The best questions often stem from the inquisitive learner. As educators, we love—and are always humbled by—those moments when we get to say, “I don’t know.”  For some of these questions, you may already know the answers. For others, you may never have thought to ask the question. For all, questions, comments, concerns, and critiques are encouraged. Welcome to the Kids Korner.

In a young infant with easy bleeding or bruising, how long do we really need to consider vitamin K-dependent bleeding (VKDB) on the differential?

There are several diagnoses on the differential when thinking of easy bleeding or bruising in young infants. Close to the top of the list are hemophilia, an acquired bleeding disorder, and non-accidental trauma (i.e., child abuse). But what about VKDB? How long does that really last? How long do we need to consider that as a cause of easy bleeding or bruising in infants? 

Considering VKDB

Vitamin K is a fat-soluble vitamin required by the liver in the synthesis of factors II, VII, IX, and X. Vitamin K poorly transfers across the placenta, and newborn infants have insufficient vitamin K stores. Additionally, there are very low concentrations of vitamin K in human milk.¹ A nursing baby has little to start and gets little when nursing, and as a result, can have significantly low levels of factors II, VII, IX, and X. Basically, think of VKDB as warfarin for babies. In the United States, newborns commonly get vitamin K supplementation as an intramuscular injection shortly after birth. Oral formulations also exist but are less common.

VKDB is typically divided into three groups: early, classic, and late. Early VKDB occurs within the first 24 hours of life in newborns born to mothers taking medications that cross the placenta and inhibit vitamin K activity.^1,2 Classic VKDB occurs between days two to seven of life and is usually idiopathic. Late VKDB begins at day eight of life and results from severe vitamin K deficiency primarily in breast-fed infants where vitamin K is poorly transmitted in breast milk. But how long do we need to consider this entity? What about the 3-month-old child with bruising?  What about the 6-month-old child with bruising? 

One study evaluated 120 cases of late VKDB in infants from Turkey from 1990-2006.¹ Of these 120 patients, 83 were boys and 37 were girls. The timing (by days) of late VKDB was days eight to 14 (6 percent); days 15-30 (21 percent); days 31-45 (36 percent); days 61-90 (11 percent); and days 91-240 (9 percent). The study does not specifically mention the case with the latest onset of VKDB, so we are only able to really gather that it occurred at least up to 91 days (about three months).

Of note, many of the signs and symptoms of late-onset VKDB were very concerning and included bulging fontanelles (70 percent), irritability (50 percent), convulsions (49 percent), and bleeding and ecchymosis (47 percent). Also, intracranial bleeding occurred in 73 percent of the infants with late VKDB, and the mortality for those who had intracranial hemorrhage was 31 percent.

So, in infants with late VKDB, intracranial hemorrhage is common, and the mortality rate is high. This just emphasizes how concerning this entity can be, why we should keep it on our differential diagnosis, and that we should ask about vitamin K in any young infant, particularly with bleeding or bruising. Regarding our question, though, we can only really say that it occurred up to three months after birth. The onset, though, was likely later.

How Late is Late?

A retrospective study that included 3,080 births identified 104 (3.4 percent) families at a tertiary care center who declined vitamin K administration after birth .³ Late VKDB was identified in seven of these children (five definite and two highly suspicious by laboratory values). The mean age at presentation was 10.3 weeks, but the range of ages extended from seven to 20 weeks. So, in short, there was a 5-month-old (20 weeks) who presented with late VKDB. This study shows that late VKDB can extend all the way up to five months of age, emphasizing the importance of inquiring about a perinatal vitamin K shot (see sidebar). Intracranial hemorrhage was also common in these children (57 percent) with late VKDB.

A more recent prospective five-year study also showed that late VKDB can extend all the way up to five months of age. The study identified 47 infants with late VKDB.² The mean age of onset was 10.5 ± 5.75 weeks, with a range of 2-21 weeks of age. This study identified infants with late VKDB all the way up through five months of age. Most deliveries were at home (55 percent) and 83 percent of infants were exclusively breastfed. Like the prior study, 23 percent of infants with late VKDB died and intracranial hemorrhage occurred in 32 percent of all infants with late VKDB.

What about later than five months of age? There is an older five-year retrospective nationwide survey in Japan of late VKDB that evaluated children from 1981-1985.⁴ The study identified 543 cases of VDKB in infants older than 2 weeks—meaning late VKDB. Of these cases, 427 cases were considered idiopathic, and 57 cases were considered “secondary” to other causes such as obvious hepatobiliary lesions, chronic diarrhea, long-term antibiotic therapy, etc.

In those cases of idiopathic late VKDB that occurred after two weeks, 269 cases (63 percent) occurred during the first and second month of age and 90 percent of infants were entirely breastfed alone. Twenty-three cases occurred between two to three months, 11 cases between three to four months, six cases between four to five months, one case between five to six months, and even a single case all the way out to seven to eight months. Although this outlier of seven to eight months is extremely rare in the medical literature in our search, this study does suggest that we should seriously consider late VKBD through at least six months of age as a cause of easy bleeding and bruising—particularly in solely breastfed infants.

Yet another retrospective study had a single child with late VKDB at 24 weeks (6 months) of age.⁵ And like the other studies, late VKDB was highly associated with intracranial bleeding (58 percent) with a mortality of 19 percent.

Summary

Late VKDB can occur up to six months after birth, particularly in babies who are solely breastfed. Asking about vitamin K administration after birth is extremely important in infants younger than 6 months with easy bleeding or easy bruising or any clinical circumstance that could be caused by life-threatening bleeding such as intracranial hemorrhage.

Dr. Jones is associate professor at the department of emergency medicine & pediatrics and the program director of pediatric emergency medicine fellowship at the University of Kentucky in Lexington, Kentucky.

Dr. Cantor is the emeritus medical director for the Central New York Poison Control Center and professor of emergency medicine and pediatrics in Syracuse, New York.

References

1. Ozdemir MA, Karakukcu M, Per H, et al. Late-type vitamin K deficiency bleeding: experience from 120 patients. Childs Nerv Syst. 2012; 28(2):247-251.
2. Al-Zuhairy SH. Late vitamin K deficiency bleeding in infants: five-year prospective study. J Pediatri (Rio J). 2021; 97(5):514-519.
3. Schulte R, Jordan LC, Morad A, et al. Rise in late onset vitamin K deficiency bleeding in young infants because of omission or refusal of prophylaxis at birth. Pediatr Neural. 2014; 50(6):564-568
4. Hanawa Y, Maki M, Murata B et al. The second nation-wide survey in Japan of vitamin K deficiency in infancy. Eur J Pediatr. 1988; 147(5):472-477.
5. Sutor AH, Dagres N, Niederhoff H. Late form of vitamin K deficiency bleeding in Germany. Klin Padiatr. 1995; 207(3):89-97.