ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY
Prevention and treatment of stroke in pregnancy
Created 30/04/2023, last revision 18/05/2023
- stroke is a relatively rare complication of pregnancy and the postpartum period
- incidence rates are reported in a very wide range of 4-11/100,000 births [Sharshar, 1995]
- the risk is highest shortly after delivery [Kittner, 1995]
- OR 0.7 during pregnancy (mainly in the 3rd trimester)
- OR 10.8 within 6 weeks after delivery [Kamel, 2014]
- lower but significant risk (OR 2.2) persists for up to 12 weeks [Kamel, 2014]
Pathophysiology
- during pregnancy, a number of physiologic changes occur that affect hemostasis and hemodynamics
- the etiology of thromboembolic events is complex; predisposing factors include venostasis and the hypercoagulable state
- pregnancy is associated with a shift to a hypercoagulable state, especially during and shortly after delivery (due to the release of thromboplastin substances during placental abruption)
- normalization occurs 3-12 weeks after delivery
| Procoagulant factors | |
| Fibrinogen | ↑ |
| Faktors VII, VIII, IX, X, XII | ↑ |
| Inhibitors of coagulation | |
| Protein C | ↓ |
| Protein S and AT III | N |
| Fibrinolysis | |
| tPA | ↓ |
| PAI-1 , PAI-2 | ↑ |
| TAFI (thrombin activatable fibrinolysis inhibitor) | ↑ |
| Others | |
| Thrombocytes | ↓ |
| D-dimer, fibrinopeptide A | ↑ |
| Thrombin/antithrombin complex | ↑ |
- during the first 10 weeks of pregnancy, there is an increase in cardiac output (up to 50%) and pulse rate, which peaks at the time of delivery and then returns to normal within 6-12 weeks
- a decrease in systemic resistance and blood pressure (lowest at 24-32 weeks)
- compliance of the veins decreases and is accompanied by slower blood flow (in the legs and pelvis)
- predisposition to orthostatic hypotension (causing presyncope and syncope)
Risk factors
- hypertension, diabetes
- thrombophilic conditions
- thrombocytopenia, anemia
- alcohol, smoking, and drug abuse
- history of migraine
- complications of delivery
- infection, transfusion, postpartum hemorrhage, electrolyte imbalance
- Cesarean delivery (SC)
- 3-12 times higher risk of stroke [Lanska, 2000]
- may be biased by the fact that particularly high-risk patients are indicated for SC
Etiology
- it is often difficult to determine whether the pregnancy is a coincidence or plays a causal role in the stroke development
- up to 46% of strokes remain etiologically unexplained (cryptogenic stroke)
| The most common causes of ischemic stroke in pregnancy |
|
| Specific causes of stroke in pregnancy: |
|
Preeclampsia/eclampsia |
- multisystem damage (kidney, liver, brain, cardiovascular system) occurring in the later stages of pregnancy (from the 20th week) up to 4-6 weeks after delivery (20%)
- higher risk of occurrence is present in young firstborns, women with multiple pregnancies, genetic predisposition (preeclampsia in the mother), or vascular diseases
- pregnant women with chronic hypertension should be distinguished, but they may also have preeclampsia
- preeclampsia/eclampsia is associated with an increased risk of stroke (6-47%) not only during pregnancy but also in the long-term
Amniotic fluid embolization (AFE) |
- a rare complication that occurs when the barrier between the maternal circulation and the amniotic fluid is disrupted
- mortality 61-86%; survivors often have a permanent neurological deficit due to hypoxia
- clinical presentation:
- acute dyspnea with hypoxia
- acute hypotension or shock
- cardiac arrest
- coagulopathy
Choriocarcinoma |
- malignancy arising from placental tissue
- a highly vascularized tumor with an increased tendency to bleed
- early metastases occur in the lungs, brain (1/5 patients), liver, and vagina
- diagnostic evaluation: massive elevation of serum hCG
- clinical presentation:
- focal symptoms (stroke)
- encephalopathy
- intracranial hypertension syndrome
- epileptic seizures
- stroke is most commonly caused by thrombosis or embolization of tumor tissue
Postpartum cerebral angiopathy |
- postpartum cerebral angiopathy belongs to reversible cerebral arterial vasoconstriction syndromes (RCVS)
Postpartum/peripartum cardiomyopathy (PPCM) |
- a rare form of dilated cardiomyopathy (DCM)
- may develop in the last month of pregnancy to 5 months after delivery in the absence of other causes of heart failure or another cardiac disease
- clinical presentation: signs of cardiac failure with leg or pulmonary edema and shortness of breath, etc.
- systemic or pulmonary embolism may occur in 25-40% of cases
- stroke, with an incidence of ~5%, is usually caused by cardioembolism or hypoperfusion (border zone infarct)
- prognosis depends on the recovery of systolic function
- in a number of cases, there is a complete or significant improvement
- approx. 11% of patients end up in the transplant program
Recanalization therapy in pregnancy
Intravenous thrombolysis (IVT)
- due to its large molecule size, tPA does not cross the placental barrier; there is no evidence of teratogenicity
- there are concerns about placental abruption, intrauterine hemorrhage, preterm delivery, or fetal death
- there are no data from RCTs (pregnancy was an exclusion criterion)
- most case reports and small series are from patients who received thrombolysis for non-stroke diagnoses than stroke (PE, valvular thrombosis, DVT, stroke, myocardial infarction)
- in 8 published cases of IVT, only 1 case of uterine bleeding occurred
- according to a published cohort of 28 patients, the risk of TL-related abortion was 8%, and the maternal risk of IVT did not differ from that of non-pregnant patients [Leonhardt, 2006]
- case reports of successful IVT for stroke in late pregnancy have also been published [Wiese, 2006] [Daprich, 2006]
- all recommendations are based on expert consensus (ESO guidelines 2022)
- IVT may be considered on an individual basis for moderate and especially severe stroke when the expected benefit of IVT outweighs the risk of uterine bleeding (ESO guidelines 2022 – expert consensus) (AHA/ASA 2019 IIb/C-LD)
- factors favoring IVT:
- severe, debilitating deficit
- likely benefit of IVT
- MR DWI/PWI mismatch and small lesion on DWI
- likely peripheral occlusion – from M2 distally
- if MT is available and LVO is involved, direct MT is preferable to bridging therapy
- stroke occurring shortly after delivery
- the safety and efficacy of IVT shortly after delivery (<10 days) are not established (AHA/ASA 2019 IIb/C-LD)
- if the stroke occurs > 10 days after delivery, IVT may be given after individual consideration (ESO guidelines 2022 – expert consensus)
if MT is available and there is a presumption of increased bleeding risk, dMT is preferred (ESO guidelines 2022 – expert consensus)
Mechanical recanalization
- there is a relatively limited experience with MT in pregnant women; no RCTs are available
- direct MT may be preferable to bridging therapy for LVO during pregnancy and shortly after delivery
- fetal shielding with lead vests is required
Stroke prevention in pregnancy
- randomized trials on stroke prevention in pregnancy are not available
- the majority of the information on the risks of anticoagulation and antiplatelet therapy comes from the treatment of DVT and high-risk cardiac patients or patients with preeclampsia
Secondary stroke prevention in low-risk patients
- in patients with a history of TIA/stroke on antiplatelet therapy, administer LMWH throughout pregnancy or prophylactic doses of LMWH in the first trimester and aspirin (50-100 mg/d) in the second and third trimesters (AHA/ASA 2011 IIb/C)
- switch back from ASA to LMWH 10-14 days before the expected delivery
- switch back from ASA to LMWH 10-14 days before the expected delivery
- other antiplatelet agents have not been tested in controlled trials during pregnancy and are not recommended (although clopidogrel is not specifically contraindicated)
- use prophylactics dosed of LMWH (e.g., enoxaparin 0.4 mL SC once daily)
| 1st trimester (week 1-13) |
2nd trimester (week 14-27) |
3rd trimester (week 28-40) |
||
| LMWH | ||||
| LMWH | aspirin | LMWH | ||
Secondary stroke prevention in high-risk patients
- patients with thrombophilia, Afib, mechanical valve, etc.
- LMWH/heparin throughout pregnancy
- LMWH SC twice daily with target anti-Xa 1-1.2 kIU/L (measured 3h after LMWH administration)
- heparin SC twice daily
- LMWH/heparin + warfarin
- LMWH – until the 14th week of pregnancy and then from the 28th week until delivery
- warfarin – from the 14th to 27th week of pregnancy and postpartum
- high-risk patients (e.g., with LV dysfunction or previous thromboembolic events) should receive concomitant aspirin 75-162 mg daily
| 1st trimester (week 1-13) |
2nd trimester (week 14-27) |
3rd trimester (week 28-40) |
||
| LMWH | ||||
| LMWH | warfarin | LMWH | ||
Antithrombotic therapy in pregnancy and lactation
Antiplatelet therapy in pregnancy and lactation
Pregnancy
- safety of aspirin in the first trimester is uncertain
- some retrospective studies have suggested an increased risk of malformations; prospective trials found no evidence of an overall increased risk of congenital malformations associated with aspirin [Kozer, 2002]
- a meta-analysis of 14 studies (n=12416) that followed women at risk of preeclampsia found no significant risk of teratogenicity or long-term side effects from aspirin [Coomarasamy, 2003]
- since the late 1st trimester, ASA (up to a dose of 150 mg/d) is considered safe (data from preeclampsia prevention)
- risks of aspirin:
- maternal or fetal bleeding
- premature closure of ductus arteriosus
- prolonged delivery (due to inhibition of uterine contraction)
- no adverse fetal effects have been observed with CLP or dipyridamole
- only case reports of successful deliveries in patients on CLP have been published; controlled studies are not available [Klinzing, 2001]
- it is preferable not to take clopidogrel during pregnancy
Lactation
- aspirin
- salicylates and their metabolites pass in small amounts into breast milk
- adverse effects on the infant have not been observed with low doses of ASA (up to 100mg/d), and it is not usually necessary to discontinue breastfeeding (AHA/ASA 2014 IIb/C)
- clopidogrel
- it is preferable not to use the drug during breastfeeding, but it is not absolutely contraindicated (it can be considered if ASA is contraindicated)
Anticoagulant therapy in pregnancy and lactation
Pregnancy
Lactation
- warfarin, heparin, and LMWH – do not pass into breast milk and can be safely used during lactation (AHA/ASA 2014 IIa/C)
- DOACs – safety and efficacy in breastfeeding women have not been established, use during lactation is contraindicated
