Clinical Characteristics, Course, and Outcomes of Vertebral Artery Dissections in the Postpartum Period; a Pooled Analysis of Published Case Reports.

The data was extracted from online published articles. None The authors have no conflict of interest to declare Not applicable Not applicable We would to express our sincere thanks to all authors of the included studies and to Medical research group of Egypt under supervision of Dr. Ahmed Negida for their support and encouragement in carrying out this project. Rehab Adel Diab: Conceptualization, Writing-Original draft, review, and editing. Nour Shaheen: Methodology, Writing-Original draft, review, and editing. Abdelrahman Mohamed: Formal Analysis Mahmoud Tarek Hefnawy: Writing-Original draft, review, and editing Dilawer chofan charo: Writing-Original draft, review, and editing Mostafa Meshref: Writing-Original draft, review, and editing. All Authors read and approved final version of the manuscript.

Vertebral artery dissection (VAD) can be extracranial or intracranial and unilateral or bilateral with different prognoses ranging from complete healing to serious neurological sequels ( 1 ). Dissection of cervical, vertebral, or carotid arteries is rare, but once occurring, it can be fatal. VADs commonly occur in young poststroke patients but rarely affect patients in the postpartum period ( 2 , 3 ). The postpartum period is a distressing period associated with headaches and other symptoms that make the diagnosis of postpartum vertebral artery dissection (PPVAD) challenging due to common symptoms between both. The incidence of headache reporting in the postpartum period is ranging from 11% to 80% ( 4 ), So the vertebral artery dissection should be considered in differential diagnosis for patients suffering from headaches in the postpartum period for early diagnosis and better outcome. The incidence of spontaneous vertebral artery dissection ranges from 1 to 1.5 per 100.00, annually ( 5 ). 2.4% of symptomatic spontaneous VAD cases presented in the postpartum period and women are 2.5 times more likely than men to get VAD ( 3 , 6 ). VAD can lead to stroke with an estimated incidence of one per 100,000 individuals annually ( 7 ), and stroke can lead to VAD ( 7 , 8 ). The etiology of spontaneous postpartum vertebral artery dissection is still unknown, but there are potential risk factors that can be considered to predispose it in the postpartum period, like hormonal and hemodynamic changes occurring during pregnancy and Valsalva maneuver ( 9 ). Due to the lack of literature about the clinical picture and management of PPVAD, our study aimed to pool and analyze the most frequent symptoms, signs, complications, and the strategies that are widely used in management of these cases.

2.1. Search strategy The literature review was conducted on Feb 24, 2022, using the terms (("Vertebral Artery"[Mesh]) OR ("Vertebral Artery Dissection"[Mesh] OR "Vertebrobasilar Insufficiency"[Mesh] OR "PICA syndrome" [Supplementary Concept]) AND ("Postpartum*"[Mesh]). Using PubMed, Google Scholar, Ovid, Web of Science, and Scopus databases, we searched for case series and case reports on VAD following childbirth. Researchers independently conducted the search to find the studies matching the keywords. All studies reporting cases of vertebral artery dissection after childbirth were included in the search ( Figure 1 ). The analysis did not include review articles or consensus statements. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used to present inclusions and exclusions ( 10 ). 2.2. Study Selection, Data Extraction, and Data Analysis Articles were selected based on predetermined criteria after title and abstract screening by two independent reviewers. The inclusion criteria were clinical case reports or series that reported the clinical characteristics, treatment protocol, and outcomes of PPVAD. Based on the following exclusion criteria, several steps were taken to select included studies. 1) Studies that are not tailored for humans (such as in vitro or animal studies), 2) Research not collecting original primary data (review, protocol, editorial, letter, etc.), 3) No full text of the research results was provided (i.e., abstracts of conference posters), and 4) Studies in a language other than English. 2.3. Quality assessment: The overall quality of the case series and the case reports was assessed. The Joanna Briggs Institute (JBI) Critical Appraisal checklist was used in the quality assessment of Case Reports ( 11 ), while the NIH Quality Assessment Tool was used for Case Series ( 12 ) ( Appendix 1 & 2 ). 2.4. Data Analysis Python 3.0 was used for data management and cleaning as well as statistical analysis. A comparison was made between patients that suffered from unilateral dissection and patients that faced a bilateral dissection. Other variables were investigated as well, like whether having multiple previous pregnancies affected the final outcome or time to dissection. The Mann-Whitney test was used for numerical data, and Fischer’s Exact test was used for categorical data.

3.1. Characteristics of included studies In total, 163 studies were found in PubMed, Google Scholar, Ovid, Web of Science, and Scopus using our search criteria. A total of 74 full-text articles were reviewed after excluding duplicate studies, studies lacking clinical data, review articles, and articles unrelated to our study objective. Based on the review, 32 studies met our inclusion criteria; therefore, 32 studies about vertebral artery dissection after birth were reviewed and analyzed ( Figure 1 ). Characteristics of included studies are summarized in tables 1 and 2 . Studies most commonly reported diagnosis via MRI with 28 (64%) and CT-angiography with 29 (66%) case. Only 8 (18%) cases reported the use of ECG as a diagnostic tool for VAD alongside one or more of the main modalities mentioned. Based on the reported data, most studies used anticoagulant and antiplatelet drugs to treat VAD, including warfarin, aspirin, and enoxaparin as well as antihypertensive drugs. 3.2. Pooled analysis of reported cases Pooled analysis of cases is presented in table 3 . The studies included a total of 44 patients who suffered from post-partum vertebral dissection with a mean age of 34.26 ± 3.50 years. The average time between delivery and dissection was 24.37 ± 13.7 days. 28 (64%) of the patients developed unilateral dissection, whereas the remaining 16 (36%) developed bilateral dissection. 20 (45%) of the patients reported delivering via vaginal delivery, 16 (36%) reported delivering via C-sections, whereas the remaining 8 (19%) did not report a specific delivery type. The most frequent signs and symptoms were headache 39 (89%) and neck pain 28 (64%). 23 (52%) of the patients had high blood pressure after pregnancy, whereas only 4 (9%) patients reported hypertension during pregnancy as well. Additionally, 14 (32%) of the patients had associated syndromes including Opal ski Syndrome, HELP syndrome, Horner Syndrome, and postpartum angiopathy. Based on the reported data, 2 (5%) patients had at least one failed pregnancy, 5 (11%) patients had trauma injury, 7 (16%) patients had surgical history (3 caesareans, 1 vacuum-assisted vaginal delivery, 1 thyroidectomy, and 2 diagnostic laparoscopies. As for the final outcome, 31 (70%) reported being fully recovered, 4 (9%) did not undergo full recovery and the remaining 9 (21%) did not provide data for follow-up final outcomes. There was no statistical difference between unilateral and bilateral cases and also gravid 1 or >1 regarding age distribution, time from delivery to dissection, and final outcomes ( Table 4 ).

VAD is a rare and serious condition in the postpartum period. According to literature, cervical dissection represents 6% of spontaneous dissections in females under 50 years of age ( 8 ). Using our results, we found that the mean age of the patients was 34.26 ± 3.50 years. Cervical dissections in the postpartum period mainly include vertebral and carotid artery dissections; both are reported to occur unilaterally or bilaterally ( 9 , 13 ). Our study showed that 64% of the included patients developed unilateral vertebral artery dissection while 36% developed bilateral vertebral artery dissection. Some studies reported the extension of VAD to include the basilar artery and other studies presented multiple vessel dissections as reported in a previous study ( 14 ) in which there was a rare case of postpartum multi-arterial dissection, involving the vertebral artery, coronary artery, and the internal mammary artery ( 6 , 15 ). The exact incidence rate of cervical dissection is unknown; however, it has an estimated incidence of 2.6–3.0 cases per 100,000 population per year, with VAD being 3–5 times less frequent than carotid artery dissection ( 16 , 17 ). Females are 2.5 times more likely to get VAD than males ( 17 ). Moreover, it has been reported that 2.4% of cervical dissections occur in females in the postpartum period ( 18 ). In addition, VAD is a leading cause of ischemic stroke among young people ( 19 ). Postpartum cervical dissection can be caused by a variety of underlying factors, but the mechanisms are unclear. There are several hypotheses in literature regarding the effects of pregnancy hormones, especially progesterone, on collagen synthesis in the tunica media of vessels, increasing its sensitivity to systemic stressors like hypertension ( 6 , 7 , 9 , 19 ). Approximately 31 (70%) of patients presented with neurological symptoms. The main clinical presentation of VAD is typically acute, severe neck pain in the occipito-cervical region, either with or without headache ( 20 ). Our results showed that VAD in females in the postpartum period was mainly presented with headache as the commonest presentation in 39 (89%) of the cases followed by neck pain in 28 (64%), hypertension in 23 (52%) and visual defects symptoms in 17 (39%) of the cases. Physical examination in VAD may reveal nystagmus, truncal ataxia, loss of taste, impairment in pain and thermal sensation, and ophthalmoplegia; however, that clinical picture may be vague, and symptoms overlap with that of the postpartum period making the differential diagnosis even more difficult ( 20 ). Investigations used to diagnose VAD are CT, CTA, and MRI. CT scan can show the ischemia in the posterior fossa, subarachnoid hemorrhage, vertebral artery occlusion and mural thrombus. MRI can also prove the diagnosis but is not always available. CTA can easily show any regularity or thickening in the vascular wall, this makes the CTA the investigation of choice in the case of VAD ( 20 ). Our finding showed that two or more of these investigations are usually used to establish the diagnosis or complications and CT was the commonest investigation used with 66% and MRI with 64% of cases. Regarding the management of VAD, antithrombotic therapy should be started as soon as possible. Both antiplatelets and anticoagulants are the main lines in treatment, in a previous randomized trial (CADISS Trial) there was no difference in the efficacy of anticoagulants and antiplatelets in preventing stroke in patients suffering from vertical artery dissections including carotid and vertebral arteries ( 21 ). Additionally, this conclusion was supported by a case series study of twelve patients who suffered cervical dissections, in which there was no difference in prognosis or complications ( 19 ). Anticoagulation is to be started with low-molecular-weight or unfractionated heparin followed by oral anticoagulation, while antiplatelets are applied for mono or dual therapy ( 10 ). Antiplatelets are widely preferred because of their availability and low cost. According to existing guidelines, antithrombotics should be continued for about three to six months, with no clear clinical evidence of the exact duration yet ( 1 , 9 ). In the absence of exact duration and choice of antithrombotic strategy, it is recommended to be individually adapted according to each case scenario ( 22 ). Clearly, this was evident from the management strategies in our included reports, in which antithrombotic choice was respected. 31 patients (70%) showed a full recovery after proper management while 4 cases (9%) showed incomplete recovery and the rest were not reported. Although postpartum VAD can carry a good prognosis it can cause permanent damages if complicated with stroke and infarction. VAD can develop complications such as cerebellar and brain stem infarctions, subarachnoid hemorrhage, pseudoaneurysm and cranial nerves affection ( 20 ). And all of these complications are reported in postpartum VAD in the included cases, either as a sign or a complication, along with stroke that developed in 10 patients (23%) and the subarachnoid hemorrhage that developed in 6 patients (14%); thus, early diagnosis and management of VAD are required, the sooner the better. PRISMA flow diagram of study screening and inclusion The Joanna Briggs Institute (JBI) Critical Appraisal checklist for Case Reports ( 11 ) The NIH Quality Assessment Tool for Case Series, Good: Met 7-9 criteria, Fair: Met 4-6 criteria, Poor: Met 0-3 criteria ( 12 ) NA: not applicable, NIH: National Institutes of Health, NR: not reported. Summary of the included studies; number of patients, mean age (years), obstetric code, delivery type, and vessels affected Not applicable ( NA ), Right ( R ), Left ( L) , Gravida 2 /Para 2 ( G2P2), PG: Primigravida, LAD : left anterior descending artery; IMA : Internal Mary artery; RSCA : right subclavian artery; PICA : Posterior inferior cerebellar artery; PCA : Posterior cerebral artery; MCA: Posterior cerebral artery; LCX : left circumflex artery ; SMA : Superior mesenteric artery. Summary of the included studies; time from delivery (days), clinical presentation, comorbidities, investigation, treatment, and final outcome SAH: subarachnoid hemorrhage; HTN: hypertension; HELLP: Hemolysis, Elevated Liver enzymes and Low Platelets; MTHFR: methylenetetrahydrofolate reductase; MRI: magnetic resonance imaging; CT: computed tomography; ECG: electrocardiography; NSTEMI: non-ST-segment elevation myocardial infarction; LAD: left anterior descending artery; ECHO: echocardiography. Pooled analysis of data of patients with post-partum vertebral artery dissection (n = 44) Data are presented as frequency (%). SD: standard deviation. Comparing the age, time from delivery to dissection, and follow-up of post-partum vertebral artery dissection based on laterality and number of gravidity Data are presented as mean (SD) or frequency (%). This study should be considered in light of several limitations. The first limitation is that there is a small number of cases, there is also lack of follow-up data. The specific dose of antithrombotic is different in each case scenario and cannot be generalized. Secondly, some clinical pictures are not completely reported when the cases are transported from one center to another or in case of long duration of hospital admission, in which not all the complications or side effects are fairly mentioned. The lack of literature about postpartum dissections is a remarkable limitation so further reports and high-quality evidence-based studies are strongly recommended.

PPVAD is a severe medical condition; most cases were fully recovered after an early and proper antithrombotic plan for each case scenario. Headache and neck pain were the commonest PPVAD presentations. Age, type of delivery, and Gravida were not statistically associated with PPVAD. Unilateral and bilateral postpartum VAD showed no statistical difference in the recorded outcomes of the patients. Most of the included studies recommend early suspicion and management for a better prognosis and prevention of complications.