Increasing the dose of oral vitamin K prophylaxis and its effect on bleeding risk

Vitamin K prophylaxis in infancy aims to reduce the risk of vitamin K deficiency bleeding (VKDB), the consequences of which are potentially lethal [14]. Most countries have implemented vitamin K prophylactic regimens, but the route of administration, the dose, the dosing frequency, and the vitamin K formulation differ widely among regimens. The molecular form of vitamin K currently used in the Netherlands and nearly all countries for intramuscular (IM) and oral vitamin K prophylaxis is phylloquinone (vitamin K1). The efficacy of a single dose of 1 mg IM vitamin K1 is firmly established and is associated with a low risk of VKDB of < 0.2/100,000 newborns [12]. However, its efficacy at a population level is currently threatened by an increasing number of parents opting out [9, 10, 15, 16, 28]. On the other hand, a single dose of oral vitamin K1 prophylaxis—while as effective in preventing classical VKDB—is associated with a much higher risk of late VKDB (roughly 4–7/100,000) [27], which is predominantly manifested by intracranial hemorrhage [20].

The vast majority of prophylactic failures occur in breastfed infants with malabsorption of vitamin K, mostly due to cholestasis [17]. Unfortunately, malabsorption often only becomes apparent after bleeding has occurred. A prophylactic regimen should therefore allow protection for all infants, including those with unrecognized cholestatic liver disease.

By using targeted surveillance of infants with biliary atresia, it was previously shown that a weekly oral dose of 1 mg vitamin K offered a protection similar to IM administration in infants with cholestasis [23]. In contrast, a daily dose of 25 μg (0.175 mg weekly) was associated with a much higher risk in breastfed infants with biliary atresia and a much higher incidence of late VKDB of ~ 2.1 per 100,000 [23, 25]. To address this, the Dutch prophylactic dose was increased sixfold, from 25 daily to 150 μg daily (1.050 mg weekly) for all breastfed infants in February 2011 [4].

A recent study in patients with biliary atresia questioned the efficacy of this new regimen and suggested that the risk had remained unchanged [29]. The aim of this study is to determine the consequences of a sixfold increase in the oral prophylactic vitamin K dose (150 μg) on the overall incidence of late VKDB and late intracranial VKDB in the Netherlands in comparison with the former oral prophylactic dose of 25 μg.

In this study, we exploited two independent nationwide surveillance strategies to determine the effect of a sixfold dose increase of oral vitamin K prophylaxis on the incidence of intracranial hemorrhages due to VKD and showed that the incidence of late intracranial VKDB was modestly reduced after introduction of the revised regimen. However, the protection obtained by this sixfold dose increase is limited in comparison with the excellent protection offered by a single dose of IM vitamin K after birth [12] and is unexpectedly lower than a regimen previously used in Denmark with the same cumulative weekly dose of vitamin K [23]. This discrepancy strongly suggests that factors other than the dose must play an important role. Compliance issues with the daily regimen might contribute to poor protection; however, this was the case in only 2 infants for the revised regimen, and previous investigations indicate compliance is generally adequate [21]. Improved fractional absorption of one larger dosage compared with multiple smaller dosages has been suggested, although evidence is currently lacking [29]. Alternatively, the formulation in which vitamin K is administered could be an explanation. Dutch oral vitamin K is dissolved in arachnid oil, the hydrophobic nature of which is likely to impede absorption in infants with suboptimal bile flow. In several countries with oral vitamin K regimens, vitamin K is administered through Konakion® mixed micelles (MM) which more closely resembles the situation in the gut. However, even this formulation does not fully prevent VKDB in infants with cholestasis due to impaired intestinal absorption [26], likely due to micellar decomposition in the stomach as a consequence of low pH [22]. A recent study describes a new formulation of vitamin K prophylaxis which circumvents gastric micellar decomposition and therefore might be a promising oral form of prophylaxis for infants with suboptimal bile flow [19].

The present study underlines the usefulness of pediatric intensive care registries in assessing the efficacy of national regimens of vitamin K prophylaxis. First, this study confirms that this targeted approach is associated with higher retrieval rates as compared with general surveillance studies [25]. Higher retrieval decreases the risk that differences in calculated incidences are due to variations in retrieval rate rather than changes in the true incidence. It is important to take the higher retrieval rate, thus higher incidences, into account when comparing incidences obtained from general surveillance with those obtained using targeted surveillance. Second, the detailed information regarding timing of events allowed us to calculate the time between events. The latter made it possible to attach statistical significance to the lower incidence of late intracranial VKDB after the change of regimen. We expect this measure to be helpful to assess the efficacy of upcoming prophylactic regimens. Virtually, all patients who develop VKDB despite prophylaxis have evidence of impaired bile flow, highlighting the importance of this risk factor. Of note, in some patients, bile flow is not completely obstructed, and therefore they do not fulfill commonly used criteria for cholestasis [23]. The inability of the 150-μg regimen to protect infants with cholestasis against VKDB has led to a recent advice by the Dutch Health Council to switch from the oral daily 150-μg regimen to a single dose of IM vitamin K prophylaxis at birth [5].

There is limited recent data of incidences of late VKDB in other countries with oral prophylactic regimens; in addition, prophylactic regimens may vary within countries. The lowest oral dosing regimen of 3 × 1 mg has been accompanied by the highest incidences of late VKDB (1.3 and 1.5 per 100,000 in Germany and Australia, respectively, for the years 1993 and 1994). An oral dosing regimen of 2 × 2 mg vitamin K in Switzerland resulted in an incidence of 1.2 per 100,000 for 1995–2002. For a dosing regimen of 3 × 2 mg, incidences varied from 0.4 to 0.8 per 100,000 in 1995–2001 (Germany), 0.43 per 100,000 (UK), and 0.87 per 100,000 since 2003 (Switzerland). The lowest incidence of late VKDB under oral vitamin K prophylaxis has been described in Denmark: 0.0 per 100,000 in 1992–2000 (2 mg vitamin K at birth, followed by 1 mg weekly for 3 months). However, Denmark switched to IM vitamin K administration in 2000 due to a lack of a licensed product. For countries with IM prophylaxis, lower incidences of 0.37 per 100,000 (Canada), 0.16 per 100,000 (New Zealand), and 0.1 per 100,000 (UK, 1 mg IM vitamin K at birth, 3 × 1 mg orally) have been described [11, 12]. Based on this superior efficacy, the NICE guidelines of 2015 recommend IM vitamin K prophylaxis for all newborns to prevent VKDB [13].

Despite its efficacy, IM administration of vitamin K increasingly encounters resistance from parents [9]. Reasons for concern include exposure of the baby to toxic ingredients, excessive dose and side effects, the fear of an, although not substantiated [7], association with cancer, and the painful injections. Inadequate information during the antenatal period about the importance of vitamin K prophylaxis can also be a reason for refusal: parents consider vitamin K unphysiological and therefore gratuitous in uncomplicated birth [16, 28]. Risk factors for parental refusal of IM vitamin K administration were previously described [9, 15]. Vitamin K refusal was more likely to be associated with planned home delivery and midwife-assisted deliveries than hospital delivery and delivery by a physician. In the Netherlands, a substantial part of newborns is delivered at home (18.4% vs. 80.7% in a hospital vs. 0.9% elsewhere) [3] and could consequently be at risk of parental IM vitamin K refusal. Proper counseling, especially during the antenatal period, is therefore of great importance. If parents persist and refuse to have their child injected, the Dutch Health Council presently recommends an oral alternative, namely, 3 doses of 2 mg vitamin K (at birth, after 4–6 days and 4–6 weeks) for breastfed infants [5], based on a Swiss study [8]. The NICE guidelines also recommend oral vitamin K as a second-line option in case of parental decline, although dose and dosage frequency are not specified [13].

There are some limitations to this study. It is possible that some cases with intracranial VKDB were not admitted to the PICU in case of few symptoms, or died elsewhere and therefore remained unreported. Furthermore, earlier detection of cholestatic liver disease, including biliary atresia, may theoretically decrease the incidence of late VKDB, as these infants are treated with higher vitamin K dosages once diagnosed. However, since there has been no change in the number of registered patients with biliary atresia or the age at diagnosis after introduction of the revised regimen [29], this is not likely to have influenced the results. Finally, targeted surveillance within relevant subpopulations requires the existence of national registries. This in turn demands a substantial and ongoing effort, the importance of which cannot easily be overstated.

In conclusion, a sixfold increase in the oral prophylactic vitamin K dose—from 25 to 150 μg daily—resulted in a significant but relatively modest reduction in the incidence of late intracranial VKDB. However, this protection compares poorly to the efficacy of IM vitamin K prophylaxis, indicating that factors other than the dose should be addressed to further improve oral vitamin K prophylactic regimens.