2022 Volume 10 Issue 4 Pages 121-124
Background Neurofibromatosis type 1 is a disorder characterized by café-au-lait spots and neurofibromas. Recent studies have suggested that neurofibromatosis type 1 may induce vascular fragility. Limited information is currently available on vascular fragility in pregnancies complicated by neurofibromatosis type 1.
Case The patient was a 40-year-old woman (gravida 3, para 1) with neurofibromatosis type 1. In her second pregnancy, blood pressure began to rise at 30 weeks of gestation. At 34 weeks of gestation, left intercostal artery rupture and massive hemothorax occurred, resulting in neonatal death. In her third pregnancy, caesarean section was performed at 30 weeks of gestation prior to the expected increase in blood pressure, resulting in a livebirth. However, the patient died three months later due to left intercostal artery rupture.
Conclusion Pregnancy complicated by neurofibromatosis type 1 is associated with vascular fragility, leading to fatal events. Thus, obstetricians should be aware of this condition. A management strategy needs to be established for vascular fragility in complicated pregnancy.
Neurofibromatosis type 1 (NF1), an autosomal dominant tumor suppressor syndrome, is characterized by histologically benign tumors of the peripheral and central nervous systems.1) The presence of vascular fragility in some patients with NF1 has recently been reported.2) Although the frequencies of hypertensive disorder of pregnancy (HDP) and preterm labor are higher in NF1-complicated pregnancies,3) to the best of our knowledge, there are currently no recommendations for the management of vascular fragility in these cases.
Here we report a case of an NF1-complicated pregnancy in a patient with a history of vascular fragility, including maternal hemorrhagic shock in the second pregnancy that resulted in neonatal death. Cesarean section (CS) was performed at 30 weeks of gestation in the third pregnancy, leading to a livebirth. However, the patient died three months later.
The patient was a 40-year-old Japanese woman, gravida 3, para 1 (spontaneous miscarriage 1, neonatal death 1), with a history of several neurofibromatosis surgeries (external auditory canal, right mandible, both upper extremities, anterior trunk, both lower extremities) and no family history of NF1. She was diagnosed with NF1 (DNB classification Stage 3, skin lesion D3: numerous neurofibromas including those on the face, neurological symptoms N0: no trans-symptoms, bone lesion B0: no bone lesions) in her childhood. After spontaneous miscarriage at age 38, she became pregnant again at age 39. Her body mass index (BMI) before the second pregnancy was 36.7 kg/m2 (153.0 cm, 85.9 kg). No abnormalities in glucose tolerance were observed throughout her second pregnancy. She was diagnosed with white-coat hypertension based on blood pressure (BP) at 30 weeks of gestation at the obstetrical office of 145/90 mmHg and at home of 120/70 mmHg. Fetal growth restriction (−1.5 SD) was detected from 31 weeks of gestation. At 34 weeks and 6 days of gestation, she suddenly developed breathing difficulties when lying on her left side and was transported to the emergency department of a different hospital from where she had her antenatal check-ups (i.e., our institute). The findings at the emergency department were reported in a previous study4) and included unclear consciousness; BP 110/90 mmHg; pulse rate 90 bpm; SpO2 97% (oxygen mask 10 L/min); and fetal heart rate (FHR) 80–100 bpm. Thirty minutes after admission, a CT scan revealed massive hemothorax on the left side (Figure 1).
CT scan of the chest showing left hemothorax (yellow triangles).
FHR decreased to 50–60 bpm. After the insertion of a thoracic drain, emergent CS was performed. However, the infant was in cardiac arrest and died. After surgery, systolic BP increased to 180–200 mmHg but was reduced to 70 mmHg by increasing the dose of propofol. Respiratory surgeons and radiologists reviewed this case and suspected that hemothorax was caused by vascular fragility associated with NF1. Angiography revealed the source of bleeding to be the left 10th intercostal artery. Bleeding was stopped by percutaneous arterial embolization, and vital signs subsequently stabilized. The patient developed fever and was diagnosed with an infected hematoma due to hemothorax. She underwent surgery to remove the hematoma and was discharged.
Three months after emergent CS, she became pregnant again and visited our hospital. The obstetrician explained the risk of perinatal mortality with the continuation of the third pregnancy due to NF1-induced vascular fragility. However, the patient wished to continue the pregnancy; she signed a consent form containing information about the risk of perinatal mortality. Maternal status and fetal growth were uneventful during the course of pregnancy, and maternal hypertension and proteinuria were not detected until after delivery. Her BMI before the third pregnancy was 30.3 kg/m2 (153.0 cm, 71.0 kg), and weight gain during pregnancy was 7.35 kg. She was managed in the hospital from 26 weeks of gestation, and CS was planned at 30 weeks of gestation to prevent an increase in vascular tension due to vascular fragility. After the administration of betamethasone, she underwent elective CS at 30 weeks and 5 days of gestation. General anesthesia was performed due to the presence of a neurofibroma around the lumbar vertebrae, which anesthesiologists regarded as a risk factor for bleeding by lumbar puncture. A female infant with a body weight 1,338 g (−0.6 SD), an Apgar score 1/3, and umbilical artery blood pH 7.320 was delivered. Blood loss during CS was 605 g, including amniotic fluid. After CS, BP remained high at approximately 140/90 mmHg, and amlodipine besilate was administered at 2.5 mg per day from postoperative day 2. This treatment reduced BP and was thus discontinued two weeks after CS. A full-body contrast-enhanced CT scan was performed on postoperative day 3 to detect aneurysms associated with NF1. Although no obvious pseudoaneurysms were identified, a 19×11 mm mass was noted in the right adrenal gland. Therefore, urinary normetanephrine and metanephrine levels were examined (0.35 and 0.26 mg/L, respectively). An endocrinologist diagnosed the mass as a pheochromocytoma because catecholamine metabolite levels were slightly elevated, and given that the patient had NF1. The mass did not require treatment because BP had been normal. Catecholamine metabolite levels were scheduled to be reexamined one year after CS.
Three months after CS, the patient suddenly developed abdominal pain and was transported to the emergency department of a nearby hospital. Her left 8th intercostal artery had again ruptured, and she died of hemorrhagic shock.
NF1 affects approximately 1 in 3,000 births.5) This autosomal dominant genetic disease is caused by abnormalities in the NF1 gene, a tumor suppressor gene,1) with more than 50% of cases having de novo mutations.6) Common clinical symptoms of NF1 include café-au-lait spots, neurofibromas, Lisch nodules as well as hypertension due to pheochromocytoma, vascular stenosis, and various benign and malignant neoplastic lesions. Although the frequency of NF1-complicated pregnancies in Japan is unknown, it is estimated to affect approximately 1 in 10,000 births in the United States.3) NF1-complicated pregnancies are associated with increased risks of HDP, stillbirth, fetal growth restriction, preterm labor, CS, and cerebrovascular diseases,3,7) possibly due to NF1-related vasculopathy.3,8,9) HDP is a complex disorder associated with endothelial dysfunction as well as preexisting hypertension and vasculopathies of various etiologies.3) Pheochromocytoma complicated by NF1-induced hypertension is considered to induce vascular spasms and reduce placental blood flow, thereby increasing the risk of miscarriage or preterm birth.10) Pheochromocytoma is also a cause of hypertensive emergencies in NF1-complicated pregnancies; the rate of pheochromocytoma complication in patients with NF1 has been reported to be 0.1–57%.10) Evaluation of the presence of pheochromocytoma is also important from the perspective of BP control.
Only a small number of NF1 cases with vascular fragility have been reported to date, and pregnant cases are even rarer. Terry et al.3) reported the largest number of cases of NF1-complicated pregnancies but did not describe vascular lesions due to NF1-induced vascular fragility. To the best of our knowledge, only limited reports exist which discuss these symptoms in pregnancy.11,12)
Vascular lesions due to NF1-induced vascular fragility are diverse and include aneurysms, arteriovenous fistulas, and arterial rupture. Comorbidity rates of these vascular lesions in NF1 range from 1.0 to 3.6%.13) Ascending aortic rupture occurred in a previous NF1-complicated pregnancy.11) The following mechanisms have been proposed for vascular fragility in NF1: (1) the direct infiltration of a neurofibroma into vascular mesothelium tissue, (2) ischemia of the vessel wall caused by the compression of a feeding artery by a neurofibroma, and (3) thinning of the vascular mesothelium and rupture of the elastic plate due to the growth of spindle-shaped cells in the vascular endothelium. These mechanisms lead to the formation of vascular lesions, vascular failure, and the weakening of the vessel wall in NF1 patients.14,15,16)
In the present case, we assumed that the patient had NF1-induced vascular fragility in the left intercostal artery based on her previous pregnancy history. Vascular lesions, such as ruptured aneurysms, are generally associated with hypertension. Our patient also developed hypertension in the third trimester of the second pregnancy during which arterial rupture occurred. Since the presence of NF1-induced vascular lesions was already speculated in the present pregnancy, CS was planned at 30 weeks of gestation to prevent maternal hypertension and achieve a good neonatal prognosis; this led to a successful livebirth. However, the patient died three months after CS. There is currently no established management for vascular fragility in NF1-complicated pregnancies. Based on the present case, we recommend that obstetricians and physicians in charge of NF1 management screen for vascular lesions related to NF1 before pregnancy. Pseudoaneurysms related to NF1 can be found with contrast-enhanced CT. We also propose that NF1 cases with vascular fragility be managed throughout life at the same hospital where treatment of vascular lesions can be offered.
The authors thank Yoshiko Ishikawa, Kumiko Hashimoto, Mayumi Okada, and Hitoshi Kikuchi for providing information.
The authors have no relevant financial or non-financial interests to disclose.
