Vitamin K and the Newborn Infant.

Intramuscular administration of vitamin K for 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 prevention of VKDB with vitamin K administration, the incidence of VKDB appears to be on the rise. This increase in incidence of VKDB is attributable to parental refusal as well as lowered efficacy of alternate methods of administration. The aim of this statement is to discuss the current knowledge of prevention of VKDB with respect to the term and preterm infant and address parental concerns regarding vitamin K administration.

Belgian Consensus Recommendations to Prevent Vitamin K Deficiency Bleeding in the Term and Preterm Infant.

Neonatal vitamin K prophylaxis is essential to prevent vitamin K deficiency bleeding (VKDB) with a clear benefit compared to placebo. Various routes (intramuscular (IM), oral, intravenous (IV)) and dosing regimens were explored. A literature review was conducted to compare vitamin K regimens on VKDB incidence. Simultaneously, information on practices was collected from Belgian pediatric and neonatal departments. Based on the review and these practices, a consensus was developed and voted on by all co-authors and heads of pediatric departments. Today, practices vary. In line with literature, the advised prophylactic regimen is 1 or 2 mg IM vitamin K once at birth. In the case of parental refusal, healthcare providers should inform parents of the slightly inferior alternative (2 mg oral vitamin K at birth, followed by 1 or 2 mg oral weekly for 3 months when breastfed). We recommend 1 mg IM in preterm <32 weeks, and the same alternative in the case of parental refusal. When IM is perceived impossible in preterm <32 weeks, 0.5 mg IV once is recommended, with a single additional IM 1 mg dose when IV lipids are discontinued. This recommendation is a step towards harmonizing vitamin K prophylaxis in all newborns.

Late vitamin K deficiency bleeding in infants: five-year prospective study

Abstract Objective: To study the presenting clinical and demographic features, risk factors, and outcome of infants with late vitamin K deficiency bleeding. Methods: Over a 5-year study period, the presenting clinical features and outcome of all 47 infants observed aged less than 6 months, who were diagnosed with late-onset primary and secondary VKDB by detailed history, physical examination, and laboratory findings were evaluated. Confirmed primary late VKDB was diagnosed when no cause other than breastfeeding could be found, while in the secondary subtype additional risk factors compromising the vitamin K effect were diagnosed. Results: Secondary late VKDB (83%, 39 patients) was more common than the primary subtype. The mean age of patients was 10.50 ± 5.75 and 9.74 ± 6.04 weeks in primary and secondary VKDB subtypes, respectively, and the age of infants did not have a significant difference (> 0.05). The male to female ratio was 2.13:1. The residency, place and mode of delivery, gestational age, and types of feeding of patients did not have a significant difference between VKDB subtypes. The skin and gastrointestinal tract (GIT) (40.4%) followed by intracranial hemorrhage (ICH) (32%), were common sites of bleeding. Neurological complications were seen in 21% of patients; however, lethality was 23%, and the outcome of patients did not have a significant difference (p > 0.05) between VKDB subtypes. Conclusion: Secondary late VKDB is more common than the primary subtypes, and late VKDB is still a serious disease in developing countries, including Iraq, when vitamin K prophylaxis isn't routinely used at birth.

Trends in and Documentation of Refusal of Common Routine Newborn Interventions: 2013-2019.

BACKGROUND: Refusals of intramuscular (IM) vitamin K, ocular prophylaxis, and hepatitis B vaccine (HBV) during the birth hospitalization continue to occur. Refusal of IM vitamin K increases the risk of life-threatening vitamin K deficiency bleeding. Trends in refusal rates and how well clinicians document IM vitamin K refusal is unknown. METHODS: We reviewed charts of livebirths admitted to 5 well newborn units from 2013 to 2019. We report trends in rates of refusal and documentation of no IM vitamin K by clinicians during the birth hospitalization and within the first 6 months of life at emergency department (ED) visits. RESULTS: Of 67 750 live births, 283 (0.4%) did not receive IM vitamin K, and 1645 (2.4%) did not receive ocular prophylaxis. Rates of IM vitamin K refusal increased slightly over time (P < .05). For HBV, 7551 (11.1%) did not receive the birth dose, but refusal rates decreased from 16.1% to 8.7% (P < .0001). Of 283 newborns who did not receive IM vitamin K, refusal was documented in 49.8% of discharge summaries, 17 (6%) had an invasive procedure without documentation of IM vitamin K administration, and 30 (10.6%) infants <6 months old had ED visits. A total of 4 infants were evaluated for potential bleeding, and there was no documentation about IM vitamin K prophylaxis. CONCLUSION: Refusal rates of IM vitamin K and ocular prophylaxis remained low, and uptake of HBV increased over time. Documentation of IM vitamin K refusal by clinicians during the birth hospitalization, before invasive procedures, and in ED visits can be improved.

Intracranial haemorrhage associated with Vitamin K deficiency in Egyptian infants.

AIM: Intracranial haemorrhage (ICH) in infancy is a rare life-threatening event. The aim of this review is to highlight the association of ICH and potentially preventable vitamin K deficiency and to describe risk factors, presentation and outcome. METHODS: Original published data on ICH related to vitamin K deficiency during 2008-2012 were extracted from records of participating centres in Egypt (Cairo and Delta region). Full data on 70 infants (0-24 weeks) have been reported in three publications. RESULTS: The first study involved premature infants where ICH was potentially preventable with administration of parenteral vitamin K prophylactic doses to mothers ahead of imminent preterm delivery. The other 2 studies involved term newborns and infants. ICH due to early or classic vitamin K deficiency was reported in nine patients while 44 were due to late vitamin K deficiency. Main risk factors for late onset were exclusive breastfeeding, persistent diarrhoea and/or prolonged antibiotic therapy. CONCLUSION: Vitamin K deficiency bleeding is a relatively frequent problem underlying ICH in infancy. Prophylactic vitamin K to mothers when anticipating preterm labour or a vitamin K boost in exclusively breast-fed infants with prolonged antibiotic usage and, or, persistent diarrhoea might have an impact on prevention and outcome.

Late vitamin K deficiency bleeding in infants: five-year prospective study.

OBJECTIVE: To study the presenting clinical and demographic features, risk factors, and outcome of infants with late vitamin K deficiency bleeding. METHODS: Over a 5-year study period, the presenting clinical features and outcome of all 47 infants observed aged less than 6 months, who were diagnosed with late-onset primary and secondary VKDB by detailed history, physical examination, and laboratory findings were evaluated. Confirmed primary late VKDB was diagnosed when no cause other than breastfeeding could be found, while in the secondary subtype additional risk factors compromising the vitamin K effect were diagnosed. RESULTS: Secondary late VKDB (83%, 39 patients) was more common than the primary subtype. The mean age of patients was 10.50 ±â€¯5.75 and 9.74 ±â€¯6.04 weeks in primary and secondary VKDB subtypes, respectively, and the age of infants did not have a significant difference (p > 0.05). The male to female ratio was 2.13:1. The residency, place and mode of delivery, gestational age, and types of feeding of patients did not have a significant difference between VKDB subtypes. The skin and gastrointestinal tract (GIT) (40.4%) followed by intracranial hemorrhage (ICH) (32%), were common sites of bleeding. Neurological complications were seen in 21% of patients; however, lethality was 23%, and the outcome of patients did not have a significant difference (p > 0.05) between VKDB subtypes. CONCLUSION: Secondary late VKDB is more common than the primary subtypes, and late VKDB is still a serious disease in developing countries, including Iraq, when vitamin K prophylaxis isn't routinely used at birth.

Temporal association between serious bleeding and immunization: vitamin K deficiency as main causative factor.

BACKGROUND: Bleeding as an adverse event following immunization (AEFI) that is rarely reported in children, although it can be a parental concern. Bleeding episodes ranging in severity from mild to severe and defined as any external and/or internal bleeding can be caused by acquired or hereditary disorders. This study analyzes whether bleeding episodes in children that were recorded as AEFIs are causally associated with immunization and elaborates their etiology. METHODS: A cross-sectional study of 388 AEFI cases in children from West Java Provincial Committee in Indonesia confirmed by case findings from 2000 until 2017. RESULTS: Of the total number of cases studied, 55 (14%) involved children aged 5 days to 12 years who presented with bleeding and were referred to a provincial hospital. Analysis revealed that 32 cases were most likely caused by acquired prothrombin complex deficiency (APCD) and 30 of these APCD cases were strongly suspected to be manifestations of vitamin K deficiency bleeding (VKDB). All VKDB subjects were aged 5 days to 3 months without a history of administration of prophylactic vitamin K. When a World Health Organization classification was used, most bleeding cases in this study became coincidental events with a temporal association with immunization. A causality assessment suggested that these cases were causally unrelated. CONCLUSION: Most cases of bleeding reported as an AEFI were found to be VKDB, which is considered a coincidental event following immunization with a temporal association, and an unrelated category based on the results of a causality assessment. Vitamin K should be administered to all newborns as a prophylactic and AEFI surveillance should be improved based on the low numbers of AEFI reported in Indonesia.

Refusal of Intramuscular Vitamin K by Parents of Newborns: A Review.

In 2019, the American Academy of Pediatrics made public education about intramuscular vitamin K administration at birth a public health priority, partly in response to reports of refusal of intramuscular vitamin K by parents of newborns that led to vitamin K deficiency bleeding (VKDB). We reviewed the literature on the frequency of, reported reasons for, and factors associated with refusal of intramuscular vitamin K, incidence of VKDB in newborns who did not receive intramuscular vitamin K, and use of oral vitamin K to prevent VKDB. Without prophylaxis, estimates of the incidence per 100 000 births of VKDB range from 250 to 1700 for early VKDB and from 10.5 to 80 for late VKDB. The frequency of refusal of intramuscular vitamin K by parents ranged from 0% to 3.2% in US hospitals, up to 14.5% in home births, and up to 31.0% in birthing centers. Reported reasons for refusal were concern of harm from the injection, a desire to be natural, and a belief in alternative methods of prophylaxis. Parents who refused intramuscular vitamin K were more likely to refuse immunizations. Many different regimens were used for orally administered vitamin K; it is not clear which is best, but all are less effective than intramuscular vitamin K. VKDB is rare but can result in either neurologic sequelae or death. In addition to continued surveillance of the frequency of both refusal of intramuscular vitamin K and VKDB, a renewed focus on education of and collaboration with parents is needed to address this major public health threat.

Vitamin K deficiency bleeding in Australian infants 1993-2017: an Australian Paediatric Surveillance Unit study.

OBJECTIVE: To undertake surveillance of vitamin K deficiency bleeding (VKDB) in Australia from 1993 to 2017, during a time of change to national recommendations and available vitamin K formulations. METHODS: Paediatricians reported cases of VKDB in infants aged <6 months and provided demographic, clinical and biochemical information via the Australian Paediatric Surveillance Unit. RESULTS: 58 cases were reported, of which 5 (9%) were early, 11 (19%) classic and 42 (72%) late VKDB. 53 (91%) were exclusively breast fed. Seven (12%) received oral prophylaxis, the majority (86%) of whom did not receive all three recommended doses. The overall reported incidence was 0.84 per 100 000 live births (95% CI: 0.64 to 1.08) and the incidence of late VKDB was 0.61 per 100 000 live births (95% CI: 0.44 to 0.82), which are similar to rates reported by other countries where intramuscular vitamin K is recommended. VKDB rates were significantly higher (2.46 per 100 000 live births; 95% CI: 1.06 to 4.85) between 1993 and March 1994 when oral prophylaxis was recommended (p<0.05). Vitamin K was not given to 33 (57%) cases, primarily due to parental refusal, and the number of parental refusals increased significantly after 2006 (p<0.05). There were six deaths, all due to intracranial haemorrhage, and three associated with home delivery and parental refusal of vitamin K. CONCLUSIONS: Incidence rates of VKDB in Australia are among the lowest in the world; however, we have identified an increasing trend of parental refusal. Ongoing surveillance and educational campaigns for health professionals and parents are needed to prevent VKDB.

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

Vitamin K prophylaxis in infancy aims to prevent life-threatening vitamin K deficiency bleeding (VKDB). The Dutch prophylactic oral daily regimen was increased sixfold from 25 to 150 µg because of a high failure rate. To evaluate the efficacy of this new regimen, incidences of intracranial VKDB under both regimens were compared using both general and targeted surveillance. Late VKDB in the general pediatric population was identified by the Netherlands Pediatric Surveillance Unit, between 1 October 2014 and 31 December 2016. Additionally, infants with intracranial vitamin K deficiency bleeding were identified using the Dutch Pediatric Intensive Care Evaluation registry. The incidence of intracranial VKDB as assessed by general and targeted surveillance decreased from 1.6 per 100,000 (95% CI, 0.4-5.1) to 1.3 per 100,000 (95% CI, 0.5-3.2) and from 3.1 per 100,000 live births (95% CI, 1.9-5.0) to 1.2 per 100,000 live births (95% CI, 0.6-2.3), respectively. Median time between consecutive cases in the latter increased from 24 to 154 days (p < 0.001).Conclusion: A sixfold increase in oral vitamin K prophylaxis was associated with a surprisingly modest reduction in the incidence of intracranial VKDB, indicating that factors other than the dose need addressing to improve efficacy. What is Known: • The efficacy of intramuscular vitamin K prophylaxis is threatened by an increasing number of parents opting out. • Oral prophylaxis represents an attractive and less invasive alternative but is inferior, especially in infants with malabsorption of vitamin K due to cholestasis. What is New: • Increasing the daily oral dose of vitamin K sixfold had a surprisingly modest effect on the incidence of late vitamin K deficiency bleeding. • This finding indicates that factors other than the dose must play an important role.

Factors Associated With Refusal of Intramuscular Vitamin K in Normal Newborns.

BACKGROUND AND OBJECTIVE: Refusal of intramuscular (IM) vitamin K administration by parents is an emerging problem. Our objective was to assess the frequency of and factors associated with refusal of IM vitamin K administration in well newborns in the United States. METHODS: We determined the number of newborns admitted to well newborn units whose parents refused IM vitamin K administration in the Better Outcomes through Research for Newborns network and, in a nested patient-control study, identified factors associated with refusal of IM vitamin K administration by using a multiple logistic regression model. RESULTS: Of 102 878 newborns from 35 Better Outcomes through Research for Newborns sites, parents of 638 (0.6%) refused IM vitamin K administration. Frequency of refusal at individual sites varied from 0% to 2.3%. Exclusive breastfeeding (adjusted odds ratio [aOR] = 3.4; 95% confidence interval [CI]: 2.1-5.5), non-Hispanic white race and/or ethnicity (aOR = 1.7; 95% CI: 1.2-2.4), female sex (aOR = 1.6; 95% CI: 1.2-2.3), gestational age (aOR = 1.2; 95% CI: 1.1-1.4), and mother's age (aOR = 1.05; 95% CI: 1.02-1.08) were significantly associated with refusal of IM vitamin K administration. Refusal of the administration of both ocular prophylaxis and hepatitis B vaccine was also strongly associated with refusal of IM vitamin K administration (aOR = 88.7; 95% CI: 50.4-151.9). CONCLUSIONS: Refusal of IM vitamin K by parents of newborns is a significant problem. Interventions to minimize risks to these newborns are needed.

Newborn vitamin K prophylaxis: an analysis of information resources for parents and professionals.

AIMS: Vitamin K prophylaxis represents one of the first healthcare decisions families make for their newborn. Information resources are an important component of this process. This study aimed to identify and analyse written information about vitamin K. METHODS: Resources concerning vitamin K prophylaxis for both parents and health professionals were accessed through tertiary hospitals in New Zealand and Australia, midwives associated with Queen Mary Maternity Centre (Dunedin, New Zealand), antenatal class providers in the Dunedin, New Zealand area, and an online search of Australian and New Zealand government and hospital websites, as well as the Centre for Disease Control (CDC) in the US. These materials were assessed with regard to coverage of information relevant to vitamin K prophylaxis, whether a statement of the recommended option was included, and information concerning parental choice. RESULTS: In Australia, the majority of centres use the Australian Government National Health and Medical Research Council (NHMRC) resource. In New Zealand, eight different resources are in use. There was variation between resources in all aspects, including use of different incidence rates for vitamin K deficiency bleeding (VKDB). No New Zealand resources were available in languages other than English. The resources for health professionals also varied, and the two available New Zealand consensus statements (Ministry of Health and College of Midwives) differed in terms of their main recommendation. CONCLUSIONS: Many different information resources are available regarding vitamin K prophylaxis in New Zealand. Standardisation of such information would be more equitable and would facilitate easier review of content and translation into multiple languages.

Vitamin K prophylaxis for prevention of vitamin K deficiency bleeding: a systematic review.

We conducted a systematic review to evaluate the burden of late vitamin K deficiency bleeding (VKDB) and the effect of vitamin K prophylaxis on the incidence of VKDB. We searched MEDLINE and other electronic databases, and included all observational studies including population surveys as well as randomized controlled trials (RCT). The median (interquartile range) burden of late VKDB was 35 (10.5 to 80) per 100 000 live births in infants who had not received prophylaxis at birth; the burden was much higher in low- and middle-income countries as compared with high-income countries-80 (72 to 80) vs 8.8 (5.8 to 17.8) per 100 000 live births. Two randomized trials evaluated the effect of intramuscular (IM) prophylaxis on the risk of classical VKDB. Although one trial reported a significant reduction in the incidence of any bleeding (relative risk (RR) 0.73, 95% confidence interval (CI) 0.56 to 0.96) and moderate to severe bleeding (RR 0.19, 0.08 to 0.46; number needed to treat (NNT) 74, 47 to 177), the other trial demonstrated a significant reduction in the risk of secondary bleeding after circumcision in male neonates (RR 0.18, CI 0.08 to 0.42; NNT 9, 6 to 15). No RCTs evaluated the effect of vitamin K prophylaxis on late VKDB. Data from four surveillance studies indicate that the use of IM/subcutaneous vitamin K prophylaxis could significantly reduce the risk of late VKDB when compared with no prophylaxis (pooled RR 0.02; 95% CI 0.00 to 0.10). When compared with IM prophylaxis, a single oral dose of vitamin K increased the risk of VKDB (RR 24.5; 95% CI 7.4 to 81.0) but multiple oral doses did not (RR 3.64; CI 0.82 to 16.3). There is low-quality evidence from observational studies that routine IM administration of 1 mg of vitamin K at birth reduces the incidence of late VKDB during infancy. Given the high risk of mortality and morbidity in infants with late VKDB, it seems appropriate to administer IM vitamin K prophylaxis to all neonates at birth. Future studies should compare the efficacy and safety of multiple oral doses with IM vitamin K and also evaluate the optimal dose of vitamin K in preterm neonates.

Prevalence and Predictors of Functional Vitamin K Insufficiency in Mothers and Newborns in Uganda.

Vitamin K deficiency bleeding (VKDB) in infancy is a serious but preventable cause of mortality or permanent disability. Lack of epidemiologic data for VKDB in sub-Saharan Africa hinders development and implementation of effective prevention strategies. We used convenience sampling to consecutively enroll mothers delivering in a southwestern Uganda Hospital. We collected socio-demographic and dietary information, and paired samples of maternal venous and neonatal cord blood for the immunoassay of undercarboxylated prothrombin (PIVKA-II), a sensitive marker of functional vitamin K (VK) insufficiency. We used univariable and multivariable logistic regression models to identify predictors of VK insufficiency. We detected PIVKA-II of ≥0.2 AU (Arbitrary Units per mL)/mL (indicative of VK insufficiency) in 33.3% (47/141) of mothers and 66% (93/141) of newborns. Importantly, 22% of babies had PIVKA-II concentrations ≥5.0 AU/mL, likely to be associated with abnormal coagulation indices. We found no significant predictors of newborn VK insufficiency, including infant weight (AOR (adjusted odds ratio) 1.85, 95% CI (confidence interval) 0.15-22.49), gender (AOR 0.54, 95% CI 0.26-1.11), term birth (AOR 0.72, 95% CI 0.20-2.62), maternal VK-rich diet (AOR 1.13, 95% CI 0.55-2.35) or maternal VK insufficiency (AOR 0.99, 95% CI 0.47-2.10). VK insufficiency is common among mothers and newborn babies in southwestern Uganda, which in one fifth of babies nears overt deficiency. Lack of identifiable predictors of newborn VK insufficiency support strategies for universal VK prophylaxis to newborns to prevent VKDB.

Neonatal vitamin K refusal and nonimmunization.

BACKGROUND: Neonatal Vitamin K prophylaxis is an effective intervention for reducing vitamin K deficiency bleeding. A recently published report of parental refusal of vitamin K prompted an investigation of the prevalence and characteristics of this group, and exploration of whether these same parents were likely to subsequently refuse immunization for their children. METHODS: We conducted a retrospective population-based cohort study of all infants born in Alberta between 2006 and 2012 by using linkage of administrative health data. Risk factors for vitamin K refusal were determined by using Poisson regression. The association between vitamin K refusal and nonimmunization was assessed using relative risk. RESULTS: Among the 282378 children in the cohort, 99.7% received vitamin K and 0.3% declined. Midwife-assisted deliveries were more likely to be associated with vitamin K refusal compared with physician-attended delivery (risk ratio 8.4, 95% confidence interval [CI] 6.5-11.0). Planned home delivery (risk ratio 4.9, CI 3.8-6.4) or delivery in a birth center (risk ratio 3.6, CI 2.3-5.6) were more likely to result in decline of vitamin K compared with hospital delivery. Vitamin K refusal was associated with a 14.6 (CI 13.9-15.3) higher relative risk of having no recommended childhood vaccines at 15 months. CONCLUSIONS: This is the first population-based study to characterize parents who are likely to decline vitamin K for their infants and whose children are likely to be unimmunized. These findings enable earlier identification of high-risk parents and provide an opportunity to enact strategies to increase uptake of vitamin K and childhood immunizations.