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Invited Commentary
Neurology
April 14, 2020

Pregnancy and Risk of Intracerebral Hemorrhage

Author Affiliations
  • 1Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
  • 2Program in Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
  • 3Department of Medicine, University of Toronto, Ontario, Canada
  • 4Department of Obstetrics and Gynecology, St. Michael’s Hospital, Toronto, Ontario, Canada
JAMA Netw Open. 2020;3(4):e202844. doi:10.1001/jamanetworkopen.2020.2844

Pregnancy is a known risk factor for stroke, and hemorrhagic stroke accounts for approximately 60% of all strokes arising in pregnancy and up to the conventional 6-week postpartum period.1 Meeks et al2 completed a US population-based cohort study including 3 314 945 pregnant women. They chose to extend the postpartum period to 24 weeks after birth and used a cohort-crossover study design to minimize cofounding. With the cohort-crossover design, a pregnant or postpartum woman was compared with her future nonpregnant self. Specifically, the pregnancy period of assessment for intracerebral hemorrhage (ICH) was from 40 weeks before the index birth up to 24 weeks thereafter (the cohort period), whereas the follow-up comparison (crossover) period started 52 weeks after the cohort period ended and continued for another 64 weeks thereafter. Sandwiched in between the cohort and crossover periods was a 52-week interim period, in which a death or subsequent pregnancy was excluded from the analyses. Clearly, a woman had to be alive at the end of the interim period, which may introduce survivor bias, in that ICH has a high case-fatality rate,1 so a woman with a fatal ICH would be missed. Moreover, it was assumed that each pregnancy ended at 40 weeks’ gestation, which is certainly not the case in women who experience ICH in pregnancy, who are at much higher risk for preterm birth. This may introduce time selection bias, because the duration of exposure to pregnancy among women in the cohort period can vary. Also, with this type of study design, potential cofounding may arise by within-person or between-time fluctuating variables.

Notwithstanding the aforementioned limitations, Meeks et al2 showed that, compared with the crossover period, the risk of ICH was increased (rate ratio, 9.15; 95% CI, 5.16-16.23) during the 12-week postpartum period but not during the 12- to 24-week postpartum period. They also identified preexisting risk factors associated with ICH, including increasing maternal age, nonwhite race, and chronic hypertension. All of these findings are informative given the paucity of data on ICH in pregnancy and the postpartum period.

Importantly, ICH arising in pregnancy or peripartum is often due to new-onset preeclampsia and eclampsia, especially when acute hypertension is not controlled.1 Meeks et al2 showed that women with gestational hypertension had a 2.73 times higher risk of ICH compared with those without gestational hypertension. In addition, approximately one-third (35.29%) of women who had ICH also had eclampsia or preeclampsia, with a corresponding 9.23 times higher risk of ICH higher than those without eclampsia or preeclampsia. Although the definitive treatment of eclampsia and preeclampsia is delivery, delivery can be delayed in some cases to gain fetal maturity; even after delivery, preeclampsia may escalate, such that, in either scenario, the prevention of severe hypertension is crucial to avoid ICH. The American College of Obstetricians and Gynecologists recommends starting antihypertensive therapy once the systolic blood pressure is greater than 160 mm Hg and/or diastolic blood pressure is greater than 110 mm Hg.3 Those with severe hypertension should be hospitalized and administered labetalol or hydralazine, for example.4

In women at higher risk of developing preeclampsia, and who do not have an evident contraindication, low-dose aspirin should be initiated at 12 to 20 weeks’ gestation.5 Level I evidence supports a clear benefit for mother and fetus.5 Even so, there are no data showing that aspirin prophylaxis reduces the risk of ICH.

Pregnant women who develop disseminated intravascular coagulation are certainly at higher risk of death.6 In the study by Meeks et al,2 9.20% of patients with ICH also had a diagnosis of nonspecific coagulopathy, and approximately one-half of those patients had disseminated intravascular coagulation, with a corresponding adjusted relative risk of 14.17 (95% CI, 9.17-21.89). Hence, in addition to blood pressure control, maternal coagulation should be normalized in women with preeclampsia, including the use of intravenous tranexamic acid and fibrinogen replacement.

Finally, the timely diagnosis of ICH is vital for subsequent management and treatment, and neuroimaging is a critical step in therein. Conventional computed tomography or magnetic resonance imaging is safe in pregnancy.7,8 Venous or arterial vessels can be further imaged by non–contrast-enhanced magnetic resonance imaging, such as time-of-flight and phase-contrast techniques, or by using computed tomography angiography or venography. If ICH arises, neurosurgical consultation is recommended, in addition to placing the affected woman in a high-acuity monitored setting.

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Article Information

Published: April 14, 2020. doi:10.1001/jamanetworkopen.2020.2844

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Aoyama K et al. JAMA Network Open.

Corresponding Author: Kazuyoshi Aoyama, MD, PhD, Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Ave, Ste 2211, Toronto, ON M5G 1X8, Canada (kazu.aoyama@utoronto.ca).

Conflict of Interest Disclosures: None reported.

References
1.
Liu  S, Chan  W-S, Ray  JG, Kramer  MS, Joseph  KS.  Stroke and cerebrovascular disease in pregnancy.   Stroke. 2019;50(1):13-20. doi:10.1161/STROKEAHA.118.023118Google ScholarCrossref
2.
Meeks  JR, Bambhroliya  AB, Alex  KM,  et al.  Association of primary intracerebral hemorrhage with pregnancy and the postpartum period.   JAMA Netw Open. 2020;3(4):e202769. doi:10.1001/jamanetworkopen.2020.2769Google Scholar
3.
American College of Obstetricians and Gynecologists Committee on Practice Bulletins.  ACOG practice bulletin no. 203: chronic hypertension in pregnancy.   Obstet Gynecol. 2019;133(1):e26-e50. doi:10.1097/AOG.0000000000003020PubMedGoogle ScholarCrossref
4.
Duley  L, Meher  S, Jones  L.  Drugs for treatment of very high blood pressure during pregnancy.   Cochrane Database Syst Rev. 2013;(7):CD001449. doi:10.1002/14651858.CD001449.pub3PubMedGoogle Scholar
5.
Bartsch  E, Medcalf  KE, Park  AL, Ray  JG; High Risk of Pre-eclampsia Identification Group.  Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies.   BMJ. 2016;353:i1753. doi:10.1136/bmj.i1753PubMedGoogle ScholarCrossref
6.
Callaghan  WM, Creanga  AA, Kuklina  EV.  Severe maternal morbidity among delivery and postpartum hospitalizations in the United States.   Obstet Gynecol. 2012;120(5):1029-1036. doi:10.1097/AOG.0b013e31826d60c5PubMedGoogle ScholarCrossref
7.
Ray  JG, Vermeulen  MJ, Bharatha  A, Montanera  WJ, Park  AL.  Association between MRI exposure during pregnancy and fetal and childhood outcomes.   JAMA. 2016;316(9):952-961. doi:10.1001/jama.2016.12126PubMedGoogle ScholarCrossref
8.
Ladhani  NNN, Swartz  RH, Foley  N,  et al.  Canadian stroke best practice consensus statement: acute stroke management during pregnancy.   Int J Stroke. 2018;13(7):743-758. doi:10.1177/1747493018786617PubMedGoogle ScholarCrossref
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