VITAMIN K: CONTROVERSY? WHAT CONTROVERSY?

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VITAMIN K: CONTROVERSY? WHAT CONTROVERSY?

By Karin Rothville DipCBEd.

For the last 40 or 50 years, it has become a generally accepted fact

that vitamin K prevents haemorrhagic disease of the newborn, and routine

administration of vitamin K to all newborns has been recommended.3, 6,

21, 34, 72 This recommendation has been questioned because results

released in 1990 from a study by Golding and colleagues26 in the UK

showed a two to three times increased risk of childhood cancers,

especially leukaemia, in children given prophylactic drugs (usually

intramuscular vitamin K) in their first week. A further study in 1992

seemed to confirm this risk.25

There was widespread anxiety among parents when these findings were

published. Parents were, understandably, reluctant to have their baby

receive a substance that could predispose it to cancer in childhood, and

many health workers were also reluctant to give, without prescription, a

possibly cancer-causing substance to prevent a disease that few, if any,

of them had ever seen. These concerns are not the first time that

vitamin K safety has been questioned. So, what is the controversy about

vitamin K? And does it predispose babies to childhood cancer?

WHAT IS VITAMIN K AND WHAT DOES IT DO?

Vitamin K is a fat-soluble substance which triggers off the

blood-clotting process. Blood clotting is a complex process and can be

described as a sequence of three stages, requiring up to 12 different

coagulation factors.72 The liver needs vitamin K to synthesise four of

these factors. Vitamin K is also needed for the formation of other

proteins found in plasma, bone and kidney.33, 58

As with other fat-soluble vitamins, a normal flow of bile and pancreatic

juice is necessary for digestion, and the presence of dietary fat,

especially short-chain fatty acids, enhances absorption. Absorbed

vitamin K is transported via the lymph into the systemic circulation.58

Normally, a significant portion (up to 55%) of absorbed vitamin K is

excreted so the amount in the body is small and its turnover is rapid

(about 30 hours).58 Vitamin K is stored and re-utilised in the body for

3-4 weeks.33

Vitamin K is found in many foods. Leafy, dark green and deep yellow

vegetables are the best sources.58 Alfalfa18 is a good source; and milk

and dairy products, eggs, cereals, fruits and other vegetables also

provide small but significant amounts. As the liver of adults contains

about equal amounts of plant and animal forms of Vitamin K, it is

assumed that vitamin K is produced in the intestinal tract by bacterial

flora. One of the reasons given for the low levels of vitamin K in

newborn babies is because their gut has not yet been colonised by the

required bacteria.

Recommended daily dietary intakes of

vitamin K58

Category Age Amount (m g)

Infants 0 10

1

Children 1 15

3

4 20

6

7 25

10

Adolescents 11 30

14

15 35

18

Adult Male 19 45

70+

Adult Female 19 35

70+

Pregnancy + 10

Lactating + 20

The dietary requirements for vitamin K in infants and children are

estimates and are based on weight and growth rates as compared to

adults. Many unsupplemented breasfed infants do not show clinical signs

of vitamin K deficiency on intakes of less than 3 m g daily and the mean

requirement for infants is estimated to be 5 m g daily based on weight.

The higher amount of 10m g is recommended for prevention of Haemorrhagic

Disease of the Newborn.58

WHAT IS HAEMORRHAGIC DISEASE OF THE NEWBORN?

Haemorrhagic Disease of the Newborn (HDN) is a bleeding disorder

associated with low levels of vitamin K in newborn babies. It was first

defined in 1894 by Townsend69 as spontaneous external or internal

bleeding occurring in newborn infants not due to trauma, accident or

inherited bleeding disorders such as haemophilia. Previously, there were

no generally agreed upon criteria to determine causes of haemorrhaging,

so any diagnosis was based solely on the opinion of the attendant

medical personnel.

Infants are born with low levels of vitamin K23 compared to adults and

this is termed & lsquo;vitamin K deficiency & rsquo;. Up to 50% of babies

develop this & lsquo;vitamin K deficiency & rsquo;, but bleeding occurs in

only a fraction of these cases.37 In most it starts after birth, becomes

Page 2

progressively more severe over 48-60 hours, then spontaneously corrects

itself by 72-120 hours.9

HDN has always been rare & ndash; in Britain where maternity units

practised a selective policy of vitamin K administration, the incidence

was no more than 1 in 20,000 in the years 1972-80. Estimates for late

onset HDN are 4-8 per 100,000.45 Incidence also seems to vary from

country to country.

HDN is divided into three categories:

1. Early onset HDN occurs in the first 24 hours. It is very rare and

mainly associated with mothers who have taken anticonvulsant,

antibiotic, antituberculous or anticoagulant drugs during

pregnancy.

2. Classic HDN occurs in the first week after birth. It is manifested

by the oozing of blood from the intestines, the nose, the cord site

and broken skin sites. Bruising at sites where there has been no

trauma can also appear.

3. Late onset HDN occurs after the first week, with a peak incidence

between the second and sixth weeks, and about half the cases

present with intracranial bleeding (bleeding into the brain).

WHAT ARE THE RISK FACTORS FOR HDN?

There has been some debate over the years as to whether or not HDN is

actually caused by vitamin K deficiency. Certainly, giving vitamin K

does arrest bleeding in the majority of cases, but this does not mean

that vitamin K deficiency causes HDN. One may as well say that an

antibiotic deficiency causes bacterial infection. There is also no

consensus as to what level of vitamin K in plasma protects against HDN.

Some researchers have found no evidence of vitamin K deficiency in

babies in their studies43, 49 and other factors have also been

suggested.52, 73, 74

Most, if no all, of the reported cases of late onset HDN have presented

with problems which affect the baby & rsquo;s ability to absorb or utilise

vitamin K.45, 56 These include: hepatitis, cystic fibrosis, chronic

diarrhoea, bile duct atresia, alpha-1-antitrypsin deficiency, coeliac

disease of insufficient plasma transport capacity. Subclinical

cytomegalovirus has also been implicated. Vitamin K-responsive bleeding

syndrome has been well documented after antibiotic therapy, especially

with cyclosporins.33

There are other factors which place the newborn at higher risk. These

include pre-term birth (as the liver is very immature), low birth

weight, instrumental or traumatic delivery, bruised or bleeding in the

first few days after birth, requiring surgery or circumcision, taking

inadequate feeds and breastfeeding.33

BREASTFEEDING: WHY IS IT A RISK?

Several authors have noted the higher incidence of HDN in solely

breastfed babies.9, 30 The incidence has been quoted as 1 in 1200.30

Studies comparing breastmilk with formula and cows milk have

shown that breastmilk is lower in vitamin K.22, 28, 32 Breastmilk

substitutes are heavily supplemented with vitamin K, however, it is

possible that, like iron, vitamin K is biologically more available to

the baby from breastmilk, and so such high

levels are not necessary.

Measured levels of vitamin K in breastmilk seemed to vary depending on

the type of measurement used; however, they all come out lower than

cows milk. Fournier22 and Greer28 found levels of around 8-9m

g/l, which would mean that if a baby was taking in about 500ml per day,

it would be getting the recommended 3-5m g daily.

Vitamin K content and availability are greater in the hind milk because

of its higher fat content and vitamin K levels are also higher in

colostrum.32 As an extra plus, breastmilk contains thromboplastin, one

of the factors in blood clotting.18

Vitamin K levels in the breastmilk rise markedly in response to the

mother eating vitamin K rich foods or taking vitamin K supplements.29,

54 Nishiguchi found no cases of low vitamin K levels in breastfed

infants whose mothers had been given supplements, as opposed to infants

who had only been given 1 or 2 doses of oral vitamin K.54

Unrestricted access to the breast in the early days after birth is

important, due to the higher levels of vitamin K in colostrum. The

importance of early feeding has been recognised since the 1940s.

Babies who have been fed within their first 24 hours have significantly

better coagulation times than babies not fed until after 24 hours.24

It is essential that, to receive the full complement of vitamin K in

breastmilk, the baby completely finishes one breast before being offered

the other. Any practice that involves restricting either the

babys time at the breast or the number of feeds will not allow

the baby to receive optimum amounts of vitamin K and will also prolong

the time it takes for the babys intestine to be colonised by

friendly, vitamin K manufacturing bacteria.

THE HISTORY OF VITAMIN K USE TO PREVENT HDN.

The search for the cause of HDN began in 1913 when Whipple82 postulated

that a lack of prothrombin activity could be a cause of HDN. In 1929,

Henrik Dam14 noticed that chicks fed a fat-free diet suffered

subcutaneous and intramuscular haemorrhages, which could be prevented if

the chicks were fed seeds, cereals and green, leafy plants. Dam

described the condition as a vitamin deficiency and named the deficient

vitamin & lsquo;vitamin K, from the Danish word

koagulation.

Research in 19378 found that prothrombin times in normal neonates were

between 30-60% adult levels, falling to 15-30% on day two, and then

gradually rising again until about day 10. This research led to the

continuing belief that these low levels in the newborn are a deficiency

and need to be corrected.

In 1939, vitamin K1 was isolated from alfalfa by Dam, for which he later

received the Nobel Prize, along with Doisy, who isolated vitamin

K2.45 Further research in 1939 by Waddell and Guerry81 found that low

plasma prothrombin levels could be elevated by the administration of

oral vitamin K.

Armed with this proof; that vitamin K deficiency caused

HDN, vitamin K was synthesised and various trials were commenced

Page 3

to ascertain which was the most effective amount and route to use in

prophylaxis.

It is difficult for us to assess these trials nowadays as they were

mostly neither double blind nor well controlled. The dosage of vitamin K

given, the route of administration and the time of administration all

varied. In many cases, the conclusions did not seem to match the

results.72

Some of the studies assessed the effect on neonatal vitamin K levels if

the mother was given vitamin K during labour.72 Results varied, with the

effectiveness of the vitamin K given depending on how soon the woman

gave birth and the dosage given. More recent studies have shown

increases in cord blood levels where mothers were supplemented

antenatally with vitamin K.1, 66 Two showed a significant difference

between the supplemented and unsupplemented groups and found that the

effect of prenatal vitamin K persisted until the fifth day after birth.1

Because of the variations in results from these early studies, further

research focussed on treating the baby after birth. One particular study

done in 194231 was intended to determine the minimal effective oral dose

of Synkavite (K3), a water-soluble synthetic form of vitamin K. The

results showed that very small daily doses were effective and that a

dose of 5m g daily would probably prevent the development of HDN, except

in early onset cases. The study also found that 1.25mg was effective in

lowering an excessively high prothrombin time to normal. However, the

author admitted that several workers found prothrombin deficiencies in

babies with no abnormal bleeding.

By 1950, most maternity units had a policy of giving infants oral

vitamin K (usually Synkavite) immediately after birth.70 This prevented

the fall in prothrombin levels that occurred in the first few days and,

presumably, the risk of excessive bleeding. This risk was higher in male

babies because of routine circumcision, and, indeed, vitamin K proved to

be of great clinical value in preventing post-circumcision bleeding.75

Then, in the mid-1950 & rsquo;s, reports of increased jaundice and

kernicterus (brain damage caused by high bilirubin levels) associated

with vitamin K prophylaxis began circulating. Reviews of maternity units

found that some were giving Synkavite in doses exceeding 50mg.70 It was

established that high doses of Synkavite caused haemolysis (destruction

of red blood cells) and high serum bilirubin levels.48

Researchers and medical professionals queried the safety

aspects of vitamin K, and there were many conflicting reports on the

appropriate dosages. Some researchers queried the need for vitamin K at

all, quoting results from studies that showed no difference in

prothrombin times or vitamin K plasma levels between babies that bled

and babies that didn't.72

Eventually, a newer preparation, intramuscular vitamin K1

(phytomenadione), was developed and approved for use, solely on the

grounds that it appeared to cause less haemolysis. Phytomenadione (trade

names Konakion (Roche) or Aquamephyton (Merck, Sharpe & Dohme)) is a

synthetic petrochemical derived from 2-methyl 1,4-naptha-quinone in a

polyethoxylated castor oil base.18 In the US, polysorbate-80 is used as

a base instead of polyethoxylated castor oil.15

In spite there being no long term trials of these preparations, the

American Academy of Pediatrics recommended that phytomenadione be

administered prophylactically to all newborn babies.72 The use of oral

vitamin K preparations fell out of favour in the USA and the

& lsquo;safer & rsquo; intramuscular route became the route of choice.

In Britain, after the jaundice scare of the1950s, many maternity

units began to practice a selective policy, giving vitamin K only to

babies at risk of haemorrhaging. McNinch reported in 1980 that less than

half the maternity units in the UK gave vitamin K to all newborns.47

Some of these babies were given oral prophylaxis and some were given

intramuscular prophylaxis.

In Germany, almost all newborn infants who required medical care and

instrumental deliveries were given intramuscular vitamin K, and some

healthy newborns also received it.76 Records have not always been kept

in New Zealand hospitals, so it is impossible to say whether or not

vitamin K was given routinely and by which route.17

Although vitamin K use seemed to prevent most cases of HDN, there was

still controversy. Not everyone believed vitamin K deficiency was the

cause of HDN. In 1977, van Doorm et al 52, 73, 74 suggested that HDN

could be caused by a heparin-like inhibitor in the newborn and he

concluded that babies given their first feed soon after birth do not

have a vitamin K deficiency. Other researchers agreed with van Doorn.49

In 1980, Malia et al43 could find no evidence of vitamin K deficiency in

babies in their study and concluded that low levels of vitamin K

dependent clotting factors were due to the immature liver. The authors

of these studies questioned whether vitamin K prophylaxis was really

necessary for healthy newborns.

Then, starting in November 1980, there was a cluster of six cases of HDN

in Britain, all within 17 months.46 Half of these cases were classic

HDN, the other half were a new manifestation of HDN & ndash; late onset.

LATE ONSET HDN

Late onset HDN was first reported in 1977.5 It mainly occurs in

breastfed infants and ¯ to ¾ of cases have an underlying liver disorder

or malabsorption syndrome,15 rather than insufficient dietary intake of

vitamin K. This means the liver cannot adequately synthesise blood

clotting factors or store adequate amounts of vitamin K. Liver function

cannot be easily diagnosed at birth without a range of invasive tests

and thus there exists an unknown risk of haemorrhaging.

Many factors contribute to poor liver function, including hepatitis,

cystic fibrosis, antibiotic therapy, biliary atresia,

alpha-1-antitrypsin deficiency, a-beta-lipoproteinaemia, coeliac

disease, chronic diarrhoea and exposure to pharmacologic agents such as

anticonvulsants, rifampin, isoniazid cephalosporins and coumarin

compounds33 When tested, most of the reported cases of late onset HDN

had hepatitis, liver malfunction or enzyme.

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