3. Management Considerations for Specific Ischemic Stroke Etiologies in Pregnancy

Stroke is a leading cause of adult neurological disability, death, and maternal morbidity and mortality in developed nations. Based on the pooled data in a recent meta-analysis (Swartz et al 2017) stroke affects 30/100,000 pregnancies. This is three times higher than rates for young adults overall (10/100,000 per year) and outcomes are dependent on rapid recognition and management. Stroke types are also more varied in pregnancy, with relatively more venous sinus thrombosis and intracranial hemorrhage. In addition, causes more commonly found in young adults (e.g. dissection, congenital cardiac complications), physiological adaptations to pregnancy (e.g., hypervolemia, increased clotting factors), and pregnancy specific disorders (e.g., HELLP, preeclampsia) combine to increase risk of stroke in pregnancy. Stroke is sufficiently common that most specialists providing either obstetrical or stroke care encounter women with a past stroke wanting to become pregnant, or women who develop a stroke during or immediately after a pregnancy. Thus, there is a need for a rational approach to management decisions, based on the best available literature, guided by expert consensus.

1. Systems in place to enable women who become pregnant or are planning pregnancy to access appropriate antenatal care.
2. Collaborative relationships established between obstetrical, maternal-fetal medicine experts and stroke specialists to optimize access and management for women who experience stroke before, during or immediately after pregnancy.
3. Development of data collection systems to monitor women who experience stroke prior to, during or immediately after a pregnancy to improve knowledge of safety and efficacy of management approaches, drive quality improvement and systems change.
4. Promote randomized controlled trials or large population-based observational studies where feasible to reduce knowledge gaps and increase the ability to move from a consensus statement to an evidence-based clinical practice guideline

1. Proportion of women with a past history of stroke who experience a recurrent stroke during pregnancy or early postpartum.
2. Proportion of women with a past history of stroke who experience a change in neurological abilities (physical, cognitive or functional) during pregnancy or early postpartum (positive or negative).
3. Pregnancy-related maternal mortality in women with a past history of stroke.
4. Proportions and rates of adverse fetal and neonatal outcomes: congenital anomalies, preterm delivery, perinatal and intrapartum morbidity and mortality.

For Professionals

• Acute stroke treatments and vascular risk reduction in non-pregnant women
• Secondary prevention of stroke
• Stroke rehabilitation
• professional.heart.org
• nice.org.uk
• The Society of Obstetricians and Gynecologists of Canada (SOGC)
• SOGC Hypertensive disorders of pregnancy guideline
• Diabetes Canada. Clinical Practice Guidelines
• The American Congress of Obstetricians and Gynecologists
• Diabetes in pregnancy 
• General teratogenicity of medications in pregnancy
• Reprotox
• General teratogenicity of medications in breast feeding - Lactmed
• Prescribing medicine in pregnancy

For Patients

• Public Health Canada Guide to healthy pregnancy
• ACOG
• Stroke Best Practices patient and family resources including Your Stroke Journey and the Post Stroke checklist

Evidence Table Underlying Causes

Secondary Prevention of Stroke in Pregnancy

Vascular Risk Reduction
This section is focused on issues of stroke prevention associated with women who have either had a stroke in the past and are now planning to become pregnant, or who have sustained a stroke during pregnancy, but who are beyond the hyperacute phase. Pregnancy is associated with an increased risk of stroke due to changes in hemodynamics and coagulation. The evidence associated with management for commonly used secondary prevention strategies, including antithrombotic medications (both antiplatelets and anticoagulants), blood pressure management, cholesterol management and diabetes care, is summarized.

Antithrombotics
While aspirin therapy has been shown to reduce the risk of future vascular events among high-risk individuals, its use for stroke prevention during pregnancy hasn’t been specifically studied. Low-dose aspirin in pregnancy has been better studied for pregnancy-related conditions, such as recurrent pregnancy loss, clotting disorders or preeclampsia. The potential benefit of low-dose aspirin was examined in high-risk women with a history of one to two previous pregnancy losses (EAGeR trial, Schisterman et al. 2014). The results of this trial indicated that among women attempting to become pregnant, there was no difference between groups (81 mg aspirin daily vs. placebo) in the number of pregnancy losses (13% vs. 12%, RR=1.06, 95% CI 0.77-1.46, p=0.78). In a meta-analysis including the results from 3 trials, low-dose aspirin was not associated with a reduction in the risk of preeclampsia, severe preeclampsia or pre-term birth (Roberge et al. 2016). More recently, the results from the ASPRE Trial (Rolnik et al. 2017) suggested that low-dose aspirin (150 mg per day), initiated from 11 to 14 weeks of gestation until 36 weeks of gestation, was associated with a reduced risk of delivery with preeclampsia before 37 weeks of gestation, compared with placebo (OR=0.38, 95% CI 0.20-0.74, p=0.04), without an increased risk of adverse events.

The safety of low-dose aspirin use in pregnancy is well-established. Nørgard et al. (2005) reported on the outcomes of 3,415 children with 4 congenital abnormalities, which were included in a national Congenital Abnormality Registry. Compared with a reference group that was composed of 19,428 children with other congenital abnormalities, exposure to aspirin was found not to significantly increase the odds of any of the 4 congenital abnormalities (including neural-tube defects, exomphalos/gastroschisis, cleft lip ± palate and posterior cleft palate). A meta-analysis including the results from 22 controlled studies yielded similar results (Kozer et al. 2002). Pooling the results from 8 and 6 studies, the overall odds of congenital malformations or cardiac malformations were not significantly higher in the aspirin-exposed group (OR=1.33, 95% CI 0.94-1.89, p=0.11 and OR=1.01, 95% CI 0.91-1.12, p=0.80, respectively). However, the incidence of gastroschisis was significantly higher in the aspirin-exposed group (OR=2.37, 95% CI 1.44-3.88, p=0.0006). There is a theoretical risk of Reye’s syndrome associated with aspirin use during pregnancy, but no confirmed reports.

Certain conditions, including the presence of artificial heart valves, or conditions related to hypercoagulability require the continued need for thromboprophylaxis, or their initiation during pregnancy. The safest known anticoagulants associated with pregnancy are low molecular weight heparin (LHWH) and unfractionated heparin (UFH), neither of which crosses the placenta. Vitamin K antagonists (VKA) are classified by the FDA as a category X substance, therefore their risks and benefits must be closely weighed, as their use has been associated with an increased risk of miscarriage, teratogenic effects in the first trimester, and risk of bleeding to both fetus and mother. In a systematic review including 28 studies examining the use of oral anticoagulants among pregnant women with mechanical heart valves, Chan et al. (2000), reported that while their use was more effective for thromboembolic prophylaxis, the frequency of congenital abnormalities was 6.4%. In a more recent review, Xu et al. (2016) included the results of 51 studies (2,113 pregnancies) of women who received anticoagulation therapy related to management of mechanical heart valves. Â The frequency of congenital fetal anomalies associated with VKA use was 2.13% and 0.68% for lose-dose VKA. There were no fetal abnormalities in the LMWH or UFH regimen groups. Maternal thromboembolic events (MTEs) and maternal deaths were lowest in the low-dose VKA subgroup (1.14% and 0.31%, respectively). The occurrences of MTEs and major antenatal hemorrhage events were highest in the UFH group (29.9% and 5.3%, respectively). Compared with low-dose VKA regimen, the incidences of spontaneous abortion and warfarin embryopathy were significantly higher compared with the high-dose VKA group.

Anticoagulants have also been examined for the prevention of pregnancy complications associated with thrombophilias, but were not found to be effective. Results from the Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) indicated that among pregnant women with thrombophilia at high risk of pregnancy complications, antepartum prophylactic dalteparin did not reduce the risk of venous thromboembolism and placenta-mediated pregnancy complications (Rodger et al. 2014). In this trial, 292 pregnant women were randomized to receive 5,000 IU dalteparin once daily from randomization to 20 weeks’ gestation and then the same dose twice daily until 37 weeks of gestation vs. no dalteparin. The primary outcome, a composite including any of proximal deep vein thrombosis, pulmonary embolism, or sudden maternal death, severe or early onset preeclampsia, oliguria, pulmonary edema, coagulopathy, birth of small-for-gestational-age SGA infant, or pregnancy loss, was not significantly reduced in the dalteparin group (risk difference of -1.8%, 95% CI -10.6%-7.1%, p=0.70). There was also no significant difference among three treatment groups (LMWH, ASA or both combined) in the percentage of live births in the Low Molecular Weight Heparin and/or Aspirin in Prevention of Habitual Abortion (HABENOX) Trial (Visser et al. 2011).

Hypertension
Women with hypertensive-disorders of pregnancy are at greater risk for stroke, especially those with traditional risk factors (Leffert et al. 2015), therefore, treatment of moderate to severe hypertension is critical to achieving a favourable outcome. A limited number of agents, including methyldopa, labetalol, and nifedipine, are known to be safe and effective during pregnancy. The potential benefit of a tight versus less tight regimen among women with moderate diastolic hypertension (90-105 mm Hg) was evaluated in the Control of Hypertension In Pregnancy Study (CHIPS) study (Magee et al. 2015). Although the frequency of severe hypertension was significantly higher among women in the less-tight control group, there was no significant difference between groups in the frequency of any of individual components of the primary outcome (miscarriage, ectopic pregnancy, elective termination, perinatal death, still birth or high-level neonatal care). The frequency of serious maternal complications was not significantly lower among women in the tight-control group (2.0% vs. 3.7%, adj OR=1.74, 95% CI 0.79-3.84). There was a single stroke/TIA in the tight-control group vs. none in the less-tight control group. A Cochrane review (Abalos et al. 2013) including 48 RCTs (4,723 women) evaluated antihypertensive drug treatment for mild to moderate hypertension during pregnancy, defined as SBP 140-169 mmHg and DBP 90-109 mmHg. Treatment contrasts compared ≥1 antihypertensive drug vs. either placebo or no antihypertensive drug (n=29), and one antihypertensive drug vs. another (n=22), with a duration of treatment of at least 7 days. Compared with women who received no treatment, the risk of severe hypertension was significantly reduced in the active treatment group. While the risk of pre-eclampsia/proteinuria was not significantly reduced in the active treatment group (RR= 0.93, 95% CI 0.80-1.08, p=0.34), in the sub group examination of beta blockers, the risk of developing proteinuria/pre-eclampsia was significantly reduced (RR=0.73, 95% CI 0.57-0.94). The risk of fetal or neonatal death, pre-term birth or small-for-gestational age were not significantly reduced for women taking antihypertensive treatment. In terms of treatment for the prevention of hypertension during pregnancy, a Cochrane review including 13 RCTs in women without hypertension examined the effectiveness of calcium supplementation to reduce the risk of hypertensive disorders of pregnancy (Hofmeyr et al. 2014). Women were randomized to receive either high-dose (≥1 g/day) or low-dose (<1 g/da) calcium supplement or placebo, until delivery. High-dose calcium supplementation was associated with significantly reduced risks of high blood pressure (RR= 0.65, 95% CI 0.53-0.81, p<0.0001) and pre-eclampsia (RR= 0.45, 95% CI 0.31-0.65, p<0.0001). Low-dose supplementation was also associated with a significantly reduced risk of high blood pressure (RR= 0.53, 95% CI 0.38-0.74, p<0.0001).

Statin Use
While the benefits of statin use for secondary prevention are well-established, statin treatment is usually not warranted during pregnancy, as lipid dysregulation is a physiologic adaptation of pregnancy. The development of certain cells (e.g myelin) and the accumulation of fat mass in the fetus, are dependent upon lipid metabolism. Statin medications have been classified in pregnancy as Category X, and are contraindicated due to their potential teratogenicity. Several reports comparing the pregnancy outcomes of women accidentally exposed to statins during pregnancy with those of women not exposed, have been published. The results are ambiguous, with some studies suggesting a significant increased risk of congenital abnormalities associated with statin use, particularly during the first trimester. In the largest cohort study (Bateman et al. 2015), statin use was associated with a significantly increased risk in the incidence of birth defects in unadjusted analysis (6.34% vs. 3.55%, RR=1.79, 95% CI 1.43-2.23), but was no longer evident in an analysis using propensity scores, adjusting for age, diabetes and other confounding factors (RR=1.07, 95% CI 0.85-1.37). Zarek & Koren (2014) included the results from 6 controlled studies in a meta-analysis, and reported that the use of statins during pregnancy was not associated with an increased risk of birth defects (RR=1.15, 95% CI 0.75-1.76, p=0.52), although there was a significant increase in risk of miscarriage (RR=1.35, 95% CI 1.04-1.75). In a case-control study, Winterfeld et al. (2013) reported the frequency of major birth defects was non-significantly higher in the statin-exposed group (4.1% vs. 2.7%, OR=1.5, 95% CI 0.5-4.5, p=0.43), while the frequency of pre-term delivery, miscarriage or fetal death was significantly higher in the statin-exposed group. Most recently, Karalis et al. (2016) reviewed the results of 16 case series, cohort studies, meta-analyses and an RCT, and concluded there was no clear evidence of a relationship linking congenital anomalies with statin use in pregnancy, suggesting they were probably not teratogenic, while at the same time, cautioning that their use should be avoided.

Diabetes
Women with gestational diabetes are at increased risk of antenatal stroke (Scott et all 2012, James et al. 2005), and may be at risk for future stroke up to 7 years after delivery (Goueslard et al. 2016). In studies that have examined the relationship between gestational diabetes and future risk of cardiovascular disease, including stroke, the strength of the relationship is attenuated after adjusting for age and subsequent diabetes or menopausal status (Archambault et al. 2014, Savitz et al. 2014, Shah et al. 2008). A low glycemic index diet has been shown to significantly reduce both fasting and 2-hour post-prandial blood glucose, compared with a control group consuming intermediate-high glycemic index foods (Ma et al. 2014). Target 1-hour postprandial blood glucose of <7.8 mmol/L has been associated with good outcomes and has been suggested as a reasonable target for women with gestational diabetes (Thompson et al. 2013).

Management Considerations for Specific Stroke Etiologies in Pregnancy
There is limited evidence concerning the management of strokes that occur during pregnancy, with specific etiologies including cardioembolic source, cerebral venous sinus thrombosis (CVST), cervical artery dissection, antiphospholipid antibody syndrome (AAS) and cryptogenic stroke. The evidence base is largely composed of case reports and case series. Regardless of the etiology, treatment with either oral anticoagulants or antiplatelets (aspirin) appears to be common practice.

Outside of pregnancy, cervical artery dissections are usually treated with either a vitamin K antagonist or antiplatelet (aspirin) for 3-6 months. Case reports of women treated for carotid and vertebral dissections occurring in both the antenatal and early post-partum period, indicate the same management strategies may be used (Shanmugalingam et al. 2016, Baffour et al. 2012, Waidelich et al. 2008) without adverse effects on the mother or baby. The use of anticoagulants or antiplatelet drugs among a series of 62 women who presented with CVST during pregnancy was reported by Ciron et al. (2013). The preventative strategies used during subsequent pregnancies included no treatment (n=3), anticoagulation therapy during entire pregnancy, with and without aspirin; anticoagulation therapy during 3rd trimester of pregnancy, with and without aspirin; and anticoagulation therapy during entire pregnancy and puerperium. Demir et al. (2013) reporting on 19 cases of pregnancy-associated CVST, noted that all women were treated with LWMH (enoxaparin) at a dose of 95 IU/kg twice daily for the duration of their pregnancy. Both aspirin and warfarin were used for secondary prevention in a study including 68 women who sustained CVST during pregnancy (Lamy et al. 2000).