Vital Measures to Prevent Bleeding from Vitamin K Deficiency

Intramuscular administration of vitamin K for the prevention of vitamin K deficiency bleeding (VKDB) has been a standard of care since the American Academy of Pediatrics recommended it in 1961. Despite the success of preventing VKDB with the administration of vitamin K, the incidence of VKDB appears to be increasing.

This increase in the incidence of VKDB is attributed to parental refusal as well as the lower effectiveness of alternative methods of administration. The objective of this publication is to discuss the current knowledge of VKDB prevention with respect to the term and preterm neonate and to address parental concerns regarding vitamin K administration.

Hemorrhagic disease of the newborn (HDN ) was first described in the literature by Townsend in the late 19th century as an entity, although bleeding in the newborn had been described in detail long before that time.1

The modern era of understanding the importance of vitamin K began when Dam and Doisy received the Nobel Prize in 1943 for their work in identifying and isolating the new vitamin.2 It was not until almost 20 years later that the American Academy of Pediatrics (AAP) published its seminal article on vitamin K and its use in pediatrics.3

This report described HDN as a “bleeding disorder of the first days of life caused by a deficiency of vitamin K and characterized by a deficiency of prothrombin, proconvertin [Factor VII], and probably other factors.” This document also recommended a single parenteral dose of 0.5 to 1.0 mg of vitamin K for all neonates as prophylaxis.

With the identification of the etiology of HDN, the disorder is now known as vitamin K deficiency bleeding (VKDB). This disorder is characterized by its time of presentation, whether early-onset, classic, or late-onset.4 Early-onset VKDB begins within the first 24 hours of life.

It usually occurs in mothers who take medications that affect the metabolism of vitamin K. These medications include anticonvulsants, antibiotics, antituberculosis agents, and warfarin. All of these agents act by inducing CYP450 enzymes in the fetal liver. These babies can present with a spectrum of diseases ranging from skin bruising to life-threatening intracranial hemorrhage.

Prenatal vitamin K supplementation has not been shown to reduce early-onset VKDB, although it has been shown to increase plasma vitamin K concentrations in the umbilical cord.5, 6 There is insufficient evidence to recommend prenatal vitamin K supplementation. to women who receive these medications.7

Classic VKDB occurs between 2 days and 1 week of age.

Although some cases can occur in babies whose mothers were taking medications that affect vitamin K metabolism, most cases are idiopathic. Before the initiation of universal vitamin K prophylaxis, a study that randomized half of the male infants in a nursery demonstrated a six-fold increase in post-circumcision bleeding8 in the untreated group.

In another study involving 3 preparations of (1) a placebo; (2) 0.1 mg intramuscular (IM) vitamin K; and (3) 5.0 mg vitamin K IM, the incidence of moderate to severe bleeding in the placebo group was significantly higher than in either treatment group. In this same study, breastfed babies were shown to have a significantly higher risk of VKDB than formula-fed babies.

Late-onset VKDB occurs between 1 week and 6 months of age, with a peak incidence between 2 and 8 weeks.10 Late-onset VKDB is usually associated with exclusively breastfed infants who did not receive vitamin K prophylaxis. at birth. It may also be associated with hepatic dysfunction secondary to neonatal hepatitis, bile duct atresia11 or intestinal malabsorption.

Late-onset VKDB most commonly presents with evidence of intracranial hemorrhage in 30% to 60% of cases. There have been no randomized trials evaluating the efficacy of early postnatal intramuscular vitamin K in clearing late VKDB12; however, there are several large national surveillance studies that have examined rates of late VKDB since the introduction of vitamin K prophylaxis in Japan, Germany, Great Britain, and Thailand.

All of these studies have shown significant reductions in late-onset VKDB in the population.13–16 The high incidence of mortality and morbidity, along with its virtual elimination with prophylactic vitamin K, has made it a focus of public health interventions in everyone.

In 2003, the AAP reaffirmed the use of vitamin K to prevent VKDB and recommended that all newborns receive a single IM dose of 0.5 to 1.0 mg of vitamin K.17

While oral vitamin K appears to be effective in preventing classic VKDB, 18–20 there are concerns about its ability to prevent late-onset VKDB.

The 2003 AAP statement cited multiple reports of late-onset VKDB in countries that established oral prophylaxis policies for infants, with a single oral dose of vitamin K after birth proven to be less effective than a parenteral dose.21 Failure to prevent late-onset VKDB remains a problem with oral prophylaxis, despite the use of multiple-dose oral regimens.

In a Swiss study using 2 oral doses of 2 mg of vitamin K on day 1 and day 4, late-onset VKDB was rare but still occurred, with an incidence of 3.79 per 100,000, and a regimen of 3 doses. 22

This program included 3 oral doses of 2 mg of vitamin K administered at birth, day 4, and week 4 of life. A 6-year follow-up surveillance study in Switzerland demonstrated a significantly lower rate of late VKDB of 0.87 per 100,000, with parental refusal of any prophylaxis and undiagnosed cholestasis being the main risk factors.23

In a national surveillance study, the Netherlands described a rate of late-onset VKDB of 3.2 per 100,000 live births, based on an oral regimen of an initial dose of 1 mg of vitamin K followed by a daily dose of 25 μg .24

As a result, the Dutch prophylactic dose was increased from 25 μg daily to 150 μg daily for 3 months after birth. Although this six-fold increase in dose decreased the incidence of confirmed late-onset VKDB from 3.2 per 100,000 to 1.8 per 100,000, the confidence intervals overlapped; therefore, these results may not be significant.25

The authors concluded that despite the increase in oral dosage, “this protection compares poorly with the efficacy of IM vitamin K prophylaxis.” Factors that decrease the effectiveness of oral vitamin K include poor parental compliance with the regimen and nonuniform absorption of the oral drug.

Premature infants have the highest potential risk of VKDB due to hematological and hepatic immaturity, as well as lack of adequate intestinal microbial colonization.

The AAP has recommended a single IM dose of vitamin K of 0.3 to 0.5 mg/kg for preterm infants weighing less than 1000 g.26 However, there is wide variability in dosing regimens for preterm infants due to the scarcity of studies carried out to evaluate the correct dose of vitamin K.

A trial assigned preterm infants with overload (vitamin K epoxide), the authors concluded that 0.2 mg IM of vitamin K achieved satisfactory vitamin K levels without overload during the first 3 weeks of life, for the duration of the study.

Twenty-seven infants weighing less than 1000 g received the 0.2 mg IM dose, which was equivalent to a mean dose of 0.279 mg/kg. Infants weighing more than 1000 g and receiving the 0.2 mg IM dose also achieved satisfactory vitamin K levels, indicating that doses less than 0.3 mg/kg also appeared effective in achieving normal serum concentrations.

Of note, IV administration caused higher baseline levels and significantly lower serum concentrations at 2 weeks, raising concerns of early vitamin K overload and late vulnerability to VKDB.

In another study in which the treating physician decided on a dose of 0.5 mg or 1.0 mg for the premature infant, vitamin K levels in both groups were more than 500 times higher than fasting adult levels in the day 10 of life.28 These studies have indicated that a dose of 0.3 mg/kg for the premature neonate weighing <1000 g is sufficient.

Minimal amounts of vitamin K are transferred across the placenta to the fetus, which explains the low levels of vitamin K found in the newborn. Breast milk, which is the preferred nutrition for all newborns, provides relatively low levels of vitamin K, making exclusively breastfed infants at particular risk for VKDB.29

Because of their low baseline levels and low intake, plasma vitamin K concentrations of exclusively breastfed infants often fall below norms from 6 weeks to 6 months after birth. This decrease in plasma vitamin K occurs despite IM vitamin K at birth.30

More than 50 years ago, breastfeeding was identified as an important factor in VKDB,9 and remains a concern to this day. In a New Zealand case surveillance, VKDB was predominantly limited to exclusively breastfed infants who did not receive vitamin K at birth.31

In most countries with oral vitamin K supplementation policies, a late dose of oral vitamin K between 4 and 12 weeks is recommended to prevent late onset of VKDB in these infants. A small number of published studies have evaluated increasing vitamin K levels in breast milk through maternal supplementation with mixed results.32, 33

In recent years, there has been an increase in the number of parents refusing IM vitamin K for their newborn babies and a resulting increase in the number of cases of late-onset VKDB.34-37

Because VKDB remains a relatively rare occurrence, most families are unaware of the serious consequences of the disease and should be counseled about the risk of rejection.

Parental objections often fall into 3 broad categories: belief systems, child well-being, and external influencing factors.38 Parental objection to child well-being is often based on a 1990 study that found an unexpected association of vitamin K administration with childhood cancer.39

Multiple larger studies since then have refuted that unexpected association, finding no evidence that vitamin K is associated with leukemia or any other cancer.40,41 Non-Hispanic white race/ethnicity, female baby, Higher gestational age and increased maternal age were significantly associated with refusal of IM vitamin K administration.42

Families may believe that a “natural” birth is best and want to avoid what appears to be a painful intervention in the process. There was also a strong association between refusal of ocular prophylaxis and hepatitis B vaccine with refusal of vitamin K. Parental reasons for refusal of IM administration of vitamin K included lack of understanding of the indication of vitamin K, the belief that it was unnecessary, concern about pain from the injection, and concern related to the preservative in the formulation.34

There is no evidence that the small amount of the preservative, benzyl alcohol, is associated with toxicity, and many babies receive vitamin K without preservatives. Outside influences often include friends and celebrities, but can also include health professionals. Pediatricians and all health care professionals caring for newborns should strongly recommend vitamin K prophylaxis.

Births that were not attended by a doctor have also been associated with parental rejection of vitamin K.37 In a New Zealand study, 100% of doctors, but only 71% of midwives, believed that It was important that babies receive a dose of vitamin K.43 Vitamin K rejection was also associated with out-of-hospital delivery and was also strongly associated with overall vaccine refusal at 15 months of age.37

Assessing and responding to parental concerns regarding vitamin K are important roles for the pediatrician. Parents should understand the importance of vitamin K and have a basic understanding of its role to make an informed decision about their baby. An excellent fact sheet on vitamin K is available from the Centers for Disease Control and Prevention.44

The discussion should be directed to the parent’s level of understanding and include a discussion of known benefits and perceived risks. The pediatrician needs to ask open-ended questions and listen carefully to the parents’ responses. Parents who decline IM vitamin K prophylaxis and request an oral dosing regimen should be aware of the increased risks of late-onset VKDB. Health care providers can develop a vitamin K refusal form that documents their discussion of VKDB risks for families who refuse IM vitamin K prophylaxis.