Muhammad Rizwan Husain, MD

Joseph NK, Kumar S, Brown Jr. RD, Lanzino G, Flemming KD. Influence of Pregnancy on Hemorrhage Risk in Women With Cerebral and Spinal Cavernous Malformations. Stroke. 2021;52:434–441.

In this entry, I discuss the publication by Nycole K. Joseph and colleagues regarding pregnancy and hemorrhagic risk with known cerebral and spinal cavernous malformations (CM). Previous studies have reported a hemorrhage risk as high as 11% in pregnant women with CM. However, those studies assumed that CM are congenital lesions, present throughout life, and that they contain both estrogen and progesterone receptors leading to their enlargement and potential rupture during pregnancy. However, over time, it has been demonstrated that CM are both acquired lesions and that they do not have, what was initially thought, the estrogen and progesterone receptors. The authors here have attempted to demonstrate how pregnancy influences the risk of hemorrhage in women of child-bearing age both in the pregnant and non-pregnant state, and included only those women with a known diagnosis of cerebral or spinal CM.

The authors first created a cavernous malformation registry in January 2015 enrolling all patients with a known diagnosis of cerebral and spinal cavernous malformations (CM). The CM was assumed to be familial if multiple CMs were seen without a developmental venous anomaly (DVA) and a sporadic form if either a single CM and a DVA or multiple CMs around a DVA were seen. All women in their potential reproductive years (taken as 15-45 years of age) were selected and the number of pregnancies (viable and non-viable) that occurred prior to and after the diagnosis of CM, as well as mode of delivery (C-Section vs normal vaginal delivery), were reviewed.  A non-viable pregnancy was assumed to be a miscarriage up to 20 weeks plus 6 weeks postpartum (total 26 weeks) and a viable pregnancy was assumed to be a live birth 40 weeks + 6 weeks postpartum (total 46 weeks). Any neurological complications that occurred during pregnancy and up to 6 weeks postpartum were collected. Clinical hemorrhage was defined as those with both a clinical event (headache, seizure or a focal deficit localized to the site of the CM) plus imaging (MRI)/surgical pathological/or CSF findings diagnostic of the CM. Non-hemorrhagic CM was defined as a new or worsening focal deficit localized to the CM but without demonstrated hemorrhage. Women were followed up in clinic and annual surveys, and prospective hemorrhages were confirmed with MRI imaging. Data on future pregnancies and complications were collected as well.

On review of the registry, from January 2015 until October 2019, 90 women out of the 160 had been diagnosed with CM at or before age 45, of which 21.9% were presumed to have familial CM, and the most common site of the CM was supratentorial-cortical (36.9%) followed by brainstem (26.9%). These 90 patients had 136 pregnancies before CM diagnosis and 36 at or after CM diagnosis. As stated earlier that CM are acquired lesions, the authors calculated the risk of prospective hemorrhage in patients with known CM during the pregnant and non-pregnant state. The length of follow up time was taken as time from diagnosis to last follow-up, or 46 years or surgical removal of sporadic CM (not familial CM, as risk of hemorrhage continues). During 402.6 years of follow-up while non-pregnant, 42 prospective hemorrhages occurred (10.4% per year risk of hemorrhage; 95% CI: 7.5-14.0). Risk factors for prospective hemorrhage were brainstem location (P=0.048) and hemorrhage at presentation (P<0.001) but not prospective pregnancies (P=0.61).

No hemorrhages occurred in the 33 prospective pregnancies during the 26.9 years of pregnancy time (26 live birth; 7 nonviable) in those with a known diagnosis of CM (0% risk of hemorrhage per year; 95%CI:0-13.6). No statistical difference was noted in the rates of hemorrhage during pregnancy and non-pregnancy time (p=0.09). The authors conclude that pregnancy did not increase the risk of hemorrhage in patients with known CM. The authors also did not find any evidence in their study or a review of past case reports about hemorrhages occurring during delivery and suggest that the choice of delivery (C-section vs vaginal) to be based on obstetric reasons.

A strength of the current study is that it differs from earlier ones in that it does not assume patients to have CM and calculates prospective hemorrhage risk in patients with known diagnosed CM. It is important to note that 4 patients had hemorrhage during pregnancy which led to the initial diagnosis of CM, all with good functional outcomes at 3 months (MRS 0-1), and one of them went on to have another successful pregnancy with no hemorrhage. The authors also mention results from 2 previous cohorts (Kalani and colleagues, and Witiw and colleagues) which also report a low rate of hemorrhage during pregnancy, of which most or all hemorrhages led to the initial diagnosis of CM with a similar conclusion of no associated increased risk of hemorrhage during pregnancy or delivery. Furthermore, in the study by Kalani et al, 4 women with hemorrhage during pregnancy all went on to have additional pregnancies without complications.

A few limitations are worth mentioning. It is possible that many women who were diagnosed to have CM or had hemorrhage during pregnancy decided against future pregnancies for concerns of recurrent hemorrhage. Patients who underwent surgical removal of the CM were censored from follow-up, and any future pregnancies that incurred hemorrhage would not have been accounted for. Familial CM have a higher risk of recurrent hemorrhage, as seen in earlier studies, and the current study had mostly sporadic CM. Only 4 patients had hemorrhage during pregnancy that led to the initial diagnosis, and a subgroup analysis to look at potential risk factors of hemorrhage during pregnancy was not possible.

The study does indeed provide evidence of: 1) a low risk of hemorrhage in pregnant women with known CM, and 2) that choice of delivery (vaginal vs C-section) really depends more from an obstetric perspective rather than presence of a CM.