Vitamin K to Neonates: Peroral versus Intramuscular Administration

ABSTRACT. In a randomized study of 300 infants, the effect of 1 mg of peroral vitamin K given at birth was compared to the same dose given as an intramuscular injection. The combined activity of coagulation factor II + VII + X taken after 48 and before 72 hours after delivery served as the primary endpoint. Prothrombin (antigen) and PIVKA II (acarboxyprothrombin) were also measured. All infants were observed for events of bleeding until discharge from the hospital, normally on the fifth day. No significant differences between the groups in any of the biochemical markers were observed. The 95% confidence limits of the differences were very narrow for all factors. No cases of bleeding were observed. We conclude that administration of 1 mg peroral vitamin K is as efficient as intramuscular administration of the same dose in the prevention of classical hemorrhagic disease of the newborn.     

The Third Nationwide Survey in Japan of Vitamin K Deficiency in Infancy

The occurrence of hemorrhagic disease due to vitamin K (VK) deficiency beyond the neonatal period has come under investigation in Japan. In 1980 the 1st nationwide survey was conducted in Japan by Nakayama and others [1], and was followed by the 2nd nationwide survey in 1985 by Hanawa [2]. The present survey was designed to further monitor the incidence of this disease in Japan during the 3-year period from July 1985 to June 1988. Questionnaires were sent to 1,315 hospitals having more than 200 beds, located throughout Japan. Responses were received from 775 hospitals, for an answer rate of 58.9%. The total number of reported cases was 175, including 129 idiopathic type, 28 secondary type and 18 near-miss type. In this survey it was revealed that the incidence rate of the idiopathic type of vitamin K deficiency in infancy (VKDI) has decreased remarkably, to about one-fourth that reported in the first survey. The declining incidence rate of VK deficiency in Japan is considered to be the result of ever more widespread prophylactic administration of VK during the neonatal period, as most occurrences of VK deficiency in infancy are preventable by prophylactic administration of VK from the neonatal period. However, in 16 cases of the idiopathic type of VK deficiency found in the present survey, VK had been administered at least once during or after the neonatal period. This shows the heterogeneity of this condition.     

Vitamin K prophylaxis and late vitamin K deficiency bleeding in infants: Fifth nationwide survey in Japan

Background: In 1980, the first nationwide survey on late vitamin K deficiency bleeding (VKDB) in infants was conducted in Japan, and it was followed by the second, third and fourth nationwide surveys in 1985, 1988 and 1991, respectively. The fifth nationwide survey was designed to ascertain the epidemiology of late VKDB between January 1999 and December 2004. Patients and methods: Questionnaires were sent to 2161 hospitals in Japan that employed members of the Japan Pediatric Society in March 2005. Responses were received from 1373 hospitals, for a response rate of 63.5%. Results: The total number of reported cases was 71, including 21 idiopathic type and 16 secondary type. The incidence of late VKDB was estimated to be 1.9 cases per 100 000 births (95% confidence interval: 1.2–3.0) during this survey period. In 34 cases, the presence or absence of any underlying disease was not clarified. A total of 67/71 infants were entirely breast‐fed. Intracranial hemorrhaging was observed in 26 (63.4%) out of 41 infants whose bleeding sites were described in the questionnaires. In 63 cases (88.7%) of late VKDB found in the present survey, however, vitamin K had been given at least once either during or after the neonatal period. Conclusions: A reevaluation of the current prophylaxis strategy for late VKDB in infants is necessary.     

Late vitamin K deficiency bleeding in infants: five-year prospective study

ObjectiveTo study the presenting clinical and demographic features, risk factors, and outcome of infants with late vitamin K deficiency bleeding.MethodsOver a 5-year study period, the presenting clinical features and outcome of all 47 infants observed aged less than 6 months, who were diagnosed with late-onset primary and secondary VKDB by detailed history, physical examination, and laboratory findings were evaluated. Confirmed primary late VKDB was diagnosed when no cause other than breastfeeding could be found, while in the secondary subtype additional risk factors compromising the vitamin K effect were diagnosed.ResultsSecondary late VKDB (83%, 39 patients) was more common than the primary subtype. The mean age of patients was 10.50 ± 5.75 and 9.74 ± 6.04 weeks in primary and secondary VKDB subtypes, respectively, and the age of infants did not have a significant difference (p > 0.05). The male to female ratio was 2.13:1. The residency, place and mode of delivery, gestational age, and types of feeding of patients did not have a significant difference between VKDB subtypes. The skin and gastrointestinal tract (GIT) (40.4%) followed by intracranial hemorrhage (ICH) (32%), were common sites of bleeding. Neurological complications were seen in 21% of patients; however, lethality was 23%, and the outcome of patients did not have a significant difference (p > 0.05) between VKDB subtypes.ConclusionSecondary late VKDB is more common than the primary subtypes, and late VKDB is still a serious disease in developing countries, including Iraq, when vitamin K prophylaxis isn’t routinely used at birth.     

Vitamin K prophylaxis and vitamin K deficiency bleeding (VKDB) in early infancy

The efficacy of vitamin K prophylaxis (1 mg im or sc, or 1-2 mg orally both given as a single dose at birth) in the prevention of vitamin K deficiency bleeding in early infancy was estimated in Germany during a 15-month period between 1988 and 1989. Cases were identified by a survey of all paediatric hospitals and population denominators by a survey of all obstetric hospitals. Response rates were 85% and 68%, respectively. Thirteen cases of vitamin K deficiency bleeding in early infancy with confirmed prophylactic states were confirmed, seven of whom had intracranial haemorrhage. The estimated efficacy of single parenteral administration of vitamin K versus no prophylaxis was 96.7% (95% confidence interval: 74-99.6%) and for single oral administration versus no prophylaxis 80.4% (9.1-95.6%). Single parenteral vitamin K prophylaxis gave substantial protection against vitamin K deficiency bleeding in early infancy. Single oral prophylaxis appeared to be less effective, although the difference was not significant, as indicated by the wide overlap of the respective 95% confidence intervals.     

Vitamin K,an update for the paediatrician

Introduction  This review summarizes current knowledge on vitamin K for the paediatrician. Vitamin K is a fat-soluble vitamin, present in plants as phylloquinone and produced by bacteria as menaquinone. It is acting as a co-factor for γ-glutamyl carboxylase. This enzyme is responsible for post-translational modification of some glutamate side chains to γ-carboxyglutamate. The majority of γ-carboxylated proteins function in blood coagulation; others play a role in calcium homeostasis. Data  Newborn babies are at particular risk of vitamin K deficiency, as placental transfer is limited and human milk is a poor source. Vitamin K prophylaxis at birth effectively prevents vitamin K deficiency bleeding (VKDB), formerly known as “haemorrhagic disease of the newborn”. Recent epidemiological studies provide data on the effectiveness of different administration routes and dosing schemes. Infants of mothers taking drugs that inhibit vitamin K are at risk of early VKDB and should receive 1 mg intramuscular (IM) as soon as possible after birth. Classic VKDB is prevented by intramuscular as well as by oral administration of 1 mg vitamin K. In exclusively breast-fed infants, single IM administration at birth is also effectively preventing (rare) late VKDB but single oral administration is not. If given orally, prophylaxis should be continued by either weekly administration of 1 mg till 12 weeks or repeating 2 mg at weeks 1 and 4. Daily administration of 25 μg offers insufficient protection. The only infants not fully protected in this way are those with yet unrecognised liver disease. Conclusions  Further work is needed before firm recommendations can be made regarding dose in preterm infants and in patients with fat malabsorption/cholestasis or regarding the role of vitamin K in the prevention of osteoporosis.     

Vitamin K in infancy

Vitamin K has regained paediatric interest due to a recurrence of bleeding caused by deficiency of the vitamin in newborns and young infants. Increasing awareness of these clinical problems, the development of new methods for the detection of vitamin K deficiency and the direct measurement of vitamin K in tissues have stimulated research. Much new data obtained from these studies has proved helpful to the understanding of vitamin K deficiency in infancy. For example low concentrations of vitamin K have been found in fetal and neonatal livers. The implications of these findings with respect to manifest vitamin K deficiency and to new methods for detection of subclinical vitamin K deficiency are discussed. Breast-feeding is a major risk factor for classical haemorrhagic disease of the newborn and for late onset bleeding due to vitamin K deficiency in young infants. The interdependencies between breast-feeding and vitamin K deficiency are discussed on the basis of new data obtained from direct measurement of vitamin K in maternal milk. The review further focusses on pathophysiological concepts of bleeding due to vitamin K deficiency in infancy and current concepts of vitamin K prophylaxis.Abbreviations HDN haemorrhagic disease of newborn - LHDN late haemorrhagic disease of newborn - PIVKA II Protein induced by vitamin K absence or inhibition for prothrombin (factor II) - HPLC-UV high performance liquid chromatography with ultraviolet light absorption     

Vitamin K prophylaxis: Leaving the old route for the new one?

Oral or parenteral administration of vitamin K is the accepted practice for prevention of early vitamin K deficiency bleeding (VKDB) in the newborn. However, vitamin K prophylaxis in the newborn continues to be a worldwide health concern, particularly in breastfed infants. This paper reviews the current status of the use of vitamin K for the prevention of early and late VKDB.     

Prophylaxis of Vitamin K Deficiency in Infancy

A prospective study was performed in Okazaki, Japan, to attempt to establish a more effective system of prophylaxis for vitamin K deficiency in infancy (VKDI). During the first year, a Normotest (Hepaplastintest) was performed in all infants at one week and at one month of age. Two mg of vitamin K was administered orally to those whose Normotest values were below 40%. i.e., the non-prophylactic administration of vitamin K (NPVK). During the second year of the study, all newborn infants received prophylactic vitamin K (PVK) within 24 hours of birth and at one week of age. The dosage was repeated at one month of age depending on the Normotest value. A total of 7,059 infants, comprising 93.3% of the live births in the city of Okazaki, were enrolled in this study. Data from 5,431 of these infants were used in the analysis of the results. In the NPVK group, 20 of the 2,791 infants had Normotest values below 40% at one month of age while 20 of the 2,640 in the PVK group had low values despite the prophylactic administration of vitamin K. Considering the prevalence of low Normotest values (40%) at one month of age and the predicted Normotest values, it was concluded that the month of birth (June September), the age of the mother (21–29 years), the birth order (first-born) and male sex are risk factors for vitamin K deficiency in infancy.     

Vitamin K deficiency bleeding in Great Britain and Ireland: British Paediatric Surveillance Unit Surveys, 1993 94 and 2001-02

Objective

To conduct and report monitoring of vitamin K deficiency bleeding (VKDB) in Great Britain and Ireland following the 1988–90 survey (VKDB‐90).

Design

Two 2‐year surveys conducted during 1993–4 (VKDB‐94) and 2001–02 (VKDB‐02).

Setting

Data collected from all consultant paediatricians in Great Britain and Ireland.

Patients

All infants presenting with bleeding resulting from vitamin K (VK) deficiency.

Main outcome measures

Incidence of VKDB, related mortality/morbidity and VK prophylaxis recommended/received, noting predisposing features.

Results

Compared with previous studies, VKDB‐02 found fewer cases of VKDB (RR: 0.27 (95% CI: 0.12 to 0.59), p<0.001) with no deaths, no long‐term morbidity and reduced incidence among those receiving any oral dosing (RR: 0.24 (95% CI: 0.06 to 1.01), p<0.059). Breast‐fed infants accounted for the vast majority of cases. The number receiving no prophylaxis fell consecutively over time: 20 of 27 in VKDB‐90, 10 of 32 in VKDB‐94 and 4 (because of parental refusal) of 7 in VKDB‐02. Seven received one oral dose of VK in VKDB‐90, 16 in VKDB‐94 and none in VKDB‐02. Underlying liver disease was found in six cases in VKDB‐90, 12 in VKDB‐94 and one in VKDB‐02.

Conclusions

In the most recent survey, the incidence of VKDB was about one third that in the two earlier studies. Late onset VKDB remains virtually confined to breast‐fed infants who have received either no VK or just one oral dose. The effectiveness of oral prophylaxis regimens has improved over the last 15 years, but parental refusal of prophylaxis has become more problematic.     

Vitamin K status of lactating mothers and their infants

Vitamin K deficiency remains a world-wide problem in the newborn. Vitamin K traverses the placenta from mother to infant very poorly and is present only in very low concentrations in human milk. Thus, it is not surprising that the newborn infant has undetectable vitamin K serum levels with abnormal amounts of the coagulation proteins and undercarboxylated prothrombin. Hemorrhagic disease of the newborn, secondary to vitamin K deficiency, remains largely a disease of breastfed infants. Lactating mothers easily achieve the recommended dietary allowance for vitamin K (1 μg kg⁻¹ d⁻¹) and the breast milk concentration is readily increased by increasing maternal vitamin K intake. Breastfed infants do not receive the recommended vitamin K intake via human milk. To prevent vitamin K deficiency in the newborn, intramuscular or oral vitamin K prophylaxis is necessary.     

新生儿脐血维生素K缺乏诱导蛋白与胎龄及地区的关系

目的 探讨新生儿脐血维生素K缺乏诱导蛋白(PIVKA-Ⅱ)水平是否与胎龄及地区有关。方法采集405例足月儿(平均胎龄39.31周,城镇259例,乡村146例)及142例早产儿(平均胎龄35.90周,城镇116例,乡村26例)脐血,用酶联免疫吸附法测定其PIVKA-Ⅱ水平,≥2μg/ml为阳性。结果 不同胎龄新生儿脐血PIVKA-Ⅱ阳性率无显著差异(P>0.05);城镇足月儿脐血PIVKA-Ⅱ阳性率32.82％,显著低于乡村65.75％(P<0.01),而城镇与乡村早产儿脐血PIVKA-Ⅱ阳性率(42.24％,46.15％)无显著差异(P>0.05)。结论新生儿脐血PIVKA-Ⅱ水平与胎龄无关,与地区有关。     

Vitamin K-Dependent Coagulation Parameters During the First Six Days of Life: Incidence of PIVKA II in Newborns

The vitamin K-dependent carboxylation of the prothrombin precursor PIVKA II (protein induced by vitamin K absence analogous to Factor II) is essential for the synthesis of prothrombin. The noncarboxylated precursor is found in peripheral blood in the presence of vitamin K deficiency. In this study prothrombin time, Factor II and Factor VII activity, and PIVKA II were investigated in 57 newborns without vitamin K prophylaxis in order to assess their vitamin K status. Two-dimensional Immunoelectrophoresis demonstrated the presence of PIVKA II in 21% of the newborns, predominantly on the second day. The PIVKA-II positive group showed significantly lower prothrombin times than the PIVKA II-negative group. An oral dose of 3 mg vitamin K (Konakion®) was administered to 35 healthy newborns in a second group with the first feeding. On the second day of life, these infants showed significantly higher vitamin K-dependent laboratory parameters than the group not given vitamin K; only 9% of the treated infants were positive for PIVKA II.     

Vitamin K in the newborn: influence of nutritional factors on acarboxy-prothrombin detectability and factor II and VII clotting activity

The incidence of acarboxy-prothrombin and the clotting activity of factors II and VII were evaluated on the fifth day of life in 183 healthy newborns, who had received no vitamin K prophylaxis. Acarboxy-prothrombin was detected in 93/183 newborns. All acarboxy-prothrombin-negative babies had factors II and VII clotting activities above 25% whereas a great variability was observed in acarboxy-prothrombin-positive babies: 21/93 had factor II and 14/93 had factor VII activities below 25%. Seventy-two of the acarboxyprothrombin-positive babies had normal factor II and VII clotting times on the fifth day of life. These babies must be suspected to have had vitamin K deficiency on one of the first 4 days, as acarboxy-prothrombin has a 50% disappearance rate of 50 h. Acarboxy-prothrombin ws mainly observed in breastfed infants (84/122) and only rarely detectable in infants receiving supplementary (7/44) or exclusive formula feeding (2/17). The type of milk feeding however might be less important for the babies' vitamin K supply than the actual milk intake. All acarboxy-prothrombin-positive babies had received small amounts of milk on the first 4 days of life. In those with low factor II and VII clotting activities the milk intake was low throughout the first 4 days of life, whereas babies with acarboxy-prothrombin and and normal clotting activities had increased their milk intake to more than 100 ml on the third and fourth day of life. Recommendations for vitamin K prophylaxis in newborns should be given with regard to the feeding on the first days of life.     

Vitamin K supplementation to prevent hemorrhagic morbidity and mortality of newborns in India and China

Background

Vitamin K deficiency bleeding (VKDB) can cause prolonged and bleeding (intracranial hemorrhage) among newborns, which can be life-threatening or lead to long-term morbidity. The aim of this review article is to reiterate empirical evidence to support the argument that vitamin K should be mandatory for newborns in India and China, as well as in other countries with a high burden of neonatal deaths.

Data sources

Studies were integrated from the PubMed/MEDLINE database search, as well as related literature available elsewhere.

Results

Both India and China have been slow in adopting an effective program for administering vitamin K injections to newborns to prevent VKDB-related morbidity and mortality. VKDB cases in China and India have shown inadequate attention to routine use of vitamin K by injection.

Conclusions

While no reliable data are publicly available, the issue of VKDB is at last receiving some attention from the Chinese public health system as well as the Indian government. In both countries, routine vitamin K administration to newborns would prove to be a cost-effective intervention to reduce preventable neonatal morbidity and mortality. VKDB is a global neonatal care issue, including countries where parental resistance is preventing babies from defense against this life-threatening condition.

     

Prevention of vitamin K deficiency bleeding with oral mixed micellar phylloquinone: results of a 6-year surveillance in Switzerland

In 1995, a new form of vitamin K prophylaxis with two oral doses of 2 mg mixed micellar phylloquinone (Konakion MM) on the 1st and 4th day of life was introduced in Switzerland. It was hoped that this new galenic preparation of phylloquinone would protect infants with insufficient or absent bile acid excretion from late vitamin K deficiency bleeding (VKDB). Subsequently, the occurrence of VKDB was monitored prospectively between July 1, 1995 and June 30, 2001 with the help of the Swiss Paediatric Surveillance Unit (SPSU). Over a period of 6 years (475,000 deliveries), there were no cases of early (<24 h of age), one case of classical (2–7 days of life), and 18 cases of late (1–12 weeks) VKDB fulfilling standard case definitions. In 13/18 patients with late VKDB there was pre-existing liver disease and in 4/18 patients, parents had refused prophylaxis. The incidence of late VKDB for infants with completed Konakion MM prophylaxis was 2.31/100,000 (95% CI: 1.16–4.14) and for the entire population 3.79/100,000 (95% CI: 2.24–5.98). There was only one case of late VKDB after complete prophylaxis in an infant without underlying liver disease. Conclusion: two oral doses of 2 mg of a mixed micellar vitamin K preparation failed to abolish VKDB. The recommendations for vitamin K prophylaxis in Switzerland have therefore been changed to include a third dose at 4 weeks of age. Starting on January 1, 2004, the incidence of vitamin K deficiency bleeding will again be monitored prospectively by the Swiss Paediatric Surveillance Unit.Abbreviations CI confidence interval - SPSU Swiss Paediatric Surveillance Unit - VKDB vitamin K deficiency bleeding