- About this Journal ·
- Abstracting and Indexing ·
- Advance Access ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Stroke Research and Treatment
Volume 2011 (2011), Article ID 606780, 13 pages
Ischemic Stroke during Pregnancy and Puerperium
1Dipartimento di Scienze Biomediche e Biotecnologie, Università degli Studi di Brescia, 25128 Brescia, Italy
2Dipartimento di Scienze Mediche e Chirurgiche, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1, 25100 Brescia, Italy
Received 10 August 2010; Accepted 4 December 2010
Academic Editor: Halvor Naess
Copyright © 2011 Elisabetta Del Zotto et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ischemic stroke during pregnancy and puerperium represents a rare occurrence but it could be a serious and stressful event for mothers, infants, and also families. Whenever it does occur, many concerns arise about the safety of the mother and the fetus in relation to common diagnostic tests and therapies leading to a more conservative approach. The physiological adaptations in the cardiovascular system and in the coagulability that accompany the pregnant state, which are more significant around delivery and in the postpartum period, likely contribute to increasing the risk of an ischemic stroke. Most of the causes of an ischemic stroke in the young may also occur in pregnant patients. Despite this, there are specific conditions related to pregnancy which may be considered when assessing this particular group of patients such as pre-eclampsia-eclampsia, choriocarcinoma, peripartum cardiomiopathy, amniotic fluid embolization, and postpartum cerebral angiopathy. This article will consider several questions related to pregnancy-associated ischemic stroke, dwelling on epidemiological and specific etiological aspects, diagnostic issue concerning the use of neuroimaging, and the related potential risks to the embryo and fetus. Therapeutic issues surrounding the use of anticoagulant and antiplatelets agents will be discussed along with the few available reports regarding the use of thrombolytic therapy during pregnancy.
Ischemic stroke is more common in men than in women until advanced age, when a higher incidence is observed in women . When younger patients are considered, females usually exceed males under 35, a period that coincides with the prime child-bearing years [2, 3]. Pregnancy and puerperium may partly contribute to this increased rate.
Ischemic stroke during pregnancy is a rare occurrence but it could be a serious and stressful event for mothers, infants, and also their families.
A conservative approach is frequently adopted because of concerns of any adverse effects of treatment and etiological investigations on the mother and the unborn fetus.
This article describes the physiological changes that may increase the risk of cerebral complications and deepens specific mechanisms, risk factors for ischemic stroke, and management of this subgroup of patients.
2. Maternal Changes during Pregnancy Predisposing to Ischemic Stroke
Maternal physiological alterations occur during pregnancy as a consequence of the variations of the hormonal status, involving the haemostatic and hemodynamic systems. Wether this adaptation could affect the risk of an ischemic stroke is still unclear and the relationship is likely complex.
2.1. Haemostatic Adaptations
Pregnancy is normally associated with significant changes in venous flow and in the molecular mediators of haemostasis, to the extent that the overall balance shifts towards a hypercoagulant effect  (Table 1).
Procoagulant changes are more marked around term and in the immediate postpartum period, presumably related to the expulsion of the placenta and release of thromboplastic substances at the site of separation. Blood coagulation and fibrinolysis get back to those of the nonpregnant state approximately 3 weeks after delivery .
This resulting hypercoagulable state in association with a venous stasis condition may likely account for an increased risk of thromboembolic complications, in particular, during the third trimester and the puerperium.
2.2. Hemodynamic Adaptations
In the first 10 weeks of pregnancy, a volume shifting develops with an increase of total body water, that remains stably increased until 1 to 2 weeks after delivery, after which it gradually returns to normal.
This hypervolemic state combined with an increasing circulatory demands of fetus and placenta results in a rise of 30% to 50% of cardiac output, stroke volume, and heart rate. Half of this change occurs during the first 8 weeks of pregnancy, reaching a peak at 25–30 weeks. During labour, there is a dramatic change in cardiac output which increases progressively as labour advances increasing by a mean value of 30%. Heart rate also increased consistently.
Then, in the first days after delivery, there is a strong fall of stroke volume and heart rate and cardiac output gradually decreases to 50% above prepregnancy level within 2 weeks after delivery and returns to normal by 6 to 12 weeks .
As a consequence of decrease in systemic vascular resistance, blood pressure starts to lower around the seventh week, hits the lowest levels at 24 to 32 weeks, and then increases progressively to prepregnancy levels at term.
Venous compliance increases throughout pregnancy, leading to decreased blood flow, increased stasis, and a tendency toward orthostatic pressure drops.
A remodelling in arterial composition with a reduction in collagen and elastin contents and a loss of distensibility that partially normalizes near term has been also observed during pregnancy .
In hospital-based and community-based reports, the incidence for ischemic strokes associated with pregnancy or puerperium varies considerably raging from 4.3 to 210 per 100,000 deliveries .
Potential explanations for this variability are: (1) differences in study designs, (2) small sample size of most studies, (3) inadequate consideration of referral bias, and (4) different definitions of strokes and stroke subtypes. Studies are also not uniform in definition of postpartum period. Moreover, estimation of incidence is influenced by those studies reported before neuroimaging use became widely available [8, 9]. When data published since 1985 are considered [7, 9–16], the incidence rates is reduced ranging from 4 to 41 per 100,000 pregnancies and decreases more considering only the three population-based studies, with a range from 4 to 11 cases per 100,000 deliveries [7, 9, 12] (Table 2).
The risk of stroke varies according to pregnancy stages. Kittner and coworkers estimated a relative risk of cerebral infarction of 0.7 (95% CI, 0.3 to 1.6) during pregnancy, which increased to 5.4 (95% CI, 2.9 to 10.0) during the six weeks after pregnancy (after a live birth or stillbirth) . In hospital–based series, the frequency of ischemic stroke has been observed to be higher in the third trimester, with a peak in the first postpartum week [7, 14, 15].
In a large Swedish cohort of over 650,000 women with over 1 million deliveries in an eight-year time period, the greatest risk of ischemic and hemorrhagic stroke was found around delivery [33,8 (95% CI 10.5 to 84.0), two days before and one day after with an increased but declining risk over the subsequent six weeks [8.3 (95% CI, 4.4 to 14.8] .
The reason of a clustering of events around delivery and postpartum period is not clear but implies a possible link with the coagulation profile of this stage. The large reduction of blood volume or the rapid hormonal changes following delivery have also been suggested to influence this stroke risk timing, perhaps through hemodynamic, coagulative, and vessel-wall changes .
4. Risk Factors and Associated Conditions
Data from the Nationwide Inpatient Sample in United States for the period from 2000 to 2001 showed that several medical conditions resulted associated with stroke in pregnancy such as hypertension, diabetes, heart disease, sickle cell disease, anemia, thrombocytopenia, and thrombophilia. Among lifestyle factors, alcohol, smoking, and substance abuse were found to be significantly associated to stroke in pregnancy . Pregnancy and delivery complications such as infection, transfusion, postpartum hemorrhage, and fluid and electrolyte imbalance were also linked to pregnancy-related stroke . However, this study was limited to data derived from discharge record abstraction and no precise information on stroke ischemic subtype were available.
Although the risk of pregnancy-related stroke is resulted to be higher among women aged 35 years and older , ischemic subtype has been associated with a younger maternal age  and a mean age under 30 has been reported in patients with pregnancy-related stroke in hospital-based series (Table 3).
Migraine headaches have been associated with a 17-fold increased risk of stroke in pregnancy , a relation which is stronger with ischemic subtype (OR 30.7, 17.4 to 34.1) . However, difficulties in differentiating between migraine as a manifestation or as a consequence of an ischemic stroke and others conditions such as severe pre-eclampsia, and migraine as an independent risk factor for ischemic stroke during pregnancy, limit the external validity of these findings.
Caesarean delivery has been shown to be associated with a 3–12 times increased risk of peripartum and postpartum stroke [20, 21]. Ischemic stroke risk was found to be significantly increased in women with Cesarean delivery and up to 6 months postpartum . However, an increased number of caesarean delivery among patients with previous stroke or with conditions that can increase the risk of stroke such as preeclampsia-eclampsia may confound this association.
5. Etiology of Ischemic Stroke in Pregnancy
As several causes of ischemic stroke in the young have been reported in pregnancy and the puerperium , in most cases it is quite difficult to distinguish whether pregnancy is coincidental or plays a role in the occurrence of the cerebral infarction. Notwithstanding, there are specific conditions related to pregnancy which may lead to ischemic stroke such as preeclampsia and eclampsia, and most rare disorders such as choriocarcinoma, amniotic fluid embolism, peripartum cardiomyopathy, and postpartum cerebral angiopathy. Since most studies included small numbers of patients and authors defined strokes and stroke etiologies differently, a comparison of the conditions that contribute to ischemic stroke in pregnancy is limited. However, while a high proportion of cases, ranging from 28% to 46%, has resulted to be undetermined, preeclampsia-eclampsia and cardioembolic causes represent the conditions that mainly contribute to ischemic stroke (Table 3).
6. Pregnancy-Specific Causes of Ischemic Stroke
6.1. Preeclampsia and Eclampsia
Preeclampsia-eclampsia, also known as toxemia, is a multisystem disorder that occurs in the later stages of pregnancy and in the first 6 to 8 weeks after delivery, accounting for a substantial maternal and perinatal mortality .
Pre-eclampsia is characterized by the presence of elevated gestational blood pressure, proteinuria, and oedema. Although this condition is usually asymptomatic, patients may complain of headaches, visual abnormalities, confusion, and impairment of consciousness. The onset of seizures or coma defines eclampsia . About 2% to 12% of patients with eclampsia develop a HELLP syndrome , a life-threatening condition characterized by hemolytic anemia (H), elevated liver enzymes (EL), and low platelet count (LP). Preeclampsia occurs in about 6% to 8% of all pregnancies, whereas eclampsia has an incidence of 1/1000 to 1/2000 deliveries in the United States .
Preeclampsia-eclampsia increases the risk of stroke [12, 22, 27]. The proportion of patients with ischemic stroke related to preeclampsia-eclampsia during pregnancies varies from 6% to 47% (Table 3). Moreover, preeclampsia is also founded to increase the risk of stroke later in life suggesting that these patients may be closely monitored and controlled for stroke risk factors also beyond the postpartum period .
Patients with severe pre-eclampsia or eclampsia may manifest focal neurological deficits, consistent with a clinical diagnosis of stroke and on neuroimaging both ischemic or hemorrhagic stroke may be found.
Clinical signs and neuroradiological lesions frequently reverse completely within a few days or weeks. Brain computed tomography (CT) and magnetic resonance imaging (MRI) show subcortical white matter lesions often with posterior predominance and, to a lesser extent, in the cortical grey matter predominantly affecting the parietooccipital region, consistent with the presence of reversible vasogenic edema. The appearance of cerebral edema on brain imaging is thought to be the consequence of disturbed cerebral autoregulation with cerebral endothelial leakage in the setting of severe hypertension. These findings are similar to those found in other vasculopathies associated to pre-eclampsia such as the posterior reversible encephalopathy syndrome (PRES). MR angiography may also show reversible vasospasm of the large and medium-sized vessels.
The pathogenesis is complex and not completely understood. This condition is characterized by abnormal vascular response to placentation and by endothelial cell dysfunction which represents common response leading to instability of vascular tone with vasospasm in various organs and activation of the coagulation system with microthrombi formation [24, 28, 29] with the consequence of ischemic damage in many organs.
The management of pre-eclampsia is aimed at delivery of the fetus and placenta and drug therapy of hypertension. Magnesium sulphate should be used for the treatment of seizures and in prophylaxis may prevent or reduce the rate of eclampsia and its complications in pre-eclamptic patients [24, 30].
Choriocarcinoma is a malignant neoplasm that arises from placental trophoblastic tissue, usually following a molar pregnancy but also term delivery, abortion, and ectopic pregnancy. It has a tendency to early metastasize, especially to the lungs, brain, liver, and vagina . Brain metastases are relatively common complication involving about one-fifth of patients. The clinical presentation of cerebral involvement includes headache, focal neurological deficits, seizures, encephalopathy, signs of elevated intracranial pressure, and excessively elevated serum β human choriogonadotrophic hormone level [32, 33].
Choriocarcinoma is a highly vascular tumor and is extremely prone to hemorrhage. In the brain, trophoblasts may invade blood vessels, just as they would in the uterus. Cerebral ischemic damage may be the result of thrombotic process in damaged vessels or consequence of trophoblastic cerebrovascular embolism .
6.3. Amniotic Fluid Embolism
Amniotic fluid embolism (AFE) is a rare complication of pregnancy, related more frequently to advanced age and multiparity. AFE occurs in the setting of a disrupted barrier between the amniotic fluid and maternal circulation. Why this entry into maternal circulation occurs in some women and not in others is not clearly understood.
The mortality rate varies from 61 to 86% and accounts for approximately 10% of all maternal deaths in the United States . AFE usually presents at term during labour and should be suspected in any pregnant patient, specifically those with ruptured membranes, who develop sudden onset dyspnea with hypoxia, acute hypotension, and/or cardiac arrest followed by a profound coagulopathy; a large percentage of survivors has a permanent hypoxia-induced neurological damage . Paradoxical cerebral amniotic fluid embolism is possible . Seizures is present in 10%–20% of cases and may be at times the first manifestation.
6.4. Postpartum Cerebral Angiopathy
Postpartum cerebral angiopathy is characterized by prolonged but reversible vasoconstriction of the cerebral arteries, usually associated with acute onset, severe, recurrent headaches, with or without additional neurologic signs and symptoms. It has been described using various labels, including postpartum angiopathy [35, 36], postpartum angiitis , and puerperal cerebral vasospasm . Although the pathophysiology is scarcely understood, a disturbance in the control of cerebral vascular tone seems to be a critical element, features similar to those observed in preeclampsia or eclampsia . Most patients have a history of uncomplicated pregnancy and normal labor and delivery, followed within days to a few weeks by acute onset of headache with or without various neurologic signs and symptoms. The brain MRI in patients with postpartum angiopathy may show areas of T2/FLAIR hyperintensity in any location, but especially in watershed areas between vascular territories. Multifocal segmental narrowing of large and medium-sized cerebral arteries may be present on both magnetic resonance angiography (MRA) and CT angiography. Arterial abnormalities are better visualized with CT angiography and conventional invasive catheter angiography; both of which require the use of iodinated contrast material. The MRI and MRA features may normalize with time, although extensive infarction may develop .
6.5. Peripartum Cardiomyopathy
Peripartum cardiomyopathy is a rare dilating cardiomyopathy, that develops in the last gestational month of pregnancy or in the first 5 months after delivery, with no identifiable cause for heart failure and in the absence of heart disease. Early development of a cardiomyopathy during pregnancy has also been described with similar clinical presentation and maternal outcome but with a higher incidence in twin pregnancies, shorter duration of pregnancy, and lower birth weight .
The true incidence of this condition is unknown; the reported rate is of 1 in 3000 to 1 in 4000 live births in the United States but there are geographical differences being rare in Europe and more common in Africa [41–43].
Risk factors include advanced age (>30 years), multiparity, obesity, twin pregnancies, preeclampsia, and severe hypertension during pregnancy [40, 44, 45]. The etiology remains uncertain. Suggested hypotheses include myocarditis, abnormal immune response to pregnancy, maladaptive response to the hemodynamic stresses of pregnancy, stress activated cytokines, viral infection, and prolonged tocolysis.
Clinical features consist of heart failure with dilated cardiac cavities. However, the diagnosis remains a challenge because many normal women in the last month of a normal pregnancy experience dyspnea, fatigue, and pedal edema, symptoms similar to early congestive cardiac failure. Peripartum cardiomyopathy is a diagnosis of exclusion, distinguished by rapid onset, occurrence in the peripartum period, and significant improvement in up to 50% of affected women.
Systemic and pulmonary embolization is frequently associated with this condition with an estimated incidence ranging from 25% to 40% . Neurologic deficits caused by thromboembolism can rarely be the presenting symptoms [46–48]. The incidence of ischemic stroke is about 5% . Additionally, cerebral infarction may result more rarely from cerebral hypoperfusion secondary to cardiac failure . Prognosis is dependent on recovery of systolic function. The majority of patients recover partially or completely but the mortality rate is high and the rate of heart transplantation is about 11% . Recurrences during subsequent pregnancies are common.
7. Brain Imaging Ischemic Stroke during Pregnancy
Imaging studies as part of the workup should be based on neurological indications but several concerns about fetal exposure to radiation arise for the clinician. The harmful effects of radiation depend on the stage of gestation at which the fetus is exposed, the total dose of radiation absorbed, and the rate at which the dose is absorbed . Fetal exposure to ionizing radiation from CT of the maternal head is extremely low. Potential risk of birth defects due to radiation are limited to the first few weeks, the embryogenesis period, when the patient may not be aware of the pregnancy. Radiation-protection precautions for the developing fetus should be used whenever the question of pregnancy arises.
A CT perfusion study should be avoided due to a significant increase of the X-ray exposure and to the necessity of administering intravenous contrast unless the information is critical to guide therapy. The use of iodinated contrast material during pregnancy may pose some risk to the fetus.
There are no evidence of adverse fetal effects in humans to the magnetic field exposure for magnetic resonance imaging (MRI). It has been hypothesized that some risk for the fetus may raise due to exposure to very powerful magnetic fields, minimal increases in body temperature, and loud tapping noises of the coils . Although a possible teratogenic effect has been found in some studies on animal models [53, 54], MRI is the preferred imaging option in pregnancy.
Regarding the use of gadolinium during MRI study, toxic effects are not known but depositions of the gadolinium ions in fetal tissue raises concerns. Moreover, animal reproduction studies showed that gadolinium at high dose have teratogenic effects [52, 55]. Therefore, the use of gadolinium should be avoided in a pregnant woman unless specifically indicated in particular situation where the decision must be made after a well-documented and thoughtful risk-benefit analysis [56, 57].
8. Treatment of Ischemic Stroke during Pregnancy
The choice of therapy for an ischemic stroke in pregnancy is complicated by potentials of fetal toxicity, in particular during the first trimester when the risk of teratogenicity is the highest. Therapeutic intervention is influenced by the identification of underlying etiology and the related effectiveness of the treatment, the possibility of adverse outcomes both to the mother and the fetus, and by the consideration of the term of pregnancy.
8.1. Prevention Treatment
Therapeutic decision is made difficult by the lack of randomized controlled trials that adequately compare treatment options for this group of patients. Therefore, the choice of agents for prophylactic strategies is largely based upon inferences from others studies, primarily on prevention of deep vein thrombosis and the use of anticoagulants in women with high-risk cardiac conditions.
According to the American Heart Association (AHA) guidelines for pregnant women with ischemic stroke or TIA and high-risk thromboembolic conditions such as coagulopathy and mechanical heart valves, three possible therapeutic alternatives may be considered: (a) adjusted-dose unfractionated heparin (UFH) throughout pregnancy, (b) adjusted-dose low molecular weight heparins (LMWHs) throughout pregnancy, (c) either UFH or adjusted-dose LMWHs until week 13, then restarted from the middle of the third trimester until delivery and warfarin at other times . For lower risk conditions, either UFH or LMWH therapy is recommended in the first trimester, followed by lowdose of aspirin for the remainder of the pregnancy .
8.2. Anticoagulant Treatment
UFH and LMWH do not have teratogenic effects since they do not cross the placenta and are not causes of fetal hemorrhage, although bleeding at the utero-placental junction is possible. Several studies strongly suggest that UFH/LMWH therapy is safe for the fetus [59–62]. By contrast, warfarin cross the placenta and can cause bleeding and malformation in the fetus [61, 63]. This agent is probable safe if administered during the first 6 weeks of gestation, but confers a risk of embryopathy if given between 6 weeks and 12 weeks of gestation . In addiction, warfarin cause an anticoagulant effect in the fetus, which is a concern, particularly at the time of delivery, when the combination with the trauma of delivery can lead to bleeding in the neonate. Therefore, warfarin is best avoided during pregnancy.
A major bleeding was reported in about 2% of the pregnant women treated with UFH , which is consistent with the observed rate in nonpregnant women receiving UFH and warfarin therapy. Since the possibility of a persistent anticoagulant effect (for up to 28 hours after the last injection of heparin), the use of UFH prior to labor may complicate the delivery increasing the risk of bleeding and contraindicates epidural analgesia. By contrast, LMWH therapy is rarely related with bleeding complications and in particular, it is not associated with an increased risk of severe peripartum bleeding . LMWH has also the advantages of producing a more stable coagulant response and lower incidence of osteoporosis. In about 3% of non pregnant patients, the UFH therapy can cause the development of the heparin-induced thrombocytopenia (HIT), an acquired immune condition IgGmediated, which is frequently complicated by extension of the preexisting thrombotic phenomena or new arterial thrombosis . In pregnant women who developed HIT and require ongoing anticoagulant therapy, use of the heparinoid danaparoid sodium is recommended because it is an effective antithrombotic agent, does not cross the placenta, and has much less cross-reactivity with UFH and, therefore, less potential to produce recurrent HIT than LMWH .
8.3. Antiplatelet Treatment
Wether treatment with aspirin during the first trimester of pregnancy is safe remains unclear. Although some retrospective studies reported an increased risk of fetal malformations in pregnant women using aspirin during first months, prospective studies did not confirmed this result.
A meta-analysis of eight studies (seven observational and one randomized) evaluated whether aspirin use during the first trimester of pregnancy is associated with an increased risk of congenital malformations and found no evidence of an overall increase in rates of major congenital malformations, suggesting that aspirin is safe even when used early in pregnancy . This analysis, however, showed that exposure to aspirin may be associated with an increased risk of gastroschisis, but the reliability of this result should be biased because of the limitations of the studies involved related to the use of other drugs, the selection of control subjects, and failure to definitively confirm the diagnosis in all patients . Potential complications of aspirin therapy in late pregnancy include fetal and maternal bleeding, premature closure of the ductus arteriosus, prolongation of labour, and delay in the onset of labor. According to data reported in another meta-analysis of 14 randomized studies including a total of 12,416 women, there is no evidence of fetal and maternal adverse effects of low-dose aspirin therapy (60 to 150 mg/d) administered during the second and the third trimester of pregnancy in women at risk for pre-eclampsia .
Therefore, available evidence suggests that low-dose aspirin (<150 mg/die) can be used safely during the second and third trimester; by contrast, the safety of higher dose of aspirin and/or aspirin ingestion during the first trimester is controversial.
Clopidogrel has not been found to cause significant feto-toxicity in animal studies at high doses, but there are no adequate and well-controlled studies in pregnant women so far. Only few case reported pregnant women who had successful outcome while taking clopidogrel [68, 69]. Thus, there are insufficient data to evaluate its safety in this setting.
Although dipyridamole has not been found to cause significant fetal adverse effects, there are no adequate data regarding safety or effectiveness of dipyridamole in humans during pregnancy.
8.4. Thrombolytic Treatment
No data are available about the use of thrombolytic treatment in pregnancy since this conditions was an exclusion criteria from clinical trials that validated these therapies. To date, the experience is limited only to case reports and case series, including different thromboembolic conditions such as pulmonary embolism, thrombosis of cardiac valve prosthesis, myocardial infarcts, and deep venous thrombosis, but also ischemic stroke . Due to its large molecular size, recombinant human tissue plasminogen activator (rt-PA) does not cross the placental barrier and studies on animal model have not shown teratogenic effects [71, 72]. However, fetal adverse effects remain largely unknown. Obstetric concerns are also raised by the possible effects on the placenta resulting in premature labor, placental abruption, or fetal demise.
In the last years, thrombolysis for acute ischemic stroke in pregnancy has been described in only 11 patients [70, 73–77] (Table 4). In most cases, patients received thrombolysis during the first trimester, sometimes inadvertently. One of six patient treated with systemic rt-PA died; the other five women were treated with catheter-based therapy (three intra-arterial rt-PA, one intra-arterial urokinase, and one local urokinase). Four patients did not have complications, while three had cerebral hemorrhage with clinical worsening in one case. Hemorrhagic complications also included intrauterine hematoma in one case and buttock hematoma in another one. Two women had an elective therapeutic abortion and one a spontaneous miscarriage.
Moreover, thrombolysis in the postpartum period was also reported, within fifteen hours after a cesarean delivery in one case and after six days from delivery in another one, without complications for the patients [78, 79].
However, because of the differences in etiologies, as well as in thrombolytic agents used and in the way of administration, it is difficult to draw any conclusion regarding safety or effectiveness although favorable maternal outcome was shown in many cases. Therefore, thrombolytic therapy should not be withheld for potentially disabling stroke during pregnancy, but in each clinical situation, since experience is limited, the ultimate choice of therapies must be based on careful assessment of the maternal and fetal risks and benefits.
9. Prognosis and Recurrence
In a previous study of late sixties, the maternal mortality immediately after stroke was reported to be 26% . Subsequently, maternal mortality following cerebral infarction has been reported not to exceed 14% and some studies reported no maternal deaths secondary to an ischemic stroke [7, 14]. However, a reliable estimate is difficult as a consequence of small number of events and different characteristic of published studies (Table 2).
In the Ile de France study, about half of the patients had a mild to moderate residual neurological deficit, with a modified Rankin score raging from 1 (3 patients) to 2 (2 patients) . Skidmore and coworkers reported that 73% of the patients were discharged home . Fetal outcome showed a death rate of about 12% .
Data regarding the influence of pregnancy on the risk of recurrent stroke are scarce, thereby making difficult to counsel women with a history of ischemic stroke about future pregnancies.
A multicenter French study on a group of 489 consecutive women aged 15 to 40 years with a first-ever arterial ischemic stroke or cerebral venous thrombosis showed that the risk of stroke recurrence associated with subsequent pregnancies is relatively small . In this study, twenty-eight patients (of 373 with arterial ischemic stroke) had the initial ischemic event during pregnancy or the puerperium. During a mean followup period of 5 years, 13 of the whole cohort had a recurrent stroke but only two of these occurred in a subsequent pregnancy, related to rare definite causes of stroke such as essential thrombocythemia and primary antiphospholipid syndrome. No woman whose initial stroke occurred during pregnancy had a recurrent stroke during subsequent pregnancies. The postpartum period, not the pregnancy itself, is associated with an increased risk of recurrent stroke (RR 9.68, 95% CI 1.2, 78.9), but these results may be limited by small number of observed events, lack of prospective record of recurrent events and subsequent pregnancies, and by a selection bias related to follow-up lost.
In line with these results, a descriptive study of a series of 23 patients with a history of a previous ischemic stroke showed no recurrence of ischemic stroke during subsequent pregnancy or after delivery .
- W. Rosamond, K. Flegal, K. Furie et al., “Heart disease and stroke statistics-2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee,” Circulation, vol. 117, no. 4, pp. e25–e46, 2008.
- J. Bogousslavsky and P. Pierre, “Ischemic stroke in patients under age 45,” Neurologic Clinics, vol. 10, no. 1, pp. 113–124, 1992.
- J. Putaala, A. J. Metso, T. M. Metso et al., “Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke the Helsinki young stroke registry,” Stroke, vol. 40, no. 4, pp. 1195–1203, 2009.
- K. A. Bremme, “Haemostatic changes in pregnancy,” Best Practice and Research: Clinical Haematology, vol. 16, no. 2, pp. 153–168, 2003.
- S. Hunter and S. C. Robson, “Adaptation of the maternal heart in pregnancy,” British Heart Journal, vol. 68, no. 6, pp. 540–543, 1992.
- K. Mackey, M. C. Meyer, W. S. Stirewalt, B. C. Starcher, and M. K. McLaughlin, “Composition and mechanics of mesenteric resistance arteries from pregnant rats,” American Journal of Physiology, vol. 263, no. 1, part 2, pp. R2–R8, 1992.
- T. Sharshar, C. Lamy, and J. L. Mas, “Incidence and causes of strokes associated with pregnancy and puerperium: a study in public hospitals of Ile de France,” Stroke, vol. 26, no. 6, pp. 930–936, 1995.
- J. N. Cross, P. O. Castro, and W. B. Jennett, “Cerebral strokes associated with pregnancy and the puerperium,” British medical journal, vol. 3, no. 612, pp. 214–218, 1968.
- D. O. Wiebers and J. P. Whisnant, “The incidence of stroke among pregnant women in Rochester, Minn, 1955 through 1979,” Journal of the American Medical Association, vol. 254, no. 21, pp. 3055–3057, 1985.
- C. C. Liang, S. D. Chang, S. L. Lai, C. C. Hsieh, H. Y. Chueh, and T. H. Lee, “Stroke complicating pregnancy and the puerperium,” European Journal of Neurology, vol. 13, no. 11, pp. 1256–1260, 2006.
- A. Awada, S. al Rajeh, R. Duarte, and N. Russell, “Stroke and pregnancy,” International Journal of Gynecology & Obstetrics, vol. 48, pp. 157–161, 1985.
- S. J. Kittner, B. J. Stern, B. R. Feeser et al., “Pregnancy and the risk of stroke,” New England Journal of Medicine, vol. 335, no. 11, pp. 768–774, 1996.
- A. G. Witlin, S. A. Friedman, R. S. Egerman et al., “Cerebrovascular disorders complicating pregnancy—beyond eclampsia,” American Journal of Obstetrics and Gynecology, vol. 176, no. 6, pp. 1139–1148, 1997.
- C. Jaigobin and F. L. Silver, “Stroke and pregnancy,” Stroke, vol. 31, no. 12, pp. 2948–2951, 2000.
- F. M. Skidmore, L. S. Williams, K. D. Fradkin, R. J. Alonso, and J. Biller, “Presentation, etiology, and outcome of stroke in pregnancy and puerperium,” Journal of Stroke and Cerebrovascular Diseases, vol. 10, no. 1, pp. 1–10, 2001.
- J. S. Jeng, S. C. Tang, and P. K. Yip, “Incidence and etiologies of stroke during pregnancy and puerperium as evidenced in Taiwanese women,” Cerebrovascular Diseases, vol. 18, no. 4, pp. 290–295, 2004.
- H. Salonen Ros, P. Lichtenstein, R. Bellocco, G. Petersson, and S. Cnattingius, “Increased risks of circulatory diseases in late pregnancy and puerperium,” Epidemiology, vol. 12, no. 4, pp. 456–460, 2001.
- A. H. James, C. D. Bushnell, M. G. Jamison, and E. R. Myers, “Incidence and risk factors for stroke in pregnancy and the puerperium,” Obstetrics and Gynecology, vol. 106, no. 3, pp. 509–516, 2005.
- C. D. Bushnell, M. Jamison, and A. H. James, “Migraines during pregnancy linked to stroke and vascular diseases: US population based case-control study,” BMJ, vol. 338, p. b664, 2009.
- D. J. Lanska and R. J. Kryscio, “Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis,” Stroke, vol. 31, no. 6, pp. 1274–1282, 2000.
- H. S. Ros, P. Lichtenstein, R. Bellocco, G. Petersson, and S. Cnattingius, “Pulmonary embolism and stroke in relation to pregnancy: how can high-risk women be identified?” American Journal of Obstetrics and Gynecology, vol. 186, no. 2, pp. 198–203, 2002.
- C. H. Tang, C. S. Wu, T. H. Lee et al., “Preeclampsia-eclampsia and the risk of stroke among peripartum in Taiwan,” Stroke, vol. 40, no. 4, pp. 1162–1168, 2009.
- J. L. Mas and C. Lamy, “Stroke in pregnancy and the puerperium,” Journal of Neurology, vol. 245, no. 6-7, pp. 305–313, 1998.
- B. Sibai, G. Dekker, and M. Kupferminc, “Pre-eclampsia,” The Lancet, vol. 365, no. 9461, pp. 785–799, 2005.
- D. Leys, C. Lamy, C. Lucas et al., “Arterial ischemic strokes associated with pregnancy and puerperium,” Acta Neurologica Belgica, vol. 97, no. 1, pp. 5–16, 1997.
- S. K. Sharma, “Pre-eclampsia and eclampsia,” Seminars in Anesthesia, vol. 19, no. 3, pp. 171–180, 2000.
- D. W. Brown, N. Dueker, D. J. Jamieson et al., “Preeclampsia and the risk of ischemic stroke among young women: results from the stroke prevention in young women study,” Stroke, vol. 37, no. 4, pp. 1055–1059, 2006.
- P. Zunker, C. Hohenstein, and G. Deuschl, “Pathophysiology of Pre-eclampsia/eclampsia syndrome,” Journal of Neurology, vol. 248, no. 5, pp. 437–438, 2001.
- J. M. Roberts and D. W. Cooper, “Pathogenesis and genetics of pre-eclampsia,” The Lancet, vol. 357, no. 9249, pp. 53–56, 2001.
- B. M. Sibai, “Magnesium sulfate prophylaxis in preeclampsia: lessons learned from recent trials,” American Journal of Obstetrics and Gynecology, vol. 190, no. 6, pp. 1520–1526, 2004.
- A. Ilancheran, S. S. Ratnam, and G. Baratham, “Metastatic cerebral choriocarcinoma with primary neurological presentation,” Gynecologic Oncology, vol. 29, no. 3, pp. 361–364, 1988.
- N. Saad, Y. M. Tang, E. Sclavos, and S. L. Stuckey, “Metastatic choriocarcinoma: a rare cause of stroke in the young adult,” Australasian Radiology, vol. 50, no. 5, pp. 481–483, 2006.
- C. Y. Huang, C. A. Chen, C. Y. Hsieh, and W. F. Cheng, “Intracerebral hemorrhage as initial presentation of gestational choriocarcinoma: a case report and literature review,” International Journal of Gynecological Cancer, vol. 17, no. 5, pp. 1166–1171, 2007.
- S. L. Clark, G. D. V. Hankins, D. A. Dudley, G. A. Dildy, and T. Flint Porter, “Amniotic fluid embolism: analysis of the national registry,” American Journal of Obstetrics and Gynecology, vol. 172, pp. 1158–1169, 1995.
- J. Bogousslavsky, P. A. Despland, F. Regli, and P. Y. Dubuis, “Postpartum cerebral angiopathy: reversible vasoconstriction assessed by transcranial Doppler ultrasounds,” European Neurology, vol. 29, no. 2, pp. 102–105, 1989.
- T. L. Williams, T. G. Lukovits, B. T. Harris, and C. Harker Rhodes, “A fatal case of postpartum cerebral angiopathy with literature review,” Archives of Gynecology and Obstetrics, vol. 275, no. 1, pp. 67–77, 2007.
- D. Farine, J. Andreyko, and A. Lysikiewicz, “Isolated angiitis of brain in pregnancy and puerperium,” Obstetrics and Gynecology, vol. 63, no. 4, pp. 586–588, 1984.
- J. J. Geraghty, D. B. Hoch, M. E. Robert, and H. V. Vinters, “Fatal puerperal cerebral vasospasm and stroke in a young woman,” Neurology, vol. 41, no. 7, pp. 1145–1147, 1991.
- A. B. Singhal, “Postpartum angiopathy with reversible posterior leukoencephalopathy,” Archives of Neurology, vol. 61, no. 3, pp. 411–416, 2004.
- U. Elkayam, M. W. Akhter, H. Singh et al., “Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation,” Circulation, vol. 111, no. 16, pp. 2050–2055, 2005.
- J. Abboud, Y. Murad, C. Chen-Scarabelli, L. Saravolatz, and T. M. Scarabelli, “Peripartum cardiomyopathy: a comprehensive review,” International Journal of Cardiology, vol. 118, no. 3, pp. 295–303, 2007.
- G. D. Pearson, J. C. Veille, S. Rahimtoola et al., “Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review,” Journal of the American Medical Association, vol. 283, no. 9, pp. 1183–1188, 2000.
- A. Cenac and A. Djibo, “Postpartum cardiac failure in Sudanese-Sahelian Africa: clinical prevalence in western Niger,” American Journal of Tropical Medicine and Hygiene, vol. 58, no. 3, pp. 319–323, 1998.
- W. N. K. A. Van Mook and L. Peeters, “Severe cardiac disease in pregnancy, part II: impact of congenital and acquired cardiac diseases during pregnancy,” Current Opinion in Critical Care, vol. 11, no. 5, pp. 435–448, 2005.
- R. M. Lang, M. B. Lampert, and A. Poppas, “Peripartal cardiomyopathy,” in Cardiac Problems in Pregnancy, U. Elkayam and N. Gleicher, Eds., Wiley-Liss, New York, NY, USA, 3rd edition, 1998.
- A. L. Heider, J. A. Kuller, R. A. Strauss, and S. R. Wells, “Peripartum cardiomyopathy: a review of the literature,” Obstetrical and Gynecological Survey, vol. 54, no. 8, pp. 526–531, 1999.
- F. G. Cunningham, J. A. Pritchard, and G. D.V. Hankins, “Peripartum heart failure: idiopathic cardiomyopathy or compounding cardiovascular events?” Obstetrics and Gynecology, vol. 67, no. 2, pp. 157–168, 1986.
- M. T. Hodgman, M. S. Pessin, and D. C. Homans, “Cerebral embolism as the initial manifestation of peripartum cardiomyopathy,” Neurology, vol. 32, no. 6, pp. 668–671, 1982.
- R. C. Connor and J. H. Adams, “Importance of cardiomyopathy and cerebral ischaemia in the diagnosis of fatal coma in pregnancy,” Journal of Clinical Pathology, vol. 19, no. 3, pp. 244–249, 1966.
- A. G. Witlin, W. C. Mabie, and B. M. Sibai, “Peripartum cardiomyopathy: an ominous diagnosis,” American Journal of Obstetrics and Gynecology, vol. 176, pp. 182–188, 1997.
- E. J. Hall and A. J. Giaccia, Radiobiology for the Radiologist, Lippincott Williams and Wilkins, Philadelphia, Pa, USA, 2006.
- ACOG Committee on Obstetric Practice, “ACOG Committee Opinion Number 299. Guidelines for diagnostic imaging during pregnancy,” Obstetrics & Gynecology, vol. 104, pp. 647–651, 2004.
- D. A. Tyndall and K. K. Sulik, “Effects of magnetic resonance imaging on eye development in the C57BL/6J mouse,” Teratology, vol. 43, no. 3, pp. 263–275, 1991.
- Y. P. Yip, C. Capriotti, S. L. Talagala, and J. W. Yip, “Effects of MR exposure at 1.5 T on early embryonic development of the chick,” Journal of Magnetic Resonance Imaging, vol. 4, no. 5, pp. 742–748, 1994.
- J. A.W. Webb, H. S. Thomsen, S. K. Morcos et al., “The use of iodinated and gadolinium contrast media during pregnancy and lactation,” European Radiology, vol. 15, no. 6, pp. 1234–1240, 2005.
- E. Kanal, J. P. Borgstede, A. J. Barkovich et al., “American College of Radiology white paper on MR safety,” American Journal of Roentgenology, vol. 178, no. 6, pp. 1335–1347, 2002.
- E. Kanal, J. P. Borgstede, A. J. Barkovich et al., “American College of Radiology white paper on MR safety. 2004 Update and revisions,” American Journal of Roentgenology, vol. 182, no. 5, pp. 1111–1114, 2004.
- R. L. Sacco, R. Adams, G. Albers et al., “Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association council on stroke—co-sponsored by the council on cardiovascular radiology and intervention. The American Academy of Neurology affirms the value of this guideline,” Stroke, vol. 37, no. 2, pp. 577–617, 2006.
- J. Lepercq, J. Conard, A. Borel-Derlon et al., “Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies,” British Journal of Obstetrics and Gynaecology, vol. 108, no. 11, pp. 1134–1140, 2001.
- T. E. Warkentin, M. N. Levine, J. Hirsh et al., “Heparin-induced thrombocytopenia in patients treated with low-molecular- weight heparin or unfractionated heparin,” New England Journal of Medicine, vol. 332, no. 20, pp. 1330–1335, 1995.
- J. S. Ginsberg, J. Hirsh, D. C. Turner, M. N. Levine, and R. Burrows, “Risks to the fetus of anticoagulant therapy during pregnancy,” Thrombosis and Haemostasis, vol. 61, no. 2, pp. 197–203, 1989.
- J. S. Ginsberg, G. Kowalchuk, J. Hirsh, P. Brill-Edwards, and R. Burrows, “Heparin therapy during pregnancy. Risks to the fetus and mother,” Archives of Internal Medicine, vol. 149, no. 10, pp. 2233–2236, 1989.
- J. G. Hall, R. M. Pauli, and K. M. Wilson, “Maternal and fetal sequelae of anticoagulation during pregnancy,” American Journal of Medicine, vol. 68, no. 1, pp. 122–140, 1980.
- I. A. Greer and C. Nelson-Piercy, “Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy,” Blood, vol. 106, no. 2, pp. 401–407, 2005.
- S. M. Bates, I. A. Greer, I. Pabinger, S. Sofaer, and J. Hirsh, “Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition),” Chest, vol. 133, no. 6, supplement, pp. 844S–886S, 2008.
- E. Kozer, S. Nikfar, A. Costei, R. Boskovic, I. Nulman, and G. Koren, “Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis,” American Journal of Obstetrics and Gynecology, vol. 187, no. 6, pp. 1623–1630, 2002.
- A. Coomarasamy, H. Honest, S. Papaioannou, H. Gee, and K. S. Khan, “Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review,” Obstetrics and Gynecology, vol. 101, no. 6, pp. 1319–1332, 2003.
- J. H. Schiff, A. Gries, R. Ehehalt, M. Elsaesser, H. A. Katus, and F. J. Meyer, “A pregnant woman with acute myocardial infarction due to coronary artery dissection: pre-hospital and in-hospital management,” Resuscitation, vol. 73, no. 3, pp. 467–474, 2007.
- P. Klinzing, U. R. Markert, K. Liesaus, and G. Peiker, “Case report: successful pregnancy and delivery after myocardial infarction and essential thrombocythemia treated with clopidrogel,” Clinical and Experimental Obstetrics and Gynecology, vol. 28, no. 4, pp. 215–216, 2001.
- G. Leonhardt, C. Gaul, H. H. Nietsch, M. Buerke, and E. Schleussner, “Thrombolytic therapy in pregnancy,” Journal of Thrombosis and Thrombolysis, vol. 21, no. 3, pp. 271–276, 2006.
- N. Kojima, M. Naya, H. Imoto, T. Hara, T. Deguchi, and H. Takahira, “Reproduction studies of GMK-527 (rt-PA). (III) Teratogenicity study in rabbits treated intravenously with GMK-527,” Japanese Pharmacology and Therapeutics, vol. 16, no. 5, pp. 107–123, 1988.
- E. Tanaka, F. Mizuno, T. Ohtsuka et al., “Reproduction studies of GMK-527 (rt-PA). (II) Teratogenicity study in rats treated intravenously with GMK-527,” Japanese Pharmacology and Therapeutics, vol. 16, no. 5, pp. 93–106, 1988.
- M. Dapprich and W. Boessenecker, “Fibrinolysis with alteplase in a pregnant woman with stroke,” Cerebrovascular Diseases, vol. 13, no. 4, p. 290, 2002.
- K. Elford, A. Leader, R. Wee, and P. K. Stys, “Stroke in ovarian hyperstimulation syndrome in early pregnancy treated with intra-arterial rt-PA,” Neurology, vol. 59, no. 8, pp. 1270–1272, 2002.
- D. M. Johnson, D. C. Kramer, E. Cohen, M. Rochon, M. Rosner, and J. Weinberger, “Thrombolytic therapy for acute stroke in late pregnancy with intra-arterial recombinant tissue plasminogen activator,” Stroke, vol. 36, no. 6, pp. e53–e55, 2005.
- K. M. Wiese, A. Talkad, M. Mathews, and D. Wang, “Intravenous recombinant tissue plasminogen activator in a pregnant woman with cardioembolic stroke,” Stroke, vol. 37, no. 8, pp. 2168–2169, 2006.
- A. Murugappan, W. M. Coplin, A. N. Al-Sadat et al., “Thrombolytic therapy of acute ischemic stroke during pregnancy,” Neurology, vol. 66, no. 5, pp. 768–770, 2006.
- J. C. Méndez, J. Masjuán, N. García, and M. De Leciñana, “Successful intra-arterial thrombolysis for acute ischemic stroke in the immediate postpartum period: case report,” CardioVascular and Interventional Radiology, vol. 31, no. 1, pp. 193–195, 2008.
- O. M. Rønning, A. Dahl, S. J. Bakke, A. I. Hussain, and E. Deilkås, “Stroke in the puerperium treated with intra-arterial rt-PA,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 5, pp. 585–586, 2010.
- C. Lamy, J. B. Hamon, J. Coste, and J. L. Mas, “Ischemic stroke in young women: risk of recurrence during subsequent pregnancies,” Neurology, vol. 55, no. 2, pp. 269–274, 2000.
- K. H. Coppage, A. C. Hinton, J. Moldenhauer, O. Kovilam, J. R. Barton, and B. M. Sibai, “Maternal and perinatal outcome in women with a history of stroke,” American Journal of Obstetrics and Gynecology, vol. 190, no. 5, pp. 1331–1334, 2004.