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Influence of pregnancy on the course of Hodgkin’s disease
Influence of pregnancy on the course of Hodgkin's disease RICHARD M. BARRY, M.D. HENRY D. DIAMOND, M.D. LLOYD F. CRAVER, M.D. New York, New York
T H E influence of pregnancy on the course of Hodgkin's disease has been a source of controversy for many decades. The physician facing the problem in his practice can turn to the medical journals and find support for any view that his prejudices may lead him to favor, from the most favorable 1 • 13 • 16 to the most dire. 2 • 4 ' 20 Early articles generally supported the view that pregnancy exerts a detrimental influence on Hodgkin's disease, 4 • 14 producing an exacerbation of symptoms often with tragic consequences. However, as physicians encountered patients with Hodgkin's disease who tolerated pregnancy quite well, articles began to appear questioning this opinion. 3 • s, 9 • n- 19• 21 • 23 Unfortunately, most articles have been based on a very limited personal experience and the subject still remains controversial. In 1956, it was reported from this institution22 that patients becoming pregnant during the onset of Hodgkin's disease had shorter survivals than those developing Hodgkin's disease and later becoming pregnant. It was also observed that those entering pregnancy
with active disease died sooner than those entering pregnancy with quiescent disease. These findings, however, might merely reflect the facts that patients with Hodgkin's disease surviving long enough and remaining healthy enough to become pregnant and patients with quiescent disease are already in a favorable situation. As noted by the authors, a limitation on the Memorial Center study and, for that matter, on all studies of Hodgkin's disease and pregnancy has been our ignorance of the natural history of this disorder in women of the childbearing age group. To fill this void we decided to review all cases of Hodgkin's disease in young women encountered at the Memorial Hospital for Cancer and Allied Diseases and the James Ewing Hospital (New York). Our purpose was to determine the effect of pregnancy on survival and activity of disease so that we could offer some rational help to the physician for use in advising and treating the young woman afflicted with Hodgkin's disease.
Methods All Memorial Hospital and James Ewing Hospital charts from 1910 to June, 1959, carrying the diagnosis of Hodgkin's disease were reviewed. The charts of female patients reporting clinical onset of symptoms between the childbearing ages of 18 and 40 were selected for study. Those in which the pathologic diagnosis of Hodgkin's disease had not been confirmed at this institution \Vere
From the Lymphoma Service, Department of Medicine, Memorial Hospital for Cancer and Allied Diseases and james Ewing Hospital, the Lymphoma Section, Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research, and t.he Department of Medicine, Cornell University Medical Collegt. Supported by funds from the Lloyd F. Craver Fund of the Memorial Hospital for Cancer and Allied Diseases.
445
446
Barry, Diamond, and Craver
discarded unless slides could be obtained and the diagnosis confirmed. Charts of patients having clinical onset of disease after June, 1954, were discarded in order to establish a minimum 5 year follow-up period. A few early charts could not be used because of inadequate information. The remaining 347 charts constituted the study group. No patients in the remembered experience of clinicians at this institution were added unless they were uncovered in the normal course of the study to avoid prejudicing the series. Data from the 34 7 cases were placed on IBM cards. Survival times were calculated from the date of onset of clinical symptoms to death or to the last hospital visit prior to June, 1959. The date of tissue diagnosis and the time the patient was first seen at the Memorial or James Ewing Hospitals often followed the onset of clinical disease by many months. It was felt that the clinical onset offered the most accurate available measure of length of survival. In most cases clinical onset of symptoms was recorded in the chart. In those cases in which it was not, the best possible estimate was made from the data available. Craver's 2 classification was used to designate the extent of disease. Class I disease, by this classification, represents unicentric disease without dissemination and without constitutional symptoms. Class II disease is disease limited to the regions above or to the regions below the diaphragm. There may or may not be constitutional symptoms. Class III disease is generalized, involving regions both above and below the diaphragm and is usually accompanied by constitutional symptoms. To determine the activity of disease in the patients in the study group, the course of illness was broken down into 12 month periods dating from the onset of symptoms. This not only divided the course of disease into yearly periods but also allowed comparison with 12 month periods associated with pregnancy, the 9 month childbearing period plus a 3 month postpartum period. Disease was considered active if the appearance of adenopathy, splenomegaly, systemic symp-
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August 15, 1962 & Gynec.
J. Obst.
Table I, Age distribution in pregnancy cases and in the age-corrected control group of cases without pregnancy in association with Hodgkin's disease
18-24 25-29 30-36
4.5 21 18
54 25 21
87
48
42
23
51
28
toms, or other parameters of progressive disease were recorded in the chart and considered significant by the physician evaluating the patient at the time. In most of these instances therapy was promptly instituted. In the periods the patients were not followed at the hospital, disease was considered active if the history obtained from the patient and the referring physician indicated activity or if our records showed that treatment had been administered in that period. Quiescent periods were periods in which the patient was symptom free and no therapy was necessary. Where adequate information was not available the activity was listed as unknown. The state of activity of disease was recorded for each of the first 7 years of illness and for the period from the end of the seventh year to death or to the most recent follow-up. Disease was always "active" in the first 12 month period since this period included the clinical onset. In cases in which pregnancy occurred, activity of disease was also recorded for the 12 month period prior to the estimated date of conception, for the period of pregnancy, and for a 3 month postpartum period, Other pertinent data were collectf'd and tabulated on the IBM cards. For comparison with survival curves in patients becoming pregnant, an age-corrected control group was set up from the cases in which no pregnancies occurred. This was done quite simply by eliminating all cases in the nonpregnant group with age at clinical onset from 36 to 40 years. This produced a group with ages proportionately distributed in the same manner as the pregnancy cases (Table I).
Volume 84
Number4
Results
Course of Hodgkin's disease in young women. Table II presents pertinent· data about the 347 patients studied and compares those whose illness was associated with one or more pregnancies with those whose illness was not. One is struck by the remarkably long survival times young women with Hodgkin's disease enjoy, the median survival being just under 5 years. Sixteen per cent survived longer than 10 years and 1 patient lived 31 years and bore 4 children after a pathologic diagnosis of Hodgkin's granuloma was established. She eventually died of disseminated Hodgkin's disease. Survival figures revealed no significant difference between the younger and older patients in the study group. Survival times for the various age groups are shown in Table III. Fig. 1 presents a flow sheet showing the activity of disease in the total group for the first 7 years of illness and the period thereafter. Some generalizations regarding the course of Hodgkin's disease in young women can be made from a perusal of these data. During the first year of illness it is impossible to predict the course the disease will take. Thereafter a pattern emerges. Patients who have had active disease during the second year of illness have little hope of a prolonged remission. Of 223 patients having activity of their disease during the second year, only 13 entered a 2 year period of quiescence. The characteristic course of the others was continued bouts of active disease at least once yearly until death. This severe degree of morbidity must be taken into consideration when advising these patients about pregnancy. In patients whose disease is quiescent during the second year of illness one can usually expect long survivals. Of 80 such patients in the study group, only 18 were known to have died before the end of the seventh year of illness. Despite this favorable survival, about 75 per cent of the 80 women ran courses characterized by recurrent symptoms. In patients whose disease remained quiescent throughout both the second and third years of illness, however, it fre~
Influence of pregnancy on Hodgkin's disease
447
Table II. Data from 347 cases of Hodgkin's disease developing in women between the ages of 18 and 40 Illness
Data
No. of cases
Total cases* 347
No. of pregnancies 1 Multiple Age distribution 18-20 21-25 26-30
31-35
36-40
Tissue diagnosis Hodgkin's granuloma Hodgkin's paragranuloma Hodgkin's sarcoma
84
228
112 61
23
46
12
31
114
85 54 48
36 22 11 3
65 52 35 45
325
79
211
6 16
3
13
165
39
111
14
47
2
4
Classification of disease At onset: Class I Class II Class III
112 70
When first Class Class Class
28 126 93
8 39 37
18 73 137
84 255 4 4
1 82 1 1
75 149 3 1
59
90
52
9-395
2-276
54
22
28
23
10
seen at center: I II III
Marital status Single Married Divorced Widowed Median survival time (months) Range of survivals (months) 10 year survivors Last known status Living, no clinical evidence of disease Living, with disease Dead of disease: With autopsy Without autopsy Dead; no clinical evidence of disease, no postmortem confirmation
2-395
31
70
8
39
281 76 205
10 64 17 47
25 192 138 54
4
0
3
*Includes 35 cases in which pregnancy status was not known.
448
Barry, Diamond, and Craver
Am.
After clinical onset , lst year
2nd year
m active
3ro year
5th year
.Uhyear
6th year
J.
Fl, 1!#)2 Oust. & Gyn
Augu~t
Remainder or survival
7th year
38 deceased 41 dece1Sedi2'3 deceas~26 decM10 decMs~B deceased 75 active 46 active )4 active 19 active HFU HFU 2LFU 2 lFU 104 active k 1 active--! active-~! deceased 2 un nown 1 unknown-! unknown-! deceased 156 active !Inactive - I Inactive- I active-~ l active f 1 inactive-! inactive 21 naellvel 1 active - - 1 active . 4 inactlve-4 inactive active--2 active- 2 deceased ILFU 2 3 LFUk { 3 actlve--3 active--3 active- 3 active 4 un nown I active --HFU
i
4 unknown {
3 active--3 active-- 3 actlve-~3 active- 3 active
1 unknown-! active--! deceased . -{ 5 inactive 9 inactive - 9 mactlve 4 active l2 Inactive { - { 2 active-- 2 active 13 inactive 3 active 1 deceased l Jctlve-- I Inactive-! inaclive-1 active • . M _ •. ft..... -{ I actiVe --1 active . , 1n~, 1ve , """'we llFU 11 actiVe -{ 1 inective - 1 inactive - I active -{ 9 active 1 deceased={ 1 1 active decMs~ed 2 deceasm 6 active 4 active 9 inactive ll inactive 1 active 16 inactive 1 dec. Nm llFU 2'3 inactive llFU 4 active - - 4 active -{ . --{ 5 active - - 5 active
i
1
24 inactive
19 deceased
Onset of disease All cases active (347 cases!
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i :::__:::-{• ~=:
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33inactive
Wactive
llFU
J 1 activ~ 'l,Jinacttve !Inactive-! inactive-! active active 9 active --{ 1 dec111~ 1 dec!lilsed 7 active 6 active-- 6 active f 1 LFU L51cllve Ill inactive I unknown-! <~ctive--1 actwe--1 actiVe 2LFU 3 INcllve f 1 Inactive - I Inactive 9 lnactl 4 1n1tt1v l 2 actlve--2 actiVe I active-- l actwe --1 act1ve . 3 active-- 3 active --3 active 4 active llnactlve-1 inactive - I act1ve 35 act1ve 2 lFU : { I inactive - I 1nact1ve --I actiVe lmattwe-110act1ve 20 active 1 act1ve 17 active 24 act1ve 3 deceasm 2 deceasm '; ::~l ~~eased -{ 1 unknown-! unknown-! actiVe--! act1ve 1 active - - 1 active _1 1 act· _.f 6 active :;{ l Inactive-! active 8 active Ll dee';;;1 I dec.easm 4 dec~sed . active act•v~--1 ~nacttve-1 act1ve 31 nactlve-l inactive - { 2•Sal 2 in&CIIVtr-2 tnactlve-2 actiVe -.ea . . .J 1 active - - I deceased 25u 3active-{ ~:~':,;-t l inactive-! LFU 5 act1ve 1 unknown- I active--! active--! deceased 12 unknown { 1 deceased.J 2 active--2 adive--2 active { 5 unknow.l 3 unknown- 3 unknown-3 active 7 unknown . -{ I active--! deceased Zacttve 1 LFU 43 inactive
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1LFU
i
2 inactive- 2 Inactive
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~
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Code--------------- ; lnactive-f'«l clinical activity ot disease during period Active -Exacerbation !II ttadgkin's
disease or death from Hodgkin's disease durl09 period Deceased-Diad of disease in prior period Unknown-status of activity 01
disease unkna~~n duri09 period
LFU --lost to follow-up Dec. Nm-diod In prior period wKhout evidence of diselse.
i
{I
Fig. 1. How sheet showing the activity of Hodgkin's disease in the total group of 347 women for the first 7 years of illness and the period thereafter.
quently remained inactive for prolonged periods. Of 43 such women in our study group, approximately 50 per cent ran courses characterized by low morbidity and only 4 were known to have died of disease before the eighth year of illness. Twenty-five per cent of the cases remained inactive 7 or more years and were still inactive at the conclusion of the study.
Influence of pregnancy on survival. Of the 34 7 patients, 84 became pregnant in association with the Hodgkin's disease. Sixty-one were pregnant once, 19 twice, 3 three times, and 1 four times, yielding a total of 112 pregnancies in association with Hodgkin's disease. The outcome of these pregnancies is charted in Table IV. Two hundred and twenty-eight women were stated not to have
Volume84 Number 4
Influence of pregnancy on Hodgkin's disease
Table III. Survival times according to age at onset of symptoms
Age group 18-20 21-25 26-30 31-35
36-40
No. of cases
46 114 85 54 48
Median survival (months)
Range (months)
57
5-395 2-277
56
9-294
66
64
4-219
55
5-264
been pregnant after the onset of illness; 106 of these were known to have been pregnant before developing Hodgkin's disease and, of these, 23 developed Hodgkin's disease following a recent pregnancy. Thirty-four of the 84 women pregnant in association with Hodgkin's disease also had had previous pregnancies. Previous pregnancies did not afl'ect the survival time (median, 57 months). Since the survival curves in Hodgkin's disease are skewed by the long-term survivors, median values have more significance than mean values. Fig. 2 presents survival curves for the total group of patients, for those patients who had pregnancies in association with Hodgkin's disease, and for the age-corrected control group of patients who had no pregnancies after onset of illness. The survival curve and the median survival time of 90 months in the group with pregnancy in association with Hodgkin's disease compare favorably with the findings for the total group (median survival, 59 months) and the age-corrected nonpregnant control group (median survival, 52 months). Onset during pregnancy. Some authors have felt that the onset of Hodgkin's disease during pregnancy adversely affected sur-
449
vival. 5 • 7 • 8 • 10 • 15 • 22 Thirty-four patients in our series had the onset of Hodgkin's disease during pregnancy. These patients had a me. dian survival of 73 months. Twenty-three patients developed Hodgkin's disease following a recent pregnancy. Their median survival was 49 months. This difference is not statistically significant ( t = 1.8) . Combined, this group of patients with onset of Hodgkin's disease intimately associated with pregnancy had a normal survival curve (median survival, 64 months) . Effect of interruption of pregnancy on survival. One of the questions we attempted to resolve was whether or not therapeutic abortion would favorably influence the survival of pregnant women with Hodgkin's disease. 5 • 11 • 12 • H, 21 In our series, 25 pregnancies were interrupted; 9 were terminated by spontaneous abortion and 16 by therapeutic abortion. All these occurred in patients who had become pregnant after the onset of Hodgkin's disease. Of the total 112 pregnancies, 79 yielded normal term deliveries and 3 ended in stillbirths. The group of pregnancies commencing after onset of disease (that is, eliminating cases pregnant during onset) included 51 normal full-term deli\·eries. These 51 were compared with the 25 interrupted pregnancies. The 2 groups were not wholly comparable because therapeutic abortions were carried out in some of the more severe cases. However, it was hoped that survival times for the 2 groups starting from the date of onset of pregnancy would demonstrate a difference. No such difference in survival was found. Instead, the curves are remarkably similar (Fig. 3). One is im-
Table IV. Hodgkin's disease m association with pregnancy (84 cases), outcome of 112 pregnancies Classification of disease at time of pregnancy
Class I Class II (all above diaphragm) Class III Unknown Total
Normal full-term delivery
Stillbirth
ISponta~eousl Therap~utic I Unknown abort1on abortion
21 40
18
6 2
0
0
9 7
2
Total
23 58
2
:~o
5
112
1
1
450 Barry, Diamond, and Craver
August 15, 1962
Am.
pressed by the longevity in both groups. The median survival after conception was 50 months for the interrupted pregnancy groups and 60 months for the normal delivery group. The median total survival times from onset of clinical symptoms were 110 months and 103 months for the 2 groups, respectively. A few patients with multiple pregnancies appeared in both groups. Activation of disease in association with pregnancy. A flow sheet for the 228 patients having no pregnancies in association with Hodgkin's disease was prepared in the same manner as demonstrated by Fig. 1. From it, the chances of activation of disease in nonpregnant women could be determined. The results were compared with similar data obtained from the pregnancy patients. Forty-four of the nonpregnant patients had quiescent disease during the second year of illness. Fifty-five per cent of these had an exacerbation of symptoms during the next 12 months. Of the pregnancy patients, 12 had quiescent disease during the second year of illness and then became pregnant. In 2 patients, disease activated during pregnancy and in an additional 4 it activated in the postpartum period. In 19 patients enjoying a year of quiescent disease and then becoming pregnant, 5 had activation of disease during pregnancy and ,4 in the postpartum period making a total of 4 7 per cent against an expected rate of 30 per cent in the con-
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4
5
6
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trol subjects. This difference is not statistically significant. These data indicate that the frequency of exacerbations of disease is not increased by pregnancy, however, the exacerbations tend to be concentrated in the postpartum period. Is activation of Hodgkin's disease in pregnancy a grave omen? Table V lists the 31 women who entered pregnancy with quiescent disease. In 15, disease activated and in 16 it did not. The survival times to June, 1959, are as good for the group that activated as for the group that remained quiescent and again the longevity is striking. One should note, however, that 12 of the 16 patients whose disease remained quiescent are living, 8 of these without evidence of disease. Ten of the 15 whose disease activated are dead and only 1 is without evidence of disease. For some reason, the cases of those patients whose disease remained quiescent are of a more recent vintage. Table V also lists patients entering pregnancy with active disease. These have a shorter survival than those entering pregnancy with quiescent disease. Patients with active disease, however, would be expected to survive less longer than those with quiescent disease as can be seen in Fig. I. Treatment during pregnancy. Most of the women with active disease during pregnancy had disease activity above the diaphragm; this was treated with ionizing radiation,
2
YE.'AR OF IUNE.'SS FROII CLINICAl. ONSET OF SYAII'TlliiiS
Fig. 2. Survival curves for the total group of patients, for those who had pregnancies in association with Hodgkin's disease, and for the age-corrected control group who had no pregnancies after the onset of illness.
Volume84 Number4
Influence of pregnancy on Hodgkin's disease
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Fig. 3. Survival curves for the group having full-term deliveries and the group in which pregnancies were interrupted by either spontaneous or therapeutic abortions.
shielding the abdomen. Standard doses were employed without any apparent adverse effects on the fetus. Systemic agents were withheld except in one notable case where a dose of 0.3 mg. per kilogram of nitrogen mustard was administered to a patient with an unrecognized 2 month gestation. Pregnancy carried to term and a healthy baby was born who was living and well at 2 months of age. Unfortunately, the child was then lost to follow-up. Outcome of pregnancy. As shown in Table IV, 91 pregnancies were allowed to proceed uninterrupted in which the outcome of pregnancy is known. Seventy-nine resulted in viable infants. No cases of Hodgkin's disease were observed in the infants and, where follow-up data were available, no disease patterns in the children born of mothers with Hodgkin's disease emerged. Long-term survivals. Of the 347 patients in the study group, 54 survived more than 10 years. Of these, 27 presented initially with Class I disease, 21 with Class II, and 6 with Class III disease. There were 52 cases of Hodgkin's granuloma, 1 of Hodgkin's paragranuloma, and 1 Hodgkin's sarcoma. This last case was a 19-year-old woman who presented initially with mediastinal and cervical disease in September, 1947. A diagnosis of Hodgkin's sarcoma was established by cervical node biopsy the following month. She survived 122 months, finally dying of the disease.
YEAR$ AFTER CONCEPTION
If pregnancy has a detrimental effect on survival, one might expect fewer pregnancies in the group of long-term survivors than in the group as a whole. Actually 3 of the long-term survivors developed Hodgkin's disease following a recent pregnancy, 3 were pregnant during the onset of Hodgkin's disease, and 19 became pregnant after the development of disease. Twenty-two of the 54 were pregnant a total of 34 times in association with Hodgkin's disease. This is a higher incidence of pregnancy than in the shorter-term survivors. Ten of the 54 women are now living and without evidence of disease. Nine of these have been without evidence of disease since the end of the second year of illness. Twelve are living with disease and the others are dead. One patient died without evidence of clinical disease but there was no postmortem confirmation. Comment
The present study fails to demonstrate any adverse effect of pregnancy on either the course or longevity of patients with Hodgkin's disease. The fact that patients frequently have exacerbations of their disease in the postpartum period is borne out but the explanation seems to lie in the fact that active disease is frequently masked during pregnancy itself, probably by hormonal factors, only to make itself known in the postpartum period. The incidence of ex-
452
Augu . . 1 EL 196:!
Barry, Diamond, and Craver
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Table V. Hodgkin's disease and pregnancy: survival in patients becoming pregnant after onset of disease ~-,,-~~~--------
- - - - (:tassifica-j Date of tion of 1 last Estimated disease at follow-up time of date of conception pregnancy (to 6/59)
---
~--------------
I
---------
I Survival
I I
Outcome of pregnancy
from date of , conception I (months)
Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Therapeutic abortion Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-tenn delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery
82 90 125 63 102 22 13 56 74 98 33 235 40 {5 70
I
Status of patient
Disease quiescent prior to onset of pregnancy and then activating 4/55 Dead of disease III 6/48 4/59 Living, with disease II 10/51 12/51 Dead of disease I 5/40 8/35 Dead of disease .'i/30 III 11/56 Dead of disease II 5/48 2/49 4/47 Dead of diseaJe III 6/59 Living, with disease II 5/58 10/53 Living, with disease II 2/49 11143 Dead of disease II 9/37 7/58 Dead of disease II 5/50 Living, no evidence of disease 2/58 I 5/55 7/47 Dead of disease II 12/27 7/49 Dead of disease II 3/46 Living, with disease 6/59 III 9/55 6154 Dead of disease II 8/48 Median survival
70
Disease quiescent prior to onset of pregnancy and remaining inactive 9/56 Living, no evidence of disease Normal full-term delivery II 6/55 Living, no evidence of disease Normal full-term delivery 4/58 II 9/55 6/59 Living, with disease 7/57 Spontaneous abortion II 9/56 II Living, no evidence of disease Normal full-term delivery 6/54 6/59 II Living, no evidence of disease Normal full-term delivery 6/57 4/58 7/50 II Living, no evidence of disease Normal full-term delivery 7/55 7/49 II Dead of disease Normal full-term delivery 6/59 Living, with disease 6/51 Spontaneous abortion II 6/59 Living, no evidence of disease Spontaneous abortion 7/52 II Living, no evidence of disease 11/58 I 6/53 Stillbirth Living, with disease 6/59 Normal full-term delivery II 6/54 5/58 Dead of disease Therapeutic abortion II 1/52 3/56 Dead of disease Normal full-term delivery II 2/50 Dead of disease Normal full-term delivery 4/55 I 5/47 11/55 Living, with disease Therapeutic abortion II 6/53 Living, no evidence of disease 10/58 Spontaneous abortion 6/4-7 I Median survival Active disease prior to the onset of pregnancy 6/59 Living, no evidence of disease II 4/42 4/59 7/49 Living, with disease II 3/59 Dead of disease III* 12/38 7/48 Dead of disease 6/44 III 11/40 Dead of disease 11/36 II 7/58 10/53 II Dead of disease 1/50 Dead of disease 11/43 I Dead of disease 2/4-6 1/29 I Dead of disease 2/46 6/35 III 7/55 4/54 II Dead of disease 12/47 Dead of disease 7/46 II 6/56 6/57 III Dead of disease 4/58 Dead of disease 9/50 II Dead of disease 2/45 III 2/47 1!/45 II 9/51 Dead of disease 4/37 III* 8/37 Dead of disease 8/56 III* 12/56 Dead of disease 5/53 6/51 III* Dead of disease 6146 2/47 Dead of disease III
Normal full-term delivery Normal full-term delivery Therapeutic abortion Nonnal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Therapeutic abortion Normal full-term delivery Normal full-term delivery Normal full-term delivery Spontaneous abortion Normal full-term delivery Normal full-term delivery Spontaneous abortion Therapeutic abortion Therapeutic abortion Therapeutic abortion
15
31
23 27 24
93 72 96 83 65 60 76 73 96 29 136
69
206 118 3 49 48 57 74 205 128 15 17 60 91 24 70 4
4 23 8
Volume 84
Influence of pregnancy on Hodgkin's disease
Number4
Table V-Cont'd Classification of Estimated disease at time of date of conception pregnancy
7/42 1/25 8/46 2/52 8/53
9/49 3/45 1/45 4/47 4/48 3/46 6/49 2/39 1/50
II II
III* II III
III III II III* III II
III* III II Median survival
..----..··-Date of last follow-up (to 6/59)
8/55 2/31 5/53 4/54 10/57 7/54 2/49 2/57 1/52 8/49 8/47 5/53 2/41 2/57
Status of patient
Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead
of of of of of of of of of of of of of of
disease disease disease disease disease disease disease disease disease disease disease disease disease disease
Outcome of Pregnancy
Spontaneous abortion Normal full-term delivery Normal full-term delivery Therapeutic abortion Normal full-term delivery Unknown Therapeutic abortion Therapeutic abortion Therapeutic abortion Normal full-term delivery Spontaneous abortion Spontaneous abortion Stillbirth Therapeutic abortion
453
Survival from date of conception (months)
157 73 81 26 50 58 47 145 57
16
17 47 24 85 50
*With extensive abdominal involvement.
acerbations during a 9 month period of pregnancy plus a 3 month postpartum period is not greater than that which would be expected during a comparable 12 month period in a group of nonpregnant women. The study also shows that activation of Hodgkin's disease during pregnancy in itself does not prevent long survivals. While pregnant patients have longer survivals than nonpregnant patients, we feel that this is a result of a more favorable state of health in women able to conceive. Others might interpret this finding differently. Therapeutic abortion could not be demonstrated to produce any favorable effect on the course of Hodgkin's disease. Our find~Y"t#"''t' .l.l.L5~
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served for desperate cases in which pregnancy prevents the use of effective therapy in the mother. The patient already pregnant, therefore, can be reassured that pregnancy will not affect her survival. Nor is there evidence that it will affect the health of the infant. But what should one say to the young woman with Hodgkin's disease who wants to become pregnant? Advising the young woman suffering from an incurable disease but deeply desirous of having children is difficult
at best. Even though pregnancy itself may do no demonstrable harm, the morbidity of the disease itself must be taken into consideration. Certain facts emerge from this study which should be of help in dealing with such Hodgkin's disease sufferers. Certainly a woman with active disease during the first and second year of illness should be advised against entering pregnancy. This study shows that these patients are faced with the prospect of repetitive bouts of sickness even if they survive for long periods. The patient whose disease is inactive or who has recently become afflicted should be urged to wait until the disease has been inactive for a 2 year period. A single year of quiescence is not long enough. By waiting until the conclusion of the proper period of quiescence, she can then look forward to a 75 per cent chance of long survival and a 50 per cent chance of a long period in relative good health regardless of pregnancy. One must interject a note of caution, however. The effect of pregnancy on the individual patient can never be determined by a study of this sort. There are 2 patients in our series each of whom twice experienced exacerbations of their disease with pregnancy after periods of greater than 3 years' quiescence. Both, fortunately, were long-
454
Barry, Diamond, and Craver
term survivors, but in these individuals' cases morbidity may have been increased. Such instances must be weighed against the individual patient's desire for children. Summary
The charts of 347 patients with Hodgkin's disease treated at the Memorial Hospital for Cancer and Allied Diseases and the James Ewing Hospital (New York) were analyzed. All were women in the childbearing age group. The mean survival time of these patients was almost 5 years. Sixteen per cent survived 10 or more years. Active disease during both the first and second years of illness carried a grave prognosis in terms of morbidity and mortality. The most favorable course was in those patients whose disease was quiescent through the second and third years of illness.
REFERENCES
1. Eichel, J.: Acta radio!. 33: 427, 1950. 2. Craver, L. F.: Cancer 7: 927, 1954. 3. Frank, H. G.: J. Obst. & Gynaec. Brit. Emp. 62: 266, 1955. 4. Genunel, A. A.: J. Obst. & Gynaec. Brit.
Emp. 30: 373, 1923. 5. Gilbert, R.: Acta radio!. 35: 71, 1951. 6. Goldman, L. B., and Victor, A. W.: New York J. Med. 45: 1313, 1945. 7. Hartvigson, B.: Acta radio!. 44: 317, 1955. 8. Hartweg, H., and Braun, H.: Strahlentherapie 94: 213, 1954. 9. Hennessy, J. P., and Rottino, A.: AM. J. 0BST. & GYNEC. 63: 756, 1952. 10. Hultberg, S.: Acta radio!. 41: 277, 1954. 11. Jackson, H., and Parker, F.: Hodgkin's Disease and Allied Disorders, Oxford, 194 7, Oxford University Press, pp. 91-92. 12. Kasdon, S. C.: AM. J. OusT. & GYNEC. 57: 282, 1949. 13. Merrill, D.: In Daland, E. M., editor: Cancer, a Manual for Practitioners, ed. 3, Boston. 1956, American Cancer Society (Massachusetts Division), pp. 218-219.
August 15, 1962 Am. J. Obst. & Gyncc.
Eighty-four women in the group had a total of 112 pregnancies. Pregnancy did not adversely affect mean survival time. The incidence of activation of disease in association with pregnancy was not greater than that expected in nonpregnant women during a comparable period of time; however, the exacerbations tended to crowd into the postpartum period. Activation of disease with pregnancy did not demonstrably shorten survival times. Therapeutic abortion had neither a favorable nor an adverse effect. Women desirous of pregnancy should be urged to wait until they have had quiescence of disease for at least 2 years. Patients with active disease should be advised against pregnancy, not because of any adverse effect of pregnancy on the mother or danger to the fetus, but because of the poor prognosis in the mother.
J. M.: J. Obst. & Gynaec. Brit. Emp. 62: 884, 1955. Papillon, J., and Chavanne, G.: ]. med. Lyon 31: 127, 1950. Perrier, H.: Schweiz. med. Wchnschr. 75: 1014, 1945. Peters, M. V., and Middlemiss, K. C. H.: Am. ]. Roentgenol. 79: 114, 1958. Portmann, U. V., and Mulvey, B. E.: Cleveland Clin. Quart. 17: 149, 1950. Riva, H. L., Andreson, P. S., and O'Grady, J. W.: AM. J. 0BST. & GYNEC. 66: 866,
14. Myles, T.
15. 16. 17.
18. 19.
1953. 20. S!:'lvaag, 0.: Nord. med. 47: 188, 1952.
21. Smith, R. B. W., Sheehy, T. W., and Rothberg, H.: A. M. A. Arch. Int. Med. 102: 777, 1958.
22. Southam,
C. M., Diamond, H. D., and Craver, L. F.: Cancer 9: 1141, 1956. 23. Stewart, H. L., and Manto, R. W.: AM. J. OnsT. & GYNEC. 63: 570, 1952. Memorial Hospital for Cancer and
Allied Diseases
New York 21, New York
T H E influence of pregnancy on the course of Hodgkin's disease has been a source of controversy for many decades. The physician facing the problem in his practice can turn to the medical journals and find support for any view that his prejudices may lead him to favor, from the most favorable 1 • 13 • 16 to the most dire. 2 • 4 ' 20 Early articles generally supported the view that pregnancy exerts a detrimental influence on Hodgkin's disease, 4 • 14 producing an exacerbation of symptoms often with tragic consequences. However, as physicians encountered patients with Hodgkin's disease who tolerated pregnancy quite well, articles began to appear questioning this opinion. 3 • s, 9 • n- 19• 21 • 23 Unfortunately, most articles have been based on a very limited personal experience and the subject still remains controversial. In 1956, it was reported from this institution22 that patients becoming pregnant during the onset of Hodgkin's disease had shorter survivals than those developing Hodgkin's disease and later becoming pregnant. It was also observed that those entering pregnancy
with active disease died sooner than those entering pregnancy with quiescent disease. These findings, however, might merely reflect the facts that patients with Hodgkin's disease surviving long enough and remaining healthy enough to become pregnant and patients with quiescent disease are already in a favorable situation. As noted by the authors, a limitation on the Memorial Center study and, for that matter, on all studies of Hodgkin's disease and pregnancy has been our ignorance of the natural history of this disorder in women of the childbearing age group. To fill this void we decided to review all cases of Hodgkin's disease in young women encountered at the Memorial Hospital for Cancer and Allied Diseases and the James Ewing Hospital (New York). Our purpose was to determine the effect of pregnancy on survival and activity of disease so that we could offer some rational help to the physician for use in advising and treating the young woman afflicted with Hodgkin's disease.
Methods All Memorial Hospital and James Ewing Hospital charts from 1910 to June, 1959, carrying the diagnosis of Hodgkin's disease were reviewed. The charts of female patients reporting clinical onset of symptoms between the childbearing ages of 18 and 40 were selected for study. Those in which the pathologic diagnosis of Hodgkin's disease had not been confirmed at this institution \Vere
From the Lymphoma Service, Department of Medicine, Memorial Hospital for Cancer and Allied Diseases and james Ewing Hospital, the Lymphoma Section, Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research, and t.he Department of Medicine, Cornell University Medical Collegt. Supported by funds from the Lloyd F. Craver Fund of the Memorial Hospital for Cancer and Allied Diseases.
445
446
Barry, Diamond, and Craver
discarded unless slides could be obtained and the diagnosis confirmed. Charts of patients having clinical onset of disease after June, 1954, were discarded in order to establish a minimum 5 year follow-up period. A few early charts could not be used because of inadequate information. The remaining 347 charts constituted the study group. No patients in the remembered experience of clinicians at this institution were added unless they were uncovered in the normal course of the study to avoid prejudicing the series. Data from the 34 7 cases were placed on IBM cards. Survival times were calculated from the date of onset of clinical symptoms to death or to the last hospital visit prior to June, 1959. The date of tissue diagnosis and the time the patient was first seen at the Memorial or James Ewing Hospitals often followed the onset of clinical disease by many months. It was felt that the clinical onset offered the most accurate available measure of length of survival. In most cases clinical onset of symptoms was recorded in the chart. In those cases in which it was not, the best possible estimate was made from the data available. Craver's 2 classification was used to designate the extent of disease. Class I disease, by this classification, represents unicentric disease without dissemination and without constitutional symptoms. Class II disease is disease limited to the regions above or to the regions below the diaphragm. There may or may not be constitutional symptoms. Class III disease is generalized, involving regions both above and below the diaphragm and is usually accompanied by constitutional symptoms. To determine the activity of disease in the patients in the study group, the course of illness was broken down into 12 month periods dating from the onset of symptoms. This not only divided the course of disease into yearly periods but also allowed comparison with 12 month periods associated with pregnancy, the 9 month childbearing period plus a 3 month postpartum period. Disease was considered active if the appearance of adenopathy, splenomegaly, systemic symp-
Am,
August 15, 1962 & Gynec.
J. Obst.
Table I, Age distribution in pregnancy cases and in the age-corrected control group of cases without pregnancy in association with Hodgkin's disease
18-24 25-29 30-36
4.5 21 18
54 25 21
87
48
42
23
51
28
toms, or other parameters of progressive disease were recorded in the chart and considered significant by the physician evaluating the patient at the time. In most of these instances therapy was promptly instituted. In the periods the patients were not followed at the hospital, disease was considered active if the history obtained from the patient and the referring physician indicated activity or if our records showed that treatment had been administered in that period. Quiescent periods were periods in which the patient was symptom free and no therapy was necessary. Where adequate information was not available the activity was listed as unknown. The state of activity of disease was recorded for each of the first 7 years of illness and for the period from the end of the seventh year to death or to the most recent follow-up. Disease was always "active" in the first 12 month period since this period included the clinical onset. In cases in which pregnancy occurred, activity of disease was also recorded for the 12 month period prior to the estimated date of conception, for the period of pregnancy, and for a 3 month postpartum period, Other pertinent data were collectf'd and tabulated on the IBM cards. For comparison with survival curves in patients becoming pregnant, an age-corrected control group was set up from the cases in which no pregnancies occurred. This was done quite simply by eliminating all cases in the nonpregnant group with age at clinical onset from 36 to 40 years. This produced a group with ages proportionately distributed in the same manner as the pregnancy cases (Table I).
Volume 84
Number4
Results
Course of Hodgkin's disease in young women. Table II presents pertinent· data about the 347 patients studied and compares those whose illness was associated with one or more pregnancies with those whose illness was not. One is struck by the remarkably long survival times young women with Hodgkin's disease enjoy, the median survival being just under 5 years. Sixteen per cent survived longer than 10 years and 1 patient lived 31 years and bore 4 children after a pathologic diagnosis of Hodgkin's granuloma was established. She eventually died of disseminated Hodgkin's disease. Survival figures revealed no significant difference between the younger and older patients in the study group. Survival times for the various age groups are shown in Table III. Fig. 1 presents a flow sheet showing the activity of disease in the total group for the first 7 years of illness and the period thereafter. Some generalizations regarding the course of Hodgkin's disease in young women can be made from a perusal of these data. During the first year of illness it is impossible to predict the course the disease will take. Thereafter a pattern emerges. Patients who have had active disease during the second year of illness have little hope of a prolonged remission. Of 223 patients having activity of their disease during the second year, only 13 entered a 2 year period of quiescence. The characteristic course of the others was continued bouts of active disease at least once yearly until death. This severe degree of morbidity must be taken into consideration when advising these patients about pregnancy. In patients whose disease is quiescent during the second year of illness one can usually expect long survivals. Of 80 such patients in the study group, only 18 were known to have died before the end of the seventh year of illness. Despite this favorable survival, about 75 per cent of the 80 women ran courses characterized by recurrent symptoms. In patients whose disease remained quiescent throughout both the second and third years of illness, however, it fre~
Influence of pregnancy on Hodgkin's disease
447
Table II. Data from 347 cases of Hodgkin's disease developing in women between the ages of 18 and 40 Illness
Data
No. of cases
Total cases* 347
No. of pregnancies 1 Multiple Age distribution 18-20 21-25 26-30
31-35
36-40
Tissue diagnosis Hodgkin's granuloma Hodgkin's paragranuloma Hodgkin's sarcoma
84
228
112 61
23
46
12
31
114
85 54 48
36 22 11 3
65 52 35 45
325
79
211
6 16
3
13
165
39
111
14
47
2
4
Classification of disease At onset: Class I Class II Class III
112 70
When first Class Class Class
28 126 93
8 39 37
18 73 137
84 255 4 4
1 82 1 1
75 149 3 1
59
90
52
9-395
2-276
54
22
28
23
10
seen at center: I II III
Marital status Single Married Divorced Widowed Median survival time (months) Range of survivals (months) 10 year survivors Last known status Living, no clinical evidence of disease Living, with disease Dead of disease: With autopsy Without autopsy Dead; no clinical evidence of disease, no postmortem confirmation
2-395
31
70
8
39
281 76 205
10 64 17 47
25 192 138 54
4
0
3
*Includes 35 cases in which pregnancy status was not known.
448
Barry, Diamond, and Craver
Am.
After clinical onset , lst year
2nd year
m active
3ro year
5th year
.Uhyear
6th year
J.
Fl, 1!#)2 Oust. & Gyn
Augu~t
Remainder or survival
7th year
38 deceased 41 dece1Sedi2'3 deceas~26 decM10 decMs~B deceased 75 active 46 active )4 active 19 active HFU HFU 2LFU 2 lFU 104 active k 1 active--! active-~! deceased 2 un nown 1 unknown-! unknown-! deceased 156 active !Inactive - I Inactive- I active-~ l active f 1 inactive-! inactive 21 naellvel 1 active - - 1 active . 4 inactlve-4 inactive active--2 active- 2 deceased ILFU 2 3 LFUk { 3 actlve--3 active--3 active- 3 active 4 un nown I active --HFU
i
4 unknown {
3 active--3 active-- 3 actlve-~3 active- 3 active
1 unknown-! active--! deceased . -{ 5 inactive 9 inactive - 9 mactlve 4 active l2 Inactive { - { 2 active-- 2 active 13 inactive 3 active 1 deceased l Jctlve-- I Inactive-! inaclive-1 active • . M _ •. ft..... -{ I actiVe --1 active . , 1n~, 1ve , """'we llFU 11 actiVe -{ 1 inective - 1 inactive - I active -{ 9 active 1 deceased={ 1 1 active decMs~ed 2 deceasm 6 active 4 active 9 inactive ll inactive 1 active 16 inactive 1 dec. Nm llFU 2'3 inactive llFU 4 active - - 4 active -{ . --{ 5 active - - 5 active
i
1
24 inactive
19 deceased
Onset of disease All cases active (347 cases!
i
i i
i :::__:::-{• ~=:
i
~
33inactive
Wactive
llFU
J 1 activ~ 'l,Jinacttve !Inactive-! inactive-! active active 9 active --{ 1 dec111~ 1 dec!lilsed 7 active 6 active-- 6 active f 1 LFU L51cllve Ill inactive I unknown-! <~ctive--1 actwe--1 actiVe 2LFU 3 INcllve f 1 Inactive - I Inactive 9 lnactl 4 1n1tt1v l 2 actlve--2 actiVe I active-- l actwe --1 act1ve . 3 active-- 3 active --3 active 4 active llnactlve-1 inactive - I act1ve 35 act1ve 2 lFU : { I inactive - I 1nact1ve --I actiVe lmattwe-110act1ve 20 active 1 act1ve 17 active 24 act1ve 3 deceasm 2 deceasm '; ::~l ~~eased -{ 1 unknown-! unknown-! actiVe--! act1ve 1 active - - 1 active _1 1 act· _.f 6 active :;{ l Inactive-! active 8 active Ll dee';;;1 I dec.easm 4 dec~sed . active act•v~--1 ~nacttve-1 act1ve 31 nactlve-l inactive - { 2•Sal 2 in&CIIVtr-2 tnactlve-2 actiVe -.ea . . .J 1 active - - I deceased 25u 3active-{ ~:~':,;-t l inactive-! LFU 5 act1ve 1 unknown- I active--! active--! deceased 12 unknown { 1 deceased.J 2 active--2 adive--2 active { 5 unknow.l 3 unknown- 3 unknown-3 active 7 unknown . -{ I active--! deceased Zacttve 1 LFU 43 inactive
13
1LFU
i
2 inactive- 2 Inactive
.i
~
_.J
Code--------------- ; lnactive-f'«l clinical activity ot disease during period Active -Exacerbation !II ttadgkin's
disease or death from Hodgkin's disease durl09 period Deceased-Diad of disease in prior period Unknown-status of activity 01
disease unkna~~n duri09 period
LFU --lost to follow-up Dec. Nm-diod In prior period wKhout evidence of diselse.
i
{I
Fig. 1. How sheet showing the activity of Hodgkin's disease in the total group of 347 women for the first 7 years of illness and the period thereafter.
quently remained inactive for prolonged periods. Of 43 such women in our study group, approximately 50 per cent ran courses characterized by low morbidity and only 4 were known to have died of disease before the eighth year of illness. Twenty-five per cent of the cases remained inactive 7 or more years and were still inactive at the conclusion of the study.
Influence of pregnancy on survival. Of the 34 7 patients, 84 became pregnant in association with the Hodgkin's disease. Sixty-one were pregnant once, 19 twice, 3 three times, and 1 four times, yielding a total of 112 pregnancies in association with Hodgkin's disease. The outcome of these pregnancies is charted in Table IV. Two hundred and twenty-eight women were stated not to have
Volume84 Number 4
Influence of pregnancy on Hodgkin's disease
Table III. Survival times according to age at onset of symptoms
Age group 18-20 21-25 26-30 31-35
36-40
No. of cases
46 114 85 54 48
Median survival (months)
Range (months)
57
5-395 2-277
56
9-294
66
64
4-219
55
5-264
been pregnant after the onset of illness; 106 of these were known to have been pregnant before developing Hodgkin's disease and, of these, 23 developed Hodgkin's disease following a recent pregnancy. Thirty-four of the 84 women pregnant in association with Hodgkin's disease also had had previous pregnancies. Previous pregnancies did not afl'ect the survival time (median, 57 months). Since the survival curves in Hodgkin's disease are skewed by the long-term survivors, median values have more significance than mean values. Fig. 2 presents survival curves for the total group of patients, for those patients who had pregnancies in association with Hodgkin's disease, and for the age-corrected control group of patients who had no pregnancies after onset of illness. The survival curve and the median survival time of 90 months in the group with pregnancy in association with Hodgkin's disease compare favorably with the findings for the total group (median survival, 59 months) and the age-corrected nonpregnant control group (median survival, 52 months). Onset during pregnancy. Some authors have felt that the onset of Hodgkin's disease during pregnancy adversely affected sur-
449
vival. 5 • 7 • 8 • 10 • 15 • 22 Thirty-four patients in our series had the onset of Hodgkin's disease during pregnancy. These patients had a me. dian survival of 73 months. Twenty-three patients developed Hodgkin's disease following a recent pregnancy. Their median survival was 49 months. This difference is not statistically significant ( t = 1.8) . Combined, this group of patients with onset of Hodgkin's disease intimately associated with pregnancy had a normal survival curve (median survival, 64 months) . Effect of interruption of pregnancy on survival. One of the questions we attempted to resolve was whether or not therapeutic abortion would favorably influence the survival of pregnant women with Hodgkin's disease. 5 • 11 • 12 • H, 21 In our series, 25 pregnancies were interrupted; 9 were terminated by spontaneous abortion and 16 by therapeutic abortion. All these occurred in patients who had become pregnant after the onset of Hodgkin's disease. Of the total 112 pregnancies, 79 yielded normal term deliveries and 3 ended in stillbirths. The group of pregnancies commencing after onset of disease (that is, eliminating cases pregnant during onset) included 51 normal full-term deli\·eries. These 51 were compared with the 25 interrupted pregnancies. The 2 groups were not wholly comparable because therapeutic abortions were carried out in some of the more severe cases. However, it was hoped that survival times for the 2 groups starting from the date of onset of pregnancy would demonstrate a difference. No such difference in survival was found. Instead, the curves are remarkably similar (Fig. 3). One is im-
Table IV. Hodgkin's disease m association with pregnancy (84 cases), outcome of 112 pregnancies Classification of disease at time of pregnancy
Class I Class II (all above diaphragm) Class III Unknown Total
Normal full-term delivery
Stillbirth
ISponta~eousl Therap~utic I Unknown abort1on abortion
21 40
18
6 2
0
0
9 7
2
Total
23 58
2
:~o
5
112
1
1
450 Barry, Diamond, and Craver
August 15, 1962
Am.
pressed by the longevity in both groups. The median survival after conception was 50 months for the interrupted pregnancy groups and 60 months for the normal delivery group. The median total survival times from onset of clinical symptoms were 110 months and 103 months for the 2 groups, respectively. A few patients with multiple pregnancies appeared in both groups. Activation of disease in association with pregnancy. A flow sheet for the 228 patients having no pregnancies in association with Hodgkin's disease was prepared in the same manner as demonstrated by Fig. 1. From it, the chances of activation of disease in nonpregnant women could be determined. The results were compared with similar data obtained from the pregnancy patients. Forty-four of the nonpregnant patients had quiescent disease during the second year of illness. Fifty-five per cent of these had an exacerbation of symptoms during the next 12 months. Of the pregnancy patients, 12 had quiescent disease during the second year of illness and then became pregnant. In 2 patients, disease activated during pregnancy and in an additional 4 it activated in the postpartum period. In 19 patients enjoying a year of quiescent disease and then becoming pregnant, 5 had activation of disease during pregnancy and ,4 in the postpartum period making a total of 4 7 per cent against an expected rate of 30 per cent in the con-
2
3
4
5
6
7
8
9
~
11
J. Obst. & Gynec.
trol subjects. This difference is not statistically significant. These data indicate that the frequency of exacerbations of disease is not increased by pregnancy, however, the exacerbations tend to be concentrated in the postpartum period. Is activation of Hodgkin's disease in pregnancy a grave omen? Table V lists the 31 women who entered pregnancy with quiescent disease. In 15, disease activated and in 16 it did not. The survival times to June, 1959, are as good for the group that activated as for the group that remained quiescent and again the longevity is striking. One should note, however, that 12 of the 16 patients whose disease remained quiescent are living, 8 of these without evidence of disease. Ten of the 15 whose disease activated are dead and only 1 is without evidence of disease. For some reason, the cases of those patients whose disease remained quiescent are of a more recent vintage. Table V also lists patients entering pregnancy with active disease. These have a shorter survival than those entering pregnancy with quiescent disease. Patients with active disease, however, would be expected to survive less longer than those with quiescent disease as can be seen in Fig. I. Treatment during pregnancy. Most of the women with active disease during pregnancy had disease activity above the diaphragm; this was treated with ionizing radiation,
2
YE.'AR OF IUNE.'SS FROII CLINICAl. ONSET OF SYAII'TlliiiS
Fig. 2. Survival curves for the total group of patients, for those who had pregnancies in association with Hodgkin's disease, and for the age-corrected control group who had no pregnancies after the onset of illness.
Volume84 Number4
Influence of pregnancy on Hodgkin's disease
C~Si£1 11A~I'Wf
451
I'I.Jll f(lfi/A Q((IV(IflfS
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Si .. lltiR CUES II'MOS£ "11£10/VAIOC~ 'oll'(fl€ 1/VTfl/fluf"TCO ~ITHffl IY $1"0Ntll/ii£01JS 011 fN[If,«f>CIITI' ABOimOI\IJ (l,CAf£$J
Fig. 3. Survival curves for the group having full-term deliveries and the group in which pregnancies were interrupted by either spontaneous or therapeutic abortions.
shielding the abdomen. Standard doses were employed without any apparent adverse effects on the fetus. Systemic agents were withheld except in one notable case where a dose of 0.3 mg. per kilogram of nitrogen mustard was administered to a patient with an unrecognized 2 month gestation. Pregnancy carried to term and a healthy baby was born who was living and well at 2 months of age. Unfortunately, the child was then lost to follow-up. Outcome of pregnancy. As shown in Table IV, 91 pregnancies were allowed to proceed uninterrupted in which the outcome of pregnancy is known. Seventy-nine resulted in viable infants. No cases of Hodgkin's disease were observed in the infants and, where follow-up data were available, no disease patterns in the children born of mothers with Hodgkin's disease emerged. Long-term survivals. Of the 347 patients in the study group, 54 survived more than 10 years. Of these, 27 presented initially with Class I disease, 21 with Class II, and 6 with Class III disease. There were 52 cases of Hodgkin's granuloma, 1 of Hodgkin's paragranuloma, and 1 Hodgkin's sarcoma. This last case was a 19-year-old woman who presented initially with mediastinal and cervical disease in September, 1947. A diagnosis of Hodgkin's sarcoma was established by cervical node biopsy the following month. She survived 122 months, finally dying of the disease.
YEAR$ AFTER CONCEPTION
If pregnancy has a detrimental effect on survival, one might expect fewer pregnancies in the group of long-term survivors than in the group as a whole. Actually 3 of the long-term survivors developed Hodgkin's disease following a recent pregnancy, 3 were pregnant during the onset of Hodgkin's disease, and 19 became pregnant after the development of disease. Twenty-two of the 54 were pregnant a total of 34 times in association with Hodgkin's disease. This is a higher incidence of pregnancy than in the shorter-term survivors. Ten of the 54 women are now living and without evidence of disease. Nine of these have been without evidence of disease since the end of the second year of illness. Twelve are living with disease and the others are dead. One patient died without evidence of clinical disease but there was no postmortem confirmation. Comment
The present study fails to demonstrate any adverse effect of pregnancy on either the course or longevity of patients with Hodgkin's disease. The fact that patients frequently have exacerbations of their disease in the postpartum period is borne out but the explanation seems to lie in the fact that active disease is frequently masked during pregnancy itself, probably by hormonal factors, only to make itself known in the postpartum period. The incidence of ex-
452
Augu . . 1 EL 196:!
Barry, Diamond, and Craver
"'"· .I.
Oh.-:. & ( ;YIWC.
Table V. Hodgkin's disease and pregnancy: survival in patients becoming pregnant after onset of disease ~-,,-~~~--------
- - - - (:tassifica-j Date of tion of 1 last Estimated disease at follow-up time of date of conception pregnancy (to 6/59)
---
~--------------
I
---------
I Survival
I I
Outcome of pregnancy
from date of , conception I (months)
Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Therapeutic abortion Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-tenn delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery
82 90 125 63 102 22 13 56 74 98 33 235 40 {5 70
I
Status of patient
Disease quiescent prior to onset of pregnancy and then activating 4/55 Dead of disease III 6/48 4/59 Living, with disease II 10/51 12/51 Dead of disease I 5/40 8/35 Dead of disease .'i/30 III 11/56 Dead of disease II 5/48 2/49 4/47 Dead of diseaJe III 6/59 Living, with disease II 5/58 10/53 Living, with disease II 2/49 11143 Dead of disease II 9/37 7/58 Dead of disease II 5/50 Living, no evidence of disease 2/58 I 5/55 7/47 Dead of disease II 12/27 7/49 Dead of disease II 3/46 Living, with disease 6/59 III 9/55 6154 Dead of disease II 8/48 Median survival
70
Disease quiescent prior to onset of pregnancy and remaining inactive 9/56 Living, no evidence of disease Normal full-term delivery II 6/55 Living, no evidence of disease Normal full-term delivery 4/58 II 9/55 6/59 Living, with disease 7/57 Spontaneous abortion II 9/56 II Living, no evidence of disease Normal full-term delivery 6/54 6/59 II Living, no evidence of disease Normal full-term delivery 6/57 4/58 7/50 II Living, no evidence of disease Normal full-term delivery 7/55 7/49 II Dead of disease Normal full-term delivery 6/59 Living, with disease 6/51 Spontaneous abortion II 6/59 Living, no evidence of disease Spontaneous abortion 7/52 II Living, no evidence of disease 11/58 I 6/53 Stillbirth Living, with disease 6/59 Normal full-term delivery II 6/54 5/58 Dead of disease Therapeutic abortion II 1/52 3/56 Dead of disease Normal full-term delivery II 2/50 Dead of disease Normal full-term delivery 4/55 I 5/47 11/55 Living, with disease Therapeutic abortion II 6/53 Living, no evidence of disease 10/58 Spontaneous abortion 6/4-7 I Median survival Active disease prior to the onset of pregnancy 6/59 Living, no evidence of disease II 4/42 4/59 7/49 Living, with disease II 3/59 Dead of disease III* 12/38 7/48 Dead of disease 6/44 III 11/40 Dead of disease 11/36 II 7/58 10/53 II Dead of disease 1/50 Dead of disease 11/43 I Dead of disease 2/4-6 1/29 I Dead of disease 2/46 6/35 III 7/55 4/54 II Dead of disease 12/47 Dead of disease 7/46 II 6/56 6/57 III Dead of disease 4/58 Dead of disease 9/50 II Dead of disease 2/45 III 2/47 1!/45 II 9/51 Dead of disease 4/37 III* 8/37 Dead of disease 8/56 III* 12/56 Dead of disease 5/53 6/51 III* Dead of disease 6146 2/47 Dead of disease III
Normal full-term delivery Normal full-term delivery Therapeutic abortion Nonnal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Normal full-term delivery Therapeutic abortion Normal full-term delivery Normal full-term delivery Normal full-term delivery Spontaneous abortion Normal full-term delivery Normal full-term delivery Spontaneous abortion Therapeutic abortion Therapeutic abortion Therapeutic abortion
15
31
23 27 24
93 72 96 83 65 60 76 73 96 29 136
69
206 118 3 49 48 57 74 205 128 15 17 60 91 24 70 4
4 23 8
Volume 84
Influence of pregnancy on Hodgkin's disease
Number4
Table V-Cont'd Classification of Estimated disease at time of date of conception pregnancy
7/42 1/25 8/46 2/52 8/53
9/49 3/45 1/45 4/47 4/48 3/46 6/49 2/39 1/50
II II
III* II III
III III II III* III II
III* III II Median survival
..----..··-Date of last follow-up (to 6/59)
8/55 2/31 5/53 4/54 10/57 7/54 2/49 2/57 1/52 8/49 8/47 5/53 2/41 2/57
Status of patient
Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead Dead
of of of of of of of of of of of of of of
disease disease disease disease disease disease disease disease disease disease disease disease disease disease
Outcome of Pregnancy
Spontaneous abortion Normal full-term delivery Normal full-term delivery Therapeutic abortion Normal full-term delivery Unknown Therapeutic abortion Therapeutic abortion Therapeutic abortion Normal full-term delivery Spontaneous abortion Spontaneous abortion Stillbirth Therapeutic abortion
453
Survival from date of conception (months)
157 73 81 26 50 58 47 145 57
16
17 47 24 85 50
*With extensive abdominal involvement.
acerbations during a 9 month period of pregnancy plus a 3 month postpartum period is not greater than that which would be expected during a comparable 12 month period in a group of nonpregnant women. The study also shows that activation of Hodgkin's disease during pregnancy in itself does not prevent long survivals. While pregnant patients have longer survivals than nonpregnant patients, we feel that this is a result of a more favorable state of health in women able to conceive. Others might interpret this finding differently. Therapeutic abortion could not be demonstrated to produce any favorable effect on the course of Hodgkin's disease. Our find~Y"t#"''t' .l.l.L5~
nrrn1l,l YYVUJ.U
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served for desperate cases in which pregnancy prevents the use of effective therapy in the mother. The patient already pregnant, therefore, can be reassured that pregnancy will not affect her survival. Nor is there evidence that it will affect the health of the infant. But what should one say to the young woman with Hodgkin's disease who wants to become pregnant? Advising the young woman suffering from an incurable disease but deeply desirous of having children is difficult
at best. Even though pregnancy itself may do no demonstrable harm, the morbidity of the disease itself must be taken into consideration. Certain facts emerge from this study which should be of help in dealing with such Hodgkin's disease sufferers. Certainly a woman with active disease during the first and second year of illness should be advised against entering pregnancy. This study shows that these patients are faced with the prospect of repetitive bouts of sickness even if they survive for long periods. The patient whose disease is inactive or who has recently become afflicted should be urged to wait until the disease has been inactive for a 2 year period. A single year of quiescence is not long enough. By waiting until the conclusion of the proper period of quiescence, she can then look forward to a 75 per cent chance of long survival and a 50 per cent chance of a long period in relative good health regardless of pregnancy. One must interject a note of caution, however. The effect of pregnancy on the individual patient can never be determined by a study of this sort. There are 2 patients in our series each of whom twice experienced exacerbations of their disease with pregnancy after periods of greater than 3 years' quiescence. Both, fortunately, were long-
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Barry, Diamond, and Craver
term survivors, but in these individuals' cases morbidity may have been increased. Such instances must be weighed against the individual patient's desire for children. Summary
The charts of 347 patients with Hodgkin's disease treated at the Memorial Hospital for Cancer and Allied Diseases and the James Ewing Hospital (New York) were analyzed. All were women in the childbearing age group. The mean survival time of these patients was almost 5 years. Sixteen per cent survived 10 or more years. Active disease during both the first and second years of illness carried a grave prognosis in terms of morbidity and mortality. The most favorable course was in those patients whose disease was quiescent through the second and third years of illness.
REFERENCES
1. Eichel, J.: Acta radio!. 33: 427, 1950. 2. Craver, L. F.: Cancer 7: 927, 1954. 3. Frank, H. G.: J. Obst. & Gynaec. Brit. Emp. 62: 266, 1955. 4. Genunel, A. A.: J. Obst. & Gynaec. Brit.
Emp. 30: 373, 1923. 5. Gilbert, R.: Acta radio!. 35: 71, 1951. 6. Goldman, L. B., and Victor, A. W.: New York J. Med. 45: 1313, 1945. 7. Hartvigson, B.: Acta radio!. 44: 317, 1955. 8. Hartweg, H., and Braun, H.: Strahlentherapie 94: 213, 1954. 9. Hennessy, J. P., and Rottino, A.: AM. J. 0BST. & GYNEC. 63: 756, 1952. 10. Hultberg, S.: Acta radio!. 41: 277, 1954. 11. Jackson, H., and Parker, F.: Hodgkin's Disease and Allied Disorders, Oxford, 194 7, Oxford University Press, pp. 91-92. 12. Kasdon, S. C.: AM. J. OusT. & GYNEC. 57: 282, 1949. 13. Merrill, D.: In Daland, E. M., editor: Cancer, a Manual for Practitioners, ed. 3, Boston. 1956, American Cancer Society (Massachusetts Division), pp. 218-219.
August 15, 1962 Am. J. Obst. & Gyncc.
Eighty-four women in the group had a total of 112 pregnancies. Pregnancy did not adversely affect mean survival time. The incidence of activation of disease in association with pregnancy was not greater than that expected in nonpregnant women during a comparable period of time; however, the exacerbations tended to crowd into the postpartum period. Activation of disease with pregnancy did not demonstrably shorten survival times. Therapeutic abortion had neither a favorable nor an adverse effect. Women desirous of pregnancy should be urged to wait until they have had quiescence of disease for at least 2 years. Patients with active disease should be advised against pregnancy, not because of any adverse effect of pregnancy on the mother or danger to the fetus, but because of the poor prognosis in the mother.
J. M.: J. Obst. & Gynaec. Brit. Emp. 62: 884, 1955. Papillon, J., and Chavanne, G.: ]. med. Lyon 31: 127, 1950. Perrier, H.: Schweiz. med. Wchnschr. 75: 1014, 1945. Peters, M. V., and Middlemiss, K. C. H.: Am. ]. Roentgenol. 79: 114, 1958. Portmann, U. V., and Mulvey, B. E.: Cleveland Clin. Quart. 17: 149, 1950. Riva, H. L., Andreson, P. S., and O'Grady, J. W.: AM. J. 0BST. & GYNEC. 66: 866,
14. Myles, T.
15. 16. 17.
18. 19.
1953. 20. S!:'lvaag, 0.: Nord. med. 47: 188, 1952.
21. Smith, R. B. W., Sheehy, T. W., and Rothberg, H.: A. M. A. Arch. Int. Med. 102: 777, 1958.
22. Southam,
C. M., Diamond, H. D., and Craver, L. F.: Cancer 9: 1141, 1956. 23. Stewart, H. L., and Manto, R. W.: AM. J. OnsT. & GYNEC. 63: 570, 1952. Memorial Hospital for Cancer and
Allied Diseases
New York 21, New York