Newborn Vitamin K Prophylaxis: A Historical Perspective to Understand Modern Barriers to Uptake

Vitamin K: Discovery

The history of vitamin K dates back to 1929, when the Danish biochemist Henrik Dam (1895–1976) observed that chicks fed fat- and cholesterol-free diets developed subcutaneous and muscular hemorrhages.² He subsequently proposed that this fat-soluble active compound was different from the other known fat-soluble vitamins A, D, and E, and that this new anti-hemorrhagic factor should be named vitamin K (in reference to koagulation from the German and Scandinavian languages).³

Subsequently, in the early 1940s, Edward Doisy confirmed the structure and identity of the 2 naturally occurring forms of vitamin K, phylloquinone (vitamin K1) and menaquinone (vitamin K2; Fig 1).^4,5 For these discoveries, Dam² and Doisy were awarded the Nobel Prize in Physiology or Medicine (1943).³

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FIGURE 1

Chemical structures of phylloquinone, menaquinone-n, MK-4, and menadione. Adapted from MacCorquodale DW, Binkley SB, Thayer SA, Doisy EA. On the constitution of vitamin K1. J Am Chem Soc. 1939;61(7):1928–1929.

Vkdb

Vitamin K is found predominantly in green, leafy vegetables and plays a role in photosynthesis. In humans, it is a cofactor for some proteins involved in bone mineralization,⁶ but primarily it is essential for the activity of several carboxylase enzymes within hepatic cells and the activation of the vitamin K–dependent coagulation factors VII, IX, X, and prothrombin. Therefore, deficiency can lead to an increased bleeding risk. This is a particular issue in newborns because they have naturally low levels of vitamin K, ∼40% to 60% of normal adult values. These values slowly increase, and we attain adult values by 6 months of age.^7,8 Contributing factors for these low levels include the following: relatively poor placental transport of vitamin K; delays in the acquisition of vitamin K–producing gut microflora (such as Bacteroides fragilis)⁹; and insufficient intake, given that breast milk levels of vitamin K are low (as opposed to fortified formula) irrespective of maternal diet.

Rarely, an infant’s relative and transient deficiency in vitamin K can lead to VKDB. This issue was first clinically appreciated in the 1930s, and it led to the experimental administration of oral vitamin K to infants with anemia and hemorrhage.¹⁰ By the 1940s, prophylactic treatment of newborns to prevent hemorrhage was being studied, as led by Jorgen Lehmann¹¹ from Sweden. He compared oral doses of 0.5 mg to up to 5 mg as well as oral doses with intramuscular (IM) administration. Lehmann concluded in these studies that 0.5 mg of oral vitamin K was as effective as a 5 mg dose, and oral and IM administration resulted in similar reductions in deaths due to hemorrhage. After this, all newborns at the women’s clinic of Sahlgrenska Hospital were treated with vitamin K to prevent hypoprothrombinemia and hemorrhagic disease of the newborn.¹¹ Lehmann also concluded in his studies that the optimal dose of vitamin K for prophylactic treatments of newborns was 0.5 to 1 mg,¹¹ the dose that 78 years later we still use.

A similar policy was soon widely adopted elsewhere, although many were unable to replicate his findings.¹² The argument, as Ethel Dunham¹³ put it in 1948, was that “since the vitamin does no harm and may do good, it is probably best to give it to all premature infants immediately after birth.” When a 1 mg dose did not stop some infants from bleeding (likely because of other causes), physicians started using larger doses. This practice was eventually put to a halt when researchers in 1956 established that these high doses (>5 mg/day) could lead to hemolysis, severe jaundice, and kernicterus.¹⁴ By the 1950s, the water-soluble product (Synkavit) started replacing the fat-soluble, natural plant form of vitamin K. This product was suggested to not cause hemolysis,¹⁵ and it has since dominated European and American markets.

In 1985, Lane and Hathaway¹⁶ further categorized VKDB into the following 3 common patterns: early, classic, and late. These are still widely accepted and used today (Table 1).¹⁷ Several countries participating in surveillance programs for VKDB, including the Netherlands, Germany, Australia, and Switzerland, have subsequently agreed on standardized case definitions of VKDB to allow for international comparison (Table 2).¹⁸

After the Swedish experiments of the 1940s, it was not until 1961 that the American Academy of Pediatrics first recommended IM vitamin K prophylaxis immediately after birth for all newborns.¹⁹ Now, nearly all developed countries have implemented vitamin K prophylaxis programs, usually recommending 1 mg of IM vitamin K (Konakion MM) at birth or 0.5 mg in preterm infants. If parents decline an IM injection, an alternative option is 2 mg of Konakion MM orally at birth and again at 3 to 5 days, followed by an additional dose at 4 to 6 weeks of age.²⁰ This option is likely less effective than IM²¹ and certainly more complicated. Because of this efficacy issue (as well as availability), the American Academy of Pediatrics, in contrast to some countries, still does not have a policy statement on the use of oral prophylaxis.²²

Minimal international data on adherence rates to vitamin K prophylaxis are available, with only single region data from New Zealand, Australia, and Canada published. Data from a single tertiary birthing unit in Otago, New Zealand revealed a 92.9% rate of IM prophylaxis and a 5.4% rate of oral prophylaxis, with 1.7% declining any prophylaxis.²³ In New Zealand, there is also evidence that oral vitamin K may be becoming more popular, with its use potentially more than doubling since 2008.²⁴ Data from New South Wales, Australia, revealed a higher rate of IM prophylaxis than New Zealand at 96.3%, with only 2.6% opting for oral prophylaxis and 1.2% declining any prophylaxis.²⁵ The highest uptake reported is from Alberta, Canada, with IM prophylaxis at 99.3% and oral prophylaxis at 0.4%, with only 0.3% declining.²⁶

The Emergence of Barriers to Vitamin K Prophylaxis

Why parents would refuse this apparently safe and effective medical intervention often puzzles us as health professionals. Gaining an increased understanding of barriers to adherence and their origins is therefore essential, and it allows us to continue to promote vitamin K and fully participate in the VKDB debate. However, addressing these barriers can be challenging because it often requires us to combine professional views about child welfare with an appropriate respect for parental autonomy. Achieving an appropriate balance between these 2 issues is essential because parents who perceive health professionals as overly coercive or manipulative may disengage not only with vitamin K prophylaxis but also with other subsequent medical services.²⁷ Therefore, we detail in the following paragraphs the known barriers to vitamin K prophylaxis and how these have evolved over time.

As with any medical intervention, vitamin K prophylaxis has both potential benefits and risks, with concerns based on child welfare issues raised by researchers as potential barriers to adherence in several recent studies.^28,29 The most important and prominent of these concerns was the association of vitamin K prophylaxis with childhood leukemia. This has its origins in a 1990 study published by Golding et al³⁰ in the British Journal of Cancer, in which the authors examined factors associated with childhood cancer and found an unexpected association with vitamin K administration. Little was made of this finding until 2 years later, when Golding et al’s³⁰ findings gained more traction in the media.³¹ After this attention, researchers in another study published in 1992 reported that the odds of leukemia in children given IM vitamin K at birth were almost doubled (odds ratio 1.97), but they noted no increased risk when it was given orally.³² In response, the British Pediatric Association recommended the routine use of oral vitamin K prophylaxis in healthy newborns, with IM prophylaxis reserved for those thought to be at a particularly high risk of VKDB.³³ Not surprisingly, this led to a subsequent decrease in the use of IM prophylaxis in Britain, with a rate of 58% IM use in 1988 falling to 38% in 1993.³³

Golding et al’s³⁰ study was the catalyst for further studies in numerous countries in which researchers tested this association between vitamin K and cancer. In 1999, a working group of the World Health Organization’s International Agency for Research on Cancer reviewed the available literature and concluded that there was “inadequate evidence in humans and experimental animals for the carcinogenicity of vitamin K substances.”³⁴ In 2002, Roman et al³⁵ combined data from 6 major case-control studies. In total, 2431 children with cancer and 6338 children without cancer were included, with the authors concluding that the “analysis provides no convincing evidence that intramuscular vitamin K is associated with childhood leukaemia.” In 2003, Fear et al³⁶ published additional data, which included 2530 children with cancer (1174 of whom had leukemia) and 4487 children without cancer. Again, the authors of this study concluded “that there is no convincing evidence that neonatal vitamin K administration, irrespective of the route by which it is given, influences the risk of children developing leukaemia or any other cancer.” Although these fears surrounding leukemia and IM vitamin K have eased since Golding et al’s^30,32 original articles, recently published studies have revealed that some health professionals and parents maintain concerns that prophylaxis may be associated with cancer.^37,38 This reveals how influential previously refuted data can be, and the vitamin K–leukemia story strongly parallels the ongoing fears and misconceptions seen between autism and the vaccination of measles, mumps, and rubella.

Likely stemming from the above cancer concerns, other, less specific concerns regarding possible side effects have more recently been raised. These include nonspecific fears that ingredients in the injection are synthetic and/or toxic and the impression that the dose of vitamin K may be excessive and therefore harmful.^28,29 Some parents and health professionals have also questioned the efficacy of and actual need for vitamin K prophylaxis. In 1 study, a parent stated, “For us it was the risks from Vitamin K were higher because he was such a normal, easy birth,”²⁹ which was paralleled by findings from Gosai et al³⁷ in which 45% of midwives felt only those who were “at risk” should receive prophylaxis.

Parental fears of perceived infant pain also appear to be a strong driver toward opting for oral vitamin K as opposed to the recommended IM route. Again, this parallels parental fears seen in the context of pediatric immunization³⁹ and newborn screening.⁴⁰ Parental fears of newborn pain may be 1 possible contributing factor in an association linking Asian and Indian ethnicities to increased uses of oral vitamin K,²³ a speculation supported by Asian and Indian parent responses in a recent qualitative study in which researchers examine why parents decline vitamin K for their newborns.²⁹

Researchers in recent literature have identified instances in which parental beliefs and values were incompatible with the use of vitamin K for reasons such as a strong identity with an alternative lifestyle, a belief that birth is a natural process that needs little interference, or religious or evolutionary values. These factors have all been linked to vitamin K refusal and are some of the hardest barriers to counteract,^29,41 contrasting with the above issues regarding pain or cancer, which, if adequately addressed, may lead to parental reassurance. The following factors aligned to a parental wish for a natural birth process or less medicalization have also been linked to parental refusal of IM vitamin K: having a vaginal delivery, delivery in a birth center as opposed to a hospital, greater gestational age, and having a planned home birth.^23,25 These infants are also more likely to have older mothers and analgesia-free deliveries.²⁵ In a recent study, up to 36% of parents who refused vitamin K prophylaxis quoted the reason for their refusal as being the desire to have a natural birthing process.²⁸ Researchers in 2 additional studies have also noted that a minority of parents and midwives promote the use of maternal diets to increase vitamin K levels in human breast milk^28,37 despite evidence that human milk does not contain enough vitamin K to be protective against VKDB.^25,42 In addition to the above, declining vitamin K prophylaxis has been associated with parents who identify as anticonformist or who are questioning of mainstream medicine.²⁹ These beliefs are also associated with refusals of other related public health initiatives such as immunization,^25,26,41,43 newborn screening,²⁹ and erythromycin eye drops.⁴¹ Again, these beliefs are extremely hard to shift, with the majority of parents in 1 study unwilling to consider alternative, scientifically accurate information and remaining steadfast in their decision to decline.²⁸ When information is made available, consistency in message and the need for availability in multiple languages have also been identified as potential aids to uptake.⁴⁴

Family pressure and choices made by other pregnant women in the social circles of parents may also be barriers to vitamin K.²⁹ These psychosocial factors as well as inaccurate media portrayal²⁹ have all been shown to have an effect on subsequent parental decision-making. A lack of awareness of the possibility for intracranial hemorrhage or death is also present.^28,45 Ensuring awareness of the serious risks appears essential, with researchers in a recent study from the United States finding that >69% of parents cited a lack of awareness of importance as a reason for vitamin K prophylaxis refusal.⁴⁶

Interestingly, there are also health professional factors associated with refusals of vitamin K prophylaxis. In a recent study in which researchers examined health professionals’ attitudes toward vitamin K prophylaxis in New Zealand, it was found that 100% of the doctors surveyed thought vitamin K should be given to all infants, compared with 55% of the surveyed midwives.³⁷ In addition, 26% of midwives in this study reported that they would not give vitamin K to their own children, and they highlighted personal concerns about safety and interference in the natural birth process.³⁷ This finding is supported by data from a Canadian study in which births attended by midwives were 8 times more likely to be associated with vitamin K refusal compared with physician-attended deliveries (risk ratio, 8.4).²⁶ These persisting fears from a minority of health professionals are particularly concerning because these sorts of negative views may also influence subsequent immunization uptake.⁴¹