Arch-Dis-Child-2013-Busfield-41-71.pdf

8/9/2019 Arch-Dis-Child-2013-Busfield-41-71.pdf

1/8

Vitamin K deciency bleeding after NICE guidanceand withdrawal of Konakion Neonatal: BritishPaediatric Surveillance Unit study, 20062008

Alison Buseld,1 Rebecca Samuel,2 Andrew McNinch,2 John H Tripp3

Additional supplementaryles are published online only.To view these les please visitthe journal online (http://dx.doi.org/10.1136/archdischild-2011-301029).

1Child and Womens Health,Royal Devon and Exeter NHSFoundation Trust, Exeter, UK2Paediatric Department, RoyalDevon and Exeter NHSFoundation Trust, Exeter, UK3Health Services Research,Peninsula Medical School,

Exeter, UK

Correspondence toDr Alison Buseld, Child andWomens Health, Royal Devonand Exeter NHS FoundationTrust, Barrack Road,Exeter EX2 5DW, UK;[email protected]

AB and RS are joint rstauthors of this paper.

Received 12 September 2011Revised 16 October 2012Accepted 17 October 2012Published Online First12 November 2012

To cite:Buseld A,Samuel R, McNinch A,et al.

Arch Dis Child2013,98,4147.

ABSTRACTObjective To survey vitamin K deciency bleeding(VKDB) and document vitamin K (VK) prophylaxispractice, and compare with ndings predatingwithdrawal of Konakion Neonatal and guidance from theNational Institute of Health and Clinical Excellence(NICE), both occurring in 2006.Design Two-year surveillance of VKDB (20062008)using British Paediatric Surveillance Unit methodology.Postal questionnaire to consultant-led maternity units.Setting UK and Irish Republic.Patients All newborns and infants under 6 months

with suspected VKDB.Main outcome measures VKDB incidence andpredisposing factors, VK prophylaxis recommended/received.Results Eleven cases of VKDB were found: six (55%)babies received no VK prophylaxis, in ve (45.5%) becauseparents withheld consent; three (27.5%) babies with lateVKDB received intramuscular (IM) Konakion MM (two hadbiliary atresia, and one was delivered preterm); two (18%)babies received incomplete oral prophylaxis. Nine babies(82%) were breast fed. Three (27%) babies had liverdisease; four (36%), including all those with liver disease,were jaundiced at presentation after 21 days. Four (36%)

babies had intracranial haemorrhage, two probablysuffering long-term morbidity. VK prophylaxis practice wasdened in 236 (100%) units. All units recommendedprophylaxis for every newborn: 169 (72%) IM, 19 (8%)oral, and 48 (20%) offered parental choice. All units thatrecommended IM prophylaxis used Konakion MM. Oralprophylaxis always involved multidose regimens forbreastfed babies; 61 (91%) units used Konakion MM,and six (9%) used unlicensed products suitable foradministration by parents.Conclusions IM Konakion MM is efcacious, butparents withholding consent for recommended IMprophylaxis reduces effectiveness. Reappraisal of NICEguidance would be appropriate. Prolonged jaundice

demands investigation. Late VKDB occasionally occursafter IM prophylaxis.

INTRODUCTIONThis is the fourth British Paediatric Surveillance Unit(BPSU) 2-year study of vitamin K deciency bleeding(VKDB); each is designated by the year of completion,making this VKDB-08. The third study, VKDB-02,found the lowest incidence of VKDB and no death orlong-term morbidity, but showed parental refusal ofprophylaxis to be a new important issue.1

Up to and including VKDB-02, KonakionNeonatal (Roche, Basel, Switzerland) was used by

almost all units that recommended intramuscular(IM) prophylaxis2; with exceedingly rare exceptions,a single 1 mg IM dose at birth protected againstVKDB. In 2006, there were two important develop-ments: rst, Konakion Neonatal was withdrawn,

leaving Konakion MM (Roche Products Limited,Welwyn Garden City, UK) as the only licensed prepar-ation for prophylaxis; second, the National Institutefor Health and Clinical Excellence (NICE) recom-mended IM in preference to oral prophylaxis.3

Increased use of IM prophylaxis with Konakion MMwas inevitable, despite the paucity of published ef-cacy data.4 The Medicines and Healthcare ProductRegulatory Agency (MHRA) advised further surveil-lance, which this study represents.

METHODCases of suspected VKDB were recruited in the UK

and Irish Republic (IRE) from October 2006 toSeptember 2008 using the well-described BPSU

What is already known on this topic

Vitamin K (VK) prophylaxis protects almost allbabies if given intramuscularly or by currentmultidose oral regimens.

The incidence of vitamin K deciency bleeding(VKDB) and the associated morbidity andmortality fell signicantly between 1994 and2002.

Early recognition of liver disease protects

against VKDB.

What this study adds

The incidence of VKDB did not signicantlyincrease after withdrawal of KonakionNeonatal.

Intramuscular prophylaxis does not prevent allcases of VKDB; investigating prolongedjaundice identies liver disease and VKdeciency. Twenty-six units (13%) lacked arecognised pathway for this.

The incidence of VKDB might be halved if allparents consented to VK prophylaxis.

31% of UK units deviated from the NICEguidance of 2006; the guidance should bereviewed to reect new data and options.

Buseld A,et al.Arch Dis Child2013;98:4147. doi:10.1136/archdischild-2011-301029 41

Original article

group.bmj.comon December 21, 2012 - Published byadc.bmj.comDownloaded from
http://dx.doi.org/10.1136/archdischild-2011-301029http://dx.doi.org/10.1136/archdischild-2011-301029http://dx.doi.org/10.1136/archdischild-2011-301029http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://adc.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://dx.doi.org/10.1136/archdischild-2011-301029http://dx.doi.org/10.1136/archdischild-2011-301029http://dx.doi.org/10.1136/archdischild-2011-301029http://dx.doi.org/10.1136/archdischild-2011-301029


2/8

methodology. They were classied by the criteria used previ-ously.1 Cases of late VKDB were also classied by moreexclusive criteria, agreed in 1994,5 to allow internationalcomparisons.

Postal questionnaires to document policies of vitamin K (VK)prophylaxis were sent to labour ward senior matrons of allconsultant-led maternity units from February 2008, repeatedlyif necessary, and nally to consultant paediatricians of non-

responding units in March 2009. Units failing to respond orproviding inconsistent data were contacted by telephone.Information requested included unit birth rate, VK regimen,consent practice, prolonged jaundice follow-up, and a writtenpolicy if available.

Birth statistics were obtained from the appropriate nationalbodies.69

Ethics and patient information advisory group approvals wereobtained before the start.

RESULTSBPSU study of VKDB resultsMonthly returns for the BPSU report cards averaged 93.9%

during the study.

NoticationsAfter 46 notications, including two directly to the investigatorsrather than via the BPSU, 43 questionnaires were returned,yielding 10 conrmed and one probable case, which were con-sidered as the 11 reported cases; 12 notications were dupli-cates, and 20 were no case or error. Three questionnaireswere not returned, two concerning the same notication,leaving two notications unclassiable.

Incidence of VKDBOverall incidence per 100 000 live births was 0.64, which is notsignicantly different from that in VKDB-02 (0.48)1; bothvalues are signicantly lower than those in VKDB-94 (1.98) andVKDB-90 (1.61).1 10

Age at bleedingOne baby, who had received no VK, bled within 24 h of birth(early VKDB). Four bled between 24 h and 7 days (classicalVKDB); three had received no prophylaxis, and one probablyhad one oral dose and spat it out. Six babies (four with intracra-nial haemorrhage (ICH), three with underlying liver disease,and two with both) bled after 7 days (late VKDB).

Case detailsCase details can be found in table 1. One infant was delivered at

24 weeks, and the remainder at term. Gender and exact weightwere not requested, to protect condentiality.

VK prophylaxisIn six of the 11 cases, no VK was given, in ve because parentswithheld consent; in one, no reason was documented. In all six,the recommended prophylaxis was IM VK. Of the ve cases forwhom consent was withheld, oral prophylaxis was also refusedin two, mistakenly not offered in one, and not documentedin two.

Three babies bled after IM VK. The preterm infant received0.4 mg/kg, bled on day 91, and had no liver disease. Patientnine received 0.5 mg and bled on day 86, and patient 10

received 1 mg and bled on day 66; both were found to havebiliary atresia.

Two patients bled after oral VK. Patient six received 1 mg atbirth but, through error, not the intended 50 g daily doses fordays 15. Prophylaxis was resumed on day 6, but ICH occurredon day 23; 1-antitrypsin deciency was later diagnosed. Patientthree, born at home, was intended to receive 1 mg orally at birthand repeated weekly for 8 weeks. The initial dose was reportedlyspat out and not repeated. Bleeding occurred on day 5.

Liver diseaseLiver function was tested in all cases. In three it was normal.One baby had raised alkaline phosphatase (411 IU/l on day 19)but no jaundice or liver disease. Four had unconjugated hyperbi-lirubinaemia and otherwise normal liver function. Three withliver disease (two with biliary atresia, and one with1-antitrypsin deciency) were clinically jaundiced at presenta-tion with bleeding, conjugated bilirubins 4493 mol/l; no add-itional VK had been given.

No other predisposing conditions were identied.

OutcomeNo deaths were directly attributable to VKDB. Patient 10 hadbiliary atresia and died from liver failure 2 months after ICH.Three others with ICH were breast fed and received either noor incomplete oral prophylaxis; two are expected to have long-term sequelae. No sequelae are expected in any others. Table 2compares data for ICH between all BPSU studies.

Late VKDBinternational comparisonCases 2, 4, 6 and 10 met the international criteria for lateVKDB.5 VKDB-08 and VKDB-021 show signicantly lower inci-dences than VKDB-90 and VKDB-941 10 and compare favour-ably with other European data5 (table 3).

VK PROPHYLAXIS SURVEY RESULTSOf 236 consultant-led units identied (217 in UK; 19 in IRE),

222 provided data by postal questionnaire, and 14 by telephone.Seventy-ve sent their written policy and 70 claried data bytelephone.

The national statistics ofces reported 843 634 births for thestudy period,69 and the units reported 842 450.

Recommended VK prophylaxis after uncomplicated termdelivery

All units recommended VK prophylaxis for every neonate.Table 4 shows the routes of administration recommended in2008 (this survey) and in 2003.2 Parental consent was sought in233 units, written in 49 (21%) of them; no data were availablefor three.

Changing practiceOf 215 units that responded, 106 (49%) reported a policychange in the previous 3 years, usually because of withdrawal ofKonakion Neonatal (78 units, 74%) or to comply with NICEguidance (37 units, 35%).

IM prophylaxisOf 217 units (92% of all units) that used IM prophylaxis, 169(78%) recommended this route, and 48 (22%) offered it aschoice. All used Konakion MM; 214 (99%) gave the licensed1 mg dose (three gave 500 g), 194 (89%) gave one dose, and23 (11%) stated no dose number.

Of 169 units that recommended IM VK, 162 (96%) offered

oral prophylaxis if the injection was declined, and sevendid not.

42 Buseld A,et al.Arch Dis Child2013;98:4147. doi:10.1136/archdischild-2011-301029

Original article

http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://adc.bmj.com/http://group.bmj.com/http://adc.bmj.com/


3/8

Table 1 Clinical features of the 11 cases of VKDB notified during the 2 years of study, 20062008

Casenumber Prophylaxis

Hospitalpolicy

Parental

consentwithheld?

Oral

alternativeoffered Feed

Age at

onset(days)

Delay inpresentation

to hospital(days)

Sites of

presentingbleed

Otherbleeding

PT in

secondsor (INR)

APTT in

secondsor (APTR)

PIVK

(arbitunits

1 None IM Yes Unknown primarilybreast

15) (>5) 55

2 None IM Yes No Breast 34 2 Bruising GIT ICH >180 >180

3 OralUncertainwhen given,perhaps day3Not takenwell

Oral 1mgat birth+weeklyfor8 weeks

No Breast 5 3 Bruising, heelprick

30.6 (2.6) 42.6 (1.6)

4 None IM Yes Yes Breast 20 0 Bruising GIT ICH Did notclot

Did notclot

5 None IM No record Unknown Breast 1 0 Bruising, heel

prick

Did not

clot

105

6 Oral1 mg at birth,50 g daily,but day 15not given

Oral1 mg atbirth,50 gdaily

No Breast 23 0 ICH >180 >180

7 None IM Yes Unknown Unknown 2 0 BruisingGIT

Veryprolonged

82

8 None IM Yes Yes Breast 5 0 Bruising (>10) >180

9 IM 0.5 mg IM No Formula 86 2 Bruising 74.6 91.9

10 IM 1 mg IM No Breast 66 0 Venepuncturesite

ICH 146 (24) 101 (3.5) 8 1

11* IM 0.3 mg IM0.4 mg/kg

No Primarilybreast

91 0 GIT 42.3 59.5

*Probable case.APTR, activated partial thromboplastin time ratio; APTT, activated partial thromboplastin time; GIT, gastrointestinal bleeding; ICH, intracranial haemorrhage; IM, intramuscular; INR, internationalPIVKA-II, protein induced by vitamin K absence/antagonism, factor II; PT, prothrombin time.


4/8

Table 2 Details of babies with intracranial haemorrhage (ICH) secondary to VKDB (classified by criteria of the BPSU studies) in the four BPSUincidence studies

VKDB-90 VKDB-94 VKDB-02 VKDB-08

Study: cases of VKDB* (n=27) (n=32) (n=7) (n=11)

Total ICH cases (of whichprobable) 10 (1) 10 (2) 0 4

Deaths from VKDB (of which probable) 2 (1) 0 0 0

Known disability or concern (of which probable) 8 6 (2) 0 2

No adverse outcome 0 3 0 1

Outcome unknown 0 1 0 0

No prophylaxis 5 3 0 2

Single oral dose VK 5 6 0 0

Multiple oral 0 0 0 1

IM prophylaxis 0 1 (1 mg) 0 1 (1 mg)

Solely breast fed 10 8 0 4

Liver disease 4 3** 0 2

Warning bleeds (number of babies) 7 5 0 2

Warning bleed duration (days), range (median) 114 (6) 14 (2) 12

Neither liver disease nor warning bleeds 1 4 0 0

*Definition of VKDB: infant under 6 months old with appropriate history of bleeding, documented prothrombin time or INR at least twice the control value, platelet count normal orraised, no evidence of infection/disseminated intravascular coagulation.

Probable case: appropriate history of bleeding, diagnosis other than VKDB unlikely but lacking full laboratory confirmation.One death due to liver failure.Incomplete administration.Soya feeds in two other cases.**Pancreatic disease in one other.Includes the case of IM prophylaxis and one probablecase.BPSU, British Paediatric Surveillance Unit; IM, intramuscular; VK, vitamin K; VKDB, vitamin K deficiency bleeding.

Table 3 Cases of late VKDB in UK and Ireland from four BPSU studies, reclassified as confirmed or probable according to internationally agreedcriteria (which are more exclusive than those used in the BPSU reports) to allow comparison with published data from other countries

Study title (each last 2 years) VKDB-90

VKDB-94 VKDB-02 VKDB-08

Birth population 1671000 1609785 1456200 1700000

(a) Idiopathic cases 11 10 0 2

(b) Secondary cases 5 13 2 2

(c) Predisposing illness 0 1 0 0

Total cases (probable included) 16 (2) 24 (3) 2 4

Total incidence a+b+c(95% CI) 0.96 (0.49 to 1.4) 1.5 (0.9 to 2.1) 0.14 (0.00 to 0.32)*** 0.24 (0.00 to 0.35)***

True incidence a+b(95% CI) 0.96 (0.49 to 1.4) 1.4 (0.84 to 2.0) 0.14 (0.00 to 0.32)*** 0.24 (0.00 to 0.35)***

Prophylaxis received

None 10 6 0 2

Oral1 6 (presumed in 1) 13 0 Regimen not used

Oral2 Regimen not used 2 1 Regimen not used

Oral3 Regimen not used 2 1 ( probably given) 0

Multiple oral Regimen not used Regimen not used 0 1 (incomplete)IM 0 1 0 1 (1 mg)

Death 1 1 0 0

Handicap 8 4 or 5 0 2

Prophylaxis failures (95% CI)

Complete prophylaxis Data not available 12 (5 to 19) 2 (0 to 5)* 1 (0 to 5)**

Complete or incomplete 16 (8 to 24) 2 (0 to 5)** 4 (1 to 7)**

Unknown 8

Probability of difference from VKDB-94 data: *p


5/8

Oral prophylaxisOral VK prophylaxis was used in 67 (28%) units (recommendedin 19 (28%), and offered for parental choice in 48 (72%)). Allunits gave three or more doses to breastfed babies (tables 5 and 6).

Seventeen (89%) of the 19 units that recommended oralprophylaxis and 20 (42%) of the 48 that offered choice hadseparate high-risk policies using Konakion MM (IM in 36, intra-venous (IV) in one).

IV prophylaxisOf the 231 units that responded, 62 (27%) sometimes used IVprophylaxis (always Konakion MM); of these, only 19 (31%)gave follow-on doses, 38 (61%) did not, and ve did notrespond.

JaundiceOf the 203 units that responded, 157 (77%) assessed infantsjaundiced at 23 weeks in a hospital-based clinic, 20 (10%)

measured conjugated bilirubin in the community, and 26 (13%),representing 90 000 deliveries/year, answered No to bothoptions, implying that they had no formal pathway for investi-gating prolonged neonatal jaundice.

DISCUSSIONThe four 2-year BPSU studies of VKDB (VKDB-90, -94, -02and -08) have documented the incidence and features of thecondition over 20 years.1 10

The incidence was signicantly lower in VKDB-02 andVKDB-08 than previously,1 10 probably for two reasons: (1) thedecline in the proportion of neonates not offered VK prophy-laxis from about 30% in 198211 to zero; (2) the changes inpracticesincreased use of single-dose IM prophylaxis, nowrecommended in 72% of units, and oral regimens becomingmultidose (extending over several weeks) for breastfed infants.2

That all four studies were conducted using consistent method-

ology and criteria supports the reliability of the ndings, but weacknowledge that occasional cases may have been missed;similar methodology was found to underestimate cases whencompared with recruitment from a disease registry.12 Lack ofPIVKA-II (protein induced by VK absence/antagonism, factor II)measurement in most cases may be considered another studylimitation.

IM Konakion MMThe change from Konakion Neonatal as the most used IM prep-aration in VKDB-021 to Konakion MM used by all in VKDB-08was not associated with a signicant increase in VKDB inci-dence. The change of solubilising agent (from Cremophor in

Konakion Neonatal to the glycocholic acid/lecithin mixture inKonakion MM) has not apparently reduced efcacy; the pro-longed protection after IM rather than oral or IV administrationmay result from the lipophilic VK forming a depot in themuscle.13

Three babies had late VKDB after IM Konakion MM at birth,presenting on days 66, 86 and 91 (two had liver diseaseonewas bottle-fed and received 0.5 mg, the other was preterm andreceived the licensed dose, 0.4 mg/kg). Late VKDB after IMprophylaxis is extremely rare, but clearly a single dose cannotprevent VKDB indenitely, even without liver disease; othercases have been reported.14 15

The dose of IM VK required to give adequate VK levels for a

prolonged period in preterm infants is uncertain, as there are nodata from a large population given IM Konakion MM in differ-ent doses.1618 Furthermore, with Konakion MM (ve timesmore concentrated than Konakion Neonatal), the risk ofinaccuracy in administering the small volume required, espe-cially for the smallest babies, is substantial.

Oral prophylaxisThe number of units recommending oral prophylaxis hasdecreased, but all doing so now use more effective multidoseregimens in breastfed infants. Failure of compliance ( possiblyprofessional) occurred in both cases associated with oralprophylaxis, implying that an appropriate oral regimen correctly

administered offers equivalent protection (indistinguishable inthese data) to that achieved by IM prophylaxisalthough we

Table 4 Recommended route of administration for vitamin Kprophylaxis in the UK and Irish Republic (IRE), in 2003 and 2008

Year of survey IM Oral Choice*Totalresponding

Totalunits

2003 number ofunits in UK (% ofresponders)

136 (59) 56 (24) 38 (17) 230 (95) 243

2008 number ofunits in UK (% ofresponders)

151 (69) 19 (9) 47 (21) 217 (100) 217

2008 number ofunits UK+IRE (% ofresponders)

169 (72) 19 (8) 48 (20) 236 (100) 236

*No route recommended by the unit; parents asked to choose.IRE was not included in the 2003 survey. IM, intramuscular.

Table 5 Oral prophylaxis regimens for exclusively breastfed infants

Regimen

No of units

(%)

Konakion MM* 2 mg3 doses 43 (64)

Konakion MM 2 mg >3 doses 9 (13.5)

Konakion MM 1 mg3 doses 9 (13.5)

Orakay1 mg at birth, then Neokaydrops 50 mg daily for3 months

4 (6)

Konakion MM 1 mg at birth, then Neokay drops 50 mg dailyfor 3 months

1 (1.5)

Orakay 1 mg at birth, then Orakay 1 mg weekly for 8 weeks 1 (1.5)

Total 67

*Licensed medicine by MHRA in this dose regimen for breastfed infants.Orakay (Dr Reddys Laboratories, Slough, UK)not licensed as a medicine byMHRA, now unavailable.Neokay drops (Neoceuticals, Knaresborough, UK)food supplement not licensed as

a medicine by MHRA.MHRA, Medicines and Healthcare Product Regulatory Agency.

Table 6 Oral prophylaxis for bottle-fed infants

Regimen No of units (%)

Konakion MM* 2 mg2 doses 31 (46)

Konakion MM 2 mg or 1 mg3 dose 20 (30)

Konakion MM 1 mg2 doses 1 (1.5)

Konakion MM 2 mg at birth 10 (15)

Orakay 1 mg at birth 5 (7.5)

Total 67

*Licensed medicine by the MHRA in this dose regimen for bottle-fed infants.MHRA, Medicines and Healthcare Product Regulatory Agency.


Original article



6/8

recognise that babies deemed at highest risk are usually selectedfor IM prophylaxis.

IV prophylaxisThis does not give the same enduring protection as thatachieved with IM prophylaxis,19 yet 38 units (61% of thoseusing IV) left infants vulnerable to late VKDB by not givingfollow-up doses.

NICE recommendationsThe UK Department of Health and NICE signicantly inuenceUK practice; the extent of their inuence in the IRE isunknown. NICE gives independent, national guidance on drugsand healthcare practices after assessing effectiveness, safety andeconomic data. When NICE published guidance for VK prophy-laxis in 2006,3 Konakion MM was the only product licensed inthe UK for oral use. Presented in glass ampoules, every doserequires administration by a healthcare professional, makingthree oral doses an expensive alternative to one IM injection.Without evidence of commensurate benet, NICE recom-mended IM administration as the most efcacious and cost-effective practice, reserving oral prophylaxis for infants whoseparents declined IM injection.3 This survey found that, while 37units (17% of all units; 34 UK, three IRE) changed their prac-tice because of NICE guidance, 67 UK units (31%) did notcomply with it. The proportion of UK units recommending IMprophylaxis increased, but oral prophylaxis was still recom-mended in 19 (9%), parents had choice in 47 (21.5%), and onegave 500 g IM not 1 mg. Oral Konakion MM was used offlicence for breastfed infants in 18 units (27%) and for bottle-fed infants in 31 (46%). Another six (9%) used unlicensed pro-ducts suitable for administration by parents.

Newly licensed productshould NICE guidance bereviewed?

In 2010, the oral VK food supplement Neokay (Neoceuticals,Knaresborough, UK), presented as a 1 mg gelatine capsule andsuitable for parents to give, was licensed as a medicine by theMHRA. Like Konakion MM, it contains phytomenadione, butin coconut oil rather than in mixed micelles with bovine bilesalts. Containing no animal products may make Neokay moreacceptable to some,20 the gelatine capsule (which is notingested) notwithstanding; those who counsel parents shouldknow of this option. The same preparation (Neokay) adminis-tered with a plastic dropper giving 50g daily (after 1 mgKonakion MM or Orakay orally at birth) was used in ve unitsduring the study, although unlicensed as a medicine. This prep-aration and presentation would be suitable for vegans and isacceptable to midwives and parents.21

Danish studies found oral prophylaxis using a Konakioncremophor preparation, 2 mg at birth and 1 mg weekly for12 weeks, to be as effective as 1 mg IM at birth, even in babieswith biliary atresia, and more effective than the three 2 mgdoses of Konakion MM used by most units in our survey.22

Denmark abandoned this regimen for lack of a licensedproduct, but a suitable product now licensed in the UK couldmake it a more acceptable option. The current drug cost usingweekly Neokay capsules equates to that of three doses ofKonakion MM, but saves the cost of administration by health-care professionals. Reappraisal by NICE would be appropriate.

Parental consent

Seeking parental consent is now standard practice. It is notablethat, in nine (53%) of the VKDB cases in the last two BPSU

studies, parents refused the recommended IM prophylaxis,whereas there were no refusals in units recommending oralprophylaxis or offering a choice (p=0.03). Similar data arereported from New Zealand: of 19 cases of VKDB (19982008), VK was not given in 17, in 11 because consent waswithheld.23

The reasons for parents refusing IM prophylaxis is poorlydocumented, including whether oral prophylaxis was offered as

an alternative. This needs addressing to improve understandingand to avoid possible litigation if bleeding occurs.

Liver disease and late VKDBLate-onset VKDB is not prevented by VK prophylaxis alone.Liver disease is known to cause VK deciency and VKDB.1 Thatthe latest two studies have reported only four VKDB cases asso-ciated with liver disease among 3.15 million newborns probablyreects three factors: universal policies for prophylaxis,improved oral regimens, and increased vigilance for liver diseaseby professionals. All three cases of late VKDB associated withliver disease in this study were associated with clinical jaundiceat presentation after 3 weeks of age. One other patient without

liver disease was clinically jaundiced at presentation on day 34.It is imperative to investigate all cases of prolonged jaundice3

and provide additional VK prophylaxis, if required, but 26 units(13%) apparently had no formal pathway for this.

In the Netherlands, oral prophylaxis using VK 1 mg at birthand 25 g daily for 3 months failed to prevent VKDB in babieswith liver disease.24 Lack of community surveillance forprolonged jaundice and lack of the equivalent of the UKsyellow alert publicity campaign probably contributed. TheNetherlands now use 150 g daily,25 equivalent to the successful1 mg weekly Danish regimen described above.22

CONCLUSION

Since the rst BPSU study, awareness of VKDB and the effective-ness of prophylaxis have improved considerably. Parental refusalof prophylaxis is now the most important issue. Those takingconsent should understand local policy, and parents consideringrefusal should be offered a senior opinion. Documentation isessential, including reasons for withholding consent. The recentlicensing of a vegetarian oral product, suitable for administrationby parents, may increase the acceptability of prophylaxis forsome parents.

VK prophylaxis alone will not prevent all cases of VKDB.Community surveillance for predisposing conditions, particu-larly liver disease, remains essential.

Correction notice This paper has been amended since it was published OnlineFirst. It should now be noted that AB and RS are joint rst authors of this paper.

Acknowledgements We thank the BPSU for supporting the studies, all reportingpaediatricians for their collaboration and forbearance, and the reviewers for theirhelpful criticism. We thank Roche Pharmaceuticals for funding this study.

Contributors Ethical approval was sought by AB, the principal investigator, whocollected and analysed data of VKDB cases. RS collected and analysed data from thesurvey of VK prophylaxis. RS and AB collaborated to write the paper. JHT and AWMhelped with study design, interpretation of results and writing of the paper. JHTobtained funding from Roche.

Funding The funders, Roche Pharmaceuticals, had no involvement in the studydesign or data analysis and no editorial rights.

Competing interests JHT and AWM have previously received funding from RochePharmaceuticals. JHT acted as an expert witness to the MHRA in the appeal forapproval of Neokay.

Ethics approval Cornwall Research Ethics Committee.Provenance and peer review Not commissioned; externally peer reviewed.

46 Buseld A,et al.Arch Dis Child2013;98:4147. doi:10.1136/archdischild-2011-301029

Original article



7/8

REFERENCES1 McNinch A, Buseld A, Tripp J. Vitamin K deciency bleeding in Great Britain and

Ireland: British Paediatric Surveillance Unit Surveys, 199394 and 200102.ArchDis Child2007;92:75966.

2 Buseld A, McNinch A, Tripp J. Neonatal vitamin K prophylaxis in Great Britain andIreland: the impact of perceived risk and product licensing on effectiveness. Arch DisChild2007;92:7548.

3 National Institute for Health and Clinical Excellence. Routine postnatal care ofwomen and their babies. NICE Clinical guideline 37 2006;1.4. http://www.nice.org.uk/CG037(accessed 28 Jun 2012).

4 Joubert P, Bolton K, Shearer M,et al. Comparison of the effects of a mixed micellarand cremophor formulation of vitamin K1 given intramuscularly to healthy neonates(abstract).J Clin Pharmacol2004;44:1195.

5 Cornelissen M, von Kries R, Loughnan P,et al. Prevention of vitamin K deciencybleeding: efcacy of different multiple oral dose schedules of vitamin K. Eur JPaediatr1997;156:12630.

6 National Ofce of Statistics.http://www.statistics.gov.uk/statbase/Product.asp?vlnk=5768(accessed 28 Jun 2012).

7 Northern Ireland Statistics and Research Agency.http://www.nisra.gov.uk(accessed28 Jun 2012).

8 General Register Ofce for Scotland.http://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.html(accessed 28 Jun 2012).

9 Central Statistics Ofce Ireland.htt p://www.cso.ie/statistics/bthsbthsmarriages/htm(accessed 28 Jun 2012).

10 McNinch AW, Tripp JH. Haemorrhagic disease of the newborn in the British Isles:two year prospective study. BMJ 1991;303:11059.

11 Handel J, Tripp JH. Vitamin K prophylaxis against haemorrhagic disease of thenewborn in the United Kingdom. BMJ 1991;303:1109.12 Visser DY, Jansen NJ, Ijland MM,et al. Intracranial bleeding due to vitamin K

deciency: advantages of using a pediatric intensive care registry. Intensive CareMed2011;37:101420.

13 Loughnan PM, McDougall PN. Does intramuscular vitamin K1 act as an unintendeddepot preparation. J Paediatr Child Health1996;32:2514.

14 Ciantelli M, Bartalena L, Bernardini M,et al. Late vitamin K deciencybleeding after intramuscular prophylaxis at birth: a case report. J Perinatol2009;29:1689.

15 Shearer MJ. Vitamin K deciency bleeding (VKDB) in early infancy. Blood Rev2009;23:4959.

16 Clarke P, Mitchell SJ, Sundaram S,et al. Vitamin K status of preterm infants with aprolonged prothrombin time. Acta Paediatr2005;94:182233.

17 Costakos DT, Greer FR, Love LA,et al. Vitamin K prophylaxis for preterm infants:

1mg versus 0.5mg. Am J Perinatol2003;20:48590.18 Clarke P, Mitchell SJ, Wynn R,et al. Vitamin K prophylaxis for preterm infants:

a randomised controlled trial of 3 regimens. Pediatrics 2006;118:e16571666.19 Loughnan PM, McDougall PN. Late onset haemorrhagic disease in premature

infants who received intravenous vitamin K1. J Paediatr Child Health1996;32:2689.

20 Harvey B. Newborn vitamin K prophylaxis: Developments and dilemmas.BrJ Midwifery2008;16:51619.

21 Strehle EM, Howey C, Jones R. Evaluation of the acceptability of a new oral vitaminK prophylaxis for breastfed infants. Acta Paediatr2010;99:37983.

22 Hansen KN, Minousis M, Ebbesen F. Weekly oral vitamin K prophylaxis in Denmark.Acta Paediatr2003;92:8025.

23 Darlow BA, Phillips AA, Dickson NP. New Zealand surveillance of neonatalvitamin K deciency bleeding (VKDB): 19982008. J Paediatr Chid Health2011;47:4604.

24 Ijland MM, Pereira RR, Cornelissen EAM. Incidence of late vitamin K deciency

bleeding in Newborns in the Netherlands in 2005: Evaluation of the currentguideline. Eur J Pediatr2008;167:1659.25 de Winter JP, Joosten KF, Ijland MM,et al. New Dutch practice guideline for

administration of vitamin K to full-term newborns. Ned Tijdschr Geneeskd2011;155:A936.


Original article

http://www.nice.org.uk/CG037http://www.nice.org.uk/CG037http://www.statistics.gov.uk/statbase/Product.asp?vlnk=5768http://www.statistics.gov.uk/statbase/Product.asp?vlnk=5768http://www.nisra.gov.uk/http://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.cso.ie/statistics/bthsbthsmarriages/htmhttp://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://adc.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://www.cso.ie/statistics/bthsbthsmarriages/htmhttp://www.cso.ie/statistics/bthsbthsmarriages/htmhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.gro-scotland.gov.uk/statistics/theme/vital-events/general/ref-tables/2007/section-3-births.htmlhttp://www.nisra.gov.uk/http://www.nisra.gov.uk/http://www.statistics.gov.uk/statbase/Product.asp?vlnk=5768http://www.statistics.gov.uk/statbase/Product.asp?vlnk=5768http://www.statistics.gov.uk/statbase/Product.asp?vlnk=5768http://www.nice.org.uk/CG037http://www.nice.org.uk/CG037http://www.nice.org.uk/CG037


8/8

doi: 10.1136/archdischild-2011-3010292012

2013 98: 41-47 originally published online November 12,Arch Dis ChildAlison Busfield, Rebecca Samuel, Andrew McNinch, et al.

2008Unit study, 2006Neonatal: British Paediatric Surveillanceguidance and withdrawal of KonakionVitamin K deficiency bleeding after NICE

http://adc.bmj.com/content/98/1/41.full.htmlUpdated information and services can be found at:

These include:

Referenceshttp://adc.bmj.com/content/98/1/41.full.html#ref-list-1

This article cites 20 articles, 5 of which can be accessed free at:

serviceEmail alerting

the box at the top right corner of the online article.Receive free email alerts when new articles cite this article. Sign up in

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

http://adc.bmj.com/content/98/1/41.full.htmlhttp://adc.bmj.com/content/98/1/41.full.html#ref-list-1http://adc.bmj.com/content/98/1/41.full.html#ref-list-1http://group.bmj.com/group/rights-licensing/permissionshttp://group.bmj.com/group/rights-licensing/permissionshttp://journals.bmj.com/cgi/reprintformhttp://journals.bmj.com/cgi/reprintformhttp://group.bmj.com/subscribe/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://adc.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://group.bmj.com/subscribe/http://journals.bmj.com/cgi/reprintformhttp://group.bmj.com/group/rights-licensing/permissionshttp://adc.bmj.com/content/98/1/41.full.html#ref-list-1http://adc.bmj.com/content/98/1/41.full.html

Arch-Dis-Child-2013-Busfield-41-71.pdf

Documents

Transcript of Arch-Dis-Child-2013-Busfield-41-71.pdf