clinical and radiologic disease activity in pregnancy and

ARTICLE OPEN ACCESS

Clinical and Radiologic Disease Activity inPregnancy and Postpartum in MSAnnika Anderson BA Kristen M Krysko MD MAS Alice Rutatangwa DO MSc Tanya Krishnakumar BA

Chelsea Chen William Rowles BA Chao Zhao MS Maria K Houtchens MD and Riley Bove MD MSc

Neurol Neuroimmunol Neuroinflamm 20218e959 doi101212NXI0000000000000959

Correspondence

Dr Bove

rileyboveucsfedu

AbstractObjectiveTo evaluate radiologic and clinical inflammatory activity in women with MS during pregnancyand postpartum

MethodsWe performed a retrospective analysis of prospectively collected clinical and MRI reports forwomen who became pregnant while followed at the University of California San Francisco MSCenter between 2005 and 2018 Proportion of brain MRIs with new T2-hyperintense orgadolinium enhancing (Gd+) lesions (primary outcome) and annualized relapse rate (ARRsecondary) were compared before and after pregnancy

ResultsWe identified 155 pregnancies in 119 women (median Expanded Disability Status Scale[EDSS] 20) For the 146 live birth pregnancies prepregnancy ARR was 033 ARR decreasedduring pregnancy particularly the third trimester (ARR 010 p = 0017) and increased in the 3months postpartum (ARR 061 p = 0012) and 16 of women experienced a clinicallymeaningful increase in EDSS Among 70 pregnancies with paired brainMRIs available 53 hadnew T2 andor Gd+ lesions postpartum compared with 32 prepregnancy (p lt 0001)Postpartum clinical relapses were associated with Gd+ lesions (p lt 0001) However even forpatients without postpartum relapses surveillance brain MRIs revealed new T2 andor Gd+lesions in 31 Protective effects of exclusive breastfeeding for ge3 months (odds ratio = 0395 confidence interval 01ndash09) were observed for relapses

ConclusionsBuilding on previous reports of increased relapse rate in the first 3 months postpartum wereport a significant association between inflammation on MRI and this clinical activity We alsodetected postpartum radiologic activity in the absence of relapses Both clinical and radiologicreassessment may inform optimal treatment decision-making during the high-risk early post-partum period

From the Weill Institute for Neurosciences (AA KMK) Department of Neurology University of California San Francisco San Francisco CA Department of Neurology (KMK RB)School of Medicine University of California San Francisco San Francisco CA Weill Institute for Neurosciences (AR TK CC WR CZ RB) Department of Neurology University ofCalifornia San Francisco San Francisco CA Department of Neurology (MH) Brigham and Womens Hospital Harvard Medical School Boston MA

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by the authors

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

MS typically begins between the ages of 20ndash40 years and has afemale-to-male ratio of 311ndash3 As such MS is primarily di-agnosed in women of reproductive age Several studies havedemonstrated that women experience fewer MS relapsesduring the immunotolerant state of pregnancy however anincrease in relapses has been observed postpartum4ndash6 Recentexceptions to this trend are notable First in the disease-modifying therapy (DMT) era women discontinuing DMTsinterfering with lymphocyte trafficking (fingolimod andnatalizumab) have increased relapse risk during pregnancydue to lsquoreboundrsquo disease activity7 Second in a more clinicallybenign population-based cohort fewer women were noted toexperience relapses postpartum8 Third exclusive breast-feeding has been associated with reduced postpartumrelapses910

Because clinical inflammatory activity postpartum could beconfused with other common neurologic conditions (such asmigraines11 meralgia paresthetica12 or DeQuervain teno-synovitis13) MRI detects new inflammatory lesions objec-tively Three small neuroimaging studies have reportedincreased inflammatory activity postpartum a cohort of 28Finnish women with MS14 women with radiologically iso-lated syndrome15 and a report of 2 patients with MS16 Thereis a need for larger case series of MRI-defined postpartuminflammatory activity

In the current study we evaluated inflammatory activity onbrain MRIs of women with MS during pregnancy and post-partum (primary) and clinical relapses (secondary) We hy-pothesized that inflammatory activity was increasedradiologically and clinically postpartum and that exclusivebreastfeeding was associated with a reduction in the rate ofboth outcomes

MethodsSample SelectionIn this retrospective analysis of prospectively collected clinicaldata we screened the electronic medical record (EMR) toidentify women followed at the University of California SanFrancisco (UCSF) MS and Neuroinflammation Center whobecame pregnant between 2015 and 2018 and for whomprospectively recorded clinical data were available We iden-tified 88 women with 103 pregnancies we also included 13additional pregnancies for these women that preceded thesearch window (2005ndash2015) From a separate study chartreview we included an additional 39 pregnancies between2005 and 2015 from 31 women Altogether we identified 119

women with 155 pregnancies Women participating in anongoing prospective pregnancy registry that began in 2018were excluded (N = 56 as of July 15 2020)

Standard Protocol Approvals Registrationsand Patient ConsentsThe UCSF Committee of Human Research approved thestudy protocol for retrospective analysis of EMRndashderived MSdata with no patient contact (Ref 13ndash11686)

Data CollectionMaternal MS clinical history was extracted from medical re-cords including year of MS onset disease course at concep-tion Expanded Disability Status Scale (EDSS) score clinicalrelapses and DMT use from the 12-month preconception tothe 12 months after delivery or pregnancy loss Both pre-scription records and clinician notes were reconciled duringchart review to determine DMT use Clinical relapses weredefined as new or worsening neurologic symptoms for at least24 hours in the absence of fever or infection as documentedin clinical records by the treating neurologist When EDSSwas not explicitly included in the treating neurologistrsquos notethis was extrapolated from the neurologic examinationdocumented symptoms and reported ambulatory abilities bya neurologist (KMK) blinded to timing of the EDSS re-garding pregnancy Any use of prophylactic steroids (pre-scribed for example when delaying DMT initiationpostpartum to allow breastfeeding but not after a clinicalrelapse) during this timeframe was also recorded

Neuroradiology reports for brain MRIs as well as spinal cord(cervical and thoracic) MRIs when available performedduring the time interval from 12-month preconception to 12months after delivery were collected Neuroimaging reportsfor MS-related brain and spinal cord MRIs were manuallyreviewed for the presence of T2-weighted hyperintense le-sions that were new relative to a previous MRI and of gado-linium enhancing (Gd+) lesions when contrast wasadministered In some cases (24 brain and 29 overall)MRIs were performed and interpreted outside of UCSF theneuroimaging report andor UCSF clinicianrsquos note were usedto identify new T2 and Gd + lesions in these cases Clinicalindication for the MRI was categorized as either ldquomonitoringrdquo(surveillance treatment planning or treatment monitoring)or ldquonew symptomrdquo based on clinical notes andor imagingorders

Obstetrical data collected from medical record review for thestudy pregnancies included gravidity and parity pre-conception use of assisted reproductive technologies

GlossaryARR = annualized relapse rateCI = confidence intervalDMT = disease modifying therapy EDSS = ExpandedDisability StatusScale EMR = electronic medical record Gd+ = gadolinium enhancing IQR = interquartile range mAb = monoclonalantibody OR = odds ratio UCSF = University of California San Francisco

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 2 | March 2021 NeurologyorgNN

pregnancy complications gestational age at delivery or pregnancyloss infant sex and breastfeeding status (exclusive nonexclusiveor not at all) up to 12months after delivery Tominimize the riskof overestimating the impact of breastfeeding on clinical out-comes breastfeeding was assumed to be nonexclusive unlessexplicitly indicated to be exclusive by the neurologistrsquos or obste-tricianrsquos notes in the EMR Duration of exclusive breastfeedingwas also collected and based on previous reports women werecategorized as ldquoexclusive breastfeedingrdquo if they did so for at least 3months17 pregnancies with shorter duration of exclusivebreastfeeding nonexclusive breastfeeding or no breastfeedingwere together categorized as ldquonot exclusive breastfeedingrdquo

Statistical AnalysesDescriptive statistics were reported with mean and SD medianinterquartile range (IQR) and range or frequency as appropri-ate For pregnancies resulting in live births we then carried outfurther analyses

To determine how MS inflammatory activity changes withpregnancy we evaluated MRI activity by the proportion ofMRIs demonstrating new T2 hyperintense andor Gd+ le-sions (ldquoactive MRIrdquo) and clinical activity by the annualizedrelapse rate (ARR) Our primary outcome was difference inMRI inflammatory activity postpartum relative to before weperformed a number of other exploratory analyses We cal-culated proportion of active MRIs and ARR for each three-month period (ldquotrimesterrdquo) in the year preconception duringpregnancy and in the year postpartum

We compared the number of clinical relapses for each trimesterduring and after pregnancy to the year preconception using amixed-effects negative binomial regression model with a ran-dom person-specific relapse rate accounting for the repeatedmeasures nature of the data andmultiple pregnancies occurringin some women The outcome in the model was relapse countwith an offset by the natural log of disease duration ARR wascalculated from themodel and parameterized as exp(constant +beta) for each time period We also performed sensitivityanalyses for ARR for these time periods in 2 conditions ex-cluding pregnancies (1) with deliveries before 2010 and (2) inwomen treated with fingolimod or natalizumab preconception

For women withMRIs available both before and after pregnancywe compared the proportion of pregnancies with active brainMRIs (new T2 andor Gd+ lesions) in the year postpartum withthose of the year before pregnancy using conditional logisticregression accounting for women who contributed more thanone pregnancy determination of yesno activity was based on allMRIs available for each time period We evaluated the relation-ship between postpartum clinical relapse and MRI activity (newGd+ lesions) when performed within 60 days of symptom onsetusing univariable logistic regression for both the first trimesterand the entire year postpartum

We also evaluated for a clinically meaningful worsening inEDSS from prepregnancy baseline to last available within 12

months of delivery (for baseline score of 0 15-point increasebaseline score 10ndash55 10-point increase baseline score ge605-point increase as previously defined18) EDSS scoreswithin 30 days after a clinical relapse were not included

We evaluated for predictors of clinical relapse in the first trimesterpostpartum using univariable logistic regression We included

c disease duration and maternal age at conception given apriori relationships with inflammatory risk

c factors previously related to postpartum inflammatoryactivity ARR in the year before pregnancy relapses duringpregnancy (no relapses vs ge1 relapse)5 and breastfeedingstatus (nonexclusive vs exclusive for at least 3 months)910

c treatment factors prophylactic steroid use DMT in theyear preconception and DMT initiation in the 3 monthspostpartum each evaluated as any use vs no use

To evaluate predictors of brainMRI activity (newGd+ lesions) inthe first trimester postpartum we performed similar univariablelogistic regressions with the exception that we additionally in-cluded the occurrence of a new Gd+ lesion in the year beforepregnancy and we determined breastfeeding status (non-exclusive vs exclusive) andDMT initiation up to the time ofMRI

Based on previous findings in reported case series we also eval-uated additional clinical scenarios We evaluated the associationof early initiation of postpartumDMT(use vs nonuse) in the first3 months from delivery with ARR (independent sample t-test)and development of Gd+ lesions on MRI brain (univariable lo-gistic regression) in the second and third postpartum trimesters

To describe use of prophylactic steroids we qualitatively assessedrelapses across the first 2 trimesters (ie months zero to 6) post-partum inwomen receiving prophylactic steroids andbreastfeedingfor at least 3 months We also qualitatively evaluated relapses andMRI activity in the subset of women who used anti-CD20monoclonal antibody (mAb) therapies before conception andpostpartum

Alpha was set at 005 and all tests were two sided The mixed-effects negative binomial regression was performed in STATA 15(College Station TX) All other analyses were performed withJMP Pro software version 1500 We did not adjust for multiplecomparisons because of the exploratory nature of secondaryanalyses

Data AvailabilityDeidentified data will be shared with any qualified investigator byrequest

ResultsCharacteristics of the Study CohortA total of 155 pregnancies in 119 women were included Allpregnancies identified in the EMR had follow-up clinical data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 2 | March 2021 3

available for the entirety of their pregnancy 145 had at least 3months of postpartum follow-up The 119 women contributed 1(n = 90) 2 (n = 22) or 3 (n = 7) pregnancies 3 of these womencontributed a twin pregnancy each Baseline characteristics weretypical for a pregnancy cohort with a mean age of 33 years atconception and median EDSS of 20 (table 1) In 109 pregnan-cies the mother received DMT in the year before conceptionDMT was stopped before conception in 51 pregnancies duringthe first or second trimester in 49 and continued throughoutpregnancy for 9 (N = 8 glatiramer acetate N = 1 elected ter-mination to continue with natalizumab infusions)

After delivery there were various treatment approaches Forthe 145 live births with first trimester postpartum data in 26women DMT was initiated within 3 months of deliverywithout breastfeeding in 81 women DMT was deferred forbreastfeeding (exclusively [N = 49] or nonexclusively [N =32]) and 9 women initiated glatiramer acetate while breast-feeding (exclusively [N = 2] and nonexclusively [N = 7]) For29 pregnancies there was no initiation of DMT or breast-feeding (for ge 3 months) in the first trimester postpartum

Brain MRIs were available for 97 pregnancies in the yearbefore conception and for 137 women in the year postpartum(among 105 live-birth pregnancies 134 with gadolinium ta-ble e-1 lwwcomNXIA414) with mean (SD) time of firstMRI since delivery of 56 (36) months Most (107) of the 137postpartumMRIs had been obtained for monitoring purposes(104 with any previous MRI for comparison) and 30 in re-sponse to changes in symptoms In 70 pregnancies brainMRIs were available from both the year before (N = 85) andafter pregnancy (N = 94) The smaller number of postpartumcervical (N = 51) and thoracic spine (N = 18) MRIs or brainMRIs from pregnancies that did not result in live births (N =6) precluded statistical analysis There were no differences inage MS duration or ARR between the women who did anddid not have paired MRIs available

Pregnancy OutcomesAmong the 155 pregnancies 146 resulted in a live birthmdash133 atterm and 13 prematurely (table 1) Reasons for pregnancy loss(N = 9) included spontaneous abortion (N = 6) elective ter-mination (N = 2) and stillbirth (N = 1) Women experiencingpregnancy loss or termination did not differ in age disease du-ration or EDSS from women who experienced live births (p gt005 in independent sample t-tests) In the 6 cases of sponta-neous abortion treatment included none (N = 3) rituximab (N= 2 23 and 30 weeks before conception) and glatiramer acetate(N = 1 stopped 6 weeks after conception) One woman expe-rienced a stillbirth at 39w1d (etiology not available) and hadreceived an ocrelizumab infusion 10 weeks before conception

Among the 146 live-birth pregnancies mean gestational age(SD) at delivery was 392 (18) weeks (available N = 129)52 of infants were boys (available N = 142) One infant hadneonatal encephalopathy and died 6 hours after delivery themother had received no DMT in the year before conception

and her only pregnancy complication was an uncomplicatedurinary tract infection in the second trimester Mothersbreastfed after 136 of the 146 live births this breastfeedingwas exclusive for at least 3 months in 51 pregnancies

Live-Birth Pregnancies MS InflammatoryActivity During and After PregnancyIn the year before pregnancy for the 146 live-birth pregnan-cies the mean baseline ARR (95 CI [confidence interval])was 033 (024ndash045) This increased in the final trimesterbefore pregnancy when a clinical relapse occurred in 17 of146 pregnancies 4 women had not received DMT in theprevious year 5 had discontinued DMT in anticipation ofconception (including fingolimod or natalizumab in 2) and 8experienced breakthrough activity while on DMT (glatirameracetate interferon-β fingolimod or natalizumab) In the 48live-birth pregnancies in which DMT was discontinued inanticipation of conception a clinical relapse occurred in 7(15) between DMT discontinuation and conception

During pregnancy mean ARR decreased beginning in the firsttrimester and significantly so in the third trimester (010[000ndash026] p = 0017) compared with the year before preg-nancy (overall effect of time period on ARR p = 0004) Amongthe 19 pregnancies with a relapse during pregnancy 7 (39)occurred in women who discontinued fingolimod or natalizu-mab each of these relapses occurred within the second or thirdtrimester comprising 64 of relapses in this period

Postpartum the ARR in the first trimester (months 1ndash3) washigher (061 [040ndash093] p = 0012) than that of the yearbefore pregnancy and thereafter decreased to prepregnancylevels Altogether 17 women had at least one relapse in thefirst 3 months postpartum (available N = 145) and 38 overthe entire year postpartum (available N = 130) (table 2 figure1) In sensitivity analyses excluding pregnancies before 2010did not affect the results however excluding pregnancies inwomen treated with fingolimod or natalizumab before con-ception (N= 24) resulted in a lower ARR (050 [030ndash082]) inthe first trimester postpartum this did not reach statisticalsignificance compared with the year prepregnancy (p = 012)

We then evaluated postpartum MRI activity Among the 70pregnancies with an MRI performed both in the year beforeconception and in the year postpartum the overall proportion ofbrain MRIs demonstrating new T2 hyperintense lesions wasstable across all three-month periods before pregnancy HoweverMRI activity increased in the year postpartum 31 (52) preg-nancies had at least one ldquoactiverdquoMRI (newT2plusmnGd+) in the yearpostpartum compared with 19 (32) in the year before con-ception (N = 59 evaluated for both T2 and Gd+) (p lt 0001)Overall in the entire year postpartum 35 pregnancies (50)showed new T2 lesions compared with 18 (30) in the previousyear (N = 60 pregnancies with a previousMRI to evaluate for T2lesions p lt 0001) and 21 (30) showed Gd + lesions comparedwith 17 (25) in the previous year (N = 69 pregnancies withgadolinium MRIs p = 017) (table 3)


We then evaluated for a relationship between MRI activity andclinical relapse using all postpartumMRIs collected (N = 137 for105 pregnancies figure 2 and table e-1 lwwcomNXIA414) Ofthe 64 relapses experienced in the year postpartum only 34 hadaccompanying brainMRIs completed within plusmn 60 days of onset ofnew symptoms 78 of these showed new T2 lesions (N = 32with a previous MRI to enable identification of new T2 lesions)and 68 of these showed Gd+ lesions There was a significantrelationship between the occurrence of a clinical relapse and theobservation of a newGd+ lesion onMRI within plusmn 60 days (figure2) for thefirst trimester postpartum(plt0001 odds ratio [OR]=300 95 CI [46ndash1943]) and the entire postpartum year (p lt0001 OR = 211 95 CI [78ndash570]) Furthermore of the 137postpartum brain MRIs completed 107 were completed formonitoring purposes ie in the absence of clinical relapse (figure2 104 received gadolinium and had previous MRI for evaluationof new T2 lesions) Among these monitoring MRIs in the post-partum year (figure 2) and 32 revealed new T2 lesions (33104) and 11 revealed Gd+ lesions (11104) altogether 33had active MRIs (33101 evaluated for both T2 and Gd+) For 4pregnancies postpartum monitoring MRIs were followed byclinical relapse within 60 days (figure 2) these showed both newT2 andGd+ lesions (N= 2) newT2 lesions only (N= 1) and nochanges (N= 1)Overall 31ofMRIs performed for postpartummonitoring with no associated clinical relapse within 60 days wereldquoactiverdquo (N = 97 evaluated for both T2 and Gd+ figure 2)

EDSS ProgressionMedian (IQR) EDSS at evaluation closest to 12 months post-partum for live-birth pregnancies (mean [SD] of 58 [40]monthssince delivery) was 15 (10ndash20) (available N = 109) Among the99 pregnancies with both preconception and postpartum EDSSscores available 15 women (16) experienced a clinicallymeaningful increase in EDSS after delivery compared withpreconception

Table 1 Characteristics of the Study Cohort Relative toEach Pregnancy (N = 155 Pregnancies)

Before conception

No of women 119

No of pregnancies 155

Disease course at conception n

Healthya 1

Clinically isolated syndrome 9

Relapsing-remitting 145

Age at conception mean years plusmn SD 33 plusmn 5

Disease duration at conception median yearsIQR (range)b

6 3ndash9 (05ndash20)

EDSS in year before conception median IQR(range)c

20 10ndash25(00ndash60)

Annualized relapse rate before conception mean(95 CI)

037 (027ndash047)

DMT use in year before conception n ()

Glatiramer acetate 34 (22)

Interferon-βs 28 (18)

Dimethyl fumarate 10 (6)

Fingolimod 13 (8)

Natalizumab 12 (8)

Rituximab 10 (6)

Ocrelizumab 2 (1)

No use 46 (30)

Gravidity before conception median IQR (range) 1 0ndash1 (0ndash7)

Parity before conception median IQR (range) 0 0ndash1 (0ndash4)

No of pregnancies using ART 24

Postpartum

Pregnancy outcomes n

Term 133

Preterm 13

Stillbirth 1

Spontaneous abortion 6

Elective termination 2

EDSS in year postpartum median IQR (range)d 15 (10 20)

Time to postpartum DMT initiation medianmonths IQR (range)e


DMT use in the year postpartum n ()f




Table 1 Characteristics of the Study Cohort Relative toEach Pregnancy (N = 155 Pregnancies) (continued)

Fingolimod 13 (9)

Teriflunomide 1 (1)

Natalizumab 11 (7)

Rituximab 15 (10)

Ocrelizumab 9 (6)

No use 48 (33)

Abbreviations ART = assisted reproductive technologies CI = confidenceinterval DMT = disease-modifying therapy EDSS = Expanded DisabilityStatus Scale IQR = interquartile rangea N = 1 Clinically Isolated Syndrome diagnosed with clinical event in thirdtrimester of pregnancyb Excluding 1 individual with disease onset in pregnancyc Information available for 121 pregnanciesd Information available for 109 pregnanciese Delivery date and postpartumDMT start date available for 33 pregnanciesf The first DMT used during the period for which there was postpartumfollow up in live-birth pregnancies


Predictors of Clinical and Radiographic ActivityAfter Live Births

Clinical ActivityIn univariable analyses the odds of having at least one clinicalrelapse during the first trimester postpartumwas increased withthe occurrence of ge1 relapse during pregnancy (OR 62 95CI 22ndash175 p lt 0001) and reduced with exclusive breast-feeding for 3 months (OR 03 95 CI 01ndash09 p = 003)compared with nonexclusive breastfeeding (table 4) Restrict-ing the analyses to visits occurring between 2013 and 2018

(N = 20 clinical relapses for 110 pregnancies) did not affect thesignificance of the results (occurrence of ge1 relapse duringpregnancy OR 68 95 CI 22ndash216 p lt 0001 exclusivebreastfeeding OR 02 95 CI 003ndash07 p = 002)

MRI ActivityIn univariable analyses there was no statistically significant asso-ciation between new Gd+ lesions in the first trimester postpartumand any of our selected predictors (table 5) However both re-lapses during pregnancy and not exclusively breastfeeding showed

Table 2 MS Relapses During Pregnancy and Postpartum in Live-Birth Pregnancies (N = 146 Pregnancies for 113Women)

Period No of pregnanciesa No of pregnancies with ge1 relapse ARR (mean 95 CI) p Valueb

Year before conception 146 54 033 (024ndash045) Ref

Pregnancy

First trimester 146 8 019 (010ndash040) 016

Second trimester 146 7 017 (008ndash036) 009

Third trimester 146 4 010 (004ndash026) 002

Year postpartum

Months 1ndash3 145 25 061 (040ndash093) 001




Abbreviations ARR = annualized relapse rate CI = confidence intervalp values lt 005 are bold to indicate significancea Number of pregnancies followed for the entire three-month period Only relapses in these pregnancies are includedb Comparison to ARR during year before pregnancy p-values are calculated from amixed-effects negative binomial regression with a random person-specific relapserate ARR was calculated from the model and parameterized as exp(constant + beta) for each time period Overall effect of time period on ARR p = 0004

Figure 1 Annualized Relapse Rate Before During and After Pregnancies That Resulted in Live Births (N = 146 pregnancies)

The x-axis denotes each trimester (3-month pe-riod) before during and after pregnancy Errorbars represent 95 confidence intervals esti-mated with mixed-effects negative binomial re-gression Only pregnancies for which the patientwas followed for the entire three-month periodwere included (see Table 2 for N in each trimester)


a trend toward increased odds of new Gd+ lesions in the firsttrimester postpartum (005 ltp lt 010) Point estimates suggestedincreased odds of a postpartumGd+ lesion in womenwith relapsein pregnancy and decreased odds in women exclusively breast-feeding Restricting the analyses to visits occurring between 2013and 2018 did not affect the significance of the results

Selected Clinical Scenarios

Prophylactic SteroidsMonthly prophylactic steroids were administered in the first 3months postpartum for 10 pregnancies women did notbreastfeed in 4 Among the 6 women receiving steroids in thesetting of at least 3 months of breastfeeding (exclusively [N =5] nonexclusively [N = 1]) none relapsed and one exclu-sively breastfeeding had new T2 and Gd+ lesions on brainMRIs completed within the first 6 months postpartum

Early Initiation of DMT PostpartumOf 35 women resuming DMT (including anti-CD20 mAbs)within 3 months of delivery 33 were followed for the first 2trimesters postpartum Five experienced relapses after re-suming glatiramer acetate (15 1 relapse in 3 pregnancies and

2 relapses in 2 pregnancies) Of 13MRIs completed within thisperiod 7 demonstrated new T2 lesions and 2Gd+ lesionswomen with MRI activity were on either interferon-β or gla-tiramer acetate We did not find a statistically significant dif-ference in ARR or proportion with Gd+ lesions on brain MRIin the second or third trimesters postpartum for women whostarted DMT in the first 3 months after delivery vs those whodid not

Treatment With Anti-CD20 mAbsOf 12 anti-CD20-associated pregnancies in 10 the mothers wereinfused within 6 months of conception 8 resulted in live births 1in spontaneous abortion (rituximab case occurred after a previouscase series19) and 1 in stillbirth (ocrelizumab details not avail-able) In 2 additional pregnancies rituximab infusion occurred gt6months before conception 1 (infusion 30 weeks before) resultedin a spontaneous abortion at 10 weeks gestational age 1 (infusion10 months before) resulted in a healthy term live-birth but aclinical relapse occurred in the second trimester of pregnancyPostpartum the mother opted to nonexclusively breastfeed offDMT she experienced 3 clinical relapses with several new T2lesions demonstrated on MRI in the third trimester postpartum

Table 3 Disease Activity on Brain MRIs in 70 Live-Birth Pregnancies (N = 59 Women) With MRI Performed in the YearBefore Pregnancy and the Postpartum Year

Period

No ofpregnanciesevaluatedfor new T2lesionsa

No ofpregnancieswith new T2lesions (n[])

pValuebd

No ofpregnancieswith Gdgiven

No ofpregnancieswith Gdlesions (n[])

pValuebd

No ofpregnanciesevaluatedfor both newT2 and Gdlesions

No ofpregnancieswith new T2andor Gdlesions (n[])

pValuecd

Year beforeconception

60 18 (30) Ref 69 17 (25) Ref 59 19 (32) Ref

Months1ndash3

21 9 (43) mdash 25 7 (28) mdash mdash mdash mdash

Months4ndash6


Months7ndash9


Months10ndash12


Yearpostpartum

70 35 (50) lt0001 70 21 (30) 017 59 31 (52) lt0001

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12


Abbreviations Gd+ = gadolinium enhancingp values lt 005 are bold to indicate significancea N reflects no of pregnancies with MRI that had a comparison or baseline MRI to allow for evaluation of new T2 lesionsb p-values calculated with conditional logistic regressionc p-values calculated with conditional logistic regression N = 59 pregnancies with evaluation for both T2 and Gd+ lesions in the year prior to conception andthe year postpartumd Conditional logistic regression was only performed for the entire year postpartum due to small sample size in individual ldquotrimestersrdquo


In the 8 live-birth pregnancies with anti-CD20 treatment in the 6months before conception (N = 7 rituximab N = 1 ocrelizumab)none of themothers experienced a relapse between treatment andconception or during pregnancy All 8 were retreated with anti-CD20mAbs within 12months from delivery none experienced aclinical relapse during the year postpartum Of the 7 who un-derwent anMRI in the year postpartum one had a new T2 lesionbefore retreatment (compared with an MRI dated more than ayear before conception) none had Gd + lesions postpartum

DiscussionIncreased MS-related clinical relapse activity after pregnancy hasbeen reported for over 20 years6 but its association with MRIactivity has been incompletely assessed In the current study ofwomen with low disability (median EDSS of 20) we advancethese clinical findings by showing that these clinical symptomswere significantly associated with MRI activity (vs non-demyelinating etiologies) and that radiologic activity was signifi-cantly increased in the postpartum period compared with the yearbefore conception Furthermore radiologic disease activity wasfrequent in the postpartum year even on MRIs performed forsurveillance purposes almost one third of surveillance MRIsdemonstrated newT2 hyperintense andor gadolinium enhancinglesions Exclusive breastfeeding seemed to reduce the odds of earlypostpartum gadolinium enhancing lesions We secondarily con-firmed previous reports of increased risk of relapse activity post-partum which was decreased by exclusive breastfeeding for at least3 months and of a loss of the protective effect of pregnancy onrelapses in women discontinuing fingolimod and natalizumab720

Recently the question has been raised whether changes in MSclinical diagnosis and management (including recent revisions tothe McDonald Criteria that allow for earlier diagnosis and DMT

initiation21 and widespread use of DMTs) have resulted in amorebenign disease course less likely to have increased postpartuminflammatory disease activity8 However in our low-disabilitycohort of women with mean age 33 years median EDSS of 20and 70 with DMT use before pregnancy we confirmed anelevated rate of relapses postpartum and this was not associatedwith preconception ARR Interestingly postpartum relapses werenot significantly related to DMT use preconception possiblybecause of broader clinical trends toward avoiding long periods offDMT and mitigating rebound risk after fingolimod and natali-zumab This odds of postpartum relapse was however decreasedby exclusive breastfeeding for at least 3 months consistent withprevious reports and a meta-analysis9101722 Relapse duringpregnancy was the only other statistically significant predictor ofrelapses in the first trimester postpartum5 Early postpartumDMTresumption was not associated with reduced odds of postpartumrelapse However all DMTs were combined and we categorizedearlyDMTresumption as use or no use any time between deliveryand 3 months postpartum which did not allow for time-dependent analysis limiting conclusions that can be drawn

In addition to evaluating clinical and radiologic disease activitypostpartum and predictors of these we further probed com-mon clinical scenarios potentially influencing postpartuminflammatory activity Women who exclusively breastfed forat least 3 months experienced a lower rate of clinical relapseIn the small subset of 10 women treated with anti-CD20 mAbtherapies within 6 months of conception in this cohort andwithin 12 months of delivery none experienced clinical re-lapses or Gd+ lesions during pregnancy or postpartum

The current study has important limitations Our overallsample size although in line with other published cohortslimited statistical evaluation of some of the observed rela-tionships This is particularly the case in analyses of predictors

Figure 2 MRIs Completed Within 1 Year Postpartum

N = 137 MRIs for 105 pregnancies in 85 women


of postpartum radiologic activity given the limited number ofMRIs obtained Our primary analyses evaluated changes inMRI activity postpartum we did not perform Bonferronicorrections or otherwise adjust for multiple comparisons forour exploratory analyses The low number of outcome eventsin our cohort resulted in odds ratios with wide imprecise CIsthat should be cautiously interpreted to identify possibletrends and predictors of disease activity This exploratorystudy strongly implicates the need for more robust pro-spective evaluation of the predictors identified Our center is alarge referral center with possible biases toward patients withmore disease activity however preconception patient age andARR were similar to those reported from a large health sys-tem and disability was only slightly higher8 Nonethelessimportant differences between population-based and referralcenter-based cohorts highlight the need to follow womenprospectively to ensure minimal loss to follow-up and adequateaccounting for baseline risk factors Reliance on clinical reportscould have led to underascertainment of relapses both beforeduring and after pregnancy We also relied on clinical noteslabeling breastfeeding as explicitly exclusive in the EMR and

assumed nonexclusive breastfeeding for all other cases Al-though this is consistent with the field (eg17) relying oncliniciansrsquo reports and possibly variable definitions of exclusivebreastfeeding likely introduced bias thereby underestimatingthe protective effect of exclusive breastfeeding MRIs were notsystematically collected at prespecified time points rathertiming varied by patient clinician and insurance As a conse-quence we likely underestimated the true extent of new lesionsacross the entire year postpartum Furthermore there wassubstantial heterogeneity for example in time since DMTdiscontinuation preconception Reassuringly 78 of post-partum MRIs were performed for surveillance purposes ratherthan in reaction to a clinical change and we benefited fromstandardized UCSF radiology protocols for most patients Inaddition evaluation of predictors of postpartum clinical andradiologic disease activities may be subject to confounding asthe low number of outcome events precluded multivariableanalyses Of note we did not assess for specific mechanisms ofimmune activation postpartum23 Our patientsrsquo low disabilityprecluded analysis of pregnancy experiences of women withmore advanced disability (as is the case inmost cohorts1724) In

Table 4 Predictors of at Least One Relapse in the First Trimester Postpartum After Live Births (N = 145 Pregnancies for112 Women N = 25 Pregnancies With Clinical Relapse in the First Trimester)

Variable OR 95 CI p Valuea

Univariable analysis

Disease duration (per 1-year increase)b 11 09ndash11 091

Maternal age at the time of conception (per 1-year increase) 09 08ndash10 010

ARR before pregnancy (per 1-unit increase) 15 08ndash27 021

Relapses during pregnancy

No relapse 1 (ref)

ge1 relapse 62 22ndash175 lt0001

DMT use in year before conception

No use 1 (ref)

Any use 18 06ndash53 025

Initiation of DMT in 3 months postpartum

No use 1 (ref)


Prophylactic steroids in 3 months postpartum

No use 1 (ref)


Breastfeeding in 3 months postpartum

Nonexclusive 1 (ref)

Exclusive 03 01ndash09 003

Abbreviations ARR = annualized relapse rate CI = confidence interval DMT = disease modifying therapy OR = odds ratiop values lt 005 are bold to indicate significancea p value is 2-tailed from logistic regression modelsb N = 144 one mother excluded due to first clinical demyelinating event in the third trimester of pregnancy


these women decision-making25 and physiologic factors couldresult in different disease outcomes Finally although preg-nancy losses did not represent a focus of the current study welikely underascertained the frequency of early pregnancy losswhich may have occurred between 2 clinical visits

Our observations have several important implications Theassociation between clinical and radiographic inflammatorychanges improved our confidence that clinical relapsesreported in our and likely also othersrsquo cohorts do reflectunderlying inflammatory activity Our observations alsosupport a now-widely reported protective effect of breast-feeding In clinical practice the presence of inflammatorylesions in patients who are not suspected of clinical relapsesunderscores the importance of obtaining routine earlypostpartum MRIs to monitor women who have not re-sumed highly effective DMTs Indeed postpartum MRI

inflammatory activity may not always lead to clinical re-lapses with their own immediate effects on clinical dis-ability but demyelinated axons are nonetheless vulnerableto neurodegeneration and progressive clinical worseningPresence of asymptomatic new lesions could prompt phy-sicians to consider earlier DMT initiation or a change tomore effective DMT in the postpartum period Althoughprospective monitoring is needed to clarify which timepoints would best capture this activity in our clinicalpractice we routinely recommend a baseline MRI beforeconception attempts followed by a surveillance MRI in thefirst trimester postpartum2426 Overall management ofwomen in the postpartum period should include strategiesto decrease both clinical and radiologic disease activity

Study FundingThe authors report no targeted funding

Table 5 Predictors of New Gadolinium Enhancing Lesions on Brain MRIs Performed in the First Trimester Postpartum(N = 44 Pregnancies for 38 Women With MRI in the First Trimester Postpartum N = 12 Pregnancies With NewGadolinium Enhancing Lesion)

Variable OR 95 CI p valuea


Disease duration (per 1-year increase) 09 07ndash11 017




No relapse 1 (ref)

ge1 relapse 48 09ndash261 006

DMT in year before conception

No use 1 (ref)


Gd+ lesion on MRI in the year before conceptionb

No 1 (ref)

Yes 32 06ndash165 016


No use (before MRI) 1 (ref)

Any use (before MRI) 11 02ndash65 093





Nonexclusive (before and at time of MRI) 1 (ref)

Exclusive (before and at time of MRI) 03 01ndash11 007

Abbreviations ARR = annualized relapse rate CI = confidence interval DMT = disease-modifying therapy Gd+ = gadolinium enhancing OR = odds ratioa p value is 2-tailed from logistic regression modelsb N = 34 with available MRI in the year prior to conception among these 34 women N = 12 women with new Gd+ lesion


DisclosureA Anderson reports no disclosures relevant to the manuscriptKM Krysko receives Fellowship support from Biogen DrRutatangwa receives Fellowship support from Biogen T Krish-nakumar W Rowles C Chen and C Zhao report no disclosuresrelevant to the manuscript M Houtchens reports consulting andadvisory board fees from Biogen EMD-Serono Genzyme-SanofiNovartis and RocheGenentech She has received research sup-port from Genzyme-Sanofi Biogen and Merck R Bove has re-ceived consulting and advisory board fees from Alexion BiogenEMD-Serono Genzyme-Sanofi Novartis Pear Therapeutics andRoche-Genentech She has received research support from AkiliTherapeutics Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationAugust 14 2020 Accepted in final form December 14 2020

References1 Whitacre CC Reingold SC OrsquoLooney PA A gender gap in autoimmunity Science

19992831277ndash12782 Sadovnick AD Ebers GC Epidemiology of multiple sclerosis a critical overview Can

J Neurol Sci 19932017ndash293 Huang WJ Chen WW Zhang X Multiple sclerosis pathology diagnosis and treat-

ments Exp Ther Med 2017133163ndash31664 Hellwig K Haghikia A Rockhoff M Gold R Multiple sclerosis and pregnancy

experience from a nationwide database in Germany Ther Adv Neurol Disord 20125247ndash253

5 Vukusic S Hutchinson M Hours M et al Pregnancy and multiple sclerosis (thePRIMS study) clinical predictors of post-partum relapse Brain 20041271353ndash1360

6 Confavreux C Hutchinson M Hours MM Cortinovis-Tourniaire P Moreau T Rateof pregnancy-related relapse in multiple sclerosis Pregnancy in Multiple SclerosisGroup N Engl J Med 1998339285ndash291

7 Alroughani R Alowayesh MS Ahmed SF Behbehani R Al-Hashel J Relapse oc-currence in women with multiple sclerosis during pregnancy in the new treatment eraNeurology 201890e840-e846

8 Langer-Gould A Smith J Albers K et al Pregnancy-related relapses in a largecontemporary multiple sclerosis cohort No increased risk in the postpartum period[abstract] Neurology 202094e1939ndashe1949

9 Langer-Gould A Huang SM Gupta R et al Exclusive breastfeeding and the risk ofpostpartum relapses in women with multiple sclerosis Arch Neurol 200966958ndash963

10 Hellwig K Rockhoff M Herbstritt S et al Exclusive breastfeeding and the effect onpostpartum multiple sclerosis relapses JAMA Neurol 2015721132ndash1138

11 Digre KB Headaches during pregnancy Clin Obstet Gynecol 201356317ndash32912 van Slobbe AM Bohnen AM Bernsen RM Koes BW Bierma-Zeinstra SM Incidence

rates and determinants in meralgia paresthetica in general practice J Neurol 2004251294ndash297

13 Schned ES DeQuervain tenosynovitis in pregnant and postpartum women ObstetGynecol 198668411ndash414

14 Paavilainen T Kurki T Parkkola R et al Magnetic resonance imaging of the brainused to detect early post-partum activation of multiple sclerosis Eur J Neurol 2007141216ndash1221

15 Lebrun C Le Page E Kantarci O et al Impact of pregnancy on conversion to clinicallyisolated syndrome in a radiologically isolated syndrome cohort Mult Scler 2012181297ndash1302

16 van Walderveen MA Tas MW Barkhof F et al Magnetic resonance evaluation ofdisease activity during pregnancy in multiple sclerosis Neurology 199444327ndash329

17 Krysko KM Rutatangwa A Graves J Lazar A Waubant E Association betweenbreastfeeding and postpartum multiple sclerosis relapses a systematic review andmeta-analysis JAMA Neurol 202077327ndash338

18 University of California SFMSET Cree BAC Hollenbach JA Bove R et al Silentprogression in disease activity-free relapsing multiple sclerosis Ann Neurol 201985653ndash666

19 Das G Damotte V Gelfand JM et al Rituximab before and during pregnancy asystematic review and a case series in MS and NMOSD Neurol NeuroimmunolNeuroinflamm 20185e453

20 Novi G Ghezzi A Pizzorno M et al Dramatic rebounds of MS during pregnancyfollowing fingolimod withdrawal Neurol Neuroimmunol Neuroinflamm 20174e377

21 Portaccio E Ghezzi A Hakiki B et al Postpartum relapses increase the risk ofdisability progression in multiple sclerosis the role of disease modifying drugsJ Neurol Neurosurg Psychiatry 201485845ndash850

22 Pakpoor J Disanto G Lacey MV Hellwig K Giovannoni G Ramagopalan SVBreastfeeding and multiple sclerosis relapses a meta-analysis J Neurol 20122592246ndash2248

23 Kaplan TB Bove R Demyelinating disease and pregnancy In OrsquoNeil M editorNeurology and Psychiatry of Women Cham Springer 2019145ndash156

24 Bove R Alwan S Friedman JM et al Management of multiple sclerosis duringpregnancy and the reproductive years a systematic review Obstet Gynecol 20141241157ndash1168

25 Alwan S Yee IM Dybalski M et al Reproductive decision making after the diagnosisof multiple sclerosis (MS) Mult Scler 201319351ndash358

26 Krysko KM Graves JS Dobson R et al Sex effects across the lifespan in women withmultiple sclerosis Ther Adv Neurol Disord 2020131756286420936166

Appendix Authors

Name Location Contribution

AnnikaAnderson BA

University ofCalifornia SanFrancisco

Designed and conceptualized thestudy analyzed and interpretedthe data and drafted themanuscript for intellectual content

Kristen MKrysko MDMAS


Major role in the acquisition ofdata interpreted the data andrevised the manuscript forintellectual content

AliceRutatungwaDO


Interpreted the data and revisedthe manuscript for intellectualcontent

TanyaKrishnakumarBA


Major role in the acquisition ofdata and revised the manuscriptfor intellectual content

Chelsea ChenBA



WilliamRowles BA


Revised the manuscript forintellectual content

Chao Zhao MS University ofCalifornia SanFrancisco


MariaHoutchensMD MSc

Brigham andWomenrsquosHospital Boston

Designed and conceptualized thestudy and revised themanuscriptfor intellectual content

Riley Bove MDMSc


Designed and conceptualized thestudy analyzed and interpretedthe data and revised themanuscript for intellectualcontent


DOI 101212NXI000000000000095920218 Neurol Neuroimmunol Neuroinflamm

Annika Anderson Kristen M Krysko Alice Rutatangwa et al Clinical and Radiologic Disease Activity in Pregnancy and Postpartum in MS

This information is current as of February 19 2021

ServicesUpdated Information amp

httpnnneurologyorgcontent82e959fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent82e959fullhtmlref-list-1

This article cites 25 articles 4 of which you can access for free at

Subspecialty Collections

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httpnnneurologyorgcgicollectionmriMRIfollowing collection(s) This article along with others on similar topics appears in the

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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

MS typically begins between the ages of 20ndash40 years and has afemale-to-male ratio of 311ndash3 As such MS is primarily di-agnosed in women of reproductive age Several studies havedemonstrated that women experience fewer MS relapsesduring the immunotolerant state of pregnancy however anincrease in relapses has been observed postpartum4ndash6 Recentexceptions to this trend are notable First in the disease-modifying therapy (DMT) era women discontinuing DMTsinterfering with lymphocyte trafficking (fingolimod andnatalizumab) have increased relapse risk during pregnancydue to lsquoreboundrsquo disease activity7 Second in a more clinicallybenign population-based cohort fewer women were noted toexperience relapses postpartum8 Third exclusive breast-feeding has been associated with reduced postpartumrelapses910

Because clinical inflammatory activity postpartum could beconfused with other common neurologic conditions (such asmigraines11 meralgia paresthetica12 or DeQuervain teno-synovitis13) MRI detects new inflammatory lesions objec-tively Three small neuroimaging studies have reportedincreased inflammatory activity postpartum a cohort of 28Finnish women with MS14 women with radiologically iso-lated syndrome15 and a report of 2 patients with MS16 Thereis a need for larger case series of MRI-defined postpartuminflammatory activity

In the current study we evaluated inflammatory activity onbrain MRIs of women with MS during pregnancy and post-partum (primary) and clinical relapses (secondary) We hy-pothesized that inflammatory activity was increasedradiologically and clinically postpartum and that exclusivebreastfeeding was associated with a reduction in the rate ofboth outcomes

MethodsSample SelectionIn this retrospective analysis of prospectively collected clinicaldata we screened the electronic medical record (EMR) toidentify women followed at the University of California SanFrancisco (UCSF) MS and Neuroinflammation Center whobecame pregnant between 2015 and 2018 and for whomprospectively recorded clinical data were available We iden-tified 88 women with 103 pregnancies we also included 13additional pregnancies for these women that preceded thesearch window (2005ndash2015) From a separate study chartreview we included an additional 39 pregnancies between2005 and 2015 from 31 women Altogether we identified 119

women with 155 pregnancies Women participating in anongoing prospective pregnancy registry that began in 2018were excluded (N = 56 as of July 15 2020)

Standard Protocol Approvals Registrationsand Patient ConsentsThe UCSF Committee of Human Research approved thestudy protocol for retrospective analysis of EMRndashderived MSdata with no patient contact (Ref 13ndash11686)

Data CollectionMaternal MS clinical history was extracted from medical re-cords including year of MS onset disease course at concep-tion Expanded Disability Status Scale (EDSS) score clinicalrelapses and DMT use from the 12-month preconception tothe 12 months after delivery or pregnancy loss Both pre-scription records and clinician notes were reconciled duringchart review to determine DMT use Clinical relapses weredefined as new or worsening neurologic symptoms for at least24 hours in the absence of fever or infection as documentedin clinical records by the treating neurologist When EDSSwas not explicitly included in the treating neurologistrsquos notethis was extrapolated from the neurologic examinationdocumented symptoms and reported ambulatory abilities bya neurologist (KMK) blinded to timing of the EDSS re-garding pregnancy Any use of prophylactic steroids (pre-scribed for example when delaying DMT initiationpostpartum to allow breastfeeding but not after a clinicalrelapse) during this timeframe was also recorded

Neuroradiology reports for brain MRIs as well as spinal cord(cervical and thoracic) MRIs when available performedduring the time interval from 12-month preconception to 12months after delivery were collected Neuroimaging reportsfor MS-related brain and spinal cord MRIs were manuallyreviewed for the presence of T2-weighted hyperintense le-sions that were new relative to a previous MRI and of gado-linium enhancing (Gd+) lesions when contrast wasadministered In some cases (24 brain and 29 overall)MRIs were performed and interpreted outside of UCSF theneuroimaging report andor UCSF clinicianrsquos note were usedto identify new T2 and Gd + lesions in these cases Clinicalindication for the MRI was categorized as either ldquomonitoringrdquo(surveillance treatment planning or treatment monitoring)or ldquonew symptomrdquo based on clinical notes andor imagingorders

Obstetrical data collected from medical record review for thestudy pregnancies included gravidity and parity pre-conception use of assisted reproductive technologies

GlossaryARR = annualized relapse rateCI = confidence intervalDMT = disease modifying therapy EDSS = ExpandedDisability StatusScale EMR = electronic medical record Gd+ = gadolinium enhancing IQR = interquartile range mAb = monoclonalantibody OR = odds ratio UCSF = University of California San Francisco


































Before conception

No of women 119



Healthya 1









037 (027ndash047)





Fingolimod 13 (8)

Natalizumab 12 (8)

Rituximab 10 (6)

Ocrelizumab 2 (1)

No use 46 (30)




Postpartum


Term 133

Preterm 13

Stillbirth 1











Fingolimod 13 (9)

Teriflunomide 1 (1)

Natalizumab 11 (7)

Rituximab 15 (10)

Ocrelizumab 9 (6)

No use 48 (33)










Pregnancy




Year postpartum
















Period



pValuebd



pValuebd



pValuecd


60 18 (30) Ref 69 17 (25) Ref 59 19 (32) Ref

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12


Yearpostpartum

70 35 (50) lt0001 70 21 (30) 017 59 31 (52) lt0001

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12






















No relapse 1 (ref)



No use 1 (ref)



No use 1 (ref)



No use 1 (ref)


















No relapse 1 (ref)



No use 1 (ref)



No 1 (ref)

Yes 32 06ndash165 016









































Appendix Authors


AnnikaAnderson BA






AliceRutatungwaDO



TanyaKrishnakumarBA



Chelsea ChenBA



WilliamRowles BA








Riley Bove MDMSc
















Reprints




































Before conception

No of women 119



Healthya 1









037 (027ndash047)





Fingolimod 13 (8)

Natalizumab 12 (8)

Rituximab 10 (6)

Ocrelizumab 2 (1)

No use 46 (30)




Postpartum


Term 133

Preterm 13

Stillbirth 1











Fingolimod 13 (9)

Teriflunomide 1 (1)

Natalizumab 11 (7)

Rituximab 15 (10)

Ocrelizumab 9 (6)

No use 48 (33)










Pregnancy




Year postpartum
















Period



pValuebd



pValuebd



pValuecd


60 18 (30) Ref 69 17 (25) Ref 59 19 (32) Ref

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12


Yearpostpartum

70 35 (50) lt0001 70 21 (30) 017 59 31 (52) lt0001

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12






















No relapse 1 (ref)



No use 1 (ref)



No use 1 (ref)



No use 1 (ref)


















No relapse 1 (ref)



No use 1 (ref)



No 1 (ref)

Yes 32 06ndash165 016









































Appendix Authors


AnnikaAnderson BA






AliceRutatungwaDO



TanyaKrishnakumarBA



Chelsea ChenBA



WilliamRowles BA








Riley Bove MDMSc
















Reprints











Pregnancy




Year postpartum
















Period



pValuebd



pValuebd



pValuecd


60 18 (30) Ref 69 17 (25) Ref 59 19 (32) Ref

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12


Yearpostpartum

70 35 (50) lt0001 70 21 (30) 017 59 31 (52) lt0001

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12






















No relapse 1 (ref)



No use 1 (ref)



No use 1 (ref)



No use 1 (ref)


















No relapse 1 (ref)



No use 1 (ref)



No 1 (ref)

Yes 32 06ndash165 016









































Appendix Authors


AnnikaAnderson BA






AliceRutatungwaDO



TanyaKrishnakumarBA



Chelsea ChenBA



WilliamRowles BA








Riley Bove MDMSc
















Reprints











Period



pValuebd



pValuebd



pValuecd


60 18 (30) Ref 69 17 (25) Ref 59 19 (32) Ref

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12


Yearpostpartum

70 35 (50) lt0001 70 21 (30) 017 59 31 (52) lt0001

Months1ndash3


Months4ndash6


Months7ndash9


Months10ndash12






















No relapse 1 (ref)



No use 1 (ref)



No use 1 (ref)



No use 1 (ref)


















No relapse 1 (ref)



No use 1 (ref)



No 1 (ref)

Yes 32 06ndash165 016









































Appendix Authors


AnnikaAnderson BA






AliceRutatungwaDO



TanyaKrishnakumarBA



Chelsea ChenBA



WilliamRowles BA








Riley Bove MDMSc
















Reprints






















No relapse 1 (ref)



No use 1 (ref)



No use 1 (ref)



No use 1 (ref)


















No relapse 1 (ref)



No use 1 (ref)



No 1 (ref)

Yes 32 06ndash165 016









































Appendix Authors


AnnikaAnderson BA






AliceRutatungwaDO



TanyaKrishnakumarBA



Chelsea ChenBA



WilliamRowles BA








Riley Bove MDMSc
















Reprints















No relapse 1 (ref)



No use 1 (ref)



No 1 (ref)

Yes 32 06ndash165 016









































Appendix Authors


AnnikaAnderson BA






AliceRutatungwaDO



TanyaKrishnakumarBA



Chelsea ChenBA



WilliamRowles BA








Riley Bove MDMSc
















Reprints

































Appendix Authors


AnnikaAnderson BA






AliceRutatungwaDO



TanyaKrishnakumarBA



Chelsea ChenBA



WilliamRowles BA








Riley Bove MDMSc
















Reprints
















Reprints




clinical and radiologic disease activity in pregnancy and

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