ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY
Prevention and treatment of stroke in pregnancy
David Goldemund M.D.
Updated on 18/05/2023, published on 30/04/2023
Updated on 18/05/2023, published on 30/04/2023
- 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 rather 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 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 (Michel, 2021)
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 prophylactic doses 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
- the safety of aspirin (ASA) 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 daily) is considered safe based on data from preeclampsia prevention
- risks of aspirin:
- maternal or fetal bleeding
- premature closure of the ductus arteriosus
- prolonged delivery due to inhibition of uterine contraction
- no adverse fetal effects have been observed with clopidogrel (CLP) or dipyridamole
- only case reports of successful deliveries in patients on CLP have been published; randomized studies are not available [Klinzing, 2001]
- it is preferable not to use clopidogrel during pregnancy
Lactation
- aspirin
- salicylates and their metabolites pass into breast milk in small amounts
- adverse effects on the infant have not been observed with low doses of ASA (up to 100mg daily); discontinuing breastfeeding is usually not necessary (AHA/ASA 2014 IIb/C)
- clopidogrel
- while it’s preferable not to use this drug during breastfeeding, it’s not an absolute contraindication and can be considered if aspirin is contraindicated
Anticoagulant therapy in pregnancy and lactation
Pregnancy
Lactation
- LMWH is the gold standard during breastfeeding because it does not transfer easily into breastmilk
- warfarin nad UFH do not pass into breast milk and can also be safely used (AHA/ASA 2014 IIa/C)
- DOACs should be avoided as safety and efficacy in breastfeeding women have not been established
