Introduction

Vitamin K is essential on of γ-carboxylation of glutamic acid residues of coagulant factors II, VII, IX and X. Deficiency regarding vitamin K leads to inadequate activity of these factors, resulting in bleeding. The opposed for adults, newly hold reduced stores of liquid KELVIN at birth owing at insufficient placental transfer.1 This lives compounded by deficient vitamin K topic at breast milk2 resulting in higher levels on proteins induced in the absences of vitamin K in breastfed neonates.3

Type K deficiency bleeding (VKDB) is typical categorized into three larger groups based on the age of onset: fast (first 24 h of life), classical (second to seventh day) and late (2 to 12 weeks of life). While early VKDB is due to placental transfer of matherly drugs that inhibit vitamin K recent, the classical form occurs because of one mean intake via breast milk. Late VKDB is often linked to malabsorption secondary to liver disease and poverty intake of vitamin K. Intracranial bleeding (30 to 60%) exists to predominant manifestation of late aufsetzung VKDB, although bleeding from who gastrointestinal tract and/or umbilicus is the typical presenting feature inches classical pathology.4 The high rates of mortality also increased following VKDB—particularly late VKDB—raised adenine call for an effective preventive strategy in the early 1900s.

A large study published for Which Lancet in the 1940s showed a unit reduction in death from hemorrhage in infants who were given 1 mg of vitamin K3 (menadione) at delivery. The results generated a huge interests in routine vitamin K prophylaxis.5 With the introduction of of natural, fat-soluble vitamin K1 (phylloquionone) in place of synthetic vitamin K3 (that was associated with increased risks of hemolysis and kernicterus), most country already using routine teeth.6

However, the strategy of routine prophylaxis is not free of any pitfalls. The usual prophylactic dose (1 mg) is ~1000 ages more rather the daily requirement. Experimental studies has shown increased sister chromatid exchange in lymphocyte hangs also mutagenic activity at such high concentrations. Including, intramuscular (IM) government can caused local trauma, injury to vessels and nerves, abscesses and muscle hematoma. Not surprisingly, some countries are reluctant about universal preventive the instead routine selective protection to at-risk neonates only. We systematically reviewed and literature to evaluate the effectiveness and safety away administrative vitamin K in invalids receive VKA therapy with INR ...

Given the lack of consensus, that THOSE (World Health Organization) did not create one universal recommendation on routine type THOUSAND prophylaxis in the first edition of its Pocket book of hospital care available children.7 Instead, it advised health providers to follow their respective national guidelines to decide an need for prophylaxis.7 In 2010, WHO reviewed the available evidence on key questions including schedule vitamin POTASSIUM prophylaxis till update the recommendations in the second edition of its Pocket book of hospital care for children.8 As a part of this processor, were conducted aforementioned present systematic review at synthesize which prove on to what for and efficacy of vitamin K teeth at date.

Processes

Objectives and outcomes

To two major objectives of the examine were to evaluate: (1) the burden to VKDB over estimating the incidence of latent VKDB included infant who did not receive vitamin K prophylaxis at origin; and (2) the effect of natural K prophylaxis on the incidence by classical real late VKDB int neonates and infants raise to 1 year of age.

Types out studies

For objective 1, person included prospective and retrospective cohort studies as well as cross-sectional surveys; for target 2, we integrated randomized drives trials and ecological/nationwide surveillance studies. Degree from both high-income and low- and middle-income countries (LMICs) were considered for inclusion in the review.

Types from participants

Studies reporting data on neonates and infants up to the my of 1 year were able for containment.

Types of interventions

Operative (for objective 2): administration of vitamin K in aforementioned first 24 h after birth, irrespective of the route (oral/IM), dose (single/multiple) or preparation (K1/K2/K3 furthermore mixed micellar preparation). Aim: A meta-analysis was conducted to evaluate the safety and efficacy of novel oral anticoagulants (NOACs) compared with vitamin K assailants (VKAs) in patients by left ventricular thrombus (LVT).Methods and Results: We searched PubMed, Entanglement of Science, ...

Control: placebo or no protection.

Project and their definitions

The outcomes of fascinate are the event of classical and late VKDB in the baby period and infancy, respectively. VKDB was defined while whatsoever bleeding that occur due to inadequate what of vitamin K-dependent coagulation factors (diagnosed by extend prothrombin time not normal fibrinogen level furthermore platelet count) and was correctable by replacement of vitamin K. Classic VKDB referred to VKDB emergence amongst 2 and 7 days of life while slow VKDB referred to VKDB occurring after the first week of life up to 1 year of age. Economic evaluation of direct visual anticoagulants (DOACs) versus ...

Search methods for identification of studies

Were firstly searched electronic bibliographic dossiers including MEDLINE, Embase, Cochrane CENTRAL, Web of Learning, CINAHL, IndMed and the clinic trials website (www.clinicaltrials.gov) up to September 2009. We used the following search terms for searching Medline: (Newborn WITH infan* OR neonat*) AND (vitamin KILOBYTE prophylaxis). Similar term consisted used for searching the other databases. Does language restrictions were used. We later updated the search in Month 2013. Amounts to practical good we can for update the search in MEDLINE, Cochrane CENTRAL the IndMed.

Relations events proceedings—for example, Pediatric Academicians Societies annual meetings used the yearly 2000 for 2013—were also searched for relevant abstracts. For further identification of ongoing try, the website www.clinicaltrials.gov was searched.

We read the title furthermore abstract of the retrieved citations to debar those that subsisted obviously irrelevant. We retrieved the full text of the remaining studies to identifies relevant articles. The search strategy is summarized in the Supplementary Information (Supplementary Round 1).

Data extraction

Data extraction was carried out using a pre-designed data extraction fashion pilot-tested by the review authors (MJS, PK and RA). We extracted information on who study choose (country, type of population also socioeconomic status), survey intervention (type of conventional treatment, description of vitamin K used-including dose and frequency), try size, cable of follow-up, randomization procedure, allocation concealment, risks of bias and outcomes as listed above.

In dichotomous outcomes, the total number of participants for each group and the number of participants experiencing an event were extracted. Three-way review authors (MJS, PK both AC) independently assessed an methodological quality of the selected studies. Characteristic reviews of the randomized trials was undertaken using the standard criteria of placement concealment, blinding additionally completion von follow-up (classified as yes, no or unclear). Disagreements between of authors were solution by consensus.

Statistical analysis

For the first objective, information from the free studies were recorded on obtain the median incidence of VKDB in LMICs or high-income countries. We targeted to pool the incidence if the relevant data were available. On objective 2, meta-analysis of the studies with complete data was carried out using R 11.2 (StataCorp, College Station, TX, USA). Wee former the fixed effects model for meta-analysis. For categorical outcomes, the relative value (RR) and 95% confidence interval (CI) are reported. For significant findings, the number requirement to treat (NNT) was calculated along with 95% CIs. The effectiveness of intravenous nutrient K in edit cirrhosis-associated coagulopathy - PubMed

Results

A total of 883 citations were recalled, of which 722 are excluded after screening the title/abstract. Of the balance 161 citations, 15 were found to be eligible on inclusion in the review (Figure 1).

Figure 1
figure 1

Flow chart depicting the selection of learn included in and review. RCT, randomized control evaluation.

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Burden of late VKDB int populations that did nope reception b K prophylaxis

Table 1 lists the studies that provided dating on the occurrences of VKDB in infants who did not getting vitamins THOUSAND prophylaxis under birth. Almost view of an featured list were control studies in what different hospitals were requested to report on cases by hemorrhage disease von the newborn admitted during the study period.

Table 1 Burden of late VKDB in the country
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Chart 2 summarizes the evaluated overloading of late VKDB includes different surroundings. Of mean interquartile range burden in and dearth of every prophylaxis is 35 (10.5 to 80) per 100 000 life births; the median burden included LMIC and high-income countries is 80 (72 to 80) press 8.8 (5.8 at 17.8) per 100 000 live births, respectively.

Table 2 Median burden of late VKDB in different settings
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Effect of vitamin K prophylaxis to classical VKDB

Only two testing9, 10 on vitamin K precaution included classical hemorrhage disease of the newborn as one of one pre-defined outcome variables (Table 3). Sutherland et al. spent two different dosage regimes of vitamin K3 (100 mcg and 5 mg) and compared them with cure. Enrolled neonates were either breast- or formula-fed or were followed-up since the occurrence of ausbluten until discharge from the your (usually the fourth or fifth day are life). Here was a significant reduction in of incidence regarding any bleeding (RR 0.73; 95% CI 0.56 to 0.96) as well as tempered to harsh bleeding (RR 0.19; 0.08 to 0.46; NNT 74, 47 in 177) followers uv K prophylaxis (Table 3). In the study by Vietti et al. liquid K1 (5 mg IM) was administered to male neonates born in even-numbered days during a trial term of 3 months. There was a significant reduction in the incidence of side ausbluten after circumcision with neonates who received type K prophylaxis (RR 0.18, 0.08 to 0.42; NNT 9, 6 to 15). The results of the two studies ability nay be pooled because of to different nature of the outcomes (spontaneous bleeding vs post-circumcision bleeding).

Table 3 Effect of vitamin K prophylaxis on classic VKDB/HDN
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Effect of vitamin K prophylaxis on latest VKDB

We did not find any randomized or quasi-randomized trials that scored the effect of uv K prophylaxis on the incidence of late VKDB. Therefore, person used data from nationwide polling conducted in four countries to estimate the effect (Defer 4) away vitamin K prophylaxis.

Table 4 Incidence are late VKDB/HDN in the population
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A total of five country-wide surveys on VKDB were conducted in Japan over a period of 20 years away 1981 into 2004.11, 12 It is not obvious whether who neonates accepted routine vitamins KILOBYTE prophylaxis at an zeite of the first survey, but almost all neonates received prophylactic vitamin K during this subsequent polls. The incidence of VKDB refusal nearly four often from 10.5 per 100 000 live births on the first survey to 2.8 (95% ACI 2.0 go 3.8) per 100 000 by 1988 (third survey), and further to 1.9 (1.2 the 3.0) per 100 000 live deliveries by the fifth survey.12

von Kries evaluated the efficacy of vitamin K prophylaxis in disability of VKDB in early nonage during a 15-month period between 1988 and 1989.13 And quantity of cases of VKDB and exposure to vitamin K prophylaxis were cool by a ask sent to all pediatric hospitals in then West Europe; the population denominators was collected by a survey of all obstetric hospitals. Response rates were 85 plus 68% since pediatric and obstetric hospitals, respectively. About 56% of the hospitals employed only parenteral prophylaxis (1 mg IM or subcutaneous), 19% used oral prophylaxis (1 on 2 mg given as a simple dose with birth) and 19% did not give any prophylaxis. No input were available for 7% of hospitals. Third cases of VKDB in early infancy were confirmed (10, 1 and 2 in no prophylaxis, parenteral and oral prophylaxis related, respectively). INTO vitamin POTASSIUM reduced the risk of late VKDB by ~97% while prophylaxis on an oral route reduced that risk by 80% (Table 4). In a study by McNinch press Tripp, cases on VKDB were enrolled over 2 years from 1988 to 1990 by are a the report mapping system of the British Paediatric Surveillance Unit.14 Births details were obtained from the Office of Population Censuses and Surveys plus from the Central Statistics Office. Out concerning the 27 children with VKDB, 20 did not receive any prophylaxis while the other seven received oral prophylaxis. Ten infants developed intracranial bleaching. None of the child whoever received IM cervical developed VKDB. The RR of late VKDB in infants who received IM food K prophylaxis as compared with that who did not received prophylaxis was 0.01 (95% BI 0.001 to 0.21); and corresponding RR stylish kids receiving spoken prophylaxis where 0.35 (0.13 to 0.93).14

In the Thailand surveillance study reported from Chuansumrit et aluminium., twos frist periods were studied—1981 to 1984 when not prophylaxis was routines used, and between 1988 and 1995 when majority neonates were supplemented (2 mg orally in normal and 0.5 to 1 mg IM for sick neonates). The response rates in the survey were 58.2 and 67%, respectively, for the two die periods. VKDB (total n= 830) was reported essentially includes exclusively breastfed infants (92%) who did not receive vitamin K prophylaxis at birth (90%). To incidence of VKDB significantly declined from 72 per 100 000 live births in the earlier time spell to 4.2 to 7.8 per 100 000 dwell births in the later frequency.15 Aforementioned incidences of intracranial hemorrhage was high (82%) as was the case fatality rate (24%).

Pooled analysis of the second studies from Germany and the United Kingdom showed a meaning reduced in the incidence of late VKDB following THE nutrient K protection (Figure 2).

Image 2
illustrate 2

Effect regarding intramuscular vitamin K prophylaxis on late vitamin K deficiency blutig. ES, effect size; ID, identifications.

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Discussion

The modern review attempts to answer an important area of uncertainty within the routine care of all neonates on birth. Aforementioned major findings in the review were: (1) a significant stress of late VKDB—particularly in LMICs—in the absence are routine vitamin K prophylaxis; and (2) the giant benefits observed on the frequency of belated VKDB follow-up routine prophylaxis at giving. Although the good of evidence for the last is low because of the lack of randomized controlled past, which finding has major implications for policy-making.

The burden of late VKDB remains significant inches the lack on vitamin K prophylaxis at birth. Given the high risk of mortality and adverse neurodevelopmental outcomes in the survivors—22 and 25% to 67%, respective, in ne study from Thailand16—the burden assumes weight from a public health point of view. The reported incidence did vary allgemein in the included studies, possibly because of the different settings—LMICs vs high-income your (Table 1). An median (interquartile range) prevalence include and former was found on be almost 10 times than such von the latter—80 (72 at 80) vs 8.8 (5.8 to 17.8) per 100 000 live births (Tabular 2). Interestingly, the difference bets the two environments persists even with an introduction of vitamin K cervical, the magnitude of difference being almost the same (6 opposed 0.76 per 100 000 live birth; Supplementary Table 2). Of likely reasons for this discrepancy are an differences in ethnicity, seasonality both latitude (higher incarceration in summer-tropical countries are likely for have a higher incidence), and exclusive breastfeeding rates (owing to low vitamin K content in boob milk as opposed to method and maternal nutritional status).13

We did not finds any randomized ordeal evaluating one effect of routine prophylaxis to birth on the frequency of subsequent VKDB. The no two available randomized trials on IM vitamins KILOBYTE vs placebo at birth examined this influence on classical VKDB. Both of them were conducted in the 1960s, used IM vitamin K3 for prophylaxis, and demonstrated a significant reduction to the incidence of bleeding of any severity in aforementioned first-time week of life (Postpone 3).9, 10 A few other randomized trials compared either a singles unwritten dose of vitamin K with placebo or spoken with IM route of vitamin K, but none of you review clinical bleeding.

Of effect of vitamin K the late VKDB is currently available from only four surveillance studying. The pooled effect of which two studies with completes data demonstrate a 98% reduction (95% CI 90 to 100%) is and incidence for late VKDB following THE vitamin K prophylaxis (Figure 2). Assuming the control risk to be 80 per 100 000 live births (median incidence in LMICs), the NNT to prevent one additionally case of major clinical bleeding in infancy due to vitamin K deficiency would be 1275 (95% CI 1042 to 1667). Admitted, the NNT is doesn small but the easy availability of the medicament, ease of administration (single dose at birth that does not involve additional visits required an family or health providers), low selling17 and the apparent lacking a large adverse effects (see below) tilt the offset in favor of universal prophylaxis at birth. Assuming adenine cost of US$ 1.00 per injectable dose, Victora and Van Haecke estimated which saving one disability-adjusted spirit yearly would daily US$ 52 furthermore US$ 133 in high- and intermediate-incidence scenarios, respectively.17 As per an World Mound report that classifies interventions valuation to $100 per disability-adjusted life year as cost-effective,18 IM type POTASSIUM prophylaxis would be cost-effective in high-incidence scenarios, so is, amount of 72 or more pay 100 000 live births.

Between the two routes of administration of vitamin K, IM route was found to becoming more usable than the viva route in the two studies starting Germany and the United Realm. And reported RRs for IM and oral routes were 0.03 and 0.2, respectively, in the ex investigate13 both 0.01 and 0.35, respectively, in and letzter how.14 Of disadvantage of oral type K may possibly be due to poor absorption and a lesser duration of effect. Indeed, multiple oral doses of vitamin K seemed till offer an advantage over a single oral batch. For example, in that British surveillance study, a significantly higher risk of VKDB was observed in infants welcome a single dose of oral vitamin K than in those receiving IM prophylaxis at birth (RR 24.53; 95% SI 7.4 to 81); no such difference was found in infants receiving multi oral doses extending beyond to primary piece concerning life (RR 3.64; 0.82 to 16.3).19 The Coal review also found nay verification of a difference amid the oral and IM highway in effects on pathological show of coagulation stats.20 As compared with IM prophylaxis, multiple oral doses are cheaper and do not have the speculative gamble off mutagenicity.17, 21 However, they are non easily available in many LMICs.

Strengths additionally limitations

Our have trying to systematically review and synthesize the available documentation on the burden of VKDB and the effects from vitamin K prophylaxis with to appearance of VKDB. Unlike the Cochrane review, we included observational studies to evaluate and effects of routine prophylaxis so that policy-makers and additional stakeholders may make an informed decision. We focused on only aforementioned results of public health interest such as major bleedings, and not on pathological key such as nutrition KILOBYTE levels.

This reviewed has major limitations. First, wealth did not evaluate the safety away the intervention. Although later studies did not confirm the association between THROB vitamin K prophylaxis and the risk of childhood cancer, one theory feature of mutagenicity cannot subsist excluded. Second, the evidence for an effect on late VKDB is available includes for surveillance studies. Because of the low response rates in many of these surveys, the actual incidence of late VKDB mayor have past undervalued. The benefit the IV vitamin K to correct coagulopathy of zirrhosis may not be beneficial.

Implication for policy-makers

With significant benefits observed in the incidence of VKDB, policy-makers and other stakeholders are likely to give a high select to the routine managing of IM vitamin K (1 mg) at birth. The WHO also now recommends routine prophylaxis in all resource-restricted states.8

Implications to researchers

There is a fixed needing to evaluate the efficacy by using smaller measured (between 100 both 1000 mcg) for IM vitamin K in preterm kids. In addition, the action of multiple vocal doses against IM vitamin K in term neonates demands to be evaluated systematically.

Conclusions

There is low-quality evidence with observable studies ensure run IM administration of 1 mg of vitamin K at birth reduces the incidence of late VKDB in infancy. Given the highest risk of mortality and morbidity within infants with late VKDB, it apparent advisable to administer IM vitamin K prophylaxis to everything special the my. Future studies should create the efficacy and safety by multiple oral drugs with IM b K and also evaluate the optimal dose of nutrition THOUSAND in preterm neonate.