Selden
Danielle Selden
1-25-2012
Vitamin K Debate – Con
Vitamin K deficiency rarely affects adults, but newborns face a great risk since their food
intake is limited to milk, which is low in Vitamin K. Their stores of the vitamin K are low
because inadequate amounts cross the placenta and their intestinal tracts are not yet populated by
vitamin K synthesizing bacteria (1). With this risk considered, routine supplementation of
Vitamin K is advised and carried out in the United States and other developing nations. The
topic of this debate; “Vitamin K injection of neonates is necessary to avoid hemorrhagic disease
of the newborn; maternal or infant supplementation is insufficient to provide protection.” Alicia
Armeli and I will be representing the con side of this debate.
Vitamin K deficiency bleeding (formerly known as hemorrhagic disease of the newborn,
HDN) comprises early (0-24hours), classic (1-7 days) and late (2-12 weeks) syndromes
according to the time of presentation (2). VKDB is a coagulation disturbance in newborns due to
vitamin K deficiency, which results in bleeding of the brain weeks after birth. As a consequence
of vitamin K deficiency, there is an impaired production of coagulation factors II, VII, IX, X, C
and S by the liver (3.) This debate is a very important topic of discussion not only in the United
States, but also in other developing countries that recommend Vitamin K supplementation soon
after birth. Furthermore, a more controversial debate surrounds the means of administration of
vitamin K prophylaxis. Currently the Food and Nutrition Board, recommends a muscular
injection (IM) of 0.5 to 1mg phylloquinone shortly after birth (4). Studies have shown a
correlation between IM Vitamin K prophylaxis and increased incidence of childhood cancer, as
suggested in a study by Golding in 1992 (5). The finding of an increased incidence of cancer in
children given the intramuscular vitamin K in the neonatal period, suggests that a relative
deficiency in Vitamin K during this critical phase of rapid growth and development may protect
vulnerable tissues from mutagenesis. The protection afforded by oral vitamin K against
hemorrhagic disease does not appear to carry the same risk of inducing malignancy, so it may be
prudent to use oral rather than intramuscular vitamin K (5). The studies we will be referencing
bring up some interesting findings that make this debate noteworthy in terms of why oral vitamin
K prophylaxis in most cases should be affective. This paper will examine the important of
administering an oral K prophylaxis as an acceptable and safe prevention method against VKDB.
1
Selden
We will begin our discussion restating Golding’s position, “The prophylactic benefits
against hemorrhagic disease are unlikely to exceed the potential adverse effects from
intramuscular vitamin K. Since oral vitamin K has major benefits but no obvious adverse effects
this could be the prophylaxis of choice” (5). Golding et al’s initial findings in 1970 surprisingly
discovered the connection between IM vitamin K prophylaxis and childhood cancer. This study
titled, “Factors associated with childhood cancer in a national cohort study”, gathered
information on 16,193 infants delivered in Great Britain in one week during April 1970. The
data was collected by midwives through the first 7 days of life. Of the surveyed population, 33
children developed cancer by the age of 10 in Great Britain. Interestingly, while looking at the
different connections that contributed to the development of childhood cancer, they found that,
the association with vitamin K was unexpected and fitted no prior hypothesis. It’s important that
this association with a certainly useful drug be tested in another series of cases (6). As stated
above in 1992, Golding et al’s research once again confirmed the suspected findings behind the
connection of childhood cancer and vitamin K prophylaxis.
A potential criticism for Golding et al’s original study in 1970 is the method in which
their data was initially and continually collected over a 10-year period. Initially, the midwives
collected information at birth or within 7 days. These children were again checked at ages 5 and
10 by the Child Health and Education Study, however, only 80% at age 5 and 94% at age 10
were successfully contacted, which can speculate room for error. Since this study was conducted
over the course of many years, data could have been lost or incomplete. Children that died had
their death certificates traced and recorded in the study. Although I do acknowledge this
limitation, I believe these findings are significant and paved the way for further research to be
conducted on this subject.
A highly insightful piece of literature by Busfield et al gathered information from over
243 consultant-led maternity units in Great Britain and Northern Ireland. This study compared
the different regimens used to administer vitamin K prophylaxis to newborns. What Busfield et
al discovered is that while IM prophylaxis, if given, provided the best protection (most
efficacious) against VKDB. However, on an intention-to-treat basis (effectiveness), there is no
statistically significant difference between the risks of VKDB after intended IM prophylaxis and
after oral prophylaxis intended to continue beyond a week. In addition, Busfield concludes that a
single 1 mg IM dose of the Cremophor EL preparation of vitamin K provides almost certain
2
Selden
protection against VKDB, but the possibility of an increased risk of childhood leukemia, perhaps
up to 10%, has not been (and probably cannot be) excluded (7). Although their research did point
out the importance of administering IM Vitamin K in preterm babies, Busfield et al’s results
further support why oral administration of Vitamin K prophylaxis is just as effective as IM
Vitamin K prophylaxis, if given beyond a week.
The authors stated a probable limitation within this article; a possibility of a slight
overestimation in the number of births that was recorded by the midwives. Of the 243 units
contacted, 230 (95%) replied, 58 provided their written policy and 38 were re-contacted for
clarification (7). The national statistics offices reported 674,789 births for 2003; an internet
directory of maternity services attributed 40,340 births/ year to the 13 non-responding units and
the cumulative number of reported deliveries was 672,538/ year, so there may have been a slight
over-estimation of births from the reporting units. Hence, the possibility of human error in any
research situation is expected. It is however still important to note the continued findings
suggesting an increased risk of childhood leukemia, and that the association between childhood
leukemia and IM prophylaxis cannot be disproven.
Cornelissen al et, established how oral vitamin K prophylaxis can be done with a very
high prevention rating if it is administered in correct doses and quite often. This supportive
article compared and contrasted the oral administration of vitamin K in 4 different countries.
The British Pediatric Association drew up the methods of this study; it was designed for the
pediatricians to provide data on the incidence of VKDB monthly in report cards completed by
the Netherlands, Germany, Australia, and Switzerland. Birth populations were recorded as
follows: Netherlands 439,000, Germany 1,200,000, Australia 325,000, and Switzerland at
83,000. The results showed that when using oral vitamin K prophylaxis, the Netherlands had the
least number of VKBD cases developed (1.1 total incidence). During the time of the study,
breast-fed “well babies” were recommended 1mg vitamin K prophylaxis at birth and .25mg oral
supplementation daily from week 1 to week 13, and breast-fed “unwell babies” were urged to
receive 1mg IM at birth, and .25mg daily after. Switzerland, Germany, and Austria reported a
total incidence of VKBD ranging from 2.5-4.7 per 100,000 live births (8). Again the
Netherlands recommends IM prophylaxis supplementation of vitamin K only for “unwell babies”
and thus has a low incidence rate of 1.1 VKDB confirming that oral vitamin K supplementation
3
Selden
can be effective if done correctly and with follow-through on the recommended dosages after
birth.
Cornelissen al et notes an important limitation to this study – that the comparison of
different oral vitamin K prophylaxis schedules is difficult to measure, and thus these results can
only be used to generate hypotheses, and should be further tested in randomized controlled trails
(8). Furthermore, these trials would be costly and require a larger sample of 700,000 children
taking different preparations and different doses. Thus, such a trail would be logically difficult
and extremely expensive. Unfortunately collecting data on such a large population, and in
different countries can be straining. However this study, like the preceding ones, further helps
understand how effective different methods of oral vitamin K prophylaxis are in the bigger
picture of this debate.
On the opposing side of this debate, an article that supports IM prophylaxis
administration, by Fear et al, notes that oral prophylaxis may not be as effective in terms of
absorbency. The efficacy of oral vitamin K is less certain as there is a recognized problem of
absorption in some babies, and additional difficulties in compliance with multi-dose regimens (9)
In addition this study also notes that even though Golding in 1992 raised reports of a connection
with childhood leukemia, since then most research has failed to find any statistically significant
associations. This study was a population based case-control study (The united Kingdom
Childhood Cancer Study), which studied 2530 cases, and 4487 controls (after exclusions were
considered). Overall 39% of cases and 42% of controls were recorded as having received IM
vitamin K shortly after birth. Children aged 0-14 years, residents in the UK and diagnosed with
pathologically confirmed malignancy between 1992 and 1996 were eligible for the inclusion (9).
Fear al et, found no evidence of an association between IM vitamin K and childhood cancer in
general, or leukemia in particular. With 2530 cases of cancer, over a thousand of which were
leukemia and 4487 controls, this is the most comprehensive study of its kind to have been
reported on the topic (9).
Although Fear et al summarizes some interesting findings, especially on that fact the
study was completed with such a large sample number, we still argue that there is room for bias
or incorrect results. The design of this study looked at five groups: A written report of having
received vitamin K by IM route, a written report of having received vitamin K orally, a written
route having received vitamin K but with an unknown route, a written record stating that have
4
Selden
not received vitamin K, and no written information or given regarding vitamin K administration.
The generalized nature of this coupled with the fact that cases born in smaller maternity units
were more likely than cases born in larger units to have no written record of administration,
suggests that a chance of bias could have played a role in this result (9). Hence, the results
stating that there is no statistically significant connection with IM vitamin K prophylaxis and
childhood leukemia is misleading. We would like to see a further scientific study with clearer
and less biased results.
A final study we looked at, Pereira et al, which examined both IM and oral vitamin K
prophylaxis, compared 44 infants that already had conjugated hyperbilirubinaemia over an 18month period. An oral dose of 2mg or 1mg IM was administered and serum concentration of
vitamin K and undercarboxylated prothrombin (PIVKA-II, a sensitive functional indicator of
vitamin K status) was measured both before the prophylaxis and 6 hours after the prophylaxis
was given. At administration, 18 infants (41%) had elevated levels of serum PIVKA-II and
eight (18%) had low vitamin K concentrations, indicative of a vitamin K deficiency. Medium
serum vitamin K concentrations were similar in the oral intravenous groups at baseline. Using
statistical analysis, following 6 hours after administration of IM vitamin K prophylaxis, serum
vitamin K levels raised from baseline (0.92 v 1.15 ng/ml) to 139 ng/ml versus only rising to
1.4ng/ml after oral administration, which is extremely low in comparison to the IM group (10).
In addition this study observed that cholestatic infants have impaired and erratic intestinal
absorption, thus IM vitamin K administration would be the most appropriate means to preventing
VKDB.
We question that Pereira et al, is generalizing the results of the IM vitamin K prophylaxis
to such a small and specific population group. Only 44 infants were measured in a small
geography area (King’s college in the UK), and in infants who are already suffering from
conjugated hyperbilirubinaemia. Furthermore, this study did not take into consideration that a
wide range of infants aged 1-26 weeks, might have already had vitamin K prophylaxis given to
them at birth, which is a common practice in UK (10). We feel these results are significant and
should be considered when treating infants with liver disease or any other high-risk preterm
infants. Yes, IM vitamin K would be the best method to treat or prevent VKDB because it
provides a fast administration of Vitamin K and increases Vitamin K plasma levels in a short
amount of time, which is needed with severely ill infants. However, we cannot place a
5
Selden
generalized label that IM vitamin K prophylaxis is most affective when administered IM versus
orally. There are just too many other elements to consider that was left out of this study.
The con side would like to stand by our position- that intramuscular vitamin K
prophylaxis is not necessary in preventing the development of VKDB and that oral
supplementation along with daily routine vitamin K administration is sufficient in providing
protection. Furthermore, we agree that parents need to be aware and able to commit to daily
administration and following through on a long and costly oral regimen to provide the best
protection possible. Besides the connection with childhood leukemia, other safety concerns for
IM prophylaxis include the recurring problem of injecting uterogenics rather than vitamin K and
the complications associated with any IM injection (vessel or nerve injury, infection, and
hemorrhage in infants with bleeding disorders). While for oral prophylaxis there have been only
three case reports of aspiration pneumonia and a single report of a possible allergic skin reaction
(7). In circumstances of unhealthy or preterm infants, the con side does support the use of 0.51mg IM vitamin K prophylaxis at birth, especially in incidences of liver failure. Above all, there
is far more research that needs to be completed on this matter before the US can recommend an
appropriate dose and means of administration of vitamin K to infants for prevention of VKDB.
Furthermore, we also have to acknowledge that we may be recommending a regimen that we just
don’t know enough about. The research the con side has completed would not refute that there is
a great deal of support of administering intramuscular Vitamin K prophylaxis and would not
deny the benefits of it. Today our job is to look at the opposing side of this important issue. It is
our hope that the evidence noted in this paper not be disregarded.
6
Selden
References
1. S Sareen, Jack L, and James L. Advanced nutrition and human metabolism. 5. Belmont, CA:
Wadsworth Pub Co, 2009. 415. Print.
2. Tandoi, F, Mosca F, Agosti M. Vitamin K Prophylaxis: leaving the old route for the new one?
Acta Paediatrica. 2005: 94 (suppl 449): 125-128
3. Wikipedia, Haemorrhagic disease of the newborn. Wikipedia The Free Encyclopedia.
www.wikipedia.org. Last revised April 6, 2011. Accessed January 25, 2012.
4. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes. Washington,
DC. National Academy Press, 2001, pp.162-96.
5. Golding J, Greenwood R, Birmingham K, Mott M. Childhood cancer, intramuscular vitamin
K and pethidinegiven during labour. BMJ. 1992; (305): 341-346.
6. Golding J, Paterson M, Kinlen, LI. Factors associated with childhood cancer in a national
cohort study. British Journal of Cancer: 1990: 62: 304-308
7. Busfield A, McNinch A, Tripp J. Neonatal vitamin K prophylaxis in Great Britain and
Ireland: the impact of perceived risk and product licensing on effectiveness. Archives of Disease
in Childhood: September 2007; 92(9): 754-758.
8. Cornelissen M, von Kries R, Loughnan P, Schubiger G. Prevention of vitamin K deficiency
bleeding: efficacy of different multiple dose oral dose schedules of vitamin K. Neonatology.
1997; (156): 126-30.
7
Selden
9. Fear, N T, Roman E, Ansell P et al. Vitamin K and childhood cancer: a report from the
United Kingdom Childhood Cancer Study. British Journal of Cancer. October 6, 2003; 89(7):
1228-1231
10. Pereira SP, Shearer MJ, Williams R, Mieli-Vergani G. Intestinal absorption of mixed
micellular phylloquinone (vitamin K) is unreliable in infants with conjugated
hyperbillirubinaemia: implications for oral prophylaxis of vitamin K deficiency bleeding.
Archives of Disease in Childhood: Fetal and Neonatal Ed. March 2003; 88 (2): F113-F118.
8