Thrombolytic therapy of acute ischemic stroke during pregnancy

Thrombolytictherapy of acuteischemic stroke

during pregnancy

AbstractmdashThe authors report eight pregnant women with acute ischemicstroke treated with thrombolysis (rt-PA [recombinant human tissue plasmino-gen activator] or urokinase) Seven women recovered Two extracranial andtwo asymptomatic intracranial hemorrhages complicated treatment onewoman died of arterial dissection complicating angiography Three patientshad therapeutic abortions two fetuses were miscarried and two babies weredelivered healthy Although pregnant women may be treated safely withthrombolytics risks and benefits to mother and fetus must be carefullyweighed

NEUROLOGY 200666768ndash770

A Murugappan MD WM Coplin MD AN Al-Sadat MD KJ McAllen PharmD LH Schwamm MDLR Wechsler MD CS Kidwell MD JL Saver MD S Starkman MD YP Gobin MD

G Duckwiler MD M Krueger MD G Rordorf MD JP Broderick MD GE Tietjen MDand SR Levine MD

Increased risk of stroke during pregnancy is contro-versial12 and there is inadequate information re-garding the use of thrombolytics in pregnant womenThe package insert for recombinant human tissueplasminogen activator (rt-PA) (Activase) denotespregnancy to be a relative contraindication for ad-ministration of the drug and labels rt-PA as preg-nancy category C (uncertain safety) Others denote itto be pregnancy category B (presumed safety basedon animal studies)3 Urokinase (UK) is classified aspregnancy category B We report a series of eightpatients who underwent thrombolysis for acute isch-emic stroke (AIS) during pregnancy We also attemptto clarify the maternal safety and efficacy of rt-PA inpregnant women

Methods When a pregnant woman presented within 3 hours ofthe onset of AIS we communicated with 96 colleagues at 40 med-ical centers in four countries regarding whether any had treated apregnant woman with rt-PA for AIS Colleagues included those

with a professed academic and clinical interest in AIS therapy orneurologic and neurosurgical emergency and critical care We re-ceived notice of eight other cases from this selected group of phy-sicians One of these cases was unavailable for report here

We queried contributors regarding clinical presentation NIHStroke Scale (NIHSS) score medical history suspected etiology ofthe index stroke details of treatment course (including complica-tions if any) and clinical outcomes of mothers and fetuses TheNIHSS was recorded before and after treatment and at the mostrecent available patient follow-up

We searched the National Library of Medicinersquos MEDLINEdatabase from 1966 until June 2005 using the medical subjectheadings of thrombolytics in pregnancy rt-PA in pregnancy andstroke in pregnancy Additionally we queried Genentech for anyreports to the company regarding the use of this drug for ALS inpregnant women

Results We identified a total of eight women treatedwith thrombolytics for AIS during pregnancy Specific de-tails are summarized in the table Brief vignettes of theeight patients are available (appendix E-1 available on theNeurology Web site at wwwneurologyorg) GenentechInc denoted no reports to the manufacturer of rt-PA usefor AIS during pregnancy

The average maternal age was 32 years and the meangestational age was 11 weeks ranging from 4 to 37 weeksSeven of the mothers were in their first trimester and onewas in the third trimester The etiologies of their strokeswere discontinuation of anticoagulants in two mechanicalheart valve patients because of nausea in one and inabilityto afford low-molecular-weight heparin in the other andhypercoagulable state in five patients with a patent fora-men ovale in one of these women and polycythemia verawith thrombocytosis in another One patient had bacterialendocarditis Three patients received IV rt-PA in two ofthese the treating physicians were unaware of the preg-nancy and of these two one received rt-PA because of timeconstraints before the results of a urine pregnancy testwere available from the laboratory and in the other pa-tient a pregnancy test was not performed because of thepatientrsquos miscalculation of her last menstrual period Onepatient received intra-arterial rt-PA in an effort to reducefetal exposure Four patients received UK one for midbasi-lar total occlusion one locally into the left middle cerebralartery and two into the cerebral venous sinuses for cere-bral venous thrombosis

With one exception mothers recovered well from their

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the March 14 issue to find the title link for this article

From the Stroke and Neurosciences Critical Care Programs Departmentsof Neurology (AM WMC ANA-S) Neurological Surgery (WMC) andPharmacy Administration (KJM) Wayne State University School of Med-icine Detroit MI the Departments of Neurology Massachusetts GeneralHospital (LHS GR) Boston MA University of Pittsburgh (LRW)Pittsburgh PA University of Cincinnati (JPB) Cincinnati OH MedicalUniversity of Ohio at Toledo (GET) Toledo OH The Mount Sinai Schoolof Medicine and Stroke Center (SRL) New York NY and the Depart-ments of Neurology (CSK JLS SS GD) Emergency Medicine (SSMK) and Radiology (YPG) University of California Los Angeles CA

Supported in part by NIH grants NS 38905 (WMC) and 43992 (SRL)

Disclosure The authors report no conflicts of interest

Received June 30 2005 Accepted in final form November 28 2005

Address correspondence and reprint requests to Dr Steven R LevineStroke Center Box 1137 Department of Neurology The Mount SinaiSchool of Medicine One Gustave L Levy Place New York NY 10029-6574e-mail stevenlevinemssmedu

768 Copyright copy 2006 by AAN Enterprises Inc

strokes Adverse outcomes in these eight mothers includedone intrauterine hematoma (drained) one buttock hema-toma (managed conservatively) two asymptomatic smallintracranial hemorrhages (one at a catheter site and oneintraparenchymal both after local UK) and one fatal ma-lignant infarction as a result of arterial dissection compli-cating angioplasty (representing the only poor maternaloutcome) This death cannot be attributed solely and di-rectly to thrombolytic therapy There were no symptomaticintracerebral hemorrhages (ICHs) Of the seven survivingmothers (875) three elected to have therapeutic abor-tions There were two miscarriages both during the firsttrimester 2 to 3 days after UK administration Autopsy inone of these fetuses revealed lethal chromosomal anoma-lies Autopsy was not performed in the other fetus and itwas presumed to be a spontaneous first trimester abortionTwo babies were delivered at term without any complica-tions (one each intra-arterial [IA] rt-PA and IA UK)

The literature review identified 175 pregnant womentreated with any thrombolytic all but 3 for diseases otherthan stroke We identified 12 pregnant women withenough useful details reported who were treated specifi-cally with rt-PA for myocardial infarction and thromboem-bolic diseases other than stroke Of the 12 fetuses 6 (50)were healthy after delivery 1 died after delivery (see be-low) and 1 died because of emergent medical terminationof pregnancy in 3 of the reports fetal outcome was notclearly stated Overall 6 of the 12 babies were deliveredpreterm electively based on maternal interest and all ofthese babies except 1 were healthy One preterm babydelivered at 35 weeks of gestation by caesarean deliverydied on day 14 of respiratory distress syndrome autopsyrevealed cerebral cerebellar and subarachnoid hemor-rhages (12 full references available in appendix E-2)

Of the three cases reporting intra-arterial rt-PA treat-ment for stroke during pregnancy4-6 two were first trimes-

Table Summary of patients in the current series

Patient

Maternal andgestational

age Stroke etiologyStroketype Thrombolysis

Time totreatment and

doseMajor

complicationsMinor

complications Fetal outcome

A 37 y MVR embolism R MCA IV rt-PA 2 3 h None Intrauterinehematoma

MTP

12 wk NIHSS 19 09 mgkg

B 31 y Decreasedprotein Sactivity

L MCA IV rt-PA 3 h None None MTP

4 wk 09 mgkg

C 29 y AVR embolism R MCA IV rt-PA 3 h Death fromdissectionduringangioplasty

None Died


D 43 y AT III proteinC and Sdeficiencies

L MCA IA rt-PA 6 h None None Healthydelivery

37 wk NIHSS 25 21 mg

E 28 y Protein Cand SdeficienciesPFO

Basilar IA UK 12 h None Buttockhematoma

Healthydelivery

6 wk 600000 U

F 40 y PCV essentialthrombolysis

SSS Local UK Day 3 pulsesprays andcontinuedinfusion 1 wk

None Partialrecanalization

Fetal demise

6 wk Thrombosis

G 21 y DRVVT CVT Local UK 2 wk None Enlargement ofIVC-relatedhemorrhage

MTP

8 wk aPLs 400000 U

100000 U

100000 U

H 25 y Bacterialendocarditis

L MCA Local UK 6 h None Asymptomatic Spontaneousabortion

Firsttrimester

700000 U over70 min

ICH

MVR mitral valve replacement R right MCA middle cerebral artery rt-PA recombinant tissue plasminogen activator MTP medical termina-tion of pregnancy NIHSS NIH Stroke Scale L left AVR aortic valve replacement AT III antithrombin III IA intra-arterial PFO patentforamen ovale UK urokinase PCV polycythemia rubra vera SSS superior sagittal sinus DRVVT dilute Russel viper venom test aPLs an-tiphospholipid antibodies CVT cerebral venous thrombosis IVC intravenous catheter ICH intracerebral hemorrhage

March (1 of 2) 2006 NEUROLOGY 66 769

ter45 and one was third trimester6 Two women hadmarked neurologic improvement46 and one initially im-proved (recanalized the M1 segment) then worsened(small ICH) then further deteriorated (larger ICH) andthen partially improved5 All had normal babies delivered

Discussion Based on these case summaries andreports obtained from literature it seems that preg-nant women generally can be safely treated with IVor IA rt-PA or UK for AIS and can (but not always)have reasonably good outcomes Effects on fetal via-bility and any potential complications of thrombolyt-ics (eg teratogenicity) remain largely unknownThis series of eight patients is too small a number todraw any major efficacy or safety conclusions

The major obstetric concern regarding the use ofthrombolytics during pregnancy is their effect on theplacenta possibly resulting in premature labor pla-cental abruption or fetal demise A summary of theliterature regarding thrombolytic (rt-PA urokinaseetc) use in pregnancy identified 172 pregnantwomen affected with thromboembolic conditions whowere treated with thrombolytics7 however none ofthese patients were treated for stroke In that re-view 5 to 8 of deliveries from patients treatedwith thrombolytics occurred preterm which iswithin the reported 10 incidence of all preterm de-liveries in the United States8

Other concerns include hemorrhage during partu-rition or caesarean delivery This risk exists if thepatient goes into labor within the context sensitivehalf-time (the time of the drugrsquos effective physiologicand pharmacologic effects in the setting of the dis-ease process being studied) after administration ofthe thrombolytic

Regarding teratogenicity there are no data in theliterature or any reports to the manufacturer regard-ing this issue either for rt-PA or for UK One mightconsider that the teratogenic effect if any might beless with IA rt-PA use because the dose of IA rt-PAis less than the IV dose

The ethical situation of a young woman being lessdisabled as a result of thrombolytics for AIS vs therisk (teratogenicity prematurity death) of the un-born baby must be considered in each clinicalsituation

AcknowledgmentThe authors thank JJ King K Smoot and ME Redman forassistance with cases They also thank Dr Jose Biller for supply-ing references pertinent to the investigation

References1 Kittner SJ Stern BJ Feeser BR et al Pregnancy and the risk of stroke

N Engl J Med 1996335768ndash7742 James AH Bushnell CD Jamison MG Myers ER Incidence and risk

factors for stroke in pregnancy and the puerperium Obstet Gynecol2005106509ndash516

3 Briggs GGFR Yaffe SJ Drugs in pregnancy and lactation a referenceguide to fetal and neonatal risk 5th ed Baltimore Williams amp Wilkins1998

4 Dapprich M Boessenecker W Fibrinolysis with alteplase in a pregnantwoman with stroke Cerebrovasc Dis 200213290

5 Elford K Leader A Wee R Stys PK Stroke in ovarian hyperstimulationsyndrome in early pregnancy treated with intra-arterial rt-PA Neurol-ogy 2002591270ndash1272

6 Johnson DM Kramer DC Cohen E Rochon M Rosner M Weinberger JThrombolytic therapy for acute stroke in late pregnancy with intra-arterial recombinant tissue plasminogen activator Stroke 200536e53ndashe55

7 Turrentine MA Braems G Ramirez MM Use of thrombolytics for thetreatment of thromboembolic disease during pregnancy Obstet GynecolSurv 199550534ndash541

8 Cooper LG Effect of maternal age on birth outcomes among young ado-lescents Social Biol 19954222ndash35

APPLY NOW FOR UCNS SUBSPECIALTY CERTIFICATION EXAMSThe deadline to apply for the subspecialty examinations in Headache Medicine and Behavioral Neurology amp Neuro-psychiatry is April 15 2006 The exams will be offered in September 2006 Visit wwwucnsorgexam for the applica-tions and more information

770 NEUROLOGY 66 March (1 of 2) 2006

DOI 10121201wnl00002012729021615200666768-770 Neurology

A Murugappan W M Coplin A N Al-Sadat et al Thrombolytic therapy of acute ischemic stroke during pregnancy

This information is current as of March 13 2006

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strokes Adverse outcomes in these eight mothers includedone intrauterine hematoma (drained) one buttock hema-toma (managed conservatively) two asymptomatic smallintracranial hemorrhages (one at a catheter site and oneintraparenchymal both after local UK) and one fatal ma-lignant infarction as a result of arterial dissection compli-cating angioplasty (representing the only poor maternaloutcome) This death cannot be attributed solely and di-rectly to thrombolytic therapy There were no symptomaticintracerebral hemorrhages (ICHs) Of the seven survivingmothers (875) three elected to have therapeutic abor-tions There were two miscarriages both during the firsttrimester 2 to 3 days after UK administration Autopsy inone of these fetuses revealed lethal chromosomal anoma-lies Autopsy was not performed in the other fetus and itwas presumed to be a spontaneous first trimester abortionTwo babies were delivered at term without any complica-tions (one each intra-arterial [IA] rt-PA and IA UK)

The literature review identified 175 pregnant womentreated with any thrombolytic all but 3 for diseases otherthan stroke We identified 12 pregnant women withenough useful details reported who were treated specifi-cally with rt-PA for myocardial infarction and thromboem-bolic diseases other than stroke Of the 12 fetuses 6 (50)were healthy after delivery 1 died after delivery (see be-low) and 1 died because of emergent medical terminationof pregnancy in 3 of the reports fetal outcome was notclearly stated Overall 6 of the 12 babies were deliveredpreterm electively based on maternal interest and all ofthese babies except 1 were healthy One preterm babydelivered at 35 weeks of gestation by caesarean deliverydied on day 14 of respiratory distress syndrome autopsyrevealed cerebral cerebellar and subarachnoid hemor-rhages (12 full references available in appendix E-2)

Of the three cases reporting intra-arterial rt-PA treat-ment for stroke during pregnancy4-6 two were first trimes-

Table Summary of patients in the current series

Patient

Maternal andgestational

age Stroke etiologyStroketype Thrombolysis

Time totreatment and

doseMajor

complicationsMinor

complications Fetal outcome

A 37 y MVR embolism R MCA IV rt-PA 2 3 h None Intrauterinehematoma

MTP


B 31 y Decreasedprotein Sactivity

L MCA IV rt-PA 3 h None None MTP

4 wk 09 mgkg

C 29 y AVR embolism R MCA IV rt-PA 3 h Death fromdissectionduringangioplasty

None Died


D 43 y AT III proteinC and Sdeficiencies

L MCA IA rt-PA 6 h None None Healthydelivery

37 wk NIHSS 25 21 mg

E 28 y Protein Cand SdeficienciesPFO

Basilar IA UK 12 h None Buttockhematoma

Healthydelivery

6 wk 600000 U

F 40 y PCV essentialthrombolysis

SSS Local UK Day 3 pulsesprays andcontinuedinfusion 1 wk

None Partialrecanalization

Fetal demise

6 wk Thrombosis

G 21 y DRVVT CVT Local UK 2 wk None Enlargement ofIVC-relatedhemorrhage

MTP

8 wk aPLs 400000 U

100000 U

100000 U

H 25 y Bacterialendocarditis

L MCA Local UK 6 h None Asymptomatic Spontaneousabortion

Firsttrimester

700000 U over70 min

ICH

MVR mitral valve replacement R right MCA middle cerebral artery rt-PA recombinant tissue plasminogen activator MTP medical termina-tion of pregnancy NIHSS NIH Stroke Scale L left AVR aortic valve replacement AT III antithrombin III IA intra-arterial PFO patentforamen ovale UK urokinase PCV polycythemia rubra vera SSS superior sagittal sinus DRVVT dilute Russel viper venom test aPLs an-tiphospholipid antibodies CVT cerebral venous thrombosis IVC intravenous catheter ICH intracerebral hemorrhage

March (1 of 2) 2006 NEUROLOGY 66 769







































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Thrombolytic therapy of acute ischemic stroke during pregnancy