Rate of Pregnancy-Related Relapse in Multiple Sclerosis
Christian Confavreux, M.D., Michael Hutchinson, M.D., Martine Marie Hours, M.D., Patricia Cortinovis-Tourniaire, M.D., Thibault Moreau, M.D., for The Pregnancy in Multiple Sclerosis Group
Background and Methods Multiple sclerosis often occurs in youngwomen, and the effect of pregnancy on the disease is poorlyunderstood. We studied 254 women with multiple sclerosis during269 pregnancies in 12 European countries. The women were followedduring their pregnancies and for up to 12 months after deliveryto determine the rate of relapse per trimester and the scoreon the Kurtzke Expanded Disability Status Scale (range, 0 to10, with higher scores indicating more severe disability). Therelapse rate in each trimester was compared with the rate duringthe year before the pregnancy. The effects of epidural analgesiaand breast-feeding on the frequency of relapse during the firstthree months post partum and the disability score at 12 monthspost partum were also determined.
Results The mean (±SD) rate of relapse was 0.7±0.9per woman per year in the year before pregnancy; it was 0.5±1.3during the first trimester (P=0.03 for the comparison with therate before pregnancy), 0.6±1.6 during the second trimester(P=0.17), and 0.2±1.0 during the third (P<0.001).The rate increased to 1.2±2.0 during the first threemonths post partum (P<0.001) and then returned to the prepregnancyrate. The mean Kurtzke disability score worsened by 0.7 pointduring 33 months of follow-up, with no apparent accelerationduring the postpartum period. Neither breast-feeding nor epiduralanalgesia had an adverse effect on the rate of relapse or onthe progression of disability in multiple sclerosis.
Conclusions In women with multiple sclerosis, the rate of relapsedeclines during pregnancy, especially in the third trimester,and increases during the first three months post partum beforereturning to the prepregnancy rate.
Multiple sclerosis affects 1 in 1000 people in Western countries,1mainly women in their childbearing years.2,3 In general, therate of relapse has been thought to decrease during pregnancyand increase in the postpartum period, but the studies havebeen small, and some have reached different conclusions.4,5,6,7,8,9The Pregnancy in Multiple Sclerosis (PRIMS) study was a Europeanmulticenter, prospective, observational study designed to determinethe effect of pregnancy and the postpartum state on the courseof the disease, along with that of breast-feeding and epiduralanalgesia.
Methods
Study Design and Recruitment of Subjects
We studied 254 women with multiple sclerosis that began beforethe pregnancy under study and that was diagnosed according tothe classification of Poser et al.10 This classification schemefor the degree of certainty regarding the diagnosis combinesthree criteria: dissemination of lesions in time; disseminationof lesions in space, evidence of which may be clinical or paraclinical(from evoked potentials, computed tomography, or magnetic resonanceimaging); and quantitative or qualitative abnormalities in immunoglobulinsin the cerebrospinal fluid. Clinically definite cases are definedby dissemination in time and space, regardless of the resultsof cerebrospinal fluid tests; laboratory-supported definitecases are defined by dissemination in time and cerebrospinalfluid abnormalities, or by dissemination in space and cerebrospinalfluid abnormalities; clinically probable cases are defined onlyby dissemination in time or space; laboratory-supported probablecases by cerebrospinal fluid abnormalities only; and suspectedcases by the lack of fulfillment of any of the three criteria.
All the women had been pregnant for at least 4 weeks but lessthan 36 weeks at entry into the study. Any European neurologistwilling to participate in the study was invited to do so andreceived the study protocol and data-collection forms designedfor use with the European Database for Multiple Sclerosis (EDMUS)system.11
Recruitment of the women began in January 1993 and ended whenthe target number of 250 pregnancies was reached in July 1995.This number was calculated to allow the study to detect a reductionof at least 33 percent in the relapse rate during the thirdtrimester of pregnancy, as compared with the rate during theyear before pregnancy. A total of 194 of the women (76 percent)were known to the study neurologist before the pregnancy. Thestudy protocol was approved by the ethics committee of St. Vincent'sHospital, Dublin, Ireland, and all the women gave informed consent.
Assessment of Subjects
After enrollment, the women were examined at 20 and 28 weeksof gestation if enrollment took place before those times. Inany case, all the women were examined at 36 weeks of gestation,and they were assessed by telephone at 40 weeks. Subsequently,they were examined 3, 6, and 12 months post partum, with telephoneassessments 1 and 9 months post partum. For each woman, thesame neurologist conducted all evaluations and completed a standardizedform on each occasion. Short courses of glucocorticoids werethe only immunologic treatment for multiple sclerosis allowedduring pregnancy.
We recorded obstetrical data on previous pregnancies and theiroutcomes, the date of the last menstrual period, any complicationsof the pregnancy under study, the method of delivery and anycomplications, the use or nonuse of epidural analgesia, whetherthe mother was breast-feeding her infant, and the weight, sex,and health status of the infant.
The following data were collected on the course of multiplesclerosis: date of onset, total number of relapses before thestudy pregnancy, number of relapses in the year before the studypregnancy, number of relapses during the study pregnancy butbefore enrollment in the study, whether the course was relapsingremittingor progressive,2,11 and the extent of neurologic disabilityone year before the last menstrual period before the study pregnancyand at the beginning of the pregnancy.
We also collected the following prospective data: extent ofneurologic disability at the time of enrollment in the study,at 36 weeks' gestation, and 3, 6, and 12 months post partum;whether there was any new relapse; and any immunologic treatments,such as glucocorticoids and immunosuppressant or immunomodulatingdrugs. For the women who became pregnant again less than a yearafter the first pregnancy, the study period for the first pregnancywas defined as ending at the time of the last menstrual periodbefore the second pregnancy.
Once completed by the neurologist, the data-collection formswere sent to the coordinating center, where the staff ensuredthat the data were internally consistent and that follow-upwas on schedule. Any inconsistencies were pointed out by thestaff, and further information was sought from the neurologist.All the data received at the coordinating center were sent backto the neurologist for final validation.
A relapse of multiple sclerosis was defined as the appearanceor worsening of symptoms of neurologic dysfunction lasting morethan 24 hours. Fatigue alone was not considered a relapse. Neurologicdisability was assessed with use of the Kurtzke Expanded DisabilityStatus Scale,12 which is based on the data from the neurologicexamination and the patient's ability to walk. Scores rangefrom 0 (indicating no neurologic abnormality) to 10 (death causedby multiple sclerosis). Residual neurologic disability was definedas the minimal level of persistent disability recorded on twoconsecutive examinations at least three months apart, excludingany transient worsening of disability related to relapses.
Statistical Analysis
The rates of relapse per woman per year during each three-monthperiod during pregnancy and the postpartum year were comparedwith the relapse rate during the year before the pregnancy beganby means of paired, two-sided t-tests. The effects of epiduralanalgesia and breast-feeding on the course of multiple sclerosiswere analyzed by logistic-regression analysis, with adjustmentfor age and the duration of disease at the beginning of pregnancyand the occurrence of relapses, for each three-month periodduring the year before the pregnancy and during pregnancy. Oneoutcome analyzed was the occurrence of a relapse during thefirst three months post partum; the second was an increase of1.0 point or more in the residual Kurtzke score as determinedat the beginning of pregnancy and the end of the postpartumyear. Finally, the method of Wei and Johnson was used to calculatean overall P value for the association of the relapse ratesand residual disability with either epidural analgesia or breast-feedingduring the entire 33-month study period from 1 year before thepregnancy began to the 12th month post partum.13 All computationswere performed with SPSS for Windows software, version 6.1.14
Results
Characteristics of the Women with Multiple Sclerosis
A total of 254 women were enrolled in the study (Figure 1).Fifteen were studied during 2 pregnancies, for a total of 269study pregnancies. The last delivery took place in February1996. The base-line characteristics of the 254 women are shownin Table 1. Among the 241 full-term pregnancies, the mean (±SD)duration of the pregnancy at the time of enrollment was 18±9weeks; 113 of the 241 women (47 percent) were enrolled duringthe first trimester, 93 (39 percent) during the second trimester,and 35 (15 percent) during the third trimester. Sixteen womenreceived glucocorticoid therapy during pregnancy. During thefirst six months after delivery, 35 women received glucocorticoidtherapy, 4 received azathioprine, and 1 received mitoxantrone;during the second six months post partum, 27 women receivedglucocorticoid therapy, 3 azathioprine, 6 recombinant interferonbeta-1b, 1 mitoxantrone, and 1 cyclophosphamide.
Figure 1. Outcomes of Pregnancy and Follow-up in Women with Multiple Sclerosis Who Were Recruited into the Study.
Eight women were pregnant with twins; in two cases, one twin was born alive and one was stillborn (these women and pregnancies appear twice in the figure).
Table 1. Base-Line Characteristics of the 254 Women with Multiple Sclerosis, According to Outcomes of Pregnancy.
Outcomes of Pregnancy
Full data on pregnancy and delivery were available for 256 pregnanciesin 241 women (Figure 1). Among the 241 full-term pregnancies(227 first pregnancies and 14 second pregnancies), there were8 twin pregnancies; 2 of these resulted in the delivery of onestillborn and one live infant. The mean duration of pregnancywas 39±3 weeks; 27 pregnancies ended at or before 36weeks. Among the live-born infants, there were 130 boys and113 girls (for 4 infants, the sex was not recorded). The meanweight at delivery was 3.3±0.6 kg; seven infants weighedless than 2.5 kg. One infant had ureteral stenosis with mildhydronephrosis. All the live-born infants were healthy at oneyear of age, except for one twin who died of sudden infant deathsyndrome at the age of three months.
There were 196 vaginal deliveries and 43 cesarean deliveries(data were missing in 2 cases). Epidural analgesia was givento 42 women. There were few complications during or after delivery.One woman had eclampsia; 12 had excessive bleeding, of whomonly 5 required blood transfusion, and 9 had infection. Amongthe 209 women for whom information was available, 122 choseto breast-feed their infants.
Relapses of Multiple Sclerosis
For each woman, only the first pregnancy during the study thatled to a live birth was included in our analyses. This amountedto a total of 227 pregnancies. The relapse rates for each three-monthperiod during the year before the pregnancy, during the pregnancy,and during the postpartum year are shown in Table 2 and Figure 2.As compared with the prepregnancy year, in which the meanrate of relapse was 0.7±0.9 per woman per year, the relapserates in the first and the second trimesters of pregnancy wereslightly lower, and that during the last trimester was substantiallylower (0.2±1.0 relapse per woman per year). After delivery,the rate during the first three months was higher than thatbefore pregnancy, but in the second, third, and fourth three-monthperiods it was similar to the rate before pregnancy.
Figure 2. Rate of Relapse per Woman per Year for Each Three-Month Period before, during, and after Pregnancy in 227 Pregnancies Resulting in a Live Birth among Women with Multiple Sclerosis.
The values shown are means and 95 percent confidence intervals.
Table 3 shows the relapse rates during the study period accordingto whether the women received epidural analgesia and breast-fedtheir infants. The risk of a relapse after delivery was notaffected by the use of epidural analgesia (odds ratio as comparedwith nonuse, 1.5; 95 percent confidence interval, 0.7 to 3.2;P=0.51) or by breast-feeding (odds ratio as compared with notbreast-feeding, 0.8; 95 percent confidence interval, 0.4 to1.5; P=0.51). When we evaluated the entire 33-month study periodby the WeiJohnson method,13 there was no significantdifference in the rate of relapse between women who underwentepidural analgesia and those who did not (P=0.54). By contrast,women who breast-fed their infants had a significantly lowerrate of relapse than women who did not (P=0.02).
Table 3. Rate of Relapse among Women with Multiple Sclerosis in Relation to the Use or Nonuse of Epidural Analgesia and Whether or Not the Women Breast-Fed Their Infants.
Disability Related to Multiple Sclerosis
The residual Kurtzke disability score worsened steadily duringthe study, with a mean increase of 0.7 by the end of the 33-monthstudy period (Table 4). There was no apparent acceleration ofthe progression of disability in the postpartum period as comparedwith the earlier periods, either among all the women or in subgroupsdefined according to whether they had received epidural analgesia(odds ratio, 1.1; 95 percent confidence interval, 0.5 to 2.6;P=0.80) or whether they had breast-fed their infants (odds ratio,1.4; 95 percent confidence interval, 0.7 to 3.0; P=0.27). Whenanalyzing the entire 33-month study period by the method ofWei and Johnson,13 we did not find any significant differencein the progression of disability according to the use or nonuseof epidural analgesia (P=0.66) or whether women breast-fed theirinfants (P=0.27).
Table 4. Residual Kurtzke Disability Score before, during, and after Pregnancy among 227 Women with Multiple Sclerosis.
Discussion
In this large prospective study of the natural history of multiplesclerosis in pregnant women, the frequency of relapses of multiplesclerosis decreased during pregnancy, particularly during thethird trimester, and increased in the first three months postpartum, as compared with the rate during the year before pregnancy.The women served as their own controls, because matching a cohortof pregnant women with multiple sclerosis with a cohort of womenwith multiple sclerosis who did not become pregnant has proveddifficult. The decision of a woman with multiple sclerosis tobecome pregnant is strongly influenced by disease activity.
Although the study formally began when the women were pregnant,52 percent had been followed prospectively by the participatingneurologist before pregnancy. If the study had begun a yearbefore the pregnancy began, the relapse rate for the prepregnancyyear would probably have been higher, and consequently the reductionin the relapse rate during pregnancy would have been greater.Furthermore, in other studies, the mean relapse rate in youngwomen with multiple sclerosis has been at least 0.5 per womanper year.2,3 The ability to detect relapses is a function ofthe frequency of evaluation.15 For that reason, given a meanrelapse rate of 0.7 per year for the year before pregnancy,detection of relapses during this period was probably adequate.
Most previous studies of the effect of pregnancy on the frequencyof relapse in women with multiple sclerosis have been retrospectiveor cohort studies; one prospective study was of eight women.16In many of the older studies,17,18,19,20,21 the relapse ratewas less than 0.5 per year, suggesting inadequate retrospectivereview, and in only one22 were the results similar to thosereported here. In the six more recent studies,16,22,23,24,25,26which enrolled a total of 203 women in whom the relapse rateswhen they were not pregnant were more than 0.5 per year, thepooled results are in agreement with ours.
The overall rate of progression of disability did not changeduring the study period, despite the increase in the relapserate in the first three months post partum. The mean increasein the residual Kurtzke score for the entire 33-month studyperiod was 0.7, a value within the expected range of what isknown about the natural history of multiple sclerosis in womenwith minimally disabling disease.3 We also found that epiduralanalgesia and breast-feeding did not increase the risk of relapseor of worsening disability in the postpartum period; this findingagrees with those of another study.21 Our results are also inaccord with studies that have shown that multiple sclerosisdoes not seem to have a deleterious effect on the course andoutcome of pregnancy or delivery.9,16,24,25,26,27,28,29
The decrease in the relapse rate during pregnancy was more markedthan any therapeutic effect reported to date.30,31,32,33 Thisclinical observation is corroborated by the cessation of diseaseactivity on magnetic resonance imaging during the third trimesterof pregnancy.34 From an immunologic point of view, normal pregnancyseems to be associated with a shift away from cell-mediatedimmunity toward increased humoral immunity.35 The fetalplacentalunit secretes cytokines such as interleukin-10 that down-regulatethe production of other cytokines mediating cellular immunityby the mother. This cell-mediated immunodepression could explainthe tolerance of the fetus by the mother. In contrast, deliverymight be associated with an inversion of this cytokine balanceand could be regarded, in some respects, as a graft-rejectionprocess.35
This concept could explain why pregnancy is associated withspontaneous remission and the postpartum period with exacerbationsin T-cellmediated autoimmune diseases such as multiplesclerosis and rheumatoid arthritis.36 Conversely, B-cellmediatedautoimmune diseases, such as systemic lupus erythematosus, tendto worsen during pregnancy.37 A better understanding of thebiologic mechanisms underlying this pregnancy-related decreasein disease activity could lead to new and effective therapeuticstrategies in multiple sclerosis.
Supported by contracts with the Commission of the European CommunitiesDirectorate General XII (BMH1-CT93-1529, CIPD-CT94-0227, andBMH4-CT96-0064) and by grants from the Ligue Françaisecontre la Sclérose en Plaques, the Association pour laRecherche sur la Sclérose en Plaques, the Hospices Civilsde Lyon, and the Multiple Sclerosis Society of Ireland.
We are indebted to the patients for their participation in thePRIMS study; to all the investigators for their contributionto the study and their review of the manuscript; to Drs. PatriceAdeleine, Annick Alperovitch, Dessa Sadovnick, Jean-Paul Soulillou,and Jean-Marie Thoulon for their helpful comments on earlierdrafts of the article; and to Mrs. Isabelle Dollaro and Mrs.Catherine Vidal for their assistance in the preparation of themanuscript.
* Other participants in the Pregnancy in Multiple Sclerosis (PRIMS)Group are listed in the Appendix.
Source Information
From the European Database for Multiple Sclerosis Coordinating Center and the Service de Neurologie, Hôpital de l'Antiquaille, Lyons, France (C.C., M.M.H., P.C.-T., T.M.); and the Department of Neurology, St. Vincent's Hospital, Dublin, Ireland (M.H.).
Address reprint requests to Professor Confavreux at the EDMUS Coordinating Center, Hôpital de l'Antiquaille, 1 rue de l'Antiquaille, 69321 Lyons, CEDEX 05, France.
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Appendix
In addition to the authors, the participants in the PRIMS Groupwere as follows: Study Design and Steering Committee A. Alpérovitch, Villejuif, France; H. Carton, Leuven,Belgium; M.B. d'Hooghe, Melsbroek, Belgium; O. Hommes, Nijmegen,the Netherlands; EDMUS Coordinating Center, Lyons, France A. Biron, J. Grimaud; Participants (numbers of pregnancies studiedare shown in parentheses) France (71): Lyons, J. Grimaud,G. Chauplannaz, D. Latombe; Toulouse, M. Clanet, G. Lau; Besançon,L. Rumbach; Brest, J.Y. Goas, F. Rouhart; Lille, A. Mazingue;Paris, E. Roullet; St. Brieuc, M. Madigand; Lomme, P. Hautecoeur;Rennes, P. Brunet, G. Edan, C. Allaire; Tours, G. Riffault;Vendome, J. Leche; Villepinte, T. Benoit; Arles, C. Simonin;Belfort, F. Ziegler; Caen, J.C. Baron, Y. Rivrain; Dijon, R.Dumas, D. Loche; Draguignan, J.C. Bourrin; Epinal, B. Huttin;Lens, B. Delisse; Le Puy-en-Velay, I. Gibert; Mulhouse, C. Boulay;Nantes, M. Verceletto; Nice, G. Durand; Orléans, G. Bonneviot;Poitiers, R. Gil; Pointe-à-Pitre, M.A. Hedreville; Reims,C. Belair; Restigné, R.J. Poitevin; Angoulème,J.L. Devoize; St. Quentin, P. Wyremblewski; Vannes, F. Delestre;VillefrancheSaône, A. Setiey; Italy (42): Milan,G. Comi, M. Fillippi, A. Ghezzi, V. Martinelli, P. Rossi, M.Zaffaroni; Ferrara, M.R. Tola; Florence, M.P. Amato; Pisa, C.Fioretti, G. Meucci; Genoa, M. Inglese, G.L. Mancardi; Chieti,D. Gambi, A. Thomas; Modena, M. Cavazzuti; Pavia, A. Citterio;Denmark (25): Roskilde, A. Heltberg; Aarhus, H.J. Hansen; Spain(25): Malaga, O. Fernandez, F. Romero; Barcelona, T. Arbizu,J.J. Hernandez; Madrid, C. De Andres de Frutos; Castellon, D.Geffner Sclarky; Las Palmas, Y. Aladro Benito, P. Reyes Yanez;Terrassa, M. Aguilar; Valencia, J.A. Burguera, R. Yaya; Valladolid,W. Bowakim Dib, D. Arzua-Mouronte; Belgium (23): Melsbroek,M.B. d'Hooghe; Brussells, C.J.M. Sindic; Leuven, H. Carton;Diepenbeek, R. Medaer; Bonheiden, H. Roose; Ekeren, K.M.J. Geens;Fraiture, D. Guillaume; Brugge, M. Van Zandycke; Lewen, J. Janssens;Seraing, M. Cornette; Turnhout, L. Mol; Germany (21): Würzburg,F. Weilbach, P. Flachenecke, H.P. Hartung; Magdeburg, J. Haas,I. Tendolkar; Bochum, E. Sindern; Erfurt, H.W. Kölmel,D. Reichel; Bielefeld, M. Rauch; Emden, S. Preuss; Göttingen,S. Poser; Schwendi, E. Mauch; Austria (18): Graz, S. Strasser-Fuchs;Vienna, H. Kollegger; United Kingdom (18): Belfast, S. Hawkins;Sheffield, S.J.L. Howell; Haywards Heath, J.E. Rees; London,A. Thompson; Leeds, M. Johnson; Stoke-on-Trent, M. Boggild;Swindon, R.P. Gregory; Newcastle upon Tyne, D. Bates; Glasgow,I. Bone; Ireland (14); the Netherlands (7): Amsterdam, C. Polman;Nijmegen, S. Frequin, P. Jongen, O. Hommes; Portugal (4): Lisbon,J. Correia de Sa; Porto, M.E. Rio; and Switzerland (1): Basel,S. Huber, J. Lechner-Scott, L. Kappos.
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