Per Wikipedia: “Vitamin K is a group of structurally similar, fat-soluble vitamins that the human body requires for complete synthesis of certain proteins that are prerequisites for blood coagulation (K from Koagulation, German for “coagulation”) and which the body also needs for controlling binding of calcium in bones and other tissues. The vitamin K-related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Preliminary clinical research indicates that deficiency of vitamin K may weaken bones, potentially leading to osteoporosis, and may promote calcification of arteries and other soft tissues.
“Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) derivatives. Vitamin K includes two natural vitamers: vitamin K1 and vitamin K2. Vitamin K2, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms.
“Vitamin K1, also known as phylloquinone, is made by plants, and is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis. It may be thought of as the plant form of vitamin K. It is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K2.”
Per Wikipedia: “Haemorrhagic disease of the newborn, also known as vitamin K deficiency bleeding (VKDB), is a coagulation disturbance in newborn infants due to vitamin K deficiency. As a consequence of vitamin K deficiency there is an impaired production of coagulation factors II, VII, IX, X, protein C and protein S by the liver, resulting in excessive bleeding (hemorrhage).”
Per the CDC: “Since babies can be affected until they are 6 months old, healthcare providers divide VKDB into three types; early, classical and late. The chart below helps explain these three different types.
- Early and classical VKDB are more common, occurring in 1 in 60 to 1 in 250 newborns, although the risk is much higher for early VKDB among those infants whose mothers used certain medications during the pregnancy.
- Late VKDB is rarer, occurring in 1 in 14,000 to 1 in 25,000 infants.
- Infants who do not receive a vitamin K shot at birth are 81 times more likely to develop late VKDB than infants who do receive a vitamin K shot at birth.”
Shall we examine this further? A clip from that CDC page:
The early form of VKDB is mainly in mothers taking certain medications. Not listed are anticoagulant medications which also cause a significant percentage of early bleeding events. Unlisted under “classical” is the number one manifestation of this form of VKDB: circumcision complications. The characteristics listed for late VKDB are deliberately misleading:
- The “30%-60%” figure is of the 1 in 14,000-25,000 listed earlier in the page. The “81 times more likely” figure uses those reference figures (the calculation is based on a large number of assumptions, but that is irrelevant to our discussion: it is without question that children who are given prophylactic vitamin K at birth have lower incidence rates of VKDB) and increases the odds. In other words, they are stating that theoretically the odds are lowered to 1 in 1-2 million.
- That it tends to have a higher incidence in exclusively breastfed infants is without question. That a vitamin K shot is the only option is absolutely false.
- Warning bleeds are not rare. Unfortunately, parents are ill-equipped to recognize these signs and they usually go unnoticed until serious damage (which often becomes permanent) occurs.
If vitamin K is of demonstrable benefit, where is the controversy?
According to Patient Safety and Quality: An Evidence-Based Handbook for Nurses, there are five rights of drug administration that must be considered for any drug given. These are as follows:
- Ensure you have the right patient
- Ensure you’re using the right drug
- Ensure you’re doing it at the right time
- Ensure you’re using the right route (oral, IV, IM, etc.)
- Ensure you’re administering the right dose
None of these measures are controversial, and are taught to all nurses as a means of preventing medical errors. The controversy involved with intramuscular vitamin K injections is that many parents, healthcare professionals, and research scientists consider the IM injections to fail the test due to incorrect dose, incorrect route, and incorrect drug.
As pointed out by Wikipedia, there are differences between different forms of vitamin K. Phylloquinone (also known as phytomenadione) is the natural form of vitamin K1, whereas phytonadione is a synthetic form of vitamin K1 that isn’t necessarily molecularly identical to phylloquinone. There has been little to no research done related to differences in bioavailability between the two forms, and as such we are not qualified to pass judgment on which form is better for infants and children. What we do know is that approximately 80% of phylloquinone is absorbed in the gut and used in the formation of clotting factors.
According to the National Institute of Health, the recommended daily dose of vitamin K for infants ages 0-6 months is 2 mcg. AquaMEPHYTON, the drug commonly injected into children, is given in a 0.5-1 mg dose: 250-500 times the recommendation of the NIH. This difference in dose is a common point of concern for those that question the wisdom of IM vitamin K administration.
The question of route is a complicated one. When you review the product insert for AquaMEPHYTON and other parenteral vitamin K medications, you find a black box warning like the following (courtesy of the FDA):
Due to the small size of infants and the variability of their fat layers, it is not safe to attempt to give the vitamin K injection subcutaneously (under the fat layer), and it is exclusively done intramuscularly, which is specifically what this black box warning warns against.
If we continue reading the insert, we find the following statements:
- “Hemolysis, jaundice, and hyperbilirubinemia in newborns, particularly in premature infants, may be related to the dose of AquaMEPHYTON. Therefore, the recommended dose should not be exceeded (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).”
- “Deaths have occurred after intravenous and intramuscular administration. (See Box Warning.)”
- “The possibility of allergic sensitivity, including an anaphylactoid reaction, should be kept in mind.”
- AquaMEPHYTON injection is a yellow, sterile, aqueous colloidal solution of vitamin K1, with a pH of 5.0 to 7.0, available for injection by the intravenous, intramuscular, and subcutaneous routes. Each milliliter contains: Phytonadione (2 mg or 10 mg); Inactive ingredients: Polyoxyethylated fatty acid derivative (70 mg), Dextrose (37.5 mg), Water for Injection, q.s. (1 mL); Added as preservative: Benzyl alcohol (0.9%)
- “Benzyl alcohol as a preservative has been associated with toxicity in newborns.”
In comparison, oral vitamin K from natural sources suffer none of the above risks, excepting cases where the child is allergic or sensitive to the specific source of the vitamin K (i.e. avocado allergy, if avocados are the food-based source of vitamin K).
It should be noted that while current medical “wisdom” states that overdosing infants with vitamin K is harmless, the medical community has long known this wasn’t the case. Vitamin K is notorious for failing to pass through the placenta in sufficient quantities, but in this study, it was demonstrated that even administration of parenteral vitamin K to the mother during pregnancy was sufficient to cause hyperbilirubinemia (extreme jaundice that can lead to brain damage) in their infants when they’re born.
“Seven cases of marked hyperbilirubinemia occurring among premature infants within the first 40 to 72 hours of life are reported. The mothers of these infants had received 72 mg of a vitamin K analogue (Hykinone®) intramuscularly or intravencusly from 2 to 112 hours prior to delivery. The evidence presented indicates that this medication predisposed the infants to hyperbilirubinemia.”
In the US, the only approved source of vitamin K for infants is IM injection: all medically approved oral products that are available in other countries have been banned from the market. Often, claims are made that oral supplementation isn’t as reliable or safe as IM vitamin K, and this is true in one specific case: if the infant has liver failure or biliary insufficiency (an extremely rare complication), they may not be able to sufficiently absorb oral vitamin K. On the other hand, hypersupplementation of vitamin K parenterally can cause these issues (the cause of hyperbilirubinemia listed in the product insert referenced above).
Many comparison studies have been done between oral and parenteral vitamin K in infants, and many countries have different recommendations for oral administration regimens leading to different outcomes. Many US-based studies have cherry-picked worst-case statistics to compare IM administration with. We will review them all.
To begin, I’d refer the reader to this study performed in India:
“One hundred term exclusively breast fed babies weighing more than 2.5 kg were evaluated to determine the efficacy of various modes and doses of Vitamin K to prevent hemorrhagic disease of newborn (HDN). The babies were grouped into four categories of 25 each: Group A–1 mg Vitamin K intramuscular (Menadione sodium disulphite) at birth; Group B–0.5 mg Vitamin K intramuscular; Group C–1 mg Vitamin K orally, and group D–no Vitamin K. The prothrombin index was estimated in all babies between 36-72 hours of age. The results revealed a prothrombin index in Groups A, B, C and D as 94.98 +/- 7.64%, 95.08 +/- 9.91%, 92.51 +/- 10.10% and 80.39 +/- 15.90%, respectively. The differences between Groups A, B and C were insignificant. However, Group D, prothrombin index was significantly reduced as compared with the other three groups. It is, therefore, concluded that oral Vitamin K is as effective as injectable Vitamin K and its usage is recommended in our country to reduce complications and costs of parenteral therapy.”
While the terminology may be above the education level of most readers, in this study they tested the specific clotting factors related to vitamin K, as opposed to testing and comparing vitamin K levels themselves: they tested the effect, rather than the cause. As lowering the prothrombin index (the time it takes blood to clot) is the purpose of vitamin K administration, this becomes extremely relevant.
In a 1997 study of multiple oral and IM dosing regimens in different countries, Cornellisen et al. compiled the following data:
It should be noted that the results in the Netherlands are similar to the statistics in the US using IM prophylaxis. One common problem, widely recognized by healthcare providers, is that compliance is a problem in the patient population. Not all parents strictly adhere to dosing schedules, forgetting or neglecting to administer medication as ordered by their provider. In examining the wide variability in outcomes between the surveyed nations, it can be safely assumed that much of this difference can be attributed to cultural attitudes towards medical compliance.
These statistics also highlight a risk factor that parents should be aware of: VKDB is most common in infants of Southeast Asian heritage. While no causal factor has been identified, the risk for this population group is widely assumed to be greater than 1 in 6000 (in the Thai results, the figure was greater than 1 in 1500).
In the US, where there is no approved oral vitamin K for prophylactic purposes, does this leave parents with a choice between accepting IM prophylaxis or going without? The official answer is yes, but the actual answer is no. While not FDA approved for prophylactic purposes, many parent administer Biotics Research Bio-K-Mulsion© to their infants in place of the IM vitamin K by putting a few drops of the solution on their (washed) finger or on a pacifier and letting their infant suck it off. Doing this daily for the first 13 weeks is the equivalent of the regimen used in the Netherlands. Parents should be warned that often, healthcare providers will not allow this to be administered in a hospital setting, and presenting this medication to staff or announcing that you intend to use it will result in its confiscation.
We didn’t opt to have IM vitamin K administered to our children, instead using an oral supplement. This may not be the best choice for everyone, and therefore we can not give this option our recommendation. Under no circumstances do we consider refusing prophylactic vitamin K administration an acceptable option: while the risks or VKDB in most populations aren’t especially high, it is truly an unnecessary risk when a single $25 bottle of vitamins or injection from your provider can almost completely negate it. We are bit aware if any research that shows that IM administration is inherently more risky than refusing prophylaxis, but given the information above, we believe that IM administration is inherently more risky than fully-compliant adherence to the Dutch oral administration schedule. It should be noted that in some states, parents are compelled by law to allow their children to be administered IM vitamin K. In many others, healthcare providers will claim this is the case even though it is not. If you choose to go with oral supplementation—and are sure that you’re going to reliably administer it without fail—then you should carefully review the law in your state to ensure you’re in compliance and notify your pediatrician of your decision so it can be noted in your child’s chart.