conclusion--vit k

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Page 4

deficiencies.6, 35, 51, 80

Birkbeck6 believes there are two processes at work; low levels of

prothrombin and vitamin K-dependent clotting factors VII, IX and X at

birth, and a further fall in these in the neonatal period. In his view

the initial low levels are not due to vitamin K deficiency as levels of

2 other non-vitamin K-dependent factors, XI and XII are also often

reduced. Thus, the situation at birth may be simply due to hepatic

immaturity.

Birkbeck6 also reports that HDN is almost unknown in central Africa and

he suggests an environmental mechanism as the cause. Associated with

this, a discussion paper from the University of Amsterdam42 raises the

idea that by-products of our industrial society such as PCBs, PCDDs and

PCDFs are the cause of late onset HDN. These chemicals can induce

enzymes in the liver which cause liver damage and prolong prothrombin

time. Although overseas studies have reported contamination of

breastmilk by these pollutants, a NZ Department of Health study on

breastmilk reported that levels of these contaminants were at the lower

end of the scale.7 The Health Department is currently conducting another

study to see if levels have changed over the past few years.

There seems to be a seasonal variance, with most cases of late onset HDN

occurring in the warmer months.6 It has been suggested that the mother

could have contracted a viral infection during pregnancy in the colder

months and this has crossed the placenta. Since viruses have an affinity

for the liver and mucous membranes, they can affect intestinal

absorption and liver function.67

Another suggested cause of late onset HDN includes use of the food

antioxidant BHT (butylated hydroxytoluene), which has produced vitamin K

deficiency.68 BHT is present in many processed foods, including

margarine. Our Western diets consist of a lot of processed food, and to

reduce fat intakes, margarine is recommended rather than butter. The

polyunsaturated fat in margarine is an inhibitor of vitamin K

absorption.68 Both of these factors could have an effect on the amount

of vitamin K available to pass through to the baby. A high level of

vitamin K in the mother & rsquo;s blood is necessary to ensure adequate

transplacental transfer of vitamin K.9, 33 It is important for the baby

to have adequate stores of vitamin K in its liver at birth to prevent

bleeding until its feeding and gut flora are established.

Of the six cases of HDN in Britain in 1980-1982, all were breastfed and

none had received vitamin K at birth.46 Two of the cases were in the

high-risk group one was born by caesarean section and had an

epileptic mother treated with phenytoin, and the other had an alcoholic

mother who had taken anti-depressants and obviously should have

received vitamin K at birth.

These cases prompted a call for the re-introduction of routine

prophylaxis. Many opposed the idea of unnecessarily injecting otherwise

healthy babies so studies40, 47, 55, 79 were therefore conducted to

determine whether oral vitamin K was as effective as intramuscular. It

was also proposed that oral vitamin K would be more cost-effective and

thus better suited for use in Third World countries.55 Results of these

studies varied. Some showed that oral vitamin K was effective in

preventing classic haemorrhagic disease but not as effective as

intramuscular vitamin K in preventing late onset HDN.47, 55, 78 Others

found oral as effective, especially a 10 year study conducted on 38,000

infants in Sweden where no cases of HDN were observed over that

period.40 Tripp and McNinch reported no cases in 25,000 babies in their

maternity unit where only those at risk were given intramuscular

prophylaxis and the rest oral prophylaxis.70

In spite of these findings that oral vitamin K prophylaxis was not

effective in preventing late onset HDN, it continued to be used in

British maternity units, especially for low risk infants.

RISKS OF VITAMIN K PROPHYLAXIS

Konakion ampoules contain phenol, propylene glycol38 and polyethoxylated

castor oil as a non-ionic surfactant. Studies in animals given

polyethoxylated castor oil have shown a severe anaphylactic reaction

associated with histamine release. Strong circumstantial evidence

implicates polyethoxylated castor oil in similar reactions in humans.

Polyethoxylated castor oil, when given to patients over a period of

several days, can also produce abnormal lipoprotein electrophoretic

patterns, alterations in blood viscosity and erythrocyte aggregation

(red blood cell clumping). Individuals sensitive to this base are

contraindicated from using Konakion. New Ethicals Compendium also warns

that the use of Konakion can cause jaundice and kernicterus in

infants.53 Other listed side effects include flushing, sweating,

cyanosis, a sense of chest constriction, and peripheral vascular

collapse. Local cutaneous and subcutaneous changes may occur in areas of

repeated intramuscular injections.

This synthetic, injectable vitamin K formulation was never subjected to

a randomised, controlled trial. In new drugs that are to be used for

prophylaxis, the usual risk/benefit analysis does not apply, since the

individual is not ill. The ethical principle of non-maleficence (primum

non nocere first do no harm) applies and the trials must thus be

larger in order to identify any previously unrecognised side effects.65

Since this did not happen, nor was there any long term follow up, we

actually have little idea of the effects of this drug on newborn babies.

The risks of injecting vitamin K into a newborn baby are nerve or muscle

damage as the preparation must be injected deeply into the muscle, not

subcutaneously under the skin. There is also the documented risk of

injecting the baby with the syntocinon intended for the mother.30, 70 As

stated in the product information,53 infants can suffer from jaundice or

kernicterus (brain damage from a build-up of bile pigments in the brain)

from Konakion. Infants who have the enzyme deficiency G6PD (glucose 6

phosphate dehydrogenase) are at particular risk from vitamin K.30 The

other risk factor is the possible increased chance of childhood cancer.

THE LINK BETWEEN CHILDHOOD CANCER AND INTRAMUSCULAR VITAMIN K

In 1970, a national cohort study of 16,193 infants born in one week in

April was begun in Britain.26 This study was to test

Page 5

hypotheses about childhood cancers and their associated factors.

Thirty-three of the children had developed cancer by age 10 and were

compared with 99 control children, matched on maternal age, parity and

social class. One of the unlooked-for risk factors was the

administration of prophylactic drugssuch as vitamin K in the first week

after birth a nearly three-fold risk. This association fitted no

prior hypothesis and the authors recommended that their finding be

tested in another series of cases.

The authors of the study approached Roche, the manufacturers of

Konakion, for funding for a further trial to examine the findings more

closely. Roche was not interested until, a few months later, the media

reported the results of the study and that vitamin K given to babies

might cause childhood cancer. Roche then decided to fund a new study.27

The new study25 was a case-control study of 195 children with cancer

born at either of two hospitals in Bristol, England, compared with 588

healthy children also born at these hospitals. One hospital

predominantly gave vitamin K orally and the other intramuscularly. The

authors found a nearly two-fold risk of leukaemia in children who had

received intramuscular vitamin K.

These findings were extremely worrying. Golding calculated that the

extra cases of leukaemia caused by vitamin K injection could be as many

as 980 in the UK alone.25 These results were supported by reports of the

potential carcinogenicity of vitamin K from Israels et al, who suggested

that low vitamin K levels in the newborn protect against the risk of

mutations during a period of rapid cell growth and division.39 Pizer et

al did not find any association between the route of vitamin K

administration and mutations in cells but concluded that his study was

too small to show any real effect.62 Another study reported no increase

in abnormalities in newborn infants, but, with only 12 infants, the

study was too small to show any real effect.10 It is worth noting that

after an intramuscular dose of vitamin K, the babys plasma levels

are almost 9000 times the normal adult levels.47 It has also been

suggested that the cancer-causing agent could be a metabolite,

N-epoxide, or some other component of the solution other than vitamin K

itself.15

Goldings study was criticised by many. One of the reasons was

that the authors had to make assumptions for some cases, as the

information on vitamin K administration was not clearly recorded. In

spite of this, expert epidemiologists considered that the results were

plausible and so could not be lightly dismissed.15 Further studies were

proposed to answer the question of cancer and vitamin K.

In 1993, results from three retrospective studies on vitamin K and

childhood cancer were published. The studies were done in the USA,

Denmark and Sweden.41, 57, 19 These studies, although large, did not

confirm the association between intramuscular vitamin K and childhood

cancer. One of the studies not only showed no association between IM

vitamin K and childhood cancer, it also showed no association between

maternal smoking and childhood cancer, a finding totally at odds with

the results from many other studies.19 The other two studies were also

not comparable to the British study. One because of differences in type

of vitamin K given41 and the other because of the use of birth cohorts

with differing regimens of vitamin K usage.57

Because of the design flaws in these studies, there was still a need for

further case-control studies. Results from two were published in 1996.2,

77 They had carefully matched controls and more accurate information on

whether vitamin K had been given or not, and by which route. One of the

studies2 reported no association between intramuscular vitamin K and

childhood cancer and the other77 found a risk of leukaemia, but only

when cases were compared with local controls (i.e. from the same

hospital) and not with controls randomly selected from the whole area

under study. This, although suggestive, was not followed up but

dismissed as a chance finding related to multiple testing.

The suggestion was then put forward that, as these studies had failed to

show a definite association between intramuscular vitamin K and

childhood cancers, worries about any potential cancer risk should be

abandoned.83

At that time, four more studies on vitamin K and cancer were in

progress.44, 59, 60, 61 The results from these four studies were

published in 1998. Two of them failed to confirm any increased risk of

childhood cancers.44 61 One of the other studies showed a twofold risk

of acute lymphoblastic leukaemia among 1-6 year olds,59 the other showed

a significant risk for all cancers.60

So, the jury is still out on whether there is an increased risk of

childhood leukaemia with the intramuscular form of vitamin K. Some

recommend that intramuscular vitamin K should still be used, as the risk

of leukaemia " seems more hypothetical than real " .76 Others believe that

public confidence in IM vitamin K has been severely shaken and will be

difficult to restore fully. They recommend an oral regimen similar to

that used in the Netherlands of 25m g daily, given by the mother. This

would avoid the grossly unphysiological peaks of vitamin K from both the

IM route and the present oral route.71

ORAL VITAMIN K VS INTRAMUSCULAR

The two main problems with giving vitamin K orally are that there is no

licensed oral formulation, meaning that babies receive the intramuscular

form orally, and that compliance with three oral doses is poor as many

doctors and midwives are reluctant to give an unlicensed formula.13 The

use of unlicensed preparations may theoretically expose professionals to

litigation in the event of prophylactic failure or unforeseen adverse

events.2

Roche, the manufacturers of Konakion, state that they do not recommend

the administration of Konakion solution orally.63 Their reasons are:

* that they have no clinical studies to support oral use,

* phenol, which has been reported to be an irritant to newborns

mouths, is used as a preservative,

* the variability in the production of bile salts in newborns may

affect absorption,

* that Konakion given orally has a small association with

anaphylactic reactions.

Page 6

The preparation was also unpleasant to taste and babies were inclined to

spit it out82 or to vomit it back up. Only about half of an orally

administered dose is absorbed.47 Even so, the plasma concentrations in

babies who were given oral vitamin K reached 300 times the adult levels,

before dropping off slightly after about 24 hours.47

After the publication of Goldings studies, further trials were

done on oral vitamin K prophylaxis and whether it gave longer term

protection. In 1992, Cornelissen11 found plasma vitamin K concentrations

were higher in the group given IM vitamin K than the oral group, but

blood coagulability, activities of factors VII, X and PIVKA-II

concentrations showed no differences. By 3 months follow-up, vitamin K

levels had dropped in both groups but more in the oral group. He

suggests that neither give long term protection. One would assume that

babies should be producing their own vitamin K by 3 months and, if not,

what other mechanism could be hindering this process.

Von Kries et al78 studied repeated oral vitamin K prophylaxis in

Germany, with 3x 1 mg doses and found that it was not as effective as a

1mg intramuscular dose at birth. Another study by Cornelissen et al12

reported on the effectiveness of differing regimens of oral vitamin K in

four different countries & ndash; the Netherlands, Germany, Switzerland

and Australia (two differing regimes). In the Netherlands, babies are

given 25 m g daily oral vitamin K for 3 months with I mg given at birth

either orally for healthy newborns or intramuscularly for unwell babies.

In Germany, the regime is 3 x 1 mg oral doses as was also the case in

Australia from 1993 to 1994. In Switzerland 2 oral doses of a new

& lsquo;mixed-micellar & rsquo; oral vitamin K is given. The Netherlands

had the lowest failure rate & ndash; 0 per 100,000. In Australia, where

the regime was changed in 1994 from oral to IM, the failure rate was 1.5

per 100,000 for oral and 0.9 per 100,000 for IM, showing that 3 oral

doses are less effective at preventing late onset HDN than one IM dose

of vitamin K. Even if Roche are persuaded to bring the mixed-micellar

preparation into New Zealand, results from Switzerland (failure rate of

1.2 per 100,000)12 show that further study needs to be done on the most

effective timing of the doses.

If New Zealand parents wish their baby to receive oral vitamin K, the

recommended regimen is for 3 x 1mg doses, 1 at birth, 1 at 5 days and 1

at 6 weeks.6, 20 It is up to parents to ensure that their baby receives

all 3 doses if they choose this form of prophylaxis.

CONCLUSION

It would seem an anachronism that babies are born with a deficiency of

such an essential vitamin and require supplementation. In fact, although

there have been many studies on differing aspects of vitamin K

prophylaxis, there has only been one39 on the possible reasons for and

the advantages (if any) of the physiological levels of vitamin K in

newborns.

The risks of prophylaxis for the majority of babies who are at low risk

of HDN are also not understood. As plasma vitamin K levels in newborns

reach 300 times normal adult levels for oral and almost 9000 times for

IM vitamin K47, some research needs to be done on the effects this may

have. Studies have shown that physiological levels of vitamin K maintain

a careful balance between coagulation and anti-coagulation and we have

no idea what the effects of upsetting that delicate balance would be.

The number of children currently developing cancer during childhood is

much higher than the number developing a life threatening or permanently

disabling problem as a result of late onset HDN. The risk of childhood

cancer is estimated to be 1.4 per 1000, from the 1970 British cohort. If

IM vitamin K caused cancer, there would be 100 extra cases of cancer per

case of HDN prevented.16 This could mean that giving IM vitamin K to

every baby would be doing more harm than good.36

The decision rests on parents shoulders the link between

intramuscular vitamin K and childhood cancer has not been definitively

proved, nor has it been completely disproved. It may be that an oral

regimen as suggested by Tripp and McNinch71 could be the answer to the

dilemma. If this is the case, then Roche needs to be lobbied to make the

European preparations available in New Zealand. In the meantime, the

choice is between no vitamin K, with the mother being aware of her

dietary intake of vitamin K, an oral regimen or the intramuscular

formulation.

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