Simon Mitchell

Vitamin K Prophylaxis for Preterm Infants: A Randomized, Controlled Trial of 3 Regimens

OBJECTIVE. Preterm infants may be at particular risk from either inadequate or excessive vitamin K prophylaxis. Our goal was to assess vitamin K status and metabolism in preterm infants after 3 regimens of prophylaxis. METHODS. Infants <32 weeks’ gestation were randomized to receive 0.5 mg (control) or 0.2 mg of vitamin K1 intramuscularly or 0.2 mg intravenously after delivery. Primary outcome measures were serum vitamin K1, its epoxide metabolite (vitamin K1 2,3-epoxide), and undercarboxylated prothrombin assessed at birth, 5 days, and after 2 weeks of full enteral feeds. Secondary outcome measures included prothrombin time and factor II concentrations. RESULTS. On day 5, serum vitamin K1 concentrations in the 3 groups ranged widely (2.9–388.0 ng/mL) but were consistently higher than the adult range (0.15–1.55 ng/mL). Presence of vitamin K1 2,3-epoxide on day 5 was strongly associated with higher vitamin K1 bolus doses. Vitamin K1 2,3-epoxide was detected in 7 of 29 and 4 of 29 infants from the groups that received 0.5 mg intramuscularly and 0.2 mg intravenously, respectively, but in none of 32 infants from group that received 0.2 mg intramuscularly. After 2 weeks of full enteral feeding, serum vitamin K1 was lower in the infants who received 0.2 mg intravenously compared with the infants in the control group. Three infants from the 0.2-mg groups had undetectable serum vitamin K1 as early as the third postnatal week but without any evidence of even mild functional deficiency, as shown by their normal undercarboxylated prothrombin concentrations. CONCLUSIONS. Vitamin K1 prophylaxis with 0.2 mg administered intramuscularly maintained adequate vitamin K status of preterm infants until a median age of 25 postnatal days and did not cause early vitamin K1 2,3-epoxide accumulation. In contrast, 0.2 mg administered intravenously and 0.5 mg administered intramuscularly led to vitamin K1 2,3-epoxide accumulation, possibly indicating overload of the immature liver. To protect against late vitamin K1 deficiency bleeding, breastfed preterm infants given a 0.2-mg dose of prophylaxis should receive additional supplementation when feeding has been established.

A comparison of transient-evoked otoacoustic emissions and automated auditory brainstem responses for pre-discharge neonatal hearing screening

The aim of this study was to compare two hearing-screening methods in well newborn infants within the postnatal ward environment prior to discharge. Eighty-one newborn infants underwent one-step hearing screening by measurement of automated auditory brainstem responses (aABRs), using the ALGO-3 screener. These were compared with a further cohort of 81 neonates who underwent two-step screening using transient-evoked otoacoustic emissions (TEOAEs) followed by aABR. The pass rate was 78/81 (96.3%) for the one-step screen, 74/81 (91.4%) for the two-step screen, and 54/81 (66.7%) for TEOAE alone. There was no significant difference between cohorts in time required to complete the screening protocol. We conclude that pre-discharge hearing screening of newborn infants on the postnatal ward is feasible and acceptable. Use of TEOAE alone for pre-discharge screening is associated with an excessively high false-positive rate. At our institution, one-step screening resulted in a lower referral rate compared with a two-step approach. The performance of aABR screening may be affected by prior TEOAE screening. Sumario El objetivo de este esludio fue comparar dos métodos de identificación auditiva en neonatos sanos, en el cunero. antes de su egrcso. A 81 neonatos se les realizó una prueba de identificación mediante la medición de potenciales evocados automatizados dc tallo cerebral (aABRs), utihzando el equipo ALGO-3. Estos resultados se eompararon con otra cohorle de 81 neonatos a los que se les efectuaron tanto emisiones otacústicas evocadas por transitorios (TEOAEs) como aABR. El critcrio de respucsta positiva fue 78/81 (96.3%) para la prueba única, 74/81 (91.4%) para las pruebas consecutivas y 54/81 (66.7%) para las TEOAE solas. No hubo diferencia significativa entre cohortes en el tiempo requerido para completar el protocolo de identificación. Concluimos que la identificación auditiva pre-egreso en los neonatos es factible y aceptable. El uso único de TEOAE en la identificatión pre-egreso se asocia a un alto grado de falsos positivos. En nuestra institución, la identificación en un paso resultó en un nivel de referenda más bajo, comparado con el protoeolo en dos pasos. Los resultados de los aABR pucden verse afectados por las pruebas previas con TEOAE.

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

BackgroundCerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families.MethodsHere we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA).ResultsA novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals.ConclusionsThis result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts.Table 4GAD1 single nucleotide substitutions detected on mutation analysis and occurring in sequences submitted to NCBI SNP database and in the literature. This is not a definitive list, but includes those described at the time of the mutational analysis. *Nucleotide positions were not provided by Maestrini et al. [47].SourceSNP position in mRNA, from the translational start site (bp)Gene position of SNP(bp)Amino acid change(A)Lappalainen et al. (2002)A(-478)DelExon 0 (73)No substitution(B)Lappalainen et al. (2002)G(-147)AExon 0 (404)No substitution(C)Lappalainen et al. (2002)A(-39)CExon 1 (25)No substitution(D)Spastic CP patients family BG(36)CExon 1 (97)Ser(12)Cys(E)NCBI collated resourceG(48)CExon 1 (104)Pro(17)Ala(F)Control samples & family A NCBI collated resourceT(110)CExon 2 (29)No substitution(G)Kure et al. (1998)T(315)CExon 4 (14)No substitution(H)Bu and Tobin (1994) Kure et al. (1998)A(407)GExon 4 (105)No substitution(I)Maestrini et al. (2002)*G/CIntron 4No substitution(J)NCBI collated resourceC(696)TExon 6 (56)No substitution(K)Lappalainen et al. (2002)T/DelIntron 7 (35)No substitution(L)In control samples Lappalainen et al. (2002)T/CIntron 8 (185)No substitution(M)Maestrini et al. (2002)*C/TIntron 9No substitution

Urinary excretion of vitamin K metabolites in term and preterm infants: relationship to vitamin K status and prophylaxis.

Little is known about the metabolic turnover and excretion of vitamin K in healthy newborn infants and the metabolic consequences of prophylactic regimens designed to protect against vitamin K deficiency bleeding (VKDB). We measured the excretion of two urinary metabolites (≤24 h) of vitamin K (5C- and 7C-aglycones) in term infants before (n = 11) and after (n = 5) a 1000 μg i.m. dose of vitamin K1 (K1) and in preterm infants after 200 μg i.m. (n = 4), 500 μg i.m. (n = 4), or 200 μg i.v. (n = 5). In preterm infants, we also measured serum K1, vitamin K1 2,3-epoxide, and PIVKA-II at 5 d postpartum. Before prophylaxis, the rate of 5C- and 7C-aglycone excretion was 25 times lower than adults, reflecting low vitamin K stores at birth. After prophylaxis, the excretion rate correlated to K1 dose (r = 0.6) but was two orders of magnitude lower than that in adults, probably reflecting the immaturity of neonatal catabolism. All term and 10 of 13 preterm infants mainly excreted 5C-aglycone. We present evidence that increased excretion of the 7C-aglycone was associated with metabolic overload because of the exposure to high-tissue K1 concentrations. Measurement of the 5C- and 7C-aglycones may facilitate longitudinal studies of vitamin K status in neonates and aid the development of improved prophylactic regimens.

Vitamin K status of preterm infants with a prolonged prothrombin time.

AIM To investigate the vitamin K status of preterm infants who have a prolonged prothrombin time (PT) in the first month of life. METHODS Measures of vitamin K status were assessed in 21 preterm infants who were found to have an abnormal PT, despite 0.2-0.5 mg vitamin K(1) prophylaxis at birth. RESULTS All infants had normal or supraphysiological vitamin K(1) concentrations and undetectable or, in one infant, insignificant PIVKA-II, indicating adequate vitamin K status. CONCLUSION In preterm infants born at <32 wk gestation who received > or = 0.2 mg vitamin K(1) after delivery, a prolonged PT in the first month of life is unlikely to be due to vitamin K deficiency.

High-flow nasal cannulae in very preterm infants after extubation.

To the Editor: In the study by Manley et al., the authors express a degree of caution, but we are concerned that this study will be interpreted as supporting the use of high-flow nasal cannulae. The statement of equivalence assumes that a 20% increase in extubation failure is clinically acceptable, nearly doubling the rate from 25% to 45%. The estimate from the trial is that the use of high-flow nasal cannulae is inferior to CPAP, with an absolute increase of 8.4% and a relative increase of 33.6% in the extubation failure rate, and the authors acknowledge that the upper limit of the 95% confidence interval was close to the already very generous equivalence limit. The article offers no justification for accepting such a large noninferiority margin, although a more clinically acceptable margin would require a substantially larger trial. We believe that this trial offers no evidence in favor of the use of high-flow nasal cannulae and that larger trials that are powered to eliminate meaningful differences in outcomes are required.From the Newborn Research Centre, Royal Women’s Hospital (B.J.M., L.S.O., L.W.D., P.G.D.), the Departments of Obstetrics and Gynaecology (B.J.M., L.S.O., L.W.D., P.G.D.) and Paediatrics (L.W.D., S.M.D.), University of Melbourne, and the Critical Care and Neurosciences Theme (B.J.M., L.S.O., L.W.D., P.G.D.) and Clinical Epidemiology and Biostatistics Unit (S.M.D.), Murdoch Children’s Research Institute, Melbourne, VIC, the Department of Neonatal Medicine, Women’s and Children’s Hospital, Adelaide, SA (C.C.A.), and Women’s and Newborn Services, Royal Brisbane and Women’s Hospital (D.W.C., M.A.P.), the Department of Paediatrics and Child Health, University of Queensland (D.W.C.), and the University of Queensland Centre for Clinical Research (M.A.P.), Brisbane, QLD — all in Australia. Address reprint requests to Dr. Manley at the Newborn Research Centre, Level 7, Royal Women’s Hospital, 20 Flemington Rd., Parkville, VIC 3052, Australia, or at brett.manley@thewomens.org.au.From the Newborn Research Centre, Royal Women’s Hospital (B.J.M., L.S.O., L.W.D., P.G.D.), the Departments of Obstetrics and Gynaecology (B.J.M., L.S.O., L.W.D., P.G.D.) and Paediatrics (L.W.D., S.M.D.), University of Melbourne, and the Critical Care and Neurosciences Theme (B.J.M., L.S.O., L.W.D., P.G.D.) and Clinical Epidemiology and Biostatistics Unit (S.M.D.), Murdoch Children’s Research Institute, Melbourne, VIC, the Department of Neonatal Medicine, Women’s and Children’s Hospital, Adelaide, SA (C.C.A.), and Women’s and Newborn Services, Royal Brisbane and Women’s Hospital (D.W.C., M.A.P.), the Department of Paediatrics and Child Health, University of Queensland (D.W.C.), and the University of Queensland Centre for Clinical Research (M.A.P.), Brisbane, QLD — all in Australia. Address reprint requests to Dr. Manley at the Newborn Research Centre, Level 7, Royal Women’s Hospital, 20 Flemington Rd., Parkville, VIC 3052, Australia, or at brett.manley@thewomens.org.au.

Total and Differential Phylloquinone (Vitamin K1) Intakes of Preterm Infants from All Sources during the Neonatal Period

All newborns require phylloquinone after birth to prevent vitamin K deficiency bleeding. Babies born prematurely may be at particular risk of deficiency without adequate supplementation during infancy. The main sources of phylloquinone in preterm babies during the neonatal period are the prophylactic dose of phylloquinone given at birth, and that derived from parenteral and/or enteral feeding. This observational study formed part of a prospective, multicentre, randomised, controlled trial that examined the vitamin K status of preterm infants after random allocation to one of three phylloquinone prophylactic regimens at birth (0.5 or 0.2 mg intramuscularly or 0.2 mg intravenously). In this nutritional sub-study we quantified the proportional and total phylloquinone intakes of preterm infants within the neonatal period from all sources. Almost all infants had average daily phylloquinone intakes that were in excess of the currently recommended amounts. In infants who did not receive parenteral nutrition, the bolus dose of phylloquinone given at birth was the major source of phylloquinone intake, whereas in infants who received parenteral nutrition, the intake from the parenteral preparation exceeded that from the bolus dose by a ratio of approximately 3:1. Our study supports the concern of others that preterm infants who receive current parenteral nutrition formulations may be receiving excessive vitamin K.

Correspondence Re: High-Flow Nasal Cannulae in Very Preterm Infants after Extubation

To the Editor: In the study by Manley et al., the authors express a degree of caution, but we are concerned that this study will be interpreted as supporting the use of high-flow nasal cannulae. The statement of equivalence assumes that a 20% increase in extubation failure is clinically acceptable, nearly doubling the rate from 25% to 45%. The estimate from the trial is that the use of high-flow nasal cannulae is inferior to CPAP, with an absolute increase of 8.4% and a relative increase of 33.6% in the extubation failure rate, and the authors acknowledge that the upper limit of the 95% confidence interval was close to the already very generous equivalence limit. The article offers no justification for accepting such a large noninferiority margin, although a more clinically acceptable margin would require a substantially larger trial. We believe that this trial offers no evidence in favor of the use of high-flow nasal cannulae and that larger trials that are powered to eliminate meaningful differences in outcomes are required.From the Newborn Research Centre, Royal Women’s Hospital (B.J.M., L.S.O., L.W.D., P.G.D.), the Departments of Obstetrics and Gynaecology (B.J.M., L.S.O., L.W.D., P.G.D.) and Paediatrics (L.W.D., S.M.D.), University of Melbourne, and the Critical Care and Neurosciences Theme (B.J.M., L.S.O., L.W.D., P.G.D.) and Clinical Epidemiology and Biostatistics Unit (S.M.D.), Murdoch Children’s Research Institute, Melbourne, VIC, the Department of Neonatal Medicine, Women’s and Children’s Hospital, Adelaide, SA (C.C.A.), and Women’s and Newborn Services, Royal Brisbane and Women’s Hospital (D.W.C., M.A.P.), the Department of Paediatrics and Child Health, University of Queensland (D.W.C.), and the University of Queensland Centre for Clinical Research (M.A.P.), Brisbane, QLD — all in Australia. Address reprint requests to Dr. Manley at the Newborn Research Centre, Level 7, Royal Women’s Hospital, 20 Flemington Rd., Parkville, VIC 3052, Australia, or at brett.manley@thewomens.org.au.From the Newborn Research Centre, Royal Women’s Hospital (B.J.M., L.S.O., L.W.D., P.G.D.), the Departments of Obstetrics and Gynaecology (B.J.M., L.S.O., L.W.D., P.G.D.) and Paediatrics (L.W.D., S.M.D.), University of Melbourne, and the Critical Care and Neurosciences Theme (B.J.M., L.S.O., L.W.D., P.G.D.) and Clinical Epidemiology and Biostatistics Unit (S.M.D.), Murdoch Children’s Research Institute, Melbourne, VIC, the Department of Neonatal Medicine, Women’s and Children’s Hospital, Adelaide, SA (C.C.A.), and Women’s and Newborn Services, Royal Brisbane and Women’s Hospital (D.W.C., M.A.P.), the Department of Paediatrics and Child Health, University of Queensland (D.W.C.), and the University of Queensland Centre for Clinical Research (M.A.P.), Brisbane, QLD — all in Australia. Address reprint requests to Dr. Manley at the Newborn Research Centre, Level 7, Royal Women’s Hospital, 20 Flemington Rd., Parkville, VIC 3052, Australia, or at brett.manley@thewomens.org.au.

Vitamin K status of preterm infants with a prolonged prothrombin time: Short communications

Aim: To investigate the vitamin K status of preterm infants who have a prolonged prothrombin time (PT) in the first month of life. Methods: Measures of vitamin K status were assessed in 21 preterm infants who were found to have an abnormal PT, despite 0.2–0.5 mg vitamin K1 prophylaxis at birth. Results: All infants had normal or supraphysiological vitamin K1 concentrations and undetectable or, in one infant, insignificant PIVKA‐II, indicating adequate vitamin K status.

54 Vitamin K Status in Preterm Infants: A Randomised Controlled Trial to Compare Three Regimes of Prophylaxis

Background: Neonatal vitamin K stores are precarious. Without adequate vitamin K prophylaxis preterm infants may be at particular risk of vitamin K deficiency bleeding (VKDB), but the optimal dose and route is unclear. Objective: To compare the vitamin K status of preterm infants during the first week of life and when on full enteral feeds, following three regimes of vitamin K prophylaxis after delivery.Design/Methods: Infants born at < 32 weeks gestation were randomised to receive vitamin K1 0.5 mg intramuscularly (IM) (group 1: control), 0.2 mg IM (group 2) or 0.2 mg intravenously (IV) (group 3) on day 1. Cord blood was obtained; venous blood samples at 5 days postnatal and 2 weeks after establishment of full enteral feeds were analysed for serum vitamin K1, vitamin K1 2,3-epoxide, descarboxyprothrombin (PIVKA-II), and prothrombin time.Results: Of 98 infants enrolled, 90 had a day 5 sample and 80 had a second sample obtained at a median (IQR) of 25 (22–31) days. Baseline characteristics (mean ±SD) for groups 1 (n=31), 2 (n=34) and 3 (n=33) were respectively: gestational age 28.3 ±2.5, 28.6 ± 2.3, and 28.1 ±2.6 weeks; birthweight 1025 ±379, 1138 ±379, and 1060 ±371 g.Serum vitamin K concentrations (ng/mL)Compared with the control group, day 5 vitamin K concentrations were significantly lower in group 2 (p = 0.04), and at the time of established feeds they were lower in group 3 (p = 0.03). Three infants (one in group 2; two in group 3) had undetectable levels of vitamin K at the time of the second sample, however in each case PIVKA-II was undetected. Eleven of ninety (12%) infants (seven in group 1; four in group 3) had detectable concentrations of vitamin K epoxide on day 5 (p = 0.007).Conclusions: Preterm infants given 0.2 mg or 0.5 mg vitamin K1 at birth have very high serum concentrations during the first week of life. The presence of vitamin K epoxide is significantly associated with a higher dose (0.5 mg) of vitamin K given IM and with a reduced dose (0.2 mg) given IV, and may reflect vitamin K overload of the immature liver by these regimes of prophylaxis. With a reduced dose given IV or IM, vitamin K can fall to undetectable levels by as early as the fourth postnatal week. The risk of subsequent late VKDB may be increased in these infants unless further vitamin K supplements are given.