Cerebral Venous Thrombosis Presenting in Early Pregnancy Complicated with Nausea and Vomiting: A Single-Institute Consecutive Case series and Literature Review

Objectives Cerebral venous thrombosis (CVT) is a rare but potentially life-threatening condition in early pregnancy. We sought to describe the manifestation, treatment and outcomes of CVT presenting in early pregnancy through a retrospective consecutive case series in a tertiary referral center, so as to improve the awareness of this rare disease. Methods Between May 2018 and November 2021, consecutive seven patients with CVT presenting in early pregnancy were enrolled in Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. All patients’ data like manifestations, laboratory and radiological data, treatment and prognosis were analyzed, and relevant literatures were also reviewed. Results All seven patients had been suffering from nausea and vomiting accompanied with headache prior to CVT occurrence. The headache was complained aggravation in severity with an average from 3.86 to 7.16 by visual analogue scale over several days. The mean age was 32.4±2.28 years, and mean BMI was 21.67 km/m 2 . All seven patients showed typical neurological symptoms on admission including epileptic seizures (n=2, 28.6%), limb weakness (n=4, 57.1%), aphasia (n=5, 71.4%), blurred vision (n=2, 28.6%), disturbed consciousness (n=3, 42.9%). Average score was 11.3 points (range from 3 to 15) on Glasgow coma scale (GCS). All patients were diagnosed with CVT at the rst visiting day by imaging examinations and multiple venous sinuses thrombosis with average number of 3.7 per patient (range from 2 to 6) were conrmed, the most involved was transverse sinus (n=7, 100%), followed by sigmoid sinus (n=5, 71.4%). All of them was initiated anticoagulation treatment with low-molecular weight heparin (LMWH) instantly as soon as the CVT was dened. Two serious patients underwent catheter thrombolysis or/and decompressive craniotomy, but both still died of CVT deterioration within 5 days of admission. Other ve patients were all performed selective induced abortion and was discharged after signicant symptomatic improvement. They were remained anticoagulation for one year. At 12-month follow-up, MRI/MRV revealed sinuses were completely recanalized. Conclusions The present retrospective study should raise awareness of diagnosis and treatment of CVT in nausea and vomiting of early pregnancy complicated with headache. GCS evaluation on admission probably correlated with the prognosis. Neuroimaging remains the cornerstone for the diagnosis and instant anticoagulation prior to severe CVT aggravation is the key for the disease prognosis. Early pregnancy combined with CVT is not a contraindication of continued pregnancy based on the literature review. retrospective tertiary post-pregnancy follow-up these Laboratory examination revealed a mild inammatory response with an elevated WBC count of 14.39*10 9 /L, D-dimer were abnormally elevated to 2.97 mg/L (range from 0.8 to 11.6 mg/L), but coagulation proles were normal. Screening for thrombophilia including protein C, protein S and homocysteine showed that only protein S is slightly lower in N3 (43.8%, normal range 50-80%), and all the coagulation factors were within normal range. Autoimmune diseases with higher risk of hypercoagulation including anticardiolipin antibody, lupus anticoagulant (LA), antinuclear antibody and anti-double strain DNA were also screened and the results showed that only N5 presented with a slightly positive antinuclear antibody (ANA) with 1:160, the rest of the antibody were all negative, and all 7 patients were excluded from autoimmune related disease by rheumatologist. Additionally, N1 and N3 underwent lumbar puncture and elevated opening pressure was revealed but without abnormalities of specic cerebrospinal uid (CSF). emergency decompressive craniotomy was performed, the brain was extremely extensive swollen with diffused thrombosis of the supercial veins. She died four days post-operation. N7 scored 11 (M6 V1 E4) points on the GCS. CT venography showed hyper density in left transverse sinus, inferior sagittal sinus, straight sinus and sinus conuence. MRI/MRV showed that massive veins including straight sinus, sinus conuence, great cerebral vein, internal cerebral vein and basilar vein were almost completely occluded. DSA indicated that sinus and deep venous were occluded but basal vein and deep vein have been compensated by sylvian vein reux, thus endovascular thrombolysis or surgical procedure was not further considered.


Introduction
Cerebral venous thrombosis (CVT), a rare but potentially life-threatening condition, is more prevalent in females and associated with prothrombotic risk factors such as thrombophilia, antiphospholipid syndrome, trauma, cancer, puerperium and pregnancy [1]. Previous research has generally suggested that the hypercoagulable state of third-trimester pregnancy and puerperium is one of the main pathophysiology associated with pregnancy-related CVT [2], however, CVT is seldom encountered during early pregnancy, thus substantial clinical trials are absent and only a few report cases on pregnancy can be found, resulting in a lack of guidance for these conditions [2]. In the present study we sought to describe the manifestation, treatment and outcomes of CVT presenting in early pregnancy through a retrospective consecutive case series in a tertiary referral center and compared our results with the other case reports published on the subject, in order to improve the awareness of this rare disease. To the best of our knowledge, this is the largest series of CVT presenting in early pregnancy complicated with nausea and vomiting/ hyperemesis gravidarum (NVP/HG) and with the longest post-pregnancy follow-up hitherto reported.

Materials And Methods
We enrolled seven patients with con rmed CVT in early pregnancy between May 2018 and November 2021, at Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. The detailed clinical data of the seven patients were retrospectively reviewed, comparative analysis and close follow-up were performed.
This study was conducted following the amended Declaration of Helsinki. Written informed consent was obtained from all participants before inclusion.
Furthermore, a systemic literature search regarding CVT in early pregnancy was conducted and totally fteen patients were included for analysis.

Patients' basic clinical characteristics
Clinical features including age, body mass index (BMI), pregnancy and reproduction history, gestation, initial symptoms, time from symptom initiation to admission, and acute neurological symptoms are described in Table 1. The mean age of seven patients was 32.4±2.28 years (range 27-42 years), and mean BMI was 21.67 km/m 2 (range 19.5-23.4 km/m 2 ). All seven patients were within 12 weeks of gestation, ve patients (71.45%) were primiparas. N1 and N2 (28.57%) were conceived through assisted reproductive technology. They had not previously been on contraceptive pills, and did not have any personal or family history of venous thrombosis, autoimmune disease, or hematologic disease. The detailed information regarding the initial symptoms, acute neurological symptoms as well as the clinical assay and treatment are summarized as below.

Initial symptoms
All seven patients had been initially suffering from nausea and vomiting accompanied with headache. Five patients (71.45%) complained severe nausea and vomiting with 5 to 10 episodes of vomiting daily which unavoidably made normal eating impossible, leading to maternal weight loss, thus hyperemesis gravidarum (HG) was diagnosed and followed by treatment of rehydration in other hospitals. The other two patients complained of mild nausea and vomiting and chose to make minor adjustments on daily diet at home. Visual analogue scale (VAS) was used to assess the headache severity of which 0-10 means the severity of pain of which "0" means no such symptoms while "10" indicates the most severe symptoms. The headache complained by the patients was mild at the beginning with an average score of 3.86, however, the headache was described as diffuse and aggravation in severity with an average from 3.86 to 7.16 over several days. Time from symptom initiation to admission was 5.7 days (range 3-10 days).

Acute Neurological symptoms
All seven patients had typical neurological symptoms when they came to our institute due to progressive headache and unresponsive nausea and vomiting.
Acute symptoms included epileptic seizures (n=2, 28.6%), limb weakness (n=4, 57.1%), aphasia (n=5, 71.4%), blurred vision (n=2, 28.6%), disturbed consciousness (n=3, 42.9%). Glasgow coma scale (GCS) was used to estimate the neurological state of these patients. They scored with an average of 11.3 (range 3-15) on the Glasgow coma scale (GCS). There was one patient of N4 (14.2%) in severe injury with a GCS score lower than 8, and she was transferred to our emergency department with deep coma by other hospital. Two patients of N6 and N7 (n=2, 28.4%) was in moderate injury with a GCS score 9-12. Both of N6 and N7 were brought to our emergency department by family members, and N6 was reported with behavioral changes and progressing to a global aphasia, N7 presented with aphasia, confusion, and impaired balance. Four patients of N1, N2, N3 and N5 (n=4, 71.4%) were in mild injury with a GCS score 13-15. The clinical symptoms of the involved 7 patients were summarized in Table 1.
Laboratory assay All 7 patients were performed with comprehensive laboratory assays as listed in Table 2. Liver and kidney function, thyroid function, echocardiography and electrocardiogram were all normal. A complete blood count, chemistry panel, sedimentation rate, and coagulation function are detected for these patients.
Laboratory examination revealed a mild in ammatory response with an elevated WBC count of 14.39*10 9 /L, D-dimer were abnormally elevated to 2.97 mg/L (range from 0.8 to 11.6 mg/L), but coagulation pro les were normal. Screening for thrombophilia including protein C, protein S and homocysteine showed that only protein S is slightly lower in N3 (43.8%, normal range 50-80%), and all the coagulation factors were within normal range. Autoimmune diseases with higher risk of hypercoagulation including anticardiolipin antibody, lupus anticoagulant (LA), antinuclear antibody and anti-double strain DNA were also screened and the results showed that only N5 presented with a slightly positive antinuclear antibody (ANA) with 1:160, the rest of the antibody were all negative, and all 7 patients were excluded from autoimmune related disease by rheumatologist. Additionally, N1 and N3 underwent lumbar puncture and elevated opening pressure was revealed but without abnormalities of speci c cerebrospinal uid (CSF).
Digital subtraction angiography (DSA) was conducted for patients when there is a need for endovascular minimally invasive surgery. Three patients of N4, N6 and N7 (n=3, 42.9%) were further proceeded with DSA. DSA con rmed cortical veins and some deep venous structures which CT or MRI/MRV may not reveal, and great cerebral vein thrombosis (n=2, 28.6%) and internal cerebral vein thrombosis (n=1, 14.3%) were demonstrated by DSA.
N4 scored 3 (M1V1 E1) points on the GCS. Emergency cranial CT revealed cerebellar hemorrhage and brain stem edema. She was performed with DSA due to rapid neurological deterioration. DSA con rmed occlusion with great cerebral vein, straight sinus, left transverse sinus and sigmoid sinus, thus immediate interventional thrombolysis was performed, a microcatheter was delivered to the distal thrombosed sinus using a microwire from the jugular bulb and thrombolysis with heparin and urokinase was injected, unfortunately, the occluded sinuses were failed to be recanalized, and N4 deteriorated unavoidably and died within four days.
N6 scored 9 (M4V1 E4) points on the GCS. CT showed left frontal lobe and bilateral parietal lobe hemorrhage, subarachnoid hemorrhage with diffused brain swelling. MRI/MRV revealed almost all intracranial venous sinuses and deep internal cerebral veins were occluded. DSA con rmed a complete super cial and deep venous occlusion. As the representative of extremely serious patients, N6 imaging was showed in Figure 1. N6 experienced rapid consciousness deterioration and herniation signs of left pupil dilatation, although endovascular thrombolysis was attempted and emergency decompressive craniotomy was performed, the brain was extremely extensive swollen with diffused thrombosis of the super cial veins. She died four days post-operation.
N7 scored 11 (M6 V1 E4) points on the GCS. CT venography showed hyper density in left transverse sinus, inferior sagittal sinus, straight sinus and sinus con uence. MRI/MRV showed that massive veins including straight sinus, sinus con uence, great cerebral vein, internal cerebral vein and basilar vein were almost completely occluded. DSA indicated that sinus and deep venous were occluded but basal vein and deep vein have been compensated by sylvian vein re ux, thus endovascular thrombolysis or surgical procedure was not further considered.
CVT anticoagulant treatment CVT management should be comprehensive including treatment and control of underlying primary disease, thrombolytic and anticoagulant therapy, intracranial pressure reduction, symptom relief and prevention of epilepsy complication. Six patients (85.7%) received dehydration therapy to depress intracranial pressure. Three patients (42.9%) received antiepileptic treatment. All 7 patients were initiated anticoagulation treatment with body-weight-adjusted subcutaneous low-molecular weight heparin (LMWH) instantly within 12 hours of admission as soon as CVT was de ned and obvious intracerebral hemorrhage was excluded. When the patient's convulsions were controlled or complaints improved which was consistent with the neuroimaging alteration indicated by partial recanalization on repeat CT or MRI/MRV, LMWH was substituted with oral warfarin in N1, N2, N3 and N5. Warfarin dose was strictly adjusted based on International Normalized Ratio (INR) with a target of 2.0 to 3.0. The most recent patient N7 was treated with LMWH for two weeks followed by oral rivaroxaban (20 mg daily) when her consciousness gradually improved. The period of LMWH bridge to warfarin or rivaroxaban averaged 13.2 days.

Pregnancy outcome and Prognosis
Of the 7 patients, N4 and N6 died within 5 days after admission due to rapid deterioration, other 5 patients progressed well with signi cant improvement and discharged nally. All these 5 patients requested induced abortion, thus when they were stabilized by evaluation of multidisciplinary team, therapeutic justi able abortion were performed with a suspension of anticoagulation for 12h, and the average days from the admission to abortion was 6.5 days (range 4-13 days). The mean hospitalization of these 5 patients were 21.4 days (range 18-22 days). N2 and N7 experienced almost complete recovery without discomfort, N1 and N5 presented slight visual ghosting, and N3 discharged with one limb slight weakness. The treatment and outcome of the seven patients were summarized in Table 4.
All these discharged 5 patients were remained anticoagulation for one year and close regular follow-up. N1 and N3 patients continued taking antiepileptic drugs and showed good recovery at one-year follow up. At 6-month follow-up, ve patients showed no neurologic or functional de cits. At 6 or 12-month follow-up, MRI/MRV revealed sinuses were recanalized in N2, N3 and N5 as showed in Figure 2.

Literature Review
In order to accumulate and summarize published case reports or case series regarding CVT in early pregnancy, a systemic literature search was conducted using Medline, Embase and Google Scholar using the relevant keywords: "early pregnancy", " rst trimester pregnancy", "cerebral venous thrombosis (CVT)", "intracranial venous thrombosis" as well as combinations of these terms. Studies that involved symptoms and management approach on the CVT presenting in early pregnancy were included in our pooled analysis, and totally fteen patients were included as showed in Table 5 [3][4][5][6][7][8][9][10][11][12][13][14][15][16].
The rst case was reported by Robert in 1957. She was misdiagnosed as nervous breakdown at the beginning, died six hours after admission and was found CVT after autopsy. The rst 3 cases reported were diagnosed as CVT after postmortem autopsy (two cases in 1957 and one case in 1978). With the advent and development of imaging modalities, all the following 12 cases were accurately diagnosed with neuroimaging examination and appropriately treated. The mean age of fteen patients was 28.9±2.28 years (range 20-42 years). Nine patients (60%) had unremarkable medical history, the other six patients (40%) had past history of seizure, migraine, antiphospholipid syndrome, oral contraceptive pills, heterozygous factor V Leiden mutation, or CVT. All 15 patients represented typical neurological symptoms, headache is the most common symptom (n=12, 80%), followed by seizures (n=6, 40%), consciousness disorder (n=3, 20%), aphasia (n=2, 13.3%) and hemiparesis (n=2, 13.3). It is noteworthy that NVP (n=5, 33.3%) and HG (n=3, 20%) was also complained in some of those patients. Eleven patients (73.3%) received therapeutic anticoagulation, which included systemic heparin, intravenous heparin, subcutaneous injection of LMWH, warfarin, acetylsalicylic acid and epti batide. One patient (6.7%) underwent direct catheter thrombolysis and thrombectomy, two patients (13.3%) experienced decompressive craniectomy. Eight patients (53.3%) experienced a complete recovery, the other four patients (26.7%) showed neurological dysfunction such as one limb weakness, a slight visual eld defect, mild neurological de cits and hemiplegia and aphasia. Six patients (40% maintained a delivery until the third trimester, two of them underwent planned Cesarean section and the newborn babies were completely healthy.

Discussion
CVT, although rare, can occur in early pregnancy. In the present study, we reported a retrospective consecutive case series of CVT presenting in early pregnancy complicated with nausea and vomiting/hyperemesis gravidarum (NVP/HG). NVP is a common condition with prevalence rates for nausea of 50-80% and for vomiting and retching of 50% [17]. NVP/HG aggravates dehydration, malnutrition, anemia and further concentration of blood. The clinical symptoms of CVT are due to two main pathophysiological processes: (1) increased venular and capillary pressure; (2) decreased cerebrospinal (CSF) absorption [19,20]. Headache, generally indicative of an increase in intracranial pressure, is the most common symptom in CVT and was present in nearly 90% of patients [21]. In our study, all 7 CVT patients were initially presented with various degree of headache with an average of 3.86 by VAS. However, NVP/HG with headache ndings of patients presents a signi cant diagnostic challenge, as subjective headache could be the corresponding clinical complaint in NVP/HG, then headache and vomiting aggravated by intracranial hypertension of potential CVT were usually overlooked by obstetricians initially. The headache in present study was described as diffuse and aggravation in severity with an average from 3.86 to 7.16 by VAS over several days. In addition, in the literature review of 15 cases, NVP was found in 5 patients and HG in 2 patients, and headache is the most common symptom (n=12, 80%). Thus, clinician should prudently differentiate the headache present in the NVP/HG patients, the persistent or aggravated headache could be an initial sign of CVT, early diagnosis and prompt treatment are important to improve prognosis. Besides headache, other neurological symptoms including hemiparesis, aphasia, vertigo, dizziness, seizures, and loss of consciousness appeared successively based on the location of the thrombosis. In this study, time from symptom initiation to hospital admission with multiple neurological symptoms was 5.7 days, a Glasgow Coma Scale score on admission may predict prognosis for CVT patients.
Of the 7 CVT patients, 2 patients were conceived through ART. Thrombophilias are likely to increase thrombotic complications after ovarian stimulation for ART [22]. A meta-analysis comparing pregnancies via ovulation induction to controls found a trend toward increased risk of stroke [23]. Infertility may result from an underlying risk of vascular disease [24]. The results suggest that infertility may re ect an underlying predisposition to vascular disease and pregnancy can unmask this predisposition in women undergoing IVF or other forms of ART, and NVP/HG present in ART pregnancy could probably further increase the thrombosis risk.
There are still no validated pretest clinical probability scores or laboratory tests that can accurately rule out CVT. Neuroimaging remains the main cornerstone for the diagnosis. A CT scan is a useful initial technique to rule out other acute cerebral disorders and reveal venous infarcts or hemorrhages, but its results can be entirely normal [29]. The golden standard for CVT is the combined visualization of thrombosed vessel or sinus on MRI and absence of the vessel or sinus on MRV [20]. Non-contrast MRI at 3 T or less is considered to be safe during any trimester of pregnancy by both the American Colleges of Radiology (ACR) and Obstetrics and Gynecology (ACOG)in updated guidelines [25]. In light of radiation exposure and contrast agent side effects on pregnancy [33], invasive modality of DSA should be reserved to emergent intervention for thrombolysis or more comprehensive examination is needed for deterioration evaluation. In our cases, CT, MRI/MRV and DSA were performed timely to make a quick and accurate diagnosis as well as treatment evaluation.
According to the International Study on Cerebral Vein and Dural Sinus Thrombosis, the most commonly affected site is the transverse sinus, followed by superior sagittal sinus and straight sinus [26]. Other less common sites are the cortical vein, jugular vein and internal cerebral vein. In most patients, thrombosis occurs in more than one sinus. Our ndings are consistent with previous reports. Thrombosis of the deep venous cerebral system veins, internal cerebral veins, vein of Galen, or the straight sinus occurs in approximately 16% of patients with CVT and is considered a risk factor for poor clinical outcome [15]. Thalamic edema is the imaging hallmark of this condition. Mortality rates among patients with this condition are reported to be between 22% and 37% [27]. The clinical features and their severity are highly variable, ranging from isolated headaches to a deep coma, depending on the extent and location of the effected sinus, the venous collateral vessels, and the rate of thrombus progression. The causes of death in our study had two common points (1) low GCS scores at admission (2) extensive deep venous cerebral system embolism with thalamic edema.
According to the guideline of the American Stroke Association/American Heart Association, anticoagulation therapy should be initiated once CVT is diagnosed with no major contraindications [20]. The rst line treatment in acute phase usually starts with intravenous heparin or subcutaneous LMWH. The included 7 patients in our study were initiated anticoagulation treatment with body-weight-adjusted subcutaneous LMWH instantly within 12 hours of admission as soon as CVT was de ned and obvious intracerebral hemorrhage was excluded. Heparin or LMWH are preferable throughout the pregnancy until delivery as a result of their feature not being transferred into placenta. Oral anticoagulation (vitamin K antagonists and new oral anticoagulants NOAC) is contraindicated during pregnancy, because they cross the placenta and can cause neurodevelopmental disorders and fetal bleeding [28]. The period of oral anticoagulation postpartum varied depending on the etiology of CVT and remains controversial [9,29]. In our cases, all the 5 patients were remained anticoagulation for one year since the initial presenting symptom: 4 patients were maintained with oral warfarin to keep a target INR between 2.0 to 3.0, and the most recent patient N7 with NOAC of rivaroxaban (20 mg daily). Both warfarin and rivaroxaban showed satisfactory effect on anticoagulant maintenance therapy in our cases.
Thrombolytic therapy is usually performed if clinical deterioration occurs despite being on an anticoagulation regime, or elevated intracranial pressure was indicated. A systematic review of CVT cases treated with mechanical thrombectomy, 40% of who had encephalopathy of coma, reported a mortality of 14%, with worsening or new intracranial hemorrhage in 9%, complete recanalization in 69%, and complete recovery in 35% [30]. Decompressive craniectomy has shown to be bene cial to critically-ill patients with CVT presenting radiological and clinical features of mass effect with signs of brainstem dysfunction and refractory intracranial hypertension [31]. However, these studies evaluate for outcomes in the general population, and speci c analyses regarding pregnant or puerperal populations are limited. In our present study, endovascular thrombolysis was performed on N4 and N6, and N6 was further proceeded with decompressive craniotomy, however, both of them experienced rapid deterioration and died within 3 days of admission.
Although all 5 live patients requested induced abortion in present study, early pregnancy with CVT is not an absolute indication for termination of pregnancy. Based on the literature review of 15 cases, six patients (40% maintained a delivery until the third trimester, two of them underwent planned Cesarean section and the newborn babies were completely healthy. Pregnancy requires special attention and consideration of differential treatment options. There is no proven evidence of bene t in abortion regarding the mother's or child's health over not interrupting pregnancy. However, we do recommend a multi-specialty approach where an obstetrics team can decide what is best for the mother's health. Although pregnancy can be maintained, the mother's health should be the priority in case of complications.

Conclusion
The present retrospective study should raise awareness of diagnosis and treatment of CVT in nausea and vomiting of early pregnancy complicated with headache. Neuroimaging especially MRI/MRV remains the cornerstone for the diagnosis and instant anticoagulation prior to severe CVT aggravation is the key for the disease prognosis. Early pregnancy combined with CVT is not a contraindication of continued pregnancy but should be prudently evaluated by multi-disciplinary team. Larger patient series with a longer follow-up are warranted to draw more de nitive conclusions on the subject. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent for publication
Informed consent was obtained from all individual participants included in the study.

Availability of supporting data
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declared that they have no con icting interest.