Relevant BNF section: 9.6.6
Newborn babies are at risk of bleeding as a result of vitamin K deficiency. Vitamin K supplements given at birth reduce this risk but it is not clear which preparation should be used. Until the early 1990s, it was standard practice to give vitamin K as a single intramuscular injection at birth (Konakion Ampoules 1mg/0.5ml - Roche). Studies published in 19901 and 19922 suggested a possible link between intramuscular vitamin K injection and childhood cancers, particularly leukaemias. Our response was to recommend that vitamin K injection be given orally (not then a licensed route) until a licensed oral preparation became available.3 Such a preparation is now marketed as Konakion MM Paediatric (Roche). In addition, the suggested association between intramuscular vitamin K and cancer has been further investigated. In this article, we update our advice.
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Relevant BNF section: 9.6.6
Vitamin K deficiency bleeding
Vitamin K deficiency bleeding may present in one of three ways.4 Classical vitamin K deficiency bleeding occurs in the first week after birth and typically presents with oral, umbilical, rectal or circumcision bleeding. Vitamin K prophylaxis was introduced to protect against this condition. Early-onset vitamin K deficiency bleeding occurs in the first 24 hours after delivery. Mothers of these infants have often taken drugs that interfere with vitamin K metabolism (such as anticoagulants, antituberculous drugs or anticonvulsants) during the third trimester. Late-onset vitamin K deficiency bleeding occurs after the first week, almost exclusively in breast-fed infants and often in those with liver disease or malabsorption. Intracranial bleeding occurs in more than 50% of babies who are diagnosed with this late form, and many die or sustain neurological disability.4 Without vitamin K prophylaxis, the incidence of this late form in Europe is around 40-100 per million live births.5 Small warning bleeds are common in babies who go on to develop late-onset vitamin K deficiency bleeding, and so any baby presenting with a nosebleed, bruising or continuous oozing from the umbilicus or after a needle prick requires urgent investigation.
Vitamin K and childhood cancer
Evidence for an association
Since the 1960s, a single 1mg dose of vitamin K given intramuscularly at birth has been widely used in the UK to prevent vitamin K deficiency bleeding. This regimen is cheap and effective, with apparently no recorded treatment failures even in children with impaired clotting factor synthesis due to liver disease. Concern about the safety of this approach surfaced in the early 1990s with the publication of two papers reporting an association between intramuscular vitamin K and later childhood cancer.1,2 In the first, 33 children who had developed cancer by the age of 10 (identified from a national cohort study) were entered into a case-control study to investigate factors associated with childhood cancer. An unexpected association was found between cancer and drugs given to the neonate, particularly intramuscular vitamin K.1 A later case-control study assessed this association by comparing 195 children with cancer born in the two major Bristol maternity hospitals from 1965-87 with 558 controls.2 An increased risk of cancer was found in children who had been given intramuscular vitamin K around birth (odds ratio 1.97, 95% confidence interval (CI), 1.30 to 3.0) but not in those given oral vitamin K prophylaxis (odds ratio 1.15, 95% CI 0.50 to 2.65).2
A retrospective case-control study reported this year involved 685 children with cancer in northern England.6 It showed a significant association between intramuscular vitamin K and acute lymphoblastic leukaemia developing 1-6 years after birth (odds ratio 1.79, 95% CI 1.02 to 3.15) but no association with other cancers.6 A meta-analysis is currently under way which might help to quantify any risk of childhood cancers. Studies so far have been hampered by the unreliable recording in patient notes of the dose and route of vitamin K given.
Case-control studies in the UK,7 USA,8 Germany9 and Sweden10 involving a total of 425 children with cancer found no further evidence to support the original findings. A Danish cohort study, comparing the rates of cancer in children given intramuscular vitamin K (all children born in Denmark from 1975-84) with those given oral (children born from 1960-64) or no vitamin K (all children born from 1945-54) found no difference in the risk of cancer between these three different birth cohorts.11 More recently, a Scottish case-control study of 417 children with cancer, aged up to 14 years, found no significant association between intramuscular vitamin K and any cancer.12
An "ecological" study published earlier this year involved a total of 3266 cases of childhood cancer from hospitals with a non-selective vitamin K policy (i.e. all babies receive intramuscular vitamin K) and hospitals with a selective policy (i.e. only "high-risk" babies receive intramuscular vitamin K).13 Use of intramuscular vitamin K was not associated with a significant increase in the risk of developing cancer.13 Another recent case-control study showed no significant increase in the risk of cancer (odds ratio 1.44, 95% CI 1.00 to 2.08, p=0.05) or leukaemia (odds ratio 1.53, 95% CI 0.82 to 2.85, p=0.17) in 597 children who had received intramuscular vitamin K.14
Oral vitamin K prophylaxis
Changes to prophylaxis policies
Following publication of the original studies reporting an association between childhood cancer and intramuscular vitamin K,1,2 national recommendations in many countries were changed to oral vitamin K prophylaxis. Our original recommendations,3 which were consistent with those of the British Paediatric Association,15 were to give all babies 500µg of injectable vitamin K orally at birth and then further oral supplements in breast-fed babies. Oral vitamin K prophylaxis policies were also adopted in Germany and Australia, where three 1mg doses were recommended. In Denmark, extended oral vitamin K prophylaxis has been recommended since 1992: this consists of a single 2mg dose initially then 1mg each week until the baby is 3 months old.16 In The Netherlands, a daily oral dose of 25µg (a dose chosen to mimic the amount of vitamin K in formula feeds) has been in use for some years.17 In 1993, the American Academy of Pediatrics concluded that "parenteral vitamin K prevents a life-threatening disease of the newborn and the risks of cancer are unproven and unlikely".18 The Academy therefore recommended a single intramuscular dose of vitamin K (0.5mg-1mg) for all neonates and the development of an appropriate licensed oral formulation.18
Risk of bleeding after oral prophylaxis
Oral vitamin K prophylaxis appears less reliable at preventing late-onset vitamin K deficiency bleeding than a single intramuscular dose. Surveillance data on late-onset bleeding has identified cases even after three 1mg oral doses have been given.19 In Germany, following the national change to three 1mg oral doses, the incidence of late-onset vitamin K deficiency bleeding was 1.8 per 100,000 in 1993-4.17 A similar failure rate was seen in Australia and subsequently national prophylaxis policy was changed back to intramuscular vitamin K.17 It is likely, however, that most of these infants received the injectable vitamin K orally and it is not known if this formulation is adequately absorbed when given by mouth. It may be that the intramuscular injection is more effective not so much because of better absorption but because it forms a depot after injection from which vitamin K is gradually released.20 The extended oral prophylaxis regimens adopted in Denmark and The Netherlands seem to have been effective, with no cases of late-onset vitamin K deficiency bleeding reported.17
Adherence to oral prophylaxis regimens
Adherence to repeated oral-dosing regimens is a recognised problem and failure to complete the course may account for some of the cases of late-onset vitamin K deficiency bleeding. In a UK study involving 162 mothers who gave birth in June 1993 and who went on to breast-feed their babies, over 10% of infants did not receive the planned second dose of vitamin K at 1 week and 61% did not receive the third dose on time. These infants were, therefore, at risk of developing late-onset vitamin K deficiency bleeding.21 During this study, many mothers reported that the GP or community midwife was reluctant to prescribe or give vitamin K because the preparation was not licensed for oral use. Adherence to oral vitamin K prophylaxis regimens appears to have been better in New Zealand with 97% of infants receiving the second dose and 75% receiving the third dose on time22 (the third dose coincides with the infants' first immunisation). However, this study found that in 44% of neonates, first doses were given more than 24 hours after delivery, putting such children at risk of early and classical vitamin K deficiency bleeding. The authors postulated that the delay may have occurred because the decision on the route of prophylaxis was left until after the baby was born.
Possible exclusions from oral prophylaxis
Many hospitals use guidelines that define "high-risk" groups of neonates who should receive intramuscular prophylaxis rather than oral prophylaxis. Neonates who might be at particular risk of bleeding include those with liver disease or malabsorption. Others may include infants of mothers who have taken antituberculous and anticonvulsant drugs, babies born by instrumental or caesarean section delivery, pre-term infants or any infant admitted to neonatal intensive care units. Although such selections seem sensible, there are no data on the effectiveness of these policies.
Konakion MM Paediatric
The newly introduced oral vitamin K preparation Konakion MM Paediatric consists of vitamin K in a mixed micelles vehicle of lecithin and a bile acid (glycocholic acid). In a study involving 25 breast-fed neonates, vitamin K blood levels after a single 3mg dose of a mixed-micellar formulation of vitamin K given by mouth were similar to those achieved after a single intramuscular dose of 1.5mg.23 Similar results were seen even in children with severe cholestasis who might be expected to have difficulty in absorbing vitamin K given by mouth.24
Large-scale experience with oral administration of mixed-micellar vitamin K comes from Switzerland, where two 2mg doses (on days 1 and 4) have been used nationally since January 1995. Between January and December 1995, when the birth population in Switzerland was about 83,000, three confirmed cases of late-onset vitamin K deficiency bleeding were reported. These were in infants who did not receive the recommended prophylaxis: in two, an old fat-soluble formulation was given and in the third, no prophylaxis was given.17
Dose and administration
Konakion MM Paediatric is licensed for use in "healthy neonates of 36 weeks gestation and older". For these babies, the manufacturer of Konakion MM Paediatric recommends a dose of 2mg orally at, or soon after, birth followed by a further 2mg oral dose at 4-7 days. If the baby is being exclusively breast-fed, an additional 2mg oral dose should be given 1 month after birth. The Summary of Product Characteristics for Konakion MM Paediatric also advises giving further monthly doses until the introduction of formula feeding but there are no efficacy or safety data available for these extra doses.
Konakion MM Paediatric is supplied in coloured glass ampoules to maintain stability. The ampoules have to be opened and the drug administered using a syringe supplied with the pack. The manufacturer recommends that the solution is drawn up and administered by a healthcare professional.
Cost of vitamin K regimens
Intramuscular vitamin K in a dose of 1mg given shortly after birth remains the only certain way to prevent the potentially fatal late-onset vitamin K deficiency bleeding, which occurs almost exclusively in breast-fed babies. This is effective even in neonates at high risk of bleeding and is cheap. However, while an association between childhood cancer and intramuscular vitamin K remains a possibility, such an approach is unlikely to be universally accepted by parents or paediatricians.
The better absorption of vitamin K from the Konakion MM Paediatric formulation should mean that this product is more effective in preventing late-onset vitamin K deficiency bleeding than the vitamin K injection given by mouth. Since three doses of the Konakion MM Paediatric formulation need to be given, there is a distinct risk of poor adherence to the regimen and, therefore, a risk of bleeding. As yet, experience with Konakion MM Paediatric is limited and evidence to confirm its efficacy and long-term safety are needed.
Despite these limitations, Konakion MM Paediatric offers parents and doctors a choice: parents should be fully informed about the possible advantages and disadvantages of giving vitamin K by intramuscular and oral routes and a decision should be agreed early enough to avoid a delay in administration of the first dose. If the oral route is chosen, parents should be told of the need to ensure the infant receives the full prophylaxis and that doses are given on time. Healthcare professionals administering vitamin K should ensure that the dose, formulation and route are clearly recorded.
[M=meta-analysis; R=randomised controlled trial]
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