Journal Scan: A case review of immediate clinical significance, harvested from major international journal
From the desk of the Editor-in-Chief
(1). Fai, Karl Njuwa, et al. Case 1-2024: a 25-Year-Old Pregnant Woman With Bleeding After a Snakebite. The New England Journal of Medicine, vol. 390, no. 2, 2024, pp. 166-173.
A 25-year-old pregnant woman presented to the emergency department of the Poli District Hospital in the North Region of Cameroon because of vaginal bleeding after a snakebite.
The patient had been in her usual state of health until 1 hour before this presentation, when she was bitten by a snake while walking with her family.
On presentation; to the emergency department, she reported fatigue, dizziness, abdominal pain, pain and numbness in her left lower leg.
The Glasgow Coma Scale score was 15 (on a scale of 3 to 15, with lower scores indicating greater alteration of consciousness).
On examination; the heart rate was 134 beats per minute, the blood pressure 100/60 mm Hg, and the respiratory rate 20 breaths per minute while the patient was breathing ambient air.
The physical examination was notable for mild conjunctival pallor and swelling in the inferior left lower leg, which had been tied with a tourniquet.
The leg was tender with ecchymosis, and two fang marks were visible on the left foot.
The patient had diffuse pain in the lower abdomen, intermittent contractions, and vaginal bleeding.
Fetal movement was detected on palpation. The fetal heart rate was 112 beats per minute; ultrasonography was not available. The remainder of the physical examination was normal.
The hemoglobin level was 7.0 g per deciliter (reference range, 11.5 to 15.0), the urea nitrogen level 145 mg per deciliter (51.8 mmol per liter; reference range, 15 to 45 mg per deciliter [5.4 to 16.1 mmol per liter]), the creatinine level 8.9 mg per deciliter (786.8 mol per liter; reference range, 0.6 to 1.3 mg per deciliter [53.0 to 114.9 mol per liter]), and the platelet count 36,000 per microliter (reference range, 150,000 to 450,000). Urine dipstick testing was positive for blood, and a 20-minute whole-blood clotting test revealed clotting abnormalities.
The patient lived with her family in the North Region of Cameroon. She reported that she was at approximately 7 months’ gestation and had received no prenatal care. She had a history of six previous pregnancies. There was no other relevant medical or family history. She had been accompanied to the emergency department by her family members, who had brought the dead snake with them for identification.
Differential Diagnosis
Dr. Karl Njuwa Fai: This 25-year-old pregnant woman presented to the hospital with vaginal bleeding, lower abdominal pain, and a viable fetus.
Other relevant clinical features included a low platelet count, possible hematuria, elevated blood levels of urea nitrogen and creatinine, a low hemoglobin level, and clotting abnormalities, as measured by the 20-minute whole-blood clotting test. In a resource-limited setting such as this one, the diagnosis is typically made on the basis of the clinical presentation and medical history of the patient.
The differential diagnosis for bleeding in the third trimester of pregnancy can be grouped into causes that are related to pregnancy and those that are not related to pregnancy.
Pregnancy-Related Causes of Bleeding
Pregnancy-related vaginal bleeding in the third trimester of pregnancy is commonly caused by placenta previa, placental abruption, ruptured uterus, or subchorionic hemorrhage.
Placenta Previa
Placenta previa, a condition in which all or part of the placenta is implanted into the lower segment of the uterus, is the most likely cause of bleeding in the third trimester of pregnancy. This patient presented to the hospital at an estimated 7 months’ gestation with vaginal bleeding and intermittent contractions, findings that are consistent with a diagnosis of placenta previa. She also had a history of multiparity at a young age, which is a risk factor for placenta previa. Other risk factors, which were not present in this patient, are a history of abortion, a history of placenta previa, multiple gestation, fibroids, advanced maternal age, and the use of tobacco products. Placenta previa can be diagnosed by means of ultrasonography during the second trimester of pregnancy. However, since this patient had not received any prenatal care, she had not undergone an ultrasound examination. Also, patients who present with placenta previa are unlikely to have clotting abnormalities detected at the time of presentation, whereas this patient had a low platelet count and coagulopathy, as measured by the 20-minute whole-blood clotting test. Although the resources were not available to perform an ultrasound examination, a vaginal examination was performed to rule out the presence of a low-lying placenta.
Placental Abruption
Placental abruption is early, extensive detachment of the placenta during pregnancy or premature detachment of a normally implanted placenta that causes blood to accumulate between the placenta and the uterus. Although this patient presented with vaginal bleeding, she did not have abdominal pain that was sudden in onset or constant or stabbing in nature, and such pain would be characteristic of placental abruption. Furthermore, the vaginal blood was not described as dark, and the patient did not present with signs of preeclampsia. Placental abruption can be associated with a history of arterial hypertension, preeclampsia, abdominal trauma, folic acid deficiency, or the use of tobacco products or cocaine, none of which were reported by the patient. The diagnosis of placental abruption is usually made by means of ultrasound examination.
Uterine Rupture
Although uterine rupture is an unlikely diagnosis in this patient owing to the absence of risk factors such as a scarred uterus, direct trauma, and mechanical dystocia, it is important to consider as a cause of bleeding in the third trimester of pregnancy since it has clinically significant implications for both the mother and the fetus. Patients with uterine rupture often present with acute, intense pain with minimal vaginal bleeding. On physical examination, the fetus is high-riding in the uterus, and the fetal parts can be detected on palpation; in this case, the fetus was low-lying in the uterus.
Subchorionic Hemorrhage
Subchorionic hemorrhage is a less common cause of bleeding in the third trimester of pregnancy than placental abruption or uterine rupture.
This patient presented with bright red vaginal blood, not dark red, and she had tachypnea and tachycardia, findings that are not consistent with a diagnosis of subchorionic hemorrhage.
Causes of Bleeding Not Related to Pregnancy
Although it is always important to consider pregnancy-related causes of vaginal bleeding in an otherwise healthy pregnant patient, the low platelet count and the development of coagulopathy are the most likely explanations for this patient’s bleeding. Given that she reported that a snakebite had occurred approximately 1 hour before presentation, envenomation is the most likely diagnosis for her bleeding disorder. The physical examination confirmed the presence of two fang marks on her left foot. Venom from certain types of snakes can cause coagulopathy and trigger the development of intermittent contractions in pregnancy due to the effects of snake venom phospholipase A2 (PLA2). Standardized assays of fibrinogen (and fibrin degradation products) and prothrombin time are the most sensitive assays for the diagnosis of coagulopathy induced by snake venom; however, these tests were not available in this hospital.
In the North Region of Cameroon, this type of coagulopathy can be caused by the venom from a carpet viper bite. On the basis of its classic appearance, the dead snake was identified as Echis ocellatus, also known as the carpet viper, which established the diagnosis of disseminated intravascular coagulation due to carpet viper envenomation.
Dr. Karl Njuwa Fai’s Diagnosis
Disseminated intravascular coagulation due to envenomation by a carpet viper (Echis ocellatus).
Discussion of Pathophysiology
Dr. Fai: The most venomous snake in sub-Saharan Africa, E. ocellatus, has venom composed of complex enzymes, peptides, and metalloproteinase. Snake venom triggers a robust inflammatory response with the synthesis and release of several substances, including nitric oxide, complement anaphylatoxins, histamine, cytokines, and eicosanoids. Macrophages and leukocytes are mobilized to the affected area, which leads to vascular permeability and the formation of an exudate. Exudates contribute to inflammation and tissue damage.
Viper venom contains phospholipases (e.g., PLA2), metalloproteinases, serine proteinases, and other cytotoxins that mediate most of the clinical manifestations after a bite occurs. The PLA2 enzymes cause myonecrosis by breaking down membrane phospholipids of muscle fibers or through hydrophobic interactions. This disruption of the plasma membrane is associated with an influx of calcium into the muscle cells, leading to the sustained contraction of myofilaments, irreversible damage of myocytes, and dysfunction of mitochondria. This muscle damage is aggravated by the action of snake venom metalloproteinases that break down type IV collagen, an essential component of the capillary basement membrane. Snake venom metalloproteinases and hyaluronidases induce microvascular damage and affect the function of other tissues.
Snake venom metalloproteinases and serine proteinases are procoagulant proteins that can not only activate coagulation factors such as factor V, factor X, and prothrombin but also act as thrombinlike enzymes. In addition, they can hydrolyze fibrinogen and fibrin. The expression of C-type lectin proteins and the microvascular damage caused by snake venom metalloproteinases can result in a decreased platelet population by blocking platelet receptors or directly interacting with von Willebrand factor. These processes all lead to disseminated intravascular coagulation and may contribute to systemic bleeding.
Pathophysiological Features of Envenomation by a Carpet Viper.
The direct cytotoxic action of PLA2s, coupled with the ensuing ischemia due to systemic bleeding, vascular damage, and degradation of the glomerular basement membrane by snake venom metalloproteinases, cause acute kidney injury. In addition, the effects of PLA2s on the membrane phospholipids and adenylate cyclase activity of smooth muscle of the uterus could have led to labor in this patient.
Discussion of Management
Dr. Linda Esso: The management of snakebites varies widely, depending on the identification of the snake involved. Not all snakes have venom, so not all patients need antivenom. It is important to remember that antivenom may still be efficacious even if it is administered days after the bite. Therefore, in situations in which the identity of the snake is unknown, it may be prudent to wait for the development of toxic effects rather than administering antivenom empirically.
The management of snake envenomation involves several important steps. First aid consists of reassuring the patient and keeping that person immobile, which can help slow the spread of the venom in the body. When possible, the patient should be placed in the recovery position (on the side with the upper leg bent to protect the airway and aid in drainage in case of vomiting).
A rapid clinical assessment is performed, along with resuscitation if necessary. Then, a more detailed assessment is done, and the snake is identified if possible. Laboratory testing is performed, with an emphasis on coagulation tests. The 20-minute whole-blood clotting test is a simple test of coagulability that is available in most resource-limited settings, and it can be used at the bedside for the detection of coagulopathy. Analgesic agents are usually administered for pain.
Treatment with antivenom may be indicated when the patient has one or more signs of envenomation, such as hemostatic abnormalities, neurotoxic signs, local swelling involving more than half the affected limb or rapid extension of swelling, the development of an enlarged lymph node draining the affected limb, cardiovascular abnormalities, acute kidney injury, or supporting laboratory evidence of systemic envenomation.2 The administration of antivenom can be crucial in the treatment of envenomation; however, the decision to use antivenom ultimately depends on the patient’s clinical status, the species of the snake, and the venom’s potential toxic effects. Antivenom would be used if the expected benefits exceed the calculated risks. Most antivenoms are administered intravenously with close monitoring of the patient so that adverse reactions related to the antivenom can be quickly identified and treated. Epinephrine is available during the administration of antivenom to limit any severe adverse reactions, including acute toxic effects (e.g., anaphylaxis or fever) and delayed reactions (e.g., serum sickness). The acute reactions are usually mild, but severe systemic anaphylaxis may occur, often within approximately 1 hour after exposure to antivenom.
If the patient is in shock, intravenous fluid is administered for resuscitation. The bite wound is cleaned and examined for signs of infection or tissue necrosis and for evidence of incisions made by family members or traditional healers to bleed the venom before the patient’s arrival at the hospital. Tetanus toxoid and antibacterial therapy are typically administered to patients who are in shock. Once immediate care is provided, the patient is usually assessed for transfer to a specialized health care center.
Follow-up
Dr. Moustafa: We administered two vials of antivenom (Inoserp PAN-AFRICA) diluted in 250 ml of normal saline immediately on the patient’s arrival in the emergency department. Second and third doses were administered 3 and 6 hours, respectively, after the first dose. Despite the administration of antivenom, a 20-minute whole-blood clotting test showed no clot formation.
On the second hospital day, the hemoglobin level remained at 7 g per deciliter. Two pints of fresh whole blood were transfused. Analgesics, glucocorticoids, and promethazine were also administered. The rest of the day was uneventful.
On the third hospital day, worsening vaginal bleeding and pelvic pain developed in the patient, features consistent with labor. A fourth dose of antivenom was administered. On a physical examination performed 3 hours later, the cervix was 5 cm dilated, and there was no bleeding. The pelvic pain persisted, and a 20-minute whole-blood clotting test showed findings consistent with persistent coagulopathy.
On the fourth hospital day, the patient delivered a live baby boy. The infant’s weight was 3400 g, a weight indicative of a near-term or full-term gestation. A moderate cervical tear and bleeding had occurred during labor, but the bleeding ceased with repair of the cervix. An additional 4 pints of fresh whole blood were transfused. Approximately 2 hours later, the vaginal bleeding recurred; another dose of antivenom was administered, and an additional 2 pints of fresh whole blood were transfused. The patient was transferred by automobile to the Garoua Regional Hospital, a tertiary care hospital located approximately 3 to 4 hours from Poli.
On arrival at the second hospital, the patient had stopped bleeding, but a diagnosis of acute kidney failure was made on the basis of a serum creatinine level of 8.9 mg per deciliter. An additional 2 pints of fresh whole blood were transfused. Despite aggressive treatment with antivenom and blood transfusion, 4 days after a snakebite by a carpet viper, the patient died.
Advocacy and Call to Action
Dr. Yap Boum II: Snakebites are a public health problem. Each year, snakebites occur in approximately 5 million people worldwide, causing about 125,000 deaths and 400,000 disabilities annually.7 In tropical climates such as sub-Saharan Africa, the burden is substantial, with about 20,000 deaths annually.
In 2015, a surveillance system was created in Cameroon to monitor mortality, enhance early detection and response, and produce evidence of the burden of snakebite disease in the country. Between 2018 and 2022, Cameroon registered 40,518 snakebite cases associated with 1056 deaths (2.6%). The Far North, Center, and North Regions are the most affected areas of the country, with more than 1500 snakebite cases reported per year.
Snakebites Occurring in Pregnancy
Snakebites in pregnant patients are a rare occurrence, but when they do occur, they are associated with substantial morbidity and mortality for both the mother and the fetus. Snakebites occurring in pregnancy are not often documented in the literature. Studies conducted in South Africa, Sri Lanka, and India showed that the prevalence of snakebites occurring in pregnancy ranged from 0.4 to 1.8%. Although rare, they can be associated with very severe adverse outcomes, as was seen in this patient, with maternal death occurring in up to 4% of reported cases and fetal loss in 20%.10 Diverse outcomes are possible for the mother and the fetus, depending on several factors, including the type of snake and the gestational age of the fetus. Fetal complications can include deformation, prematurity, and in severe cases, death. As seen in this case, maternal complications can include antepartum hemorrhage, coagulopathy, spontaneous abortion, labor, and kidney injury. Antivenoms can be used to treat snakebites in pregnant patients even though their safety has not been established in this population; however, they are not widely accessible because of their cost and a lack of availability.
Timely medical treatment and the early administration of antivenom, when indicated, have been shown to influence the outcomes of snakebites in pregnancy. This patient arrived at the hospital for medical attention approximately 1 hour after the snakebite had occurred, which is earlier than most other patients in this region would arrive. Patients typically arrive 2 to 3 days after the snakebite, after they have sought care from traditional healers and received treatments associated with limited scientific evidence of improved outcomes. The availability and affordability of antivenom is a notable issue in Africa. It is usually difficult to obtain antivenom in the remote areas of Cameroon, where the highest number of snakebites occurs. When antivenom is available, the cost is high ($100 to $200 per dose) for these communities, which have an average monthly income of less than $60 per person. This patient had immediate access to antivenom because the hospital was participating in a pharmacovigilance study that provided antivenom for free. Changes in the attitudes of international health stakeholders (e.g., community leaders, pharmaceutical companies, the Ministry of Public Health, Africa Centers for Disease Control and Prevention, and the World Health Organization) toward snakebites, universal health coverage, and local production of antivenom can go a long way in making antivenom more affordable.
The observed complications in this patient were coagulopathy, obstetric hemorrhage, cervical tear, hypovolemic shock, anemia, and labor and delivery. The baby survived, but the mother died. A combination of the systemic envenomation from a carpet viper bite and the resulting complications led to the fatal outcome in the mother. Immediate delivery of the fetus certainly played an important part in the survival of the baby.
The personnel of Poli District Hospital had been trained in the rapid bedside diagnosis of coagulopathy with the use of the 20-minute whole-blood clotting test in the absence of hematologists and well-equipped laboratories. Although the health care providers made an early diagnosis of anemia and coagulopathy, the hospital had an insufficient supply of appropriate blood products such as clotting factors. In this case, the patient received a total of 10 pints of fresh whole blood.
Snakebites pose a substantial threat to the health and well-being of communities across Africa. Venomous bites often lead to serious complications, disability, and even death if not treated promptly and effectively. The management of this neglected tropical disease depends on rapid detection and the administration of adequate antivenom. Antivenom is often the most effective treatment for snakebites since it neutralizes the venom, preventing further damage. In Cameroon, only the Inoserp antivenom, which is not effective against all snake venoms, is available.13 Because of its cost, this antivenom is not available at all health care facilities, and it is not affordable for the at-risk populations in the tropics, including rural communities and indigenous populations that practice farming. Promoting local production and advocating for the availability and accessibility of snakebite antivenoms in Africa is therefore of paramount importance. Improved access to affordable antivenom, snakebite prevention, and community education can save lives, reduce the burden on health systems, and help achieve the Sustainable Development Goals. Together, we can make a substantial difference in the fight against snakebite and improve the health of African people.
Final Diagnosis
Carpet Viper (Echis Ocellatus) Envenomation.