multiple sclerosis in pregnancy

8/8/2019 Multiple Sclerosis in Pregnancy

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Multiple sclerosis, or MS, is aninflammatory, demyelinatingdisease of the central nervoussystem.

Continual deposition of scleroticplaques leads to progressivephysical disability. Etiologicagents, exacerbating or remittingagents, and curative modalitieshave not been firmly established.

OVERV IEW



In 1868, French neurologistJean-Martin Charcot becamethe first person to describemultiple sclerosis as a distinct

disease, calling it sclerose en plaques .Charcot's triad of multiplesclerosis refers to nystagmus,intention tremor, and telegraphicspeech. He was one of theforemost neurologists of his day,and many other medical termsalso bear his name: Charcot's

joint, Charcot-Marie- Toothdisease, Charcot-Leydencrystals, and others.



Multiple Sclerosis is the most common neurological disease affectingadults in Canada*Canada has one of the highest rates of Multiple Sclerosis in the world*

It is much more common among white persons living in northern

latitudes, but individuals who move to northern climates before the ageof 15 years also have an increased risk.Females are twice as likely as males to develop MS, and it mostcommonly affects adults aged 18-50.

In some MS natural-history studies, overall life expectancy has beenshown to be only 5-7 years shorter, but patients usually die from

complications associated with MS and not from the disease itself

* Canadian Network of Multiple Sclerosis Clinics



Image courtesy of the W orld Health Organization



Multiple sclerosis refers to the plaques that are deposited in theparenchyma of the brain, brain stem, optic nerves, and spinal cord

These MS lesions are perivenular infiltration of lymphocytes andmacrophages that most commonly involve the white matter



Common findings include localized weakness, focal sensorydisturbances, hyperreflexia, stiffness, ocular findings, and gait

disturbances.Secondary problems include infections, skin ulcers, andmusculoskeletal complaints.

The 10-point Kurtzke Expanded Disability Status Scale allows for accurate rating of disease sign and symptom severity.

COMMON PROBLEMS



Medications used to treat MS are classified as either disease-modifying or symptomatic managementNo currently approved medications offer any hope of cure.For acute exacerbations, methylprednisolone is given to shorten the

flare duration.For patients with relapsing MS, interferon beta (1a or 1b), natalizumab,glatiramer acetate, and mitoxantrone are FD A approved.Mitoxantrone is also approved for secondary-progressive andprogressive-relapsing MS.No approved treatments are available for primary-progressive MS.

MED IC ATI ONS



Multiple Sclerosis is primarily a disease of women in their childbearing yearsMany women around the world diagnosed with MS are

fighting to live a normal life including becoming mothersBut« How informed are women about the diseaseinteraction with pregnancy?

MS A ND P A REN T HOOD



A lbrecht et al. BMC ResearchNotes 2010 3:91



The questionnaire was mailed to 300 women with definitive MS whohad been in contact with the Department of Neurology of the Universityof Luebeck in the past

G eneral demography, course of disease and medical treatment,

Perceived course of MS during and after pregnancy;Knowledge and personal beliefs regarding:a possible effect of MS on pregnancya possible effect of pregnancy on MSa possible effect of the puerperium on MSa possible effect of breastfeeding on MS




94 (62.7%) of 150 women had at least one child In 36 women (24%) the diagnosis MS was known at the time of their

last pregnancyFour questions concerning MS and pregnancy were asked using

multiple-choice. Four possible answers to each question were given,one of which was correct. Of a total of 146 patients, only sevenpatients (4.8%) gave correct answers to all four questions

The level of knowledge concerning issues related to MS andpregnancy in the group of patients with the diagnosis MS at the time of their last pregnancy was significantly higher (p < 0.001, chi-square-

test).




Scant information on the influence of MS on pregnancy and birthoutcomes in WW MS has been available

It has been generally assumed, from small studies, that the impact isminimal*

A PubMed scan using keywords ³MS and pregnancy outcomes´reveals 97 publications, compared to 554 citations using ³epilepsy andpregnancy outcomes.´

The majority of registries for MS are focused on the impact of pregnancy on disease or are specific to individual immune-modulatingdrugs in postmarketing surveillance efforts

MS EFFEC T S ON PRE G N A NCY

*Mueller B A , Zhang J, Critchlow C W . Birth outcomes and need for hospitalization after delivery among women with multiple sclerosis. A mJ Obstet G ynecol 2002;186:446±452.* W orthington J, Jones R, Crawford M, Forti A . Pregnancy and multiple sclerosis: a 3-year prospective study. J Neurol 1994;241:228 ±233* G iesser B. Reproductive issues in persons with multiple sclerosis: National Multiple Sclerosis Society: 2008: Clinical Bulletin: Informationfor Health Professionals.



Birth outcomes and need for hospitalization after delivery amongwomen with multiple sclerosis. Mueller B A , Zhang J, Critchlow C W . A m J Obstet G ynecol. 2002 Mar;186(3):446-52

This was a population-based cohort study that used W ashington State

linked birth certificate-hospital discharge records for singleton birthsfrom 1987 through 1996198 women with multiple sclerosis and a comparison group of 1584women

W ith the exception of maternal anemia, women with multiple sclerosiswere no more likely to have pregnancy or delivery complications, nor

were their infants more likely to be low birth weight or preterm or tohave malformations



P lanned vaginal births in women with multiple sclerosis: deliveryand birth outcome, Dahl J , Myhr KM , Daltveit A K, G ilhus NE . A ctaNeurol Scand Suppl. 2006;183:51-4. (Norway)Medical Birth Registry of Norway from 1988 to 2002. Intended vaginal

births in this time period were 449 births given by MS mothers and851,060 control births The MS mothers had a higher rate of induction of labour, and there

was a strong trend for slower progression of second stage of labour and increased use of forceps

The MS group had lower birth weight and length of the neonates The frequency of birth defects and the neonatal mortality were not

increased in the MS group



P regnancy, delivery and birth outcome in different stages of maternalmultiple sclerosis. Dahl J , Myhr KM , Daltveit A K, G ilhus NE . JNeurol. 2008 May;255(5):623-7 (Norway)

Mothers with MS were identified through linkage of the Norwegian MSRegistry and the Medical Birth Registry of Norway (1967-2002). A ll pre MSbirths (n = 1910), early MS births (n = 555), and manifest MS births (n =308) were compared

There was a significantly lower mean birth weight in term births (adjustedfor gestation in weeks, mother's age, time period and caesarean section)in the manifest MS compared to the pre MS group (P = 0.046)

The rate of birth complications and interventions did not differ between thethree groups



D oes multiple sclerosis increase risk of adverse pregnancyoutcomes? A population-based study, Chen YH , Lin HL, Lin HC . MultScler. 2009 May;15(5):606-12 ( Taiwan)

Two nationwide population-based datasets, the birth certificate registryand the Taiwan National Health Insurance Research Dataset174 women who gave birth from 2001 to 2003, who were diagnosed withMS within the 2 years preceding the index deliveriescompared with healthy mothers, MS was independently associated with a2.25-fold risk of preterm birth (95% C I = 1.37-3.70) and a 1.89-fold (95%C I = 1.30-2.76) higher risk of babies small for gestational age, after adjusting for family income and maternal, paternal, and infantcharacteristicsMothers with MS were also more likely to have cesarean deliveries



O bstetric outcomes in women with multiple sclerosis andepilepsy.

Kelly VM, Nelson LM , Chakravarty EF .Neurology. 2009 Dec 1;73(22):1831-6

Studied the 2003-2006 Nationwide (US A ) Inpatient Sample, of theHealthcare Cost and Utilization Project, to estimate the number of deliveries in women with MS, epilepsy, DM, and the general obstetricpopulation.



Pregnancy outcomes included length of hospital stay, hypertensivedisorders including preeclampsia (H T N), premature rupture of membranes (PROM), intrauterine growth restriction ( IUG R), andcesarean delivery

Multivariable regression analyses used maternal age andrace/ethnicity as covariatesOf an estimated 18.8 million deliveries, 10,055 occurred in women withMS

Kelly VM, Nelson LM, Chakravarty EF: O bstetric outcomes in women with multiple sclerosis and epilepsy. Neurology. 2009 Dec1;73(22):1831-6



Kelly VM, Nelson LM, Chakravarty EF: O bstetric outcomes in women with multiple sclerosis and epilepsy. Neurology. 2009 Dec1;73(22):1831-6



The available published data confirms a significant increase in IUG R inwomen with MS.Patients with MS require more antenatal admissions

There is probably a higher risk of having a caesarean section.

Limited data suggests an increased risk of preterm birth.Because the available published data does not account for diseaseseverity and disability during pregnancy, we can not categorizepatients as ³High Risk´ or ³Low Risk´ MS patients.

The effect of concurrent use of long term medications, immune-modulators, and acute therapy of relapses during pregnancy is diluted

in the registry data.

SO«.



G latiramer A cetate is a category B drug. Limited data on perinatalexposure.1 case report of ureteral stenosis after 30-day exposure to glatiramer acetate 20 mg among 3 exposed patients*

Salminen HJ, Leggett H, Boggild M: G latiramer acetate exposure in pregnancy: preliminarysafety and birth outcomes. J Neurol. 2010 Jul 13

W eber-Schoendorfer C, Schaefer C: Multiple sclerosis, immunomodulators, and pregnancyoutcome: a prospective observational study. Mult Scler. 2009 Sep;15(9):1037-42Fragoso YD, Finkelsztejn A , Comini-Frota ER, da G ama PD, G rzesiuk A K, Khouri JM, A lves-LeonSV, Morales Rde R, Lana-Peixoto M A , Rocha CF: P regnancy and multiple sclerosis: the initialresults from a Brazilian database. A rq Neuropsiquiatr. 2009 Sep;67(3 A ):657-60

* N Fernández Liguori et al.: (EMEMAR study) M ultiple Sc lerosis , M ay 2009; vol. 15, 5: pp. 555-562

MS MED IC ATI ONS A ND PRE G N A NCY



Interferon Beta-1a and 1b are both category C drugs in pregnancy.Limited data of safety.³Ductus and oval foramen´ after 15-day exposure to interferon beta 1b250 g and hip dysplasia after 2-month exposure to interferon beta 1a

44 g among 23 patients exposed* W eber-Schoendorfer C, Schaefer C: Multiple sclerosis, immunomodulators, and pregnancy

outcome: a prospective observational study. Mult Scler. 2009 Sep;15(9):1037-42Hellwig K, Haghikia A , G old R: P arenthood and immunomodulation in patients with multiplesclerosis. J Neurol. 2010 A pr;257(4):580-3* N Fernández Liguori et al: (EMEMAR study) M ultiple Sc lerosis , M ay 2009; vol. 15, 5: pp. 555-562




Natalizumab is category C. But no data on human exposure exists inthe literature.

Mitoxantrone is category D. Only one patient is reported of having

used it in pregnancy.T

he baby hadIU

GR but no congenitalmalformations.*

De Santis M, Straface G , Cavaliere A F, Rosati P, Batocchi A P, Caruso A : T he first case of mitoxantrone exposure in early pregnancy. Neurotoxicology. 2007 May;28(3):696-7




Apart from methotrexate and cyclophosphamide, most drugs usedregularly to treat MS can safely be used by pregnant women

Intravenous steroids may be used with relative safety duringpregnancy

Maternal use of azathioprine is not associated with an increased risk of congenital malformations, though impaired foetal immunity, intrauterinegrowth retardation and prematurity are occasionally observedCyclosporin is not teratogenic, but may be associated with growthretardation and prematurity

IVIG is relatively safe in pregnancy




The influence of pregnancy in multiple sclerosis has been a matter of controversy for a long time

W omen with multiple sclerosis were discouraged from contemplatingpregnancy (Douglass and Jorgensen, 1948; T illman, 1950; Sweeney,

1953; Hutchinson, 1993; Sadovnick et al ., 1994; Rudick, 1995) due tothe possible deleterious effect of pregnancy on multiple sclerosis

PRE G N A NCY EFFEC T S ON MS



Korn-Lubetzki and colleagues found, in a large retrospective study,that the frequency of relapses of multiple sclerosis decreased duringpregnancy, increased in the immediate post-partum period and wassimilar to the frequency observed out of pregnancy when considering

the pregnancy year (9 months of pregnancy and the first 3 monthspost-partum).

KORN-LUBE T ZKI

Korn-Lubetzki I, Kahana E, Cooper G , A bramsky O. A ctivity of multiple sclerosis during pregnancy and puerperium. A nnNeurol 1984; 6 : 229±31



The Pregnancy in Multiple Sclerosis (PR IMS) study was the first largeprospective study of the natural history of multiple sclerosis in pregnantwomen254 women with multiple sclerosis during 269 pregnancies in 12

European countriesShowed a significant decline in the relapse rate during pregnancy,most marked in the third trimester, with a rebound increase in the first3 months post-partum. T here was no apparent acceleration of disability during the puerperium and neither breast-feeding nor epiduralanalgesia had any specific adverse effect.

PR IMS

Confavreux C, Hutchinson M, Hours MM, Cortinovis- Tourniaire P, Moreau T, Pregnancy in Multiple Sclerosis G roup. Rate of

pregnancy-related relapse in multiple sclerosis. New Engl J M

ed 1998; 339 : 285±9



PR IMS



Almost A LL published literature following the PR IMS trial confirms thesame findings.. It is currently common knowledge that pregnantwomen with MS have a considerable improvement during pregnancyand high rates of relapse during the first 3 months post partum.



P regnancy changes the expression of inflammation-related genesin patients with multiple sclerosis.

G enome-wide transcription analysis in peripheral blood mononuclear cells (PBMCs) from 12 women (7 MS patients and 5 healthy controls)

followed during their pregnancy Altered expression of 347 transcripts in non-pregnant MS patients withrespect to non-pregnant healthy controlsComplementary changes in expression, occurring during pregnancy,reverted the previous imbalance particularly for seven inflammation-related transcripts, SOCS2, T NF AI P3, NR4 A 2, CXCR4, POLR2J,

F A M49B, and S TAG 3L1

W HY T HE IMPROVEMEN T ?

G illi F et al. PLoS One. 2010 Jan 29;5(1):e8962.



During pregnancy, there is a measurable increase in the number of circulating CD4(+) IFN-gamma-producing cells

A decline in circulating CD4(+) IFN-gamma-producing cells leads topostpartum MS relapses. Our findings also suggest that the decline in

these cells may begin during late pregnancy and that lactationalamenorrhea induced by exclusive breastfeeding may be able tointerrupt this process.

W HY T HE IMPROVEMEN T ?

Langer- G ould A et al. Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple

sclerosis. A rch Neurol. 2010 Jan;67(1):51-7.



Hypothesis: Sexual steroids could exert beneficial effects through amodulation of the immune state with a lowering of the pro-inflammatorylymphocyte responses of the T h1 type and an enhancement of anti-inflammatory responses of the T h2 type. T hey may also play a direct

role in remyelination of central nervous system lesions, as they do inthe peripheral nervous system, where progesterone increases theextent of myelin sheath formation after a cryolesion of the male mousesciatic nerveP revention of P ost- P artum Relapses with P rogestin and Estradiolin Multiple Sclerosis Study G roup : J Neurol Sci. 2009 Nov 15;286(1-

2):114-8

PRO G ES TI NS A ND ES T R A DIOL?



Serum leptin increases significantly in pregnant women. The third trimester serum leptin levels in healthy women were

comparable, 29.4 +/- 19.0 ng/ml, to MS pregnant womenSerum leptin levels (and serum leptin receptor) after delivery dropped

to 18.5 +/- 12.8 ng/ml in women with MS (P < 0.001) and to a lesser extend (22.0 +/- 17.5 ng/ml) in healthy women (P = 0.04) The postdelivery drop was associated with the occurrence of

postpartum relapse

SERUM LEP TI N?

Neuteboom RF et al. Serum leptin levels during pregnancy in multiple sclerosis. Mult Scler. 2009 A ug;15(8):907-12.



Data suggest that the expansion of circulatingCD4(+)CD25(+)Foxp3(+) regulatory T cells and the lower expressionof T -bet in CD4(+) T cells may account for the decreased MS activityduring pregnancy.

The expression of

T-bet, pS

TAT1 and pS

TAT3 in peripheral bloodCD4(+) and CD8(+) T cells and monocytes could be useful to identify

MS patients who will develop a relapse after delivery

CELLUL A R CH A NG ES?

Iorio R et al. T -bet, pS TAT1 and pS TAT 3 expression in peripheral blood mononuclear cells during pregnancy correlates

with post-partum activation of multiple sclerosis. Clin Immunol. 2009 A pr;131(1):70-83



The common knowledge after PR IMS and similar trials was thatbreastfeeding does not cause more relapse in women with MS.Exclusive breastfeeding and concomitant suppression of mensessignificantly reduce the risk of postpartum relapses in MS. T hese findingscall into question the benefit of foregoing breastfeeding to start MStherapies and should be confirmed in a larger prospective studies.

Hellwig K, G old R. Breastfeeding and multiple sclerosis in a G erman cohort. Mult Scler. 2008Jun;14(5):718.Hellwig K, Haghikia A , A gne H, Beste C, G old R. P rotective effect of breastfeeding in postpartumrelapse rate of mothers with multiple sclerosis.Iorio R, Nociti V, Frisullo G , Patanella A K, Tonali P A , Batocchi A P. Breastfeeding and multiplesclerosis. A rch Neurol. 2009 Dec;66(12):1580Kieseier BC, W iendl H. P ostpartum disease activity and breastfeeding in multiple sclerosisrevisited. Neurology. 2010 A ug 3;75(5):392-3A iras L, Jalkanen A , A lanen A , Pirttilä T, Marttila RJ. Breast-feeding, postpartum and prepregnancydisease activity in multiple sclerosis. Neurology. 2010 A ug 3;75(5):474-6.Langer- G ould A , Huang SM, G upta R, Leimpeter A D, G reenwood E, A lbers KB, Van Den EedenSK, Nelson LM. Exclusive breastfeeding and the risk of postpartum relapses in women withmultiple sclerosis. A rch Neurol. 2009 A ug;66(8):958-63

HO W A BOU T BRE A S T FEED ING ?



Langer- G ould A , Huang SM, G upta R, Leimpeter A D, G reenwood E, A lbers KB, Van Den Eeden SK, Nelson

LM. Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. A rch Neurol. 2009 A ug;66(8):958-63

multiple sclerosis in pregnancy

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