregnancies in 12 patients who had acute recurrent or acute glomerulonephritis or lipoid nephrosis. Only 3 of these pregnancies went to spontaneous delivery at term. One patient underwent cesarean section and sterilization at thirty -seven weeks of gestation. Three pregnancies terminated in spontaneous abortions at thirteen, eighteen, and twenty-three weeks. The remaining 6 pregnancies were interrupted between the tenth and eighteenth weeks of pregnancy, and 4 of these patients
lOGO
}<;LIZABETH MUSSEY
were sterilized. The outcome of pregnancy is not given m other references to acute glomerulonephritis in pregnancy. Among patients who have chronic glomerulonephritis the outlook is by no means uniformly unfavorable. Goodall detailed his experiences with a nulligravida, 28 years of age, who exhibited severe albuminuria and elevation of blood pressure to 170 systolic and 90 diastolic. She was given a poor prognosis in regard to childbearing but nonetheless she married and subsequently became pregnant. At ten weeks of gestation, she was found to have further elevation of blood pressure to 190/105, together with a large amount of albumin and a few hyaline and granular casts in the urine. Therapeutic abortion was advised but refused. Surprisingly, she showed gradual improvement: the blood pressure decreased to 110/70 at four and onehalf months of gestation and remained at that level until term, when she had a normal delivery and a living baby. Within the next six months, the blood pressure was never greater than 120/80, and the urine contained no casts and only an occasional trace of albumin. Goodall alluded to 4 "other cases of a similar nature" hut did not report them in detail. Reid and Teel described the course of pregnancy in 15 patients who had chronic glomerulonephritis antedating gestation. In 11 cases, fairly adequate medical records were available during and since the known occurrence of acute or subacute glomerulonephritis from one to sixteen years previously. In 7 cases albuminuria increased during pregnancy, and in 8 the blood pressure rose. Severe preeclampsia developed in 1 case and cesarean section was performed. In 1 case pregnancy terminated spontaneously during the sixth month with delivery of a macerated, nonviable fetus. In 7 cases labor was induced during the last six weeks of gestation. All of the mothers and 14 of the infants survived. Admittedly, most of these patients "did not show renal insufficiency at the onset of pregnancy." The authors stated that, although they were surprised at the generally favorable results obtained, one should be cautious about minimizing the potential hazards of chronic glomerulonephritis complicating pregnancy. Dodds and Browne reported that 8 of their 17 patients had an exacerbation of their symptoms during gestation and 9 went through pregnancy without any sign of deterioration of their renal status. Of the 8 who became worse, 6 died within the follow-up period of six months to twelve years. The other two had uremia, extreme hypertension and albuminuric retinitis within six years and two years, respectively, of the observed pregnancy.
GLOMEHULONEPHRI'l'Ul IN
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M ussey and Keith gave an account of pregnancy in a primigravid patient who had glomerulonephritis of twenty-one years' duration. There was no appreciable alteration in the signs and symptoms of renal di~ease until the appearance at the thirty-eighth week of pregnancy of increased hypertension and albuminuria. Termination of the pregnancy was successfully accomplished by cesarean section. They were of the opinion that, because of the potential hazards to both the fetus and the mother, a second pregnancy should not be undertaken or should be interrupted if it occurred. Subsequent to their report, the patient did become pregnant and submitted to therapeutic abortion during the first trimester. Dieckmann 9 has stated that it is unusual for a patient who has chronic glomerulonephritis to carry her pregnancy to term, the usual outcome being abortion or premature delivery. In none of the 4 cases reported by Wellen did pregnancy remain uncomplicated. In 3 cases superimposed toxemia of pregnancy developed and in 2 eases stillborn babies were delivered in spite of cesarean section. The fourth patient suffered her initial attack of glomerulonephritis at the onset of her pregnancy, which was terminated therapeutically at the third month. Four specific questions with regard to simultaneous pregnancy and chronic glomerulonephritis should be considered: 1. Does the presence of preexisting nephritis alter the course or increase the risk of gestation? 2. Does the occurrence of a pregnancy have a detectable effect on the previous renal damage? 3. What is the prognosis for the fetus? 4. Is the subsequent course of the renal disease altered by the occurrence of pregnancy? Effect of Nephritis on Pregnancy. Probably renal disease results in increased susceptibility to development of preeclampsia or eclampsia. 4 • 6 Of Wellen's 3 patients suffering from chronic glomerulonephritis, all showed evidence of superimposed toxemia, and the 2 multiparas had had similar episodes in all previous pregnancies. Nearly half of the patients whose cases were reported by Dodds and Browne exhibited an exaggeration of already present abnormal findings which might have represented preeclampsia, although the data are insufficient to permit definite conclusions. Bell reported postmortem analysis of the histories of 20 women who had chronic glomerulonephritis. These women had had 55 pregnancies, which resulted in 17 spontaneous and 6 induced abortions during the first trimester, 2 premature labors (1 spontaneous and 1 induced), 2 stillbirths, and 10 instances of preeclampsia or eclampsia which resulted in living babies at birth. Only 18 pregnancies proceeded normally. However, in the series
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published by Reid and Teel, preeclampsia appeared in only lout of the 15 cases. Effect of Pregnancy on Nephritis. Data are not available to determine with finality whether pregnancy per se has an effect on the glomerulonephri-tic kidney, and opinions in this regard are conflicting. Miller spoke of the added burden imposed by pregnancy on the already damaged kidney and stated that progressive deterioration is the exception rather than the rule as pregnancy advances. With each successive pregnancy the aggravation of symptoms appears earlier and is more pronounced. Termination of gestation appears to be of at least temporary benefit. Bell likewise referred to the additional load thrown on the kidneys by pregnancy, and Fishberg agreed that an adverse effect is usually exerted on glomerulonephritis by a coincident pregnancy. He failed, however, to find an adequate explanation for the mechanism of the progressive renal impairment so often noted. Few cases, he concluded, manifest a so-called lighting-up of the glomerulonephritic process, and he inclined toward the belief that "the addition of pressure on the ureters and renal veins will, more readily than in individuals starting with healthy kidneys, impair renal function and, through the intermediacy of lessened renal blood flow, elevate the blood pressure." On the other hand, Theobald stated that "a woman with chronic glomerulonephritis may pass through pregnancy without further damaging her kidneys providing that the condition has not progressed sufficiently far to embarrass her general health and that certain tests for renal efficiency prove satisfactory." The 2 patients studied by Wellen and associates gave no evidence of significant progression of the renal lesions during gestation or for twenty-eight and sixteen months postpartum. Evaluation of these patients was made by rather complete clearance studies which demonstrated a probably slight diminution of all functions measured but no abrupt decrease which could be attributed to the pregnancy. There is no conclusive evidence that normal pregnancy actually throws a greater load on normal kidneys. Dieckmann 7 has found lowered concentration of urea in the blood and, during the last half of normal pregnancy, a decrease in urea clearance by individual patients. There is delayed or decreased elimination of water by the kidneys and a decrease in the chloride and urea content of urine. Chesley demonstrated wide variations in uric acid and urea clearance in nonhypertensive pregnancy but the mean values were more than 100 per cent of normal. Numerous reports 5 are available of pregnancy occurring after nephrectomy, with the remaining kidney, if normal, capable of maintaining adequate excretory function. Herrick, how-
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ever, pointed out that any organ may function satisfactorily until its factor of safety is abolished. In the kidney damaged by chronic glomerulonephritis what reserve remains may be absorbed by pregnancy, the demands of which, in his opinion, vary directly with the age and size of the fetus. Although the earlier literature frequently contained statements suggesting that pregnancy may predispose to the subsequent appearance of "nephritis" or that preeclampsia and eclampsia are a common cause of "chronic nephritis," it is now generally agreed that normal pregnancy cannot result in the appearance of renal damage and that residual damage from specific toxemia, when it occurs, is vascuiar rather than glomerular.l' 3 Prognosis for the Fetus. It has been rather generally coneeded that fetal loss is significantly increased by the presence of glomerulonephritis in pregnancy. As previously noted, Dieckmann9 stated that such pregnancies rarely continue to term but commonly terminate spontaneously after from twelve to twenty-six weeks. In Miller's opinion fetal salvage of more than 33 per cent eannot be anticipated. The survival in Do~lds and Browne's series was 62 per cent; in that of Bell, about 50 per cent; in that of Reid and Teel, 93.3 per cent. Herrick stated that the later months of pregnancy bring the greatest load on the kidneys and offer the greatest hazard to the fetus, which is likely to die in utero or be expelled prematurely. Although Dieckmann 9 considered that vascular damage to the placenta is the explanation of the increase in fetal death, Herrick did not agree that the evidence is conclusive that such damage occurs or is significant. Ultimate Prognosis. Most authors lo • 13, 18,29 express the opinion that pregnancy in a patient who has chronic glomerulonephritis not only is accompanied by gradual increase in renal damage but that renal function subsequent to the period of gestation is found to be in an even more precarious state than it was prior to pregnancy. Further, the occurrence of another pregnancy eauses earlier appearance and more severe manifestations of renal breakdown. 18 1t is true that some patients whose renal damage is mild appear to tolerate pregnancy well and may be found subsequently to have little or no evidence of their glomerulonephritis.l3 • 29 Reid and Teel found 11 of their 15 patients to be in no worse condition six months to five years after pregnancy, and Dodds and Browne made the same observation in 9 out of 17 patients. The latter stated that they were unable to ascertain that the worsened renal status in the other patients was induced solely by the pregnancy rather than by the usual downhill course of the glomerulonephritis itself. Mortality statistics are of little help in elucidating the problem
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ELIZABETH MUSSEY
because of the lack of uniform terminology to which allusion wafl previously made. Thus, Stander and Peckham~4 have stated that more than 40 per cent of patients die within ten years following recognition of nephritis during pregnancy, and Paxson found that 3.25 per cent of 1,349 puerperal deaths in Philadelphia in the years 1931 through 1938 were attributable to chronic nephritis. Yet it is fairly certain that the term "chronic nephritis" has been loosely used to include renal disease of arteriosclerotic origin as well as glomerulonephritis. Apparently no figures are available to support 01' refute the assertion that occurrence of a pregnancy reduces the already lessened life expectancy of the woman suffering from chronic glomerulonephritifl. Theobald on the other hand assembled mortality rates for England and Wales since vital statistics had been collected and found the death rates for chronic nephritis to be higher in men than in women. During the same period (1911 to 1922) the mortality rates for chronic nephritis were approximately equal in married and single women up to the age of 55 years. He interpreted his findings as indicating no causal relation between pregnancy and chronic nephritis. The problem with regard to acute glomerulol}ephritis is no more elearly illuminated, owing to the rarity of the disease. It is generally agreed that complete recovery from an attack of acute glomerulonephritis is compatible with a normal rather than an increased riflk during a subsequent pregnancy.8, 13 There ifl no evidence that such women are prediflposed to the development of toxemia of pregnancy or to a recurrence of acute glomerulonephritis. MANAGEMENT
Treatment of glomerulonephritis (discussed elsewhere in this volume)27 of the pregnant woman does not differ from that advised for the nonpregnant patient except that more elose and frequent observation is essential. A balanced diet, especially for replacement of protein, adequate rest and avoidance of infection are basic measureH. Careful elinical and laboratory evaluation should be performed as early as possible and repeated often enough to detect promptly the adverse Higns of renal decompensation or preeclampHia. Hospitalization is imperative in many cases. The fundamental question which is raised when a gravid patient is found to have evidence of chronic glomerulonephritis concerns the advisability of terminating the pregnancy. Peckham stated that, generally speaking, a diagnosis of chronic nephritis is sufficient indication to consider emptying the uterus although the situation should be thoroughly discussed and the preference of the patient and her husband should be respected if possible. Dodds and Browne agreed
GLOMEHULONEPHRl'l'IS IN PREGNANCY
lOG!)
but pointed out from their experienee that patients with mild chronic nephritis may weather a pregnancy without mishap. In their opinion elevation of the blood urea to more than 40 mg. per 100 cc., albuminuric retinitis, edema and much albuminuria indicate a prognosis so had for both mother and infant that the pregnancy should not be allowed to continue. Miller likewise was of the opinion that a diagnosis of chronic nephritis is justification for interruption of pregnancy particularly in the multipara whose obstetrical future is "practically hopeless." For the primigravid patient one might be more lenient since this pregnancy might represent her only chance for a living child. Evidence of progressive renal insufficiency or the appearance of signs and symptoms of preeclampsia are forewarnings of the possibility of fetal death and warrant prompt intervention. There is, however, no indicator to reveal the answer to the question of whether waiting for fetal viability will mean a delay that only results in intra-uterine death of the infant. If continued rest in bed in a hospital does not reverse a rising blood pressure and increasing albuminuria or if there is progression of retinal changes, interruption of the pregnancy, regardless of its duration, is justified. Detailed discussion of the methods of emptying the uterus is not pertinent to the subject. In brief, the following accepted procedures may be considered. Prior to the fourth month of pregnancy, dilatation and curettage is indicated. During the middle trimester, hysterotomy is usually the operation of choice. When viability of the fetus has been attained and the cervix is properly effaced, induction of labor with pitocin or amniotomy or both is the most conservative means available. There are, however, cases in which cesarean section may appropriately be employed in spite of the added hazard of abdominal delivery. The indication for performance of a cesarean section is urgency of termination of pregnancy in the patient who has an "unripe" cervix and, usually, has had no prior vaginal delivery. Prevention of future pregnancies is advisable for most patients who have chronic glomerulonephritis and is imperative in those patients manifesting any degree of renal insufficiency or progressive impairment of function. If the contraindication to pregnancy is absolute, one should rarely rely on measures which are only relatively effective, such asyaginal medicaments and diaphragms. Ultimately, therefore, the patient and her husband will be confronted with the question of sterilization if personal beliefs do not forbid contemplation of such a procedure. Bilateral tubal ligation or excision can be done at the time of cesarean section but the abdominal route of delivery should not be
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elected solely for this purpose. It is preferable to deliver the baby vaginally and to perform salpingectomy either in the immediate puerperium through a small midline abdominal incision or after an interval of six to twelve weeks through the vaginal or abdominal approach. Vasectomy in the male is sometimes advised, but such a procedure hardly seems justified when the reason for avoidance of pregnancy lies in the female partner for whom the prognosis as to future life and health must be considered guarded at best. SUMMARY
The pertinent literature relative to acute and chronic glomerulonephritis in pregnancy has been reviewed. Patients who have renal damage of mild degree may tolerate pregnancy well although they possibly tend to be more susceptible to the development of preeclampsia. Patients who have marked renal involvement may be expected to exhibit increasing hypertension, albuminuria and pathologic changes in the retina which at any time may necessitate interruption of pregnancy. The prognosis for ultimate survival of the fetus is reduced by the presence of severe chronic glomerulonephritis. REFERENCES 1. Bell, E. T.: Renal Diseases. Philadelphia, Lea & Febiger, 1946,434 pp. 2. Browne, F. J.: Chronic Hypertension and Pregnancy. Brit. M. J. 2:283287 (Aug. 23) 1947. 3. Browne, F. J. and Dodds, Gladys H.: The Remote Prognosis of the Toxaemias of Pregnancy; Based on a Follow-up Study of 400 Patients in 589 Pregnancies for Periods Varying From 6 Months to 12 Years. J. Obst. & Gynaec. Brit. Emp. 46:443-461 (June) 1939. 4. Chesley, L. C.: Simultaneous Renal Clearances of Urea and Uric Acid in the Differential Diagnosis of the Late Toxemias. Am. J. Obst. & Gynec. 59:960-969 (May) 1950. 5. Crabtree, E. G. Urological Diseases of Pregnancy. Boston, Little, Brown and Company, 1942, 472 pp. 6. Dexter, Lewis and Weiss, Soma: Preeclamptic and Eclamptic Toxemia of Pregnancy. Boston, Little, Brown and Company, 1941, 415 pp. 7. Dieckmann, W. J.: Renal Function in the Toxemias of Pregnancy. Am. J. Obst. & Gynec. 29:472-488 (Apr.) 1935. 8. Dieckmann, W. J.: Acute Nephritis and Pregnancy. Am. J. Obst. & Gynec. 32:227-240 (Aug.) 1936. 9. Dieckmann, W. J.: The Toxemias of Pregnancy. St. Louis, The C. V. Mosby Company, 1941, 521 pp. 10. Dodds, Gladys H. and Browne, F. J.: Chronic Nephritis in Pregnancy. Proc. Roy. Soc. Med. 33 (pt. 2) :737-740 (Sept.) 1940. 11. Eastman, N.: Quoted by Dieckmann, W. J.B 12. Elden, C. A. and Cooney, J. W.: The Addis Sediment Count and Blood Urea Clearance Test in Normal Pregnant Women. J. Clin. Investigation. 14:889-891 (N ov.) 1935.
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13. Fishberg, A. M.: Hypertension and Nephritis. Ed. 4, Philadelphia, Lea & Febiger, 1939, 779 pp. 14. Gareis, L. C.: Chronic Nephritis in Pregnancy With Special Reference to the Diagnosis. Bull. School Med. Univ. Maryland. 33:18-25 (July) 1948. 15. Goodall, J. R.: Nephritis and Pregnancy. Am. J. Obst. & Gynec. 26:556569 (Oct.) 1933. 16. Greenhill, J. P.: Toxemia [Editors Note.] In: The 1950 Year Book of Obstetrics and Gynecology. Chicago, The Year Book Publishers, 1950, pp. 109-110. 17. Hallum, A. V.: Retinal Arterioles in the Hypertensions of Pregnancy. Tr. Am. Ophth. Soc. 43:585-607, 1945. 18. Herrick, W. W.: The Vascular and Renal Complications of Pregnancy. Bull. New York Acad. Med. 14:429-446 (July) 1938. 19. Herrick, W. W. and Tillman, A. J. B.: Toxemia of Pregnancy: Its Relation to Cardiovascular and Renal Disease; Clinical and Necropsy Observations With a Long Follow-up. Arch. Int. Med. 55:643-664 (Apr.) 1935. 20. Hollenhorst, R. W.: The Ophthalmologic Aspects of Chronic Renal Disease. M. CLIN. NORTH AMERICA. (This Issue.) 21. Irving, F. C.: A Study of Consecutive Cases of Hypertension and Albuminuria in Pregnancy. Pennsylvania M. J. 44:557-562 (Feb.) 1941. 22. Keith, N. M.: Discussion. Proc. Staff Meet., Mayo Clin. 24:145-148 (Mar. 16) 1949. 23. Kellogg, F. S. and Reed, D. E.: The Classification of Hypertension and Albuminuria in Pregnancy. In: Proceedings of the American Congress on Obstetrics and Gynecology, Cleveland, Ohio, September 11-15, 1939. Evanston, Illinois, The Mumm Print Shop, Inc., 1941, pp. 165172. 24. Kuder, K. and Stander, H. J.: Nephritis and Pregnancy. New York State J. Med. 34:5-9 (Jan. 1) 1934. 25. Miller, Douglas: Observations on Eclamptic Toxaemia and on Essential Hypertension and Chronic Nephritis in Pregnancy. Edinburgh M. J. 49:209-233 (Apr.) 1942. 26. Mussey, M. E.: Chronic Glomerulonephritis Complicating Pregnancy. Proc. Staff Meet., Mayo Clin. 24:145-148 (Mar. 16) 1949. 27. Odel, H. M. and Daugherty, G. W.: M. CUN. NORTH AMERICA. (This issue.) 28. Paxson, N. F.: Chronic Nephritis and Pregnancy Fatalities in Philadelphia. Am. J. Obst. & Gynec. 40:995-1001 (Dec.) 1940. 29. Peckham, C. H.: Chronic Nephritis Complicating Pregnancy. Am. J. Surg. 35:325-330 (Feb.) 1937. 30. Peters, J. P.: The Nature of the Toxemias of Pregnancy. J.A.M.A.110:329331 (Jan. 29) 1938. 31. Rayer: Quoted by Fishberg, A. M.13 32. Reid, D. E. and Teel, H. M.: Nonconvulsive Pregnancy Toxemias: Their . Relationship to Chronic Vascular and Renal Disease. Am ..J. Obst. & Gynec. 37:886-896 (May) 1939. 33. Stander, H. J. and Peckham, C. H.: A Classification of the Toxemias of the Latter Half of Pregnancy. Am. J. Obst. & Gynec. 11 :583-602 (May) 1926. 34. Stander, H. J. and Peckham, C. H.: Prognosis in Nephritis Complicating Pregnancy. Am. J. Obst. & Gynec. 22:626-636 (Oct.) 1931.
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35. Theobald, G. W.: Further Observations on the Relation of Pregnancy to Hypertension and Chronic Nephritis. J. Obst. & Gynaec. Brit. Emp. 43:1037-1052 (Dec.) 1936. 36. Wegner, Carl: Quoted by Dieckmann, W. J.8 37. Wellen, Irwin: Specific "Toxemia," Essential Hypertension, and Glomerulonephritis Associated With Pregnancy. Am. J. Obst. & Gynec. 3.9:1624 (Jan.) 1940. 38. Wellen, Irwin, Welsh, Catherine A. and Taylor, H. C., Jr.: The Effect of Pregnancy on Renal Function in Women With Pre-existing Essential Hypertension and With Chronic Diffuse Glomerulonephritis ..1. Clin. Investigation. 23:742-749 (Sept.) 1944. 3!l. Welsh, Catherine A., Wellen, Irwin and Taylor, H. C., Jr.: The Filtration Rate, Effective Renal Blood Flow, Tubular l';xcretory Mass and Phenol Red Clearance in Normal Pregnancy. J. Clin. Invest.igation. 21 :57-61 (Jan.) 1942.