Perinatal/Neonatal Case Presentation &&&&&&&&&&&&&& Neonatal Sinovenous Thrombosis Associated With Homozygous Thermolabile Methylenetetrahydrofolate Reductase in Both Mother and Infant
Jennifer L. Grow, MD At 4 hours of life, he developed coarse jerky movements of all four Paola J. Fliman, MD extremities that lasted approximately 5 minutes and recurred Steven W. Pipe, MD periodically throughout the day. Concerned regarding the infant’s drowsy state requiring stimulation to awaken him for feedings, he was transferred to the neonatal intensive care unit for diagnostic evaluation and therapy. On physical exam, the patient was pale yet The C677T mutation in 5,10-methylenetetrahydrofolate reductase without physical anomalies. He was difficult to arouse. Coarse (MTHFR) predicts substitution of valine for alanine at residue 223 rhythmic movements of all four extremities could not be (A223V). This thermolabile form of MTHFR has 50% reduced activity, has extinguished. The remainder of the physical exam was unremark- been associated with hyperhomocystinemia, and is a described risk factor for able. Blood chemistries, cerebral spinal fluid analysis and cultures, thrombosis in adults.1–3 In addition, it has been associated with birth and head computed tomography were normal. Homocysteine level defects in the infants of affected mothers and with recurrent fetal losses.4–6 was 5 (normal level) on the first day of life. The electro- We report the occurrence of sinovenous thrombosis in a newborn infant who encephalogram showed spikes in the temporal region. Brain presented with seizures. Both infant and mother were subsequently identified magnetic resonance imaging with venogram showed a superior as having homozygous C677T alleles for MTHFR. sagittal sinovenous thrombosis (SVT) and bilateral parietal and Journal of Perinatology (2002) 22, 175 – 178 DOI: 10.1038/sj/jp/7210615 frontal lobe infarcts. Investigations to identify inherited risk factors for thrombosis were negative for factor V Leiden mutation and prothrombin G20210A mutation. Relevant plasma protein levels were compared to published normal values for term infants7 and were as CASE PRESENTATION follows: antithrombin III activity 66% (term normal, 41% to 93%), protein C activity 38% (term normal, 20% to 64%), protein C A 42-week gestational age, 3.7-kg, Caucasian, male infant was antigen 40% (term normal, 20% to 64%), and free protein S antigen evaluated in the neonatal intensive care unit at 6 hours of life 89%. He was positive for homozygous C677T alleles of MTHFR. The for generalized tonic–clonic seizures. He was born to a 35-year- patient was treated with phenobarbital for seizure control to a old gravida 3 para 1 female with unremarkable prenatal phenobarbital level of 24 at discharge and empirically started on folic screening tests. There was no family history of seizures or acid supplementation. He had normal kidney and liver function tests. thrombosis. The mother was a vegetarian. Pregnancy was Anticoagulation was not initiated. complicated by maternal anemia, which was treated with ferrous Familial screening showed that his mother was also homozygous sulfate and prenatal vitamins. Prolonged rupture of membranes for the C677T alleles of MTHFR. His father and sibling were and arrest of descent complicated delivery, resulting in the heterozygous for the alleles. The mother’s homocysteine level was 5 mother receiving two doses of ampicillin prior to caesarian two months post-partum. She began vitamin B12 and folic acid section. Initially cyanotic and without spontaneous respiratory supplementation. Follow-up at 2, 4, and 6 months of life showed a effort, the infant recovered after 30 seconds of bag–mask developmentally normal male infant. He was weaned off his ventilation. The Apgar score at 5 minutes was 9, and the infant phenobarbital at 4 months of life with no subsequent seizure activity. went to the mother–infant unit. On subsequent computed tomographies, his thrombosis had neither progressed nor resolved.
Division of Neonatal – Perinatal Medicine ( J.L.G. ), Department of Pediatrics ( J.L.G., P.J.F., S.W.P. ), Division of Hematology and Oncology ( S.W.P. ), University of Michigan, Ann Arbor, MI, USA. DISCUSSION Address correspondence and reprint requests to Steven W. Pipe, MD, Hemophilia and Coagulation Disorders Program, University of Michigan, L2110 Women’s Hospital, 1500 East The superior sagittal sinus drains cortical venous blood into the Medical Center Drive, Ann Arbor, MI 48109, USA. right lateral sinus and ultimately the jugular vein. Drainage is
Journal of Perinatology 2002; 22:175 – 178 # 2002 Nature Publishing Group All rights reserved. 0743-8346/02 $25 www.nature.com/jp 175 Grow et al. Neonatal Sinovenous Thrombosis
passive and there are no venous valves. Disturbance of normal homocysteine. We speculate that this mother had elevated levels of blood flow in the sinuses, most commonly the superior sagittal, can homocysteine during the pregnancy, which exposed the case patient precipitate thrombus formation and in turn lead to infarction in to elevated homocysteine and increased his risk for SVT. Although the affected brain distribution.8–10 SVT is most commonly this infant had no physical malformations, exposure to elevated associated with bacterial infection and associated vascular invasion. homocysteine levels, even transiently in utero, may have led to Non-septic SVT may be caused by a number of processes including endothelial abnormalities within the cerebral sinuses, which is one hypernatremia with dehydration, disseminated intravascular of the leading mechanisms by which hyperhomocysteinemia leads 1 coagulation, treatment with the chemotherapy agent L -asparagi- to thrombosis. However, since we have no longitudinal data on nase, and polycythemia.11 Hypercoagulable states are also associated plasma homocysteine levels for this mother prior to delivery, we with SVT, with the most common including: protein C deficiency, present the homozygosity for thermolabile MTHFR for the mother protein S deficiency, antithrombin III deficiency, antiphospholipid and infant as an association and not as proven cause for the SVT antibody, and factor V Leiden.12 Approximately 50% of SVT in complication. childhood occurs in neonates and young infants. Mechanical Anticoagulation has not been demonstrated to improve outcome distortion of the cerebral sinuses during the birth process may or alter the clinical course of infants or children with SVT.12 We did contribute to the propensity for SVT in newborns. However, not initiate anticoagulation in this infant primarily due to the cerebrovascular accidents such as SVT and acute ischemic stroke associated areas of infarction and risk for secondary hemorrhage. (AIS) are still very rare in childhood with an estimated incidence The favorable outcome in this infant is encouraging; however, of 0.063 to 0.12 per 10,000 children with a ratio of AIS:SVT of 3:1.12 extended follow-up is necessary due to the propensity for late Most children with SVT have an identifiable cause, with dehydration presentation of neurologic signs because of maturational central most common in neonates. The majority of children have more nervous system changes over the first year of life. than a single identified risk factor. Symptomatic thrombotic events have been reported to occur in Most of the literature concerning infant SVT consist of case 0.07/10,000 children, 5.3/10,000 hospital admissions of children, reports or case series.13–16 It is known to be a fairly rare event for and 2.4/1000 admissions of newborns to intensive care units.42 neonates.11 However, approximately two thirds of infants with SVT Studies in developmental hemostasis have demonstrated that presents with seizure activity.11,13 Seizures from SVT are not although newborns have approximately 50% of adult values of the consistently focal, unlike unilateral cerebral infarction.11 Slightly vitamin K–dependent coagulation factors (II, VII, IX, X) and more than 50% of infants with central venous thrombosis present contact factors (XI, XII, prekallikrein, and high-molecular weight with lethargy,11,17 as did our patient. The unusual presentation of kininogen), the vitamin K–dependent anticoagulants (proteins C SVT in a term infant, with no readily identifiable cause in this case, and S) are also low.7 In turn, newborns have lower concentrations of prompted investigation for inherited prothrombotic risk factors. An antithrombin III and heparin cofactor II and demonstrate reduced association of SVT with thermolabile MTHFR has not previously fibrinolytic capacity. This places neonates at a greater risk of been described in pediatric literature.9,18–22 Review of adult thromboembolic complications than older children. Data registries literature reveals that 12% to 21% of the general population is have demonstrated that the incidence of vascular accidents and other homozygous for the thermolabile MTHFR,1,23–25 and 35% of the thromboembolic complications decreases significantly after the first population carries a heterozygous genotype.26–28 Thermolabile year of life.42 Although acquired risk factors for thromboembolic MTHFR has been shown to result in hyperhomocystinemia, which complications such as the use of central lines, sepsis, asphyxia, and causes oxidative injury. Some studies have shown a chronic dehydration predominate in the neonatal intensive care setting, elevation of homocysteine to be a risk for thrombosis in thromboembolism is a multicausal pathology with contributions adults.25,28–30 Other studies have failed to demonstrate increased from both acquired and genetic risk factors. Even in the newborn risk of thrombosis.31–34 The situation in this report is intriguing setting, idiopathic thromboembolic complications should still invoke since both mother and infant were both homozygous for a search for underlying genetic prothrombotic risk factors. Continued thermolabile MTHFR. Obstetrical literature has noted that certain clinical investigations across all pediatric age groups will eventually pregnant women who manifest infants with neural tube defects,35,36 guide appropriate screening investigations for inherited thrombo- abruptio placentae or infarction,36,37 spontaneous abortions,38 or philia, highlighting those genetic risk factors that are of most preeclampsia17 may demonstrate elevated plasma homocysteine importance to neonates compared to older children and adults with levels. Also women who have pregnancy-related venous throm- thromboembolism. boembolism have an increased incidence of factor V Leiden and This case report highlights several clinical points. SVT should be MTHFR mutation.39 The metabolic consequence of thermolabile considered as an etiology for neonates with unexplained seizure MTHFR is exacerbated by folic acid deficiency and can be abrogated activity, even if other factors such as hypernatremic dehydration are by folic acid supplementation.40 Malinow et al.41 demonstrated a present. Inherited prothrombotic risk factors should be investigated descending concentration gradient of homocysteine from maternal and DNA analysis for MTHFR mutations should be considered for vein to umbilical veins and arteries, suggesting a transfer of both the infant and mother.
176 Journal of Perinatology 2002; 22:175 – 178 Neonatal Sinovenous Thrombosis Grow et al.
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