Epidemiology of Pregnancy- Associated Cerebral Venous Thrombosis (CVT) in Three Referral Hospitals in Khartoum, Sudan

Cerebral venous thrombosis (CVT) is a rare form of stroke that results from thrombosis of the cerebral veins. There are several other terms for the condition, such as cerebral venous and sinus thrombosis (superior), sagittal sinus thrombosis, dural sinus thrombosis, and intracranial venous thrombosis as well as the older term cerebral thrombophlebitis. It has an overall incidence of < 1/100,000 in the general population [1]. Symptoms may include headache, abnormal vision, or any of the symptoms of stroke such as weakness of the face and limbs on one side of the body, and seizures. The diagnosis is usually made by computed tomography (CT/CAT scan) or magnetic resonance imaging (MRI/ MRV) employing radio-contrast to demonstrate obstruction of the cerebral veins by thrombus [2]. Pregnancy induces several changes in the coagulation system, which persists into the postpartum period resulting in a pro-thrombotic state. These have all been regarded as important factors contributing to the risk of CVT in pregnancy and the postpartum period [3]. Risks of both antepartum and postpartum CVT increase with hypertension, advancing maternal age, caesarean delivery, associated infections and excess vomiting during pregnancy [4]. Cerebral venous thrombosis is more common in women than men, with a female to male ratio of 3:1 [5,6]. The imbalance may be due to the increased risk of CVT associated with pregnancy and puerperium and with oral contraceptives [7]. Women using combined oral contraceptives have an increased risk of CVT by approximately 20% in comparison with those not using this method [7]. To our knowledge no available data on pregnancy related cerebral venous thrombosis in Sudan, thus the current study designed and directed to investigate the epidemiology of cerebral venous thrombosis aiming to provide the health care providers with fundamental data to deal with this rare condition.


Introduction
Cerebral venous thrombosis (CVT) is a rare form of stroke that results from thrombosis of the cerebral veins.There are several other terms for the condition, such as cerebral venous and sinus thrombosis (superior), sagittal sinus thrombosis, dural sinus thrombosis, and intracranial venous thrombosis as well as the older term cerebral thrombophlebitis.It has an overall incidence of < 1/100,000 in the general population [1].Symptoms may include headache, abnormal vision, or any of the symptoms of stroke such as weakness of the face and limbs on one side of the body, and seizures.The diagnosis is usually made by computed tomography (CT/CAT scan) or magnetic resonance imaging (MRI/ MRV) employing radio-contrast to demonstrate obstruction of the cerebral veins by thrombus [2].Pregnancy induces several changes in the coagulation system, which persists into the postpartum period resulting in a pro-thrombotic state.These have all been regarded as important factors contributing to the risk of CVT in pregnancy and the postpartum period [3].Risks of both antepartum and postpartum CVT increase with hypertension, advancing maternal age, caesarean delivery, associated infections and excess vomiting during pregnancy [4].Cerebral venous thrombosis is more common in women than men, with a female to male ratio of 3:1 [5,6].The imbalance may be due to the increased risk of CVT associated with pregnancy and puerperium and with oral contraceptives [7].Women using combined oral contraceptives have an increased risk of CVT by approximately 20% in comparison with those not using this method [7].To our knowledge no available data on pregnancy related cerebral venous thrombosis in Sudan, thus the current study designed and directed to investigate the epidemiology of cerebral venous thrombosis aiming to provide the health care providers with fundamental data to deal with this rare condition.

Material and Methods
This was a case control, hospital-based study conducted from 1 st January 2011 to 31 st December 2012 to investigate the epidemiology of cerebral venous thrombosis during pregnancy and postpartum period (from delivery and up to six weeks post delivery) in three main referral hospitals in Khartoum, capital city, Sudan.Khartoum occupies 28000 km 2 and it is the most densely populated city in the country with about 5,323,248 million populations according to 2008 population census.The cases were all pregnant and puerperal women (with neurological symptoms or signs and in whom the diagnosis of CVT was confirmed by MRI/MRV) who were attending the obstetrical and gynecological units in these referral hospitals in Khartoum (Khartoum hospital, Omdurman maternity hospital and Khartoum North hospital).These symptoms and signs included headache, abnormal vision, or any of the symptoms of stroke such as weakness of the face and limbs, and seizures.Women to whom MRI/MRV was not done and women with other causes of stroke during pregnancy or puerperium were excluded from the study.After informed written consent the data was collected using structured questionnaire.Those who were confused or comatose the consent was obtained from the guardian.Information sought in the questionnaire included socio-demographic characteristics (age, residence), obstetrical history (parity, antenatal care utilization, preeclampsia, mode of delivery and use of combined oral contraceptive pills), the presenting complaint, medical history (anemia, deep vein thrombosis, diabetes mellitus, hypertension, thrombophillia, nephritic syndrome, etc.) and the disease outcome (improvement, residual impairment and death).Proper systemic and neurological examination was performed to each patient by physician including cardiovascular, respiratory, abdomen, musculoskeletal, CNS (including high cerebral function, cranial nerves, motor and sensory systems).Baseline investigations were performed for every patient on admission and repeated when clinically indicated.These included levels of hemoglobin, serum urea, serum creatinine, and serum bilirubin as well as the white blood cell count and radiological imaging MRI (venous study with contrast); MRI (venous study without contrast) and thrombophilia work up (Factor V Leiden, Protein S free, Protein C and Antiphospholipid antibodies).Anticoagulants (Low Molecular Weight Heparin (LMWH) 30000 -40000 IU through infusion pump for seven days and then 10000 IU subcutaneous LMWH for six months in case of antenatal CVT; but in case of postnatal period instead of subcutaneous heparin we prescribed oral anticoagulant; warfarin tablets) and supportive management were given according to the hospital guidelines.All patients were under multidisciplinary care and were closely followed up during hospital stay and up to six months after hospital discharge.For each case we used two consecutive women who delivered in the hospitals without CVT to act as controls.The different variables were compared between the cases and controls using logistic regression analysis.

Statistical Analysis
Data were entered into a computer database and SPSS software (SPSS Inc., Chicago, IL, USA, version 16.0) and double checked before analysis.Univariate and multivariate analyses were performed.CVST was the dependent variable and socio-demographic characteristics were independent variables.Confidence intervals of 95% were calculated and p < 0.05 was considered significant.In case of discrepancy between the results of univariate and the results of multivariate analyses, the later was taken as final.

Ethics
The study received ethical clearance from the Health Research Board at Khartoum Teaching Hospital, Khartoum Sudan.

Discussion
This study showed an incidence rate of 0.01 per 100.000deliveries for CVT during pregnancy and puerperium.Also the study revealed that among the different risk factors there was strong association between age, mode of delivery, anemia, preeclampsia and pregnancy-associated CVT.It is worth mentioning that there were no pre-existing local data regarding the true incidence of CVT in pregnancy and puerperium, to compare it with our study.It is little bit difficult to regard this rate as an actual incidence rate of CVT in our community since very large population bases are required for reliable estimation.A number of previous studies demonstrated increasing incidence of CVT in Iran and other countries [8].Its increasing prevalence may be attributed to not only increased ease of diagnosis by modern imaging tools such as magnetic resonance imaging (MRI), but also to the increment of underlying causes including use of oral contraceptive pills [9,10].Pregnancy and postpartum period are important risk for CVT.High predominance of female involvement was noticed with sex ratio of 2.3 in Morocco [11].Pregnancy itself is a thrombophilic state due to the changes in blood like increased factor VIII, fibrinogen, decreased Protein S, decreased fibrinolysis, hyperemesis gravidarum, obesity, caesarean section, immobilization and other mechanical and haemodynamic factors due to pregnant state [12].Most pregnancy-related strokes occur in the third trimester or puerperium, and this obviously explained the higher proportion of the cases been identified in postnatal period [13].This is in consistent with study carried out in Taiwan which showed that 73% of CVTs occurred in the puerperium [3].In the present study more than one quarter (25.8%) of patients were primarily admitted and treated as eclampsia because of the similar presentations, and the diagnosis was made after failure to respond to conventional treatment of eclampsia.this is because the modern radio imaging facilities are not always available and most of the cases have been seen in primary and secondary level facilities.Thus increased index of suspicion for such disorder is therefore required among obstetricians and other health providers for early diagnosis, management and favorable outcome.In our study there was two patients died as a result of pregnancy-associated CVT.The rate of death from all causes of CVT is 2-10%, although mortality is significantly less for pregnancy-associated CVT [13].When maternal deaths occur, they usually result from secondary intracranial hemorrhages although one analysis reported the most common cause of death to be transtentorial herniation [14].With regards to the risk factors for pregnancy-associated CVT, our findings are in line with what was reported in the literature [15].Caesarean delivery was highly significant risk factor for CVT however; and in contrast to our findings Lanka et., reported that CVT was more prevalent in younger women [15].This difference in age might be attributed to other environmental and individual factors which possibly act as confounders.Oral contraceptives have long been attributed to the development of CVT [9].In our study only 9.6% of the patients were using oral contraceptives and there was no significant statistical association between contraceptive use and CVT.This may simply reflect the low oral contraceptives prevalence in this region of the world [16].Anemia in pregnancy is a major public health problem and it is highly prevalent in Sudan [17].Moreover Ali et., in recent study reported that women with severe anemia were at 3.6 times at higher risk of preeclampsia [18].This association between anemia and preeclampsia may explain preeclampsia and anemia being obvious risk factors for pregnancy associated-CVT.Abnormal endothelium and abnormal blood flow seen in preeclampsia are possible etiological and risk factor for CVT in preeclampsia [19].

Limitations
Limitations of the study is partly due to the short duration and being confined to only three hospitals which underestimate the actual incidence rate of the problem and this of no doubt increase the probability of population bias.

Conclusion
CVT presented with extremely varied signs and symptoms in pregnancy which represents a challenge for the diagnosis and management and easily mistaken for those due to eclampsia.Caesarean delivery, older age, anemia and preeclampsia are the dominant risk factors for pregnancy-associated CVT.

Figure 1 :
Figure 1:The outcome of cerebral venous sinuous thrombosis during pregnancy and postpartum period using the modified Rankin scale in Khartoum, Sudan.Score 0 = No symptoms at all Score 1 = No significant disability despite symptoms; able to carry out all usual duties and activities Score 2 = Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance Score 3 = Moderate disability; requiring some help, but able to walk without assistance Score 4 = Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance Score 5 = Severe disability; bedridden, incontinent and requiring constant nursing care and attention Score 6 = Dead

Table 1 :
despite symptoms; able to carry out all usual duties and activities Score 2 = Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance Score 3 = Moderate disability; requiring some help, but able to walk without assistance Score 4 = Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance Clinical presentations (Symptoms) of cerebral venous thrombosis during pregnancy and postpartum period in Khartoum, Sudan, total number = 31(Data are shown as number (%) as applicable).

Table 2 :
Risk factors of cerebral venous thrombosis during pregnancy and pueperium in Khartoum, Sudan using univariate and multivariate analyses.(OR: Odds Ratio; CI: Confidence Interval; COCs: Combined Oral Contraceptive Pills; DVT: Deep Vein Thrombosis)