Abstract
Objective: The purpose of our study was to assess the influence of pregnancy on the course of neuromyelitis optica (NMO) and the impact of epidural analgesia and breastfeeding on its activity in the postpartum period.
Methods: We performed a retrospective study of patients with NMO diagnosed according to Wingerchuk criteria. We noted the number of relapses during the year before pregnancy (BP), during pregnancy (first trimester, second trimester, third trimester), and the year after (Y + 1: first trimester, second trimester [PP2], and third and fourth trimesters postpartum). Epidural analgesia and breastfeeding were recorded. Disability was evaluated with the Kurtzke Expanded Disability Status Scale (EDSS). The annualized relapse rate (ARR) was calculated.
Results: We identified 124 patients (85 female) in the French NOMADMUS cohort on November 1, 2010. A total of 20 women (including 25 pregnancies) were informative with complete files. Comparisons between the ARR of each period and BP (1.0 ± 0.09) only showed an increased tendency for PP2 (0.8 ± 0.06, p = 0.07). Epidural analgesia and breastfeeding had no influence on the course of NMO. The EDSS score increased from 1.5 ± 1.7 BP to 2.6 ± 1.9 Y + 1 (p = 0.027).
Conclusion: This study shows that pregnancy influences the activity of NMO, a finding that justifies close medical monitoring. We found no evidence to suggest that either epidural analgesia or breastfeeding has an aggravating effect on NMO.
GLOSSARY
- ARR=
- annualized relapse rate;
- BP=
- before pregnancy;
- EDMUS=
- European Database for MS;
- EDSS=
- Expanded Disability Status Scale;
- IgG=
- immunoglobulin G;
- MS=
- multiple sclerosis;
- NMO=
- neuromyelitis optica;
- NOMADMUS=
- European Database for MS adapted to neuromyelitis optica specificities;
- PP1=
- first trimester postpartum;
- PP2=
- second trimester postpartum;
- PP3=
- third trimester postpartum;
- PP4=
- fourth trimester postpartum;
- Y + 1=
- year after pregnancy.
Neuromyelitis optica (NMO) is a rare demyelinating disease of the CNS characterized by severe relapses of optic neuritis and longitudinal extensive transverse myelitis. Although NMO can affect women in their childbearing years,1 the influence of pregnancy on its course has never been assessed. As NMO is a TH2-mediated disease, its activity may be influenced by the cytokines secreted during pregnancy. In multiple sclerosis (MS), the most similar demyelinating disease, a study reported a decrease in relapse risk during pregnancy but an increase in the early postpartum period.2 Furthermore, some data seem to suggest that breastfeeding may influence MS activity.
The purpose of our study was to assess the influence of pregnancy and the postpartum period on the course of NMO and the impact of epidural analgesia and breastfeeding on NMO activity in the postpartum period.
METHODS
We performed a retrospective study of patients with NMO from 6 tertiary medical centers in France. NMO was diagnosed according to the 2006 revised criteria for NMO.3 Data were collected from the French NOMADMUS cohort on November 1, 2010. NOMADMUS is the European Database for MS (EDMUS) adapted to NMO specificities.4 Biological and MRI data were obtained from hospital files and all patients were contacted to complete the information on pregnancy, miscarriage, or termination of pregnancy. We included as informative any woman in whom the first attack of NMO occurred before or around the time of a pregnancy.
For each patient we assessed demographic data, neuroimaging data, and treatment. NMO-immunoglobulin G (IgG) status was tested in Lyon, France.5 We noted the number of relapses during the year before pregnancy (BP), during pregnancy (first trimester: DP1; second trimester: DP2; third trimester: DP3), and the year after (Y + 1: first trimester [PP1], second trimester [PP2], and third and fourth trimesters [PP3 + 4] postpartum). Epidural analgesia and breastfeeding were also recorded. Expanded Disability Status Scale (EDSS) scores were obtained 1 year before and after the pregnancy. Worsening of disability was defined as a 1-point progression in EDSS score sustained for at least 3 months. The annualized relapse rate (ARR) corresponding to the number of relapses per patient and per year was calculated for each period.
For the 13 women in whom the disease started before pregnancy, we compared the ARR during each studied period (DP1, DP2, DP3, PP1, PP2, PP3 + 4) to the year before pregnancy (BP) using the Wilcoxon test. The effects of epidural analgesia and breastfeeding on the course of NMO were compared with a χ2 test. The ARRs of patients with NMO and MS followed up in the PRIMS study2 were also compared with a χ2 test. Statistical analysis was performed with NCSS software.
Standard protocol approvals, registrations, and patient consents.
The French data protection authority approved the study. All patients gave their informed consent to participate in the study.
RESULTS
Details of the study population are given in figure 1. We identified 124 patients, 85 of whom were female, in the French NOMADMUS cohort. There were only 20 informative women, corresponding to 25 informative pregnancies, and 54 noninformative women (i.e., women in whom NMO started years after their last pregnancy). Patients (informative and non informative) had their first child at 25.6 ± 4.3 years (mean ± SD). Among patients, mean age at onset of NMO was 32.3 ± 13.7 years and mean disease duration before informative pregnancies was 5.4 ± 8.2 years. There were no differences in terms of the number of pregnancies, parity, disease activity, NMO-IgG positivity, or disability between informative and noninformative women (table). Two patients received treatment before pregnancy, 1 with glatiramer acetate (stopped 5 months before) and the other with rituximab (suspended when the patient became pregnant). The management of attacks during pregnancy consisted of methylprednisolone infusions for 3 to 5 days. After delivery, additional treatment such as plasma exchange was also administered if necessary (n = 6).
Informative: neuromyelitis optica (NMO) occurring before, during, or in the year after pregnancy. Attack timing in these 3 groups: the 13 women whose NMO started before pregnancy had their first event more than 1 year before. Concerning the 15 remaining women, we detailed the period in which NMO occurred. Attended number of miscarriages for the studied population (12%–15%): 9–12. All terminations of pregnancies occurred in noninformative women.
Comparison between informativea and noninformative women
The ARR was 1.0 ± 0.09 BP, 0.5 ± 0.06 DP1 and DP2, 1.2 ± 0.1 DP3, 2.2 ± 0.09 in PP1, 0.8 ± 0.06 in PP2, 1.1 ± 0.09 in PP3 + 4, and 1.2 ± 0.03 in Y + 1. Comparisons between the ARR of each period and BP did not show significant differences. We compared the ARR of our patients to those of patients with MS in the PRIMS study6 but found no differences.
The mean EDSS score was 1.5 ± 1.7 before delivery and increased to 2.6 ± 1.9 1 year after (p = 0.027).
Data concerning epidural analgesia and breastfeeding are complete for 22 of the informative pregnancies. The majority of women had epidural analgesia (13/22) and only one-third breastfed (7/22). We did not note any delivery complications or adverse immediate outcome for any of the babies. Neither epidural analgesia (ARR = 0.8 ± 0.04 in Y + 1 compared to 1.4 ± 0.25 in the group without epidural analgesia; NS) nor breastfeeding (ARR = 0.9 ± 0.09 in the breastfeeding group compared to 1.2 ± 0.14 in the group without breastfeeding) influenced NMO activity.
DISCUSSION
This study shows a decrease in the ARR during DP1 and DP2 before an increase during DP3 and, moreover, during PP1 and the whole Y + 1 period. Although not significant, these data contrast with previous reports on MS in which activity decreased in DP3 (figure 2). Concerning the influence of pregnancy on disability, we noted an increase in the EDSS score (from 1.5 ± 1.7 to 2.6 ± 1.9, p = 0.027), suggesting that pregnancy might have a greater effect on disability in NMO than in MS.2 The low EDSS score in Y-1 may be explained by the younger age at disease onset among informative women and the short disease duration: 5.4 ± 8.2 years. This bias is probably due to the fact that women who choose to become pregnant are highly selected in the whole population of NMO (younger, less disabled).
BP = year before pregnancy; DP1/2/3 = 1st/2nd/3rd trimester of pregnancy; PP1/PP2/PP3 + 4 = 1st/2nd/3rd + 4th trimester postpartum.
The greater increase in EDSS score in patients with NMO compared to that reported in patients with MS could be due to the fact that NMO is a severe inflammatory disease in which relapses are more frequently responsible for irreversible disability. Moreover, it might be argued that the most disabled patients are less likely to become pregnant, e.g., our informative women had a less severe disease.
Neither epidural analgesia nor breastfeeding seemed to influence the course of the disease in our patients but this result must be interpreted cautiously because of the small group size. Among breastfeeding women, we did not distinguish between those who did so exclusively and those who did not. It should be noted that women with MS who exclusively breastfed are reported to have a 5-fold decrease in postpartum relapse risk.7 Nevertheless this study was biased by the fact that women had to remain relapse-free to continue exclusively breastfeeding. Furthermore, another study failed to confirm this result.8
The influence of pregnancy on autoimmune diseases is in part due to the imbalance of TH1 and TH2 cytokines. During pregnancy the fetoplacental unit synthesizes TH2 cytokines (interleukin-6, interleukin-10), responsible for an increase in estrogen levels, leading to a relative immune tolerance.9 This induces an imbalance between TH1 and TH2 cytokines, partly explaining the effect of pregnancy on other autoimmune diseases: either deleterious in the case of systemic lupus erythematosus, a TH2-mediated autoimmune disease, or beneficial in the case of MS and rheumatoid arthritis, which are TH1 mediated. Since NMO is a TH2-mediated autoimmune disease,10 the increased ARR found in DP3 is not surprising. Nevertheless, NMO activity seemed to decrease in DP1 and DP2, as in the case of MS.6 It therefore seems unlikely that the TH1/TH2 cytokine balance is the main pathophysiologic pathway of NMO activity during pregnancy.
This study shows that pregnancy influences the activity of NMO, a finding that justifies close medical monitoring. Our results also suggest that neither epidural analgesia nor breastfeeding has an aggravating effect on NMO: patients should feel free to choose these options. Nevertheless, in view of the few informative patients and the few disease events, a larger, prospective study is now needed in order to confirm these findings.
AUTHOR CONTRIBUTIONS
Dr. Bourre participated in drafting/revising the manuscript for content, including medical writing for content, study concept and design, analysis acquisition or interpretation of data, and statistical analysis. Dr. Marignier participated in revising the manuscript for content. Dr. Zéphir participated in revising the manuscript for content. Dr. Papeix participated in revising the manuscript for content. Dr. Brassat participated in revising the manuscript for content. Dr. Castelnovo participated in revising the manuscript for content. Dr. Collongues participated in revising the manuscript for content. Dr. Vukusic participated in revising the manuscript for content. Dr. Labauge participated in revising the manuscript for content. Dr. Outteryck participated in revising the manuscript for content. Dr. Fontaine participated in revising the manuscript for content. Dr. Vermersch participated in revising the manuscript for content. Dr. Confavreux participated in revising the manuscript for content. Dr. de Seze participated in drafting/revising the manuscript for content, including medical writing for content, study design, interpretation of data, and study supervision/coordination.
DISCLOSURE
Dr. Bourre, Dr. Marignier, and Dr. Zéphir report no disclosures. Dr. Papeix serves on scientific advisory boards for Bayer Schering Pharma, Novartis, and Teva. Dr. Brassat, Dr. Castelnovo, and Dr. Collongues report no disclosures. Dr. Vukusic serves on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Teva; has received funding for travel from Merck Serono; and receives research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Teva. Dr. Labauge and Dr. Outteryck report no disclosures. Dr. Fontaine serves on the editorial board of Gene and Immunity and receives research support from INSERM, CNRS, and sanofi-aventis. Dr. Vermersch serves on scientific advisory boards for and has received funding for travel or speaker honoraria from sanofi-aventis, Biogen Idec, Merck Serono, Teva, and Novartis; serves as a consultant for Merck Serono, sanofi-aventis, Teva, Biogen Idec, and Bayer Schering Pharma; and receives research support from Biogen Idec, Bayer Schering Pharma, Novartis, Merck Serono, Teva, and sanofi-aventis. Dr. Confavreux serves on scientific advisory boards for Biogen Idec, Genzyme, Novartis, sanofi-aventis, Teva, and UCB; has received speaker honoraria from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Teva; receives publishing royalties for Mcalpine's Multiple Sclerosis, 4th ed (Elselvier, 2005); serves as a consultant for Biogen Dompé, Biogen Idec, Gemacbio, Genzyme, Hertie Foundation, Novartis, sanofi-aventis, Teva, and UCB Pharma; and receives research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, Teva, AFFSAPS, French Ministry of Health (PHRC programme), ARSEP, LFSEP, ELA Foundation, and The Myelin Project. Dr. de Seze has served on scientific advisory boards for Biogen Idec, LFB, Merck Serono, sanofi-aventis, and Bayer Schering Pharma; and has received research support from Biogen Idec, LFB, Merck Serono, sanofi-aventis, and Bayer Schering Pharma.
ACKNOWLEDGMENT
The authors thank Baradi Brice and Celine Rabadeux for help in data collection and the Eugene Devic EDMUS Foundation for granting access to its database. Statistical analysis was performed by P. Meyer, Hôpital Civil, Strasbourg, France.
Footnotes
Editorial, page 846
See also page 867
Supplemental data at www.neurology.org
Coinvestigators are listed on the Neurology® Web site at www.neurology.org.
- Received June 8, 2011.
- Accepted September 29, 2011.
- Copyright © 2012 by AAN Enterprises, Inc.
REFERENCES
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