Acta neurol. scandinav. 59, 108-118, 1979 Department of Neurology, University of Gottingen Department of Neurology, Kommunehospitalet, Copenhagen Department of Neurology, University of Helsinki
Pregnancy, oral contraceptives and multiple sclerosis* SIGRIDPOSER,N. E. RAUN,J. WIKSTROM AND W. POSER
All female patients with Multiple Sclerosis (MS) from an epidemiological area of Southern Lower Saxony completed a questionnaire in connection with a standardized neurological examination. The family status of these 179 patients differed significantly from the expected distribution. MS patients were more often single (observed 24, expected 16.5) and divorced (observed 13, expected 5.3). The degree of disability was higher and the duration of the disease longer for the group of divorced patients. Married, widowed and divorced patients had a lower mean number of children (1.63) than would be expected from the general population (1.91). This difference results from a higher percentage of married women without any children and from the small number of families with more than three children. 204 out of 250 children were born before disease onset, 46 during the disease. The percentage of spontaneous abortions and congenital malformations was similar for the pregnancies before and during the disease. 46 % of the patients in the reproductive age used contraceptive methods, most often oral contraceptives (21 %). The influence of pregnancy and oral contraceptives on the course of the disease was investigated in 446 female patients. In addition to the 179 patients mentioned above, the data of 267 female patients could be gained from a central data pool. In the whole material neither pregnancy nor oral contraceptives had an effect on prognosis - defined as the degree of disability reached after a known period of illness. The patients with pregnancy before disease onset and intake of oral contraceptives during the disease exhibited a higher degree of disability compared to the corresponding groups of “no pregnancy” and “pregnancy during the disease”. Young patients seemed less disabled when taking the pill, a finding which needs further prospective investigation. K e y words: Family status tives - pregnancy
*
- fertility - multiple
sclerosis - oral contracep-
Dedicated to Prof. H. J. Bauer on the occasion of his 65th birthday. 0001-6314/79/020108-11$0.2.50/0 @ 1979 Munksgaard, Copenhagen
109 The possible influence of gestational processes on the course of Multiple Sclerosis (MS) is of interest for two reasons: Young females are more often affected by the disease than any other age group. Therefore, marriage, pregnancy and birth control are practical problems in clinical work. On the other hand, essential features of the disease such as the preponderance of females are still poorly understood. Little research activity has been concentrated on this aspect lately, though it might contribute to our pathogenetic understanding of the disease process. In the literature, case histories on a negative influence of pregnancy on MS prevail. The retrospective studies performed on larger groups of patients yielded conflicting results: Whereas Miiller (1959), Tillman (1950) and McAlpine & Compston (1952) could not find an important influence of pregnancy and child birth on the relapse rate, Millar et al. (1959) found an increase in the attack rate during the 3 months after delivery. Leibowitz et al. (1967) reported on an increased risk of first symptoms to appear during the 2 years following pregnancy. The results of the last two studies favor the view that these exacerbations are “anticipated” and do not influence the overall prognosis. Married women with pregnancies were found to be even less disabled when reexamined in comparison to single women (Millar 1961). In contrast to these results, Schapira et al. (1966) found an increased relapse rate in women with a history of pregnancies and women with onset of illness after pregnancy were more disabled than married women without pregnancies. The possible role of sex hormones has been discussed in this context but no systematic study is available on this subject. Similarly, a possible influence of oral contraceptives on MS has been assumed, but only case histories have been published (McFarland 1969). Other diseases, which have some features in common with MS are better investigated and might yield some analogies. In experimental allergic encephalomyelitis oral contraceptives (ethinyl estradiol and melengestrol acetate) showed prophylactic or therapeutic activity (Arnason & Richman 1969, Greig et al. 1970, Elliott et al. 1973) in animals. The use of oral contraceptives reduced the incidence of rheumatoid arthritis (prospective study of the Royal College 1978), probably by suppression of cell-mediated immunity. An influence of oral contraceptives on the cellular limb of the immune system was demonstrated by Barnes et al. (1974). It is of interest whether the cell-mediated immune processes which are known to be disturbed in MS (for a review see Knight 1977) are similarly influenced by the use of oral contraceptives. There is only little information on basic female-specific data of MS patients (Heier 1973). Does the disease influence the family status, the fertility
110
and the contraceptive behavior of the women? Is the rate of miscarriages and/or malformations increased in MS? In spite of the well-known disadvantages of retrospective studies we decided to analyze the problems involved in a well-defined MS population. We did not expect the results to be decisive in all points but they should help us to ask the (questions more precisely and to plan a prospective study more effectively. METHODS
In the epidemiological area of Southern Lower Saxony (Wikstriim et al. 1977) all patients were reexamined during the period 1975-1977. At that time the area included six counties which are no longer under investigation. The relevant data from the medical history and the actual physical findings were recorded with a standardized documentation system (Poser 1978). Together with the invitation to the examination, a questionnaire was sent to all female patients (N = 189). They were requested to mark the correct answers to the 57 questions on the data sheet at home and return it to the physician at the time of examination. In case of difficulties encountered the questionnaire was completed with his help. Thus, the gynaecological and obstetrical history of 179 female patients could be correlated to the medical history, the physical findings and the present disability. The analysis of these data was informative for basic data such as family status, number of living children, frequency of abnormal reproductive processes, etc. These figures are representative for patients with MS because nearly all women of a defined area were reexamined. Those who were too disabled to come to the clinic were visited at home or in their nursing homes and the questions were presented orally to them in case they could not read or write. Only five patients refused to answer, two patients were confused and three questionnaires were lost. Some patients did not complete the questionnaire or they misunderstood the ‘questions, therefore N is for some items less than 179. The expected numbers of single, married, widowed and divorced women adjusted for age and sex were computed from the population of Lower Saxony (3,711,000 women see Statistisches Bundesamt 1974). In a similar way, the expected numbers of children for the married, widowed and divorced women were computed. For the questions concerning pregnancy and the use of oral contraceptives in relation to disability, the figures proved to be too small for statistical analysis and therefore the study was extended. The data stored in a documentation pool (Poser 1978) offered the possibility t o select the patients according to the items pregnancy no-yes and oral contraceptives no-yes. All females with a positive answer to one of these items were sent to the above-mentioned questionnaire. The patients were grouped according to the answers: no pregnancy pregnancy before disease onset pregnancy during the disease.
Within these groups patients who had never taken oral contraceptives were called “no pill” and patients who had taken them during their disea:e for at least 3 months were called “with pill”. Women who had taken the pill only before disease onset or less than 3 months were omitted (N = 17) because it was not possible to build extra groups for
111 this small number. Twenty-five patients who were pregnant before and during the disease were randomly allocated to one of the groups in question. Duration of the disease, present age and present degree of disability were known for all patients. Thus, a further grouping could be performed according to the duration of the disease: 0-4, 5-9, 10-14, more than 14 years for all females (N = 446). Patients recorded during an acute bout of their disease were excluded from the study. Their present performance would reflect the severity of the bout rather than their permanent disability which is used as a parameter for prognosis in this study. The number of bouts does not influence the overall prognosis (Fog & Linnemann 1970), therefore a detailed analysis of the bout frequency and relation to pregnancy andlor intake of oral contraceptives was not performed. To get an impression of the patients’ own judgment on their condition, bouts and deterioration during or after the times of hormonal fluctuation were registered in the questionnaire. The patients were informed about the scientific aspect and anonymous handling of the data. They did not know what was expected from the study. The data from the history and the physical findings were recorded on two optical mark reader sheets, transferred to three punched cards by an IBM optical mark reader 1232 and fed into an IBM 370/158 computer. For the description of the program for data analysis see Poser & Brauns (1974). The disability grade of the patients was based on the scale of Kurtzke (1961). The statistical analysis of the data was performed by application of SPSS programs (Nie et al. 1975) at the computer center of the University of Copenhagen. Though disability is a variable between the ordinal and interval level with 10 different values (0-9), gaussian statistics have been applied. This is justified by the distribution of observations of disability (N = 446, mean = 4.44, median = 4.72, S.D. = 2.36). As analysis of variance (ANOVA) is not too sensitive to moderate deviations from normality, a three-way ANOVA with one covariate model has been set up. Effect of covariation of age with disability is first excluded and hence the effects of the three factors: use of contraceptives, history of pregnancy and duration of disease are estimated separately.
RESULTS
A total of 179 female patients completed the [questionnaire in connection with the clinical examination in our department or at home (epidemiological group). These 179 patients had a mean present age of 43.5 years (range 20-73). The mean duration of their disease was 13.2 years; the mean degree of disability was 3.55. The family status of 176 women is shown in Table 1. The comparison of the observed numbers of single, married, widowed and divorced women with the expected numbers (computed for similar age groups of the general population of Lower Saxony) shows significant differences: MS patients are more often single and divorced, less often married and widowed. The mean number of children was 1.4 for all women and 1.63 for married, widowed and divorced women. Five women did not have children because of their disease and five women would have preferred not to have chddren because of their disease. The expected mean number of children for married,
112 Table 1 . Observed and expected family status of female MS patients ( N = 176, status o f three patients unknown) ~~~~
Observed Single Married Widowed Divorced
~
~
Expected
24 128 11 13
16.54 135.42 18.73 5.31
I
P
< 0.0005
f test
widowed and divorced women was computed from the general population to be 1.91. The pattern of children is shown in Figure 1 for married, widowed and divorced women (N = 152) and compared to the expected numbers of the general population. More women with MS had no children and two children, whereas women from the general population had more often one child and more than three children; 204 of the 250 children alive were born before disease onset, of these, nine (4.4 %) had congenital malformations; 36 spontaneous abortions (18 % of live births) occurred before disease onset. Forty-six children were born after disease onset, two of these (4.3 %) were malformed. Eight spontaneous abortions (17 % of live births) occurred during the disease, seven interruptions were performed. During one pregnancy after disease onset an exacerbation was recorded, in three cases an improvement. In eight cases a deterioration occurred after
:I_ number of women
[? observed
0 expected n
30
20
10
0
1
2
3
number of children
Figure 1. Observed and expected number of married, divorced or widowed female MS patients ( N = 152) with 0, I , 2, 3, 4 and > 4 children,
113 Table 2 . Present method of contraception used by 92 women with multiple sclerosis aged between 20 and 45 years
None Oral contraceptives Sterilization Condom of the partner Intrauterine device Vaginal creams and gels Basal temperature recording Coitus interruptus Others
N
%
50 19 5 3 2 1
54 21 5 3 2 1
e, e,
e, e,
12
13
Table 3. Reason f o r taking oral contraceptives at any time during the course of multiple sclerosis ( N = 46)
Contraception (own decision) Contraception (advice from doctor) Disturbance of menstruation Multiple sclerosis Other reasons Unknown
N
%
24 8 4 2 2 5
54 17 9 4 4 11
childbirth (seven cases up to 3 months, one case between 3 and 6 months after delivery). The disease started during a pregnancy in six cases, in 13 cases up to 6 months after childbirth. The method of contraception currently used by 92 patients in the reproductive age is shown on Table 2. 54 % did not use any protection, 21 % used oral contraceptives. Figures for the general population are known for the intake of oral contraceptives (30 %, Wenig 1974), but not for the other methods. Only two patients were taking the pill because of their disease, the rest for contraception or other reasons (Table 3). Forty-six patients took oral contraceptives at some time during their disease for more than 3 months. Three of these stated a deterioration, nine an improvement and six the beginning of the symptoms during the use of oral contraceptives. In no case was an onset or deterioration after discontinuation of the pill (up to 4 weeks) observed. For the analysis of prognosis the data of 446 females were available (179 epidemiological patients and 267 women from the general data pool).
8 Acta neurol. scandinav. 592'3
114
0
grade of
no oral contraceptives
c]with no pregnancy
oral contracept I ves
5
4 3 2 1
I
pregnancy during the disease
N.li
Figure 2 . Mean disability of 446 female MS patients. Comparison of groups with the variables: duration of disease (years), history of pregnancy and use of oral contraceptives.
Comparison of the present disability reached after a defined period of time is shown in Table 4 and Figure 2 for groups with the variables: duration of disease, history of pregnancy and use of the pill. Mean values of observed degrees of disability in the different groups are given in the left column of Table 4.When these as result of analysis of variance are adjusted for age (accounting for 7 % of the total variation, P < 0.001) and the other independent variables, there is no significant effect of taking oral contraceptives nor of history of pregnancy (P = 0.999), but a significant effect of duration of disease ( P < O.OOl), accounting for additionally 6 % of the total variation. The only two-way interaction of statistical significance was found between the factors: use of oral contraceptives and history of pregnancy, showing a relatively high disability for those women who had been pregnant before the beginning of MS and were taking oral contraceptives. In patients who had never been pregnant, the pill users seemed to be less disabled than the non-users in all groups of disease duration. This differnce reached statistical significance in a preliminnray study when considering only patients under the age of 30 (Poser & Wikstrom, unpublished data). The
115 Table 4. Disability
Factors
N
Mean values of observations
Mean values corrected for age andthe other factors
Contraceptives
Not taken Taken
345 101
4.62 3.83
4.48 4.31
167
4.54
4.62
Pregnant
Never Before start of MS During course of MS
222
4.38
4.32
57
4.39
4.38
62 128 102 154
2.79 4.08 4.56 5.33
3.05
Duration of MS
1-4 years 5-9 " 10-14 " 2 15 "
4.20 4.61 5.09
Level of significance P
0.999
0.999
< 0.001
significance disappeared in the whole material when correction for age and duration was performed. Altogether it follows from our data of the whole material that women with a history of pregnancy before or during the disease have an overall prognosis similar to women without pregnancies, and women taking oral contraceptives during their disease reach a degree of disability comparable to patients who never took them. DISCUSSION
In a representative sample of 179 women with MS, the family status was different from the general population: The observed number of single and divorced women was higher than expected; this demonstrates that MS has a negative influence on contraction and stability of a marriage. The figure of 7.4 % divorced women (vs. 3.0 % expected) agree well with Heier's data (1973). The degree of disability was found to be higher for the 13 divorced women (5.0 vs. 4.0 for the marriaged and widowed) and the mean duration of the disease longer (17.5 vs. 12.8 years). Thus, marriages are at risk with increasing disability of the women. Women with MS have fewer children than would be expected (mean number 1.63 vs. 1.91). This difference results from the high percentage of women without any children and from the small number of families with more than three children. From our data it is known that five out of 152
116 women did not want to have children because of their disease, seven pregnancies were interrupted during the disease and five women had a sterilization performed. We conclude that MS does not influence the biological fertility but favors the decision not to have (more) children. The frequency of malformations was similar for children born before and during the disease (4.4 and 4.3 %) and did not differ from the rate in non-MS children (review see Janz 1978). The ratio of spontaneous abortions was not different for pregnancies before and during the disease. In addition to the spontaneous abortions, seven interruptions were performed during the disease. With better contraceptive advice, interruption should become a rare event. At the present time 54 % of the women with MS between 20 and 45 years of age did not use any contraceptive method and only 21 % used oral contraceptives. This relatively low figure (general population 30 %) might reflect the fear that their disease could get worse by taking the pill. Our data suggest that this fear is not justified. In case there is a contraindication for oral contraceptives an alternative method should be recommended. Some of the patients reported an exacerbation (one case) or an improvement (three cases) during pregnancy or shortly after childbirth (eight deteriorations). During the use of oral contractptives three got worse, nine improved. The statistical analysis of the data for 446 women with MS revealed, however, that pregnancy and the use of oral contraceptives had no substantial influence on the overall prognosis. For pregnancy these data stand between the findings of MiZZar (1961) who found a better prognosis for women with pregnancies and Schapira et al. (1966) whose patients with pregnancies were found to be more disabled than women without pregnancies. For the oral contraceptives no comparable data are known from the literature. Though oral contraceptives have no effect on disability in the whole material, two groups show a different pattern: Women taking the pill and having a history of pregnancy before disease onset exhibit a higher degree of disability compared to the corresponding groups of “no pregnancy” and “pregnancy during the disease”. This difference is most prominent for the group with short duration of the disease. Further prospective investigation is needed to find out whether this ditlerence is real or accidential. In the younger age groups, users of oral contraceptives were less disabled than non-users. This corresponds to the subjective judgment of the patients (nine improvements vs. three deteriorations during the use of oral contraceptives). This might mean only that less disabled women take the pill more often and heavily disabled do not need such a protection. Our data do not support this explanation, because most of the young patients - whether users or non-users - were distributed among the lower degress of disability which
117
'
would not prevent sexual intercourse. Other factors might have influenced the decision to take oral contraceptives and the type and duration of oral contraceptives used might be important. We could not include these variables because of the small numbers within the groups. By the present data it cannot be excluded that oral contraceptives have a positive influence on early MS in women. In analogy to the findings in experimental allergic encephalomyelitis and in rheumatoid arthritis one could speculate that the influence of oral contraceptives on the cellular immune system, which is involved in the pathogenesis of MS (see Knight 1977) alters the early course of the disease. Two kinds of prospective studies are warranted for the problems in question: 1. The incidence of MS in a population of users and non-users has to be determined in an approach similar to the study of the Royal College of General Practitioners. 2. Patients with early MS with different methods of contraception should be followed prospectively. From the statistician's point of view the patients must be allocated to the different forms of contraception randomly. The oral contraceptive taken should be standardized and no difference in other medications should be allowed. This is hardly feasible and therefore the patients have to be matched as carefully as possible. The follow up should include not only clinical symptoms and disability scores but a whole battery of immunological tests in order to elucidate the influence of oral contraceptives on the immune system. As long as these studies are not available, patients can be reassured that their overall prognosis does not change by pregnancy or by taking oral contraceptives. ACKNOWLEDGMENTS This work was supported by the Deutsche Forschungsgemeinschaft. The authors thank Prof. Bauer for giving the stimulation for this study and Mrs. Eckhardt for assistance with the manual handling of the data. REFERENCES Arnason, B. G. & D. P. Richman (1969): Effect of oral contraceptives on experimental demyelinating disease. Arch. Neurol. 21, 103-108. Barnes, E. W., A. C. MacCuish, N. B. Loudon, J. Jordan & W. J. Irvine (1974): Phytohaemagglutinin-induced lymphocyte transformation and circulating autoantibodies in women taking oral contraceptives. Lancet I, 898-900. Elliott, G. A., A. J. Gibbons & M. E. Greig (1973): A comparison of the effects of melengestrol acetate with a combination of hydrocortisone acetate and medroxyprogesterone acetate and with other steroids in the treatment of experimental allergic encephalomyelitis in Wistar rats.. Acta Neuropath. (Berl.) 23, 95-104.
118 Fog, T. & F. Linnemann (1970): The course of multiple sclerosis. Acta Neurol. Scand. 46, Suppl. 47, 1-175. Greig, M. E., A. J. Gibbons & G. A. Elliott (1970): A comparison of the effects of melengestrol acetate and hydrocortisone acetate on experimental allergic encephalomyelitis in rats. J. Pharmacol. Exp. Therap. 173, 85-93. Heier, D. (1973): Die Lebenssituation von Multiple Sklerose-Kranken. Gerhards u. Co, Frankfurt. Janz, D. (1978): Haben Antiepileptika eine teratogene Wirkung beim Menschen? Deutsch. med. Wschr. 103, 485-487. Knight, S . C. (1977): Cellular immunity in multiple sclerosis. Br. Med. Bull. 33, 45-50. Kurtzke, J. F. (1961): On the evaluation of disability in multiple sclerosis. Neurol. 11, 686-694. Leibowitz, U., A. Antonovsky, R. Kats & M. Alter (1967): Does pregnancy increase the risk of multiple sclerosis? J. Neurol. Neurosurg. Psychiat. 30, 354-357. McAlpine, D. & N. Compston (1952): Some aspects of the natural history of disseminated sclerosis. Quart. J. Med. 21, 135-167. McFarland, H. R. (1969): The management of multiple sclerosis. Miss. Med. 66, 209-211. Millar, J. H. D. (1961): The influence of pregnancy on disseminated sclerosis. Proc. Roy. SOC.Med. 54, 4-7. Millar, J. H. D., S. Allison, E. A. Cheeseman & J. D. Merrett (1959): Pregnancy as a factor influencing relapse in disseminated sclerosis. Brain 82, 417-426. Miiller, R. (1949): Studies on disseminated sclerosis. Acta Med. Scand., Suppl. 222, 1214. Nie, N. H., C. H. Hull, J. G. Jenkins, K. Steinbrenner & D. H. Bent (1975): SPSS, Statistical Package for the Social Sciences, 2nd ed., McGraw-Hill, New York. Poser, Sigrid (1978): Multiple Sclerosis. Springer, Berlin, Heidelberg, New York. Poser, S. & K.-H. Brauns (1974): Der Einsatz des Markierungsbelegverfahrens im Rahmen einer multizentrischen Studie iiber die Multiple Sklerose. Methods Inf. Med. 13, 70-79. Royal College of General Practitioners' Oral Contraception Study (1978): Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Lancet I, 569-571. Schapira, K., D. C. Poskanzer, D. J. Newel1 & H. Miller (1966): Marriage, pregnancy and multiple sclerosis. Brain 89, 419-428. Statistisches Bundesamt Wiesbaden (ed.) (1974): BevGlkerung und Kultur, Fachserie A, Kohlhammer, Stuttgart, Mainz. Tillman, A. J. B. (1950): The effect of pregnancy on multiple sclerosis and its management. Res. Pub]. Ass. Res. Nerv. Ment. Dis. 28, 548-582. Wikstrom, J., G. Ritter, S. Poser, W. Firnhaber & H. J. Bauer (1977): Das Vorkommen von Multipler Sklerose in Siidniedersachsen. Nervenarzt 48, 494-499. Wenig, Ch. (1974): Zerebrale Ischamie und Ovulationshemmer. Dtsch. Med. Wschr. 99, 1521-1525. 1
Received January 17, accepted February 2, 1979
Prof. Sigrid Poser, M.D. Department of Neurology University of G'ottingen Robert-Kochstr. 40 3400 Gijttingen FRG
Pregnancy, oral contraceptives and multiple sclerosis* SIGRIDPOSER,N. E. RAUN,J. WIKSTROM AND W. POSER
All female patients with Multiple Sclerosis (MS) from an epidemiological area of Southern Lower Saxony completed a questionnaire in connection with a standardized neurological examination. The family status of these 179 patients differed significantly from the expected distribution. MS patients were more often single (observed 24, expected 16.5) and divorced (observed 13, expected 5.3). The degree of disability was higher and the duration of the disease longer for the group of divorced patients. Married, widowed and divorced patients had a lower mean number of children (1.63) than would be expected from the general population (1.91). This difference results from a higher percentage of married women without any children and from the small number of families with more than three children. 204 out of 250 children were born before disease onset, 46 during the disease. The percentage of spontaneous abortions and congenital malformations was similar for the pregnancies before and during the disease. 46 % of the patients in the reproductive age used contraceptive methods, most often oral contraceptives (21 %). The influence of pregnancy and oral contraceptives on the course of the disease was investigated in 446 female patients. In addition to the 179 patients mentioned above, the data of 267 female patients could be gained from a central data pool. In the whole material neither pregnancy nor oral contraceptives had an effect on prognosis - defined as the degree of disability reached after a known period of illness. The patients with pregnancy before disease onset and intake of oral contraceptives during the disease exhibited a higher degree of disability compared to the corresponding groups of “no pregnancy” and “pregnancy during the disease”. Young patients seemed less disabled when taking the pill, a finding which needs further prospective investigation. K e y words: Family status tives - pregnancy
*
- fertility - multiple
sclerosis - oral contracep-
Dedicated to Prof. H. J. Bauer on the occasion of his 65th birthday. 0001-6314/79/020108-11$0.2.50/0 @ 1979 Munksgaard, Copenhagen
109 The possible influence of gestational processes on the course of Multiple Sclerosis (MS) is of interest for two reasons: Young females are more often affected by the disease than any other age group. Therefore, marriage, pregnancy and birth control are practical problems in clinical work. On the other hand, essential features of the disease such as the preponderance of females are still poorly understood. Little research activity has been concentrated on this aspect lately, though it might contribute to our pathogenetic understanding of the disease process. In the literature, case histories on a negative influence of pregnancy on MS prevail. The retrospective studies performed on larger groups of patients yielded conflicting results: Whereas Miiller (1959), Tillman (1950) and McAlpine & Compston (1952) could not find an important influence of pregnancy and child birth on the relapse rate, Millar et al. (1959) found an increase in the attack rate during the 3 months after delivery. Leibowitz et al. (1967) reported on an increased risk of first symptoms to appear during the 2 years following pregnancy. The results of the last two studies favor the view that these exacerbations are “anticipated” and do not influence the overall prognosis. Married women with pregnancies were found to be even less disabled when reexamined in comparison to single women (Millar 1961). In contrast to these results, Schapira et al. (1966) found an increased relapse rate in women with a history of pregnancies and women with onset of illness after pregnancy were more disabled than married women without pregnancies. The possible role of sex hormones has been discussed in this context but no systematic study is available on this subject. Similarly, a possible influence of oral contraceptives on MS has been assumed, but only case histories have been published (McFarland 1969). Other diseases, which have some features in common with MS are better investigated and might yield some analogies. In experimental allergic encephalomyelitis oral contraceptives (ethinyl estradiol and melengestrol acetate) showed prophylactic or therapeutic activity (Arnason & Richman 1969, Greig et al. 1970, Elliott et al. 1973) in animals. The use of oral contraceptives reduced the incidence of rheumatoid arthritis (prospective study of the Royal College 1978), probably by suppression of cell-mediated immunity. An influence of oral contraceptives on the cellular limb of the immune system was demonstrated by Barnes et al. (1974). It is of interest whether the cell-mediated immune processes which are known to be disturbed in MS (for a review see Knight 1977) are similarly influenced by the use of oral contraceptives. There is only little information on basic female-specific data of MS patients (Heier 1973). Does the disease influence the family status, the fertility
110
and the contraceptive behavior of the women? Is the rate of miscarriages and/or malformations increased in MS? In spite of the well-known disadvantages of retrospective studies we decided to analyze the problems involved in a well-defined MS population. We did not expect the results to be decisive in all points but they should help us to ask the (questions more precisely and to plan a prospective study more effectively. METHODS
In the epidemiological area of Southern Lower Saxony (Wikstriim et al. 1977) all patients were reexamined during the period 1975-1977. At that time the area included six counties which are no longer under investigation. The relevant data from the medical history and the actual physical findings were recorded with a standardized documentation system (Poser 1978). Together with the invitation to the examination, a questionnaire was sent to all female patients (N = 189). They were requested to mark the correct answers to the 57 questions on the data sheet at home and return it to the physician at the time of examination. In case of difficulties encountered the questionnaire was completed with his help. Thus, the gynaecological and obstetrical history of 179 female patients could be correlated to the medical history, the physical findings and the present disability. The analysis of these data was informative for basic data such as family status, number of living children, frequency of abnormal reproductive processes, etc. These figures are representative for patients with MS because nearly all women of a defined area were reexamined. Those who were too disabled to come to the clinic were visited at home or in their nursing homes and the questions were presented orally to them in case they could not read or write. Only five patients refused to answer, two patients were confused and three questionnaires were lost. Some patients did not complete the questionnaire or they misunderstood the ‘questions, therefore N is for some items less than 179. The expected numbers of single, married, widowed and divorced women adjusted for age and sex were computed from the population of Lower Saxony (3,711,000 women see Statistisches Bundesamt 1974). In a similar way, the expected numbers of children for the married, widowed and divorced women were computed. For the questions concerning pregnancy and the use of oral contraceptives in relation to disability, the figures proved to be too small for statistical analysis and therefore the study was extended. The data stored in a documentation pool (Poser 1978) offered the possibility t o select the patients according to the items pregnancy no-yes and oral contraceptives no-yes. All females with a positive answer to one of these items were sent to the above-mentioned questionnaire. The patients were grouped according to the answers: no pregnancy pregnancy before disease onset pregnancy during the disease.
Within these groups patients who had never taken oral contraceptives were called “no pill” and patients who had taken them during their disea:e for at least 3 months were called “with pill”. Women who had taken the pill only before disease onset or less than 3 months were omitted (N = 17) because it was not possible to build extra groups for
111 this small number. Twenty-five patients who were pregnant before and during the disease were randomly allocated to one of the groups in question. Duration of the disease, present age and present degree of disability were known for all patients. Thus, a further grouping could be performed according to the duration of the disease: 0-4, 5-9, 10-14, more than 14 years for all females (N = 446). Patients recorded during an acute bout of their disease were excluded from the study. Their present performance would reflect the severity of the bout rather than their permanent disability which is used as a parameter for prognosis in this study. The number of bouts does not influence the overall prognosis (Fog & Linnemann 1970), therefore a detailed analysis of the bout frequency and relation to pregnancy andlor intake of oral contraceptives was not performed. To get an impression of the patients’ own judgment on their condition, bouts and deterioration during or after the times of hormonal fluctuation were registered in the questionnaire. The patients were informed about the scientific aspect and anonymous handling of the data. They did not know what was expected from the study. The data from the history and the physical findings were recorded on two optical mark reader sheets, transferred to three punched cards by an IBM optical mark reader 1232 and fed into an IBM 370/158 computer. For the description of the program for data analysis see Poser & Brauns (1974). The disability grade of the patients was based on the scale of Kurtzke (1961). The statistical analysis of the data was performed by application of SPSS programs (Nie et al. 1975) at the computer center of the University of Copenhagen. Though disability is a variable between the ordinal and interval level with 10 different values (0-9), gaussian statistics have been applied. This is justified by the distribution of observations of disability (N = 446, mean = 4.44, median = 4.72, S.D. = 2.36). As analysis of variance (ANOVA) is not too sensitive to moderate deviations from normality, a three-way ANOVA with one covariate model has been set up. Effect of covariation of age with disability is first excluded and hence the effects of the three factors: use of contraceptives, history of pregnancy and duration of disease are estimated separately.
RESULTS
A total of 179 female patients completed the [questionnaire in connection with the clinical examination in our department or at home (epidemiological group). These 179 patients had a mean present age of 43.5 years (range 20-73). The mean duration of their disease was 13.2 years; the mean degree of disability was 3.55. The family status of 176 women is shown in Table 1. The comparison of the observed numbers of single, married, widowed and divorced women with the expected numbers (computed for similar age groups of the general population of Lower Saxony) shows significant differences: MS patients are more often single and divorced, less often married and widowed. The mean number of children was 1.4 for all women and 1.63 for married, widowed and divorced women. Five women did not have children because of their disease and five women would have preferred not to have chddren because of their disease. The expected mean number of children for married,
112 Table 1 . Observed and expected family status of female MS patients ( N = 176, status o f three patients unknown) ~~~~
Observed Single Married Widowed Divorced
~
~
Expected
24 128 11 13
16.54 135.42 18.73 5.31
I
P
< 0.0005
f test
widowed and divorced women was computed from the general population to be 1.91. The pattern of children is shown in Figure 1 for married, widowed and divorced women (N = 152) and compared to the expected numbers of the general population. More women with MS had no children and two children, whereas women from the general population had more often one child and more than three children; 204 of the 250 children alive were born before disease onset, of these, nine (4.4 %) had congenital malformations; 36 spontaneous abortions (18 % of live births) occurred before disease onset. Forty-six children were born after disease onset, two of these (4.3 %) were malformed. Eight spontaneous abortions (17 % of live births) occurred during the disease, seven interruptions were performed. During one pregnancy after disease onset an exacerbation was recorded, in three cases an improvement. In eight cases a deterioration occurred after
:I_ number of women
[? observed
0 expected n
30
20
10
0
1
2
3
number of children
Figure 1. Observed and expected number of married, divorced or widowed female MS patients ( N = 152) with 0, I , 2, 3, 4 and > 4 children,
113 Table 2 . Present method of contraception used by 92 women with multiple sclerosis aged between 20 and 45 years
None Oral contraceptives Sterilization Condom of the partner Intrauterine device Vaginal creams and gels Basal temperature recording Coitus interruptus Others
N
%
50 19 5 3 2 1
54 21 5 3 2 1
e, e,
e, e,
12
13
Table 3. Reason f o r taking oral contraceptives at any time during the course of multiple sclerosis ( N = 46)
Contraception (own decision) Contraception (advice from doctor) Disturbance of menstruation Multiple sclerosis Other reasons Unknown
N
%
24 8 4 2 2 5
54 17 9 4 4 11
childbirth (seven cases up to 3 months, one case between 3 and 6 months after delivery). The disease started during a pregnancy in six cases, in 13 cases up to 6 months after childbirth. The method of contraception currently used by 92 patients in the reproductive age is shown on Table 2. 54 % did not use any protection, 21 % used oral contraceptives. Figures for the general population are known for the intake of oral contraceptives (30 %, Wenig 1974), but not for the other methods. Only two patients were taking the pill because of their disease, the rest for contraception or other reasons (Table 3). Forty-six patients took oral contraceptives at some time during their disease for more than 3 months. Three of these stated a deterioration, nine an improvement and six the beginning of the symptoms during the use of oral contraceptives. In no case was an onset or deterioration after discontinuation of the pill (up to 4 weeks) observed. For the analysis of prognosis the data of 446 females were available (179 epidemiological patients and 267 women from the general data pool).
8 Acta neurol. scandinav. 592'3
114
0
grade of
no oral contraceptives
c]with no pregnancy
oral contracept I ves
5
4 3 2 1
I
pregnancy during the disease
N.li
Figure 2 . Mean disability of 446 female MS patients. Comparison of groups with the variables: duration of disease (years), history of pregnancy and use of oral contraceptives.
Comparison of the present disability reached after a defined period of time is shown in Table 4 and Figure 2 for groups with the variables: duration of disease, history of pregnancy and use of the pill. Mean values of observed degrees of disability in the different groups are given in the left column of Table 4.When these as result of analysis of variance are adjusted for age (accounting for 7 % of the total variation, P < 0.001) and the other independent variables, there is no significant effect of taking oral contraceptives nor of history of pregnancy (P = 0.999), but a significant effect of duration of disease ( P < O.OOl), accounting for additionally 6 % of the total variation. The only two-way interaction of statistical significance was found between the factors: use of oral contraceptives and history of pregnancy, showing a relatively high disability for those women who had been pregnant before the beginning of MS and were taking oral contraceptives. In patients who had never been pregnant, the pill users seemed to be less disabled than the non-users in all groups of disease duration. This differnce reached statistical significance in a preliminnray study when considering only patients under the age of 30 (Poser & Wikstrom, unpublished data). The
115 Table 4. Disability
Factors
N
Mean values of observations
Mean values corrected for age andthe other factors
Contraceptives
Not taken Taken
345 101
4.62 3.83
4.48 4.31
167
4.54
4.62
Pregnant
Never Before start of MS During course of MS
222
4.38
4.32
57
4.39
4.38
62 128 102 154
2.79 4.08 4.56 5.33
3.05
Duration of MS
1-4 years 5-9 " 10-14 " 2 15 "
4.20 4.61 5.09
Level of significance P
0.999
0.999
< 0.001
significance disappeared in the whole material when correction for age and duration was performed. Altogether it follows from our data of the whole material that women with a history of pregnancy before or during the disease have an overall prognosis similar to women without pregnancies, and women taking oral contraceptives during their disease reach a degree of disability comparable to patients who never took them. DISCUSSION
In a representative sample of 179 women with MS, the family status was different from the general population: The observed number of single and divorced women was higher than expected; this demonstrates that MS has a negative influence on contraction and stability of a marriage. The figure of 7.4 % divorced women (vs. 3.0 % expected) agree well with Heier's data (1973). The degree of disability was found to be higher for the 13 divorced women (5.0 vs. 4.0 for the marriaged and widowed) and the mean duration of the disease longer (17.5 vs. 12.8 years). Thus, marriages are at risk with increasing disability of the women. Women with MS have fewer children than would be expected (mean number 1.63 vs. 1.91). This difference results from the high percentage of women without any children and from the small number of families with more than three children. From our data it is known that five out of 152
116 women did not want to have children because of their disease, seven pregnancies were interrupted during the disease and five women had a sterilization performed. We conclude that MS does not influence the biological fertility but favors the decision not to have (more) children. The frequency of malformations was similar for children born before and during the disease (4.4 and 4.3 %) and did not differ from the rate in non-MS children (review see Janz 1978). The ratio of spontaneous abortions was not different for pregnancies before and during the disease. In addition to the spontaneous abortions, seven interruptions were performed during the disease. With better contraceptive advice, interruption should become a rare event. At the present time 54 % of the women with MS between 20 and 45 years of age did not use any contraceptive method and only 21 % used oral contraceptives. This relatively low figure (general population 30 %) might reflect the fear that their disease could get worse by taking the pill. Our data suggest that this fear is not justified. In case there is a contraindication for oral contraceptives an alternative method should be recommended. Some of the patients reported an exacerbation (one case) or an improvement (three cases) during pregnancy or shortly after childbirth (eight deteriorations). During the use of oral contractptives three got worse, nine improved. The statistical analysis of the data for 446 women with MS revealed, however, that pregnancy and the use of oral contraceptives had no substantial influence on the overall prognosis. For pregnancy these data stand between the findings of MiZZar (1961) who found a better prognosis for women with pregnancies and Schapira et al. (1966) whose patients with pregnancies were found to be more disabled than women without pregnancies. For the oral contraceptives no comparable data are known from the literature. Though oral contraceptives have no effect on disability in the whole material, two groups show a different pattern: Women taking the pill and having a history of pregnancy before disease onset exhibit a higher degree of disability compared to the corresponding groups of “no pregnancy” and “pregnancy during the disease”. This difference is most prominent for the group with short duration of the disease. Further prospective investigation is needed to find out whether this ditlerence is real or accidential. In the younger age groups, users of oral contraceptives were less disabled than non-users. This corresponds to the subjective judgment of the patients (nine improvements vs. three deteriorations during the use of oral contraceptives). This might mean only that less disabled women take the pill more often and heavily disabled do not need such a protection. Our data do not support this explanation, because most of the young patients - whether users or non-users - were distributed among the lower degress of disability which
117
'
would not prevent sexual intercourse. Other factors might have influenced the decision to take oral contraceptives and the type and duration of oral contraceptives used might be important. We could not include these variables because of the small numbers within the groups. By the present data it cannot be excluded that oral contraceptives have a positive influence on early MS in women. In analogy to the findings in experimental allergic encephalomyelitis and in rheumatoid arthritis one could speculate that the influence of oral contraceptives on the cellular immune system, which is involved in the pathogenesis of MS (see Knight 1977) alters the early course of the disease. Two kinds of prospective studies are warranted for the problems in question: 1. The incidence of MS in a population of users and non-users has to be determined in an approach similar to the study of the Royal College of General Practitioners. 2. Patients with early MS with different methods of contraception should be followed prospectively. From the statistician's point of view the patients must be allocated to the different forms of contraception randomly. The oral contraceptive taken should be standardized and no difference in other medications should be allowed. This is hardly feasible and therefore the patients have to be matched as carefully as possible. The follow up should include not only clinical symptoms and disability scores but a whole battery of immunological tests in order to elucidate the influence of oral contraceptives on the immune system. As long as these studies are not available, patients can be reassured that their overall prognosis does not change by pregnancy or by taking oral contraceptives. ACKNOWLEDGMENTS This work was supported by the Deutsche Forschungsgemeinschaft. The authors thank Prof. Bauer for giving the stimulation for this study and Mrs. Eckhardt for assistance with the manual handling of the data. REFERENCES Arnason, B. G. & D. P. Richman (1969): Effect of oral contraceptives on experimental demyelinating disease. Arch. Neurol. 21, 103-108. Barnes, E. W., A. C. MacCuish, N. B. Loudon, J. Jordan & W. J. Irvine (1974): Phytohaemagglutinin-induced lymphocyte transformation and circulating autoantibodies in women taking oral contraceptives. Lancet I, 898-900. Elliott, G. A., A. J. Gibbons & M. E. Greig (1973): A comparison of the effects of melengestrol acetate with a combination of hydrocortisone acetate and medroxyprogesterone acetate and with other steroids in the treatment of experimental allergic encephalomyelitis in Wistar rats.. Acta Neuropath. (Berl.) 23, 95-104.
118 Fog, T. & F. Linnemann (1970): The course of multiple sclerosis. Acta Neurol. Scand. 46, Suppl. 47, 1-175. Greig, M. E., A. J. Gibbons & G. A. Elliott (1970): A comparison of the effects of melengestrol acetate and hydrocortisone acetate on experimental allergic encephalomyelitis in rats. J. Pharmacol. Exp. Therap. 173, 85-93. Heier, D. (1973): Die Lebenssituation von Multiple Sklerose-Kranken. Gerhards u. Co, Frankfurt. Janz, D. (1978): Haben Antiepileptika eine teratogene Wirkung beim Menschen? Deutsch. med. Wschr. 103, 485-487. Knight, S . C. (1977): Cellular immunity in multiple sclerosis. Br. Med. Bull. 33, 45-50. Kurtzke, J. F. (1961): On the evaluation of disability in multiple sclerosis. Neurol. 11, 686-694. Leibowitz, U., A. Antonovsky, R. Kats & M. Alter (1967): Does pregnancy increase the risk of multiple sclerosis? J. Neurol. Neurosurg. Psychiat. 30, 354-357. McAlpine, D. & N. Compston (1952): Some aspects of the natural history of disseminated sclerosis. Quart. J. Med. 21, 135-167. McFarland, H. R. (1969): The management of multiple sclerosis. Miss. Med. 66, 209-211. Millar, J. H. D. (1961): The influence of pregnancy on disseminated sclerosis. Proc. Roy. SOC.Med. 54, 4-7. Millar, J. H. D., S. Allison, E. A. Cheeseman & J. D. Merrett (1959): Pregnancy as a factor influencing relapse in disseminated sclerosis. Brain 82, 417-426. Miiller, R. (1949): Studies on disseminated sclerosis. Acta Med. Scand., Suppl. 222, 1214. Nie, N. H., C. H. Hull, J. G. Jenkins, K. Steinbrenner & D. H. Bent (1975): SPSS, Statistical Package for the Social Sciences, 2nd ed., McGraw-Hill, New York. Poser, Sigrid (1978): Multiple Sclerosis. Springer, Berlin, Heidelberg, New York. Poser, S. & K.-H. Brauns (1974): Der Einsatz des Markierungsbelegverfahrens im Rahmen einer multizentrischen Studie iiber die Multiple Sklerose. Methods Inf. Med. 13, 70-79. Royal College of General Practitioners' Oral Contraception Study (1978): Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Lancet I, 569-571. Schapira, K., D. C. Poskanzer, D. J. Newel1 & H. Miller (1966): Marriage, pregnancy and multiple sclerosis. Brain 89, 419-428. Statistisches Bundesamt Wiesbaden (ed.) (1974): BevGlkerung und Kultur, Fachserie A, Kohlhammer, Stuttgart, Mainz. Tillman, A. J. B. (1950): The effect of pregnancy on multiple sclerosis and its management. Res. Pub]. Ass. Res. Nerv. Ment. Dis. 28, 548-582. Wikstrom, J., G. Ritter, S. Poser, W. Firnhaber & H. J. Bauer (1977): Das Vorkommen von Multipler Sklerose in Siidniedersachsen. Nervenarzt 48, 494-499. Wenig, Ch. (1974): Zerebrale Ischamie und Ovulationshemmer. Dtsch. Med. Wschr. 99, 1521-1525. 1
Received January 17, accepted February 2, 1979
Prof. Sigrid Poser, M.D. Department of Neurology University of G'ottingen Robert-Kochstr. 40 3400 Gijttingen FRG
