Paige is 20 minutes old born at 30 weeks’ gestation. Her condition is stable. Her mother intends to breast feed. As per unit protocol you are about to administer vitamin K. For your Case Study you are required to demonstrate knowledge and understanding of the:
- The possible reasons why vitamin K is necessary for Paige
- Physiology of vitamin K deficiency in the neonate and impact of this deficiency on the health of baby Paige
- Current evidence based management of Paige in relation to vitamin K deficiency
- Role and responsibility of the midwife in the care of baby Paige and support of the parents
Introduction TO COMPLETE
It is widely accepted practise in the UK to offer Vitamin K (VK), with consent, to the newborn infant (NICE, 2006). Vitamin K is essential for effective blood clotting and is given at birth as a form of prophylaxis in order to prevent Vitamin K Deficiency Bleeding (VKDB), formerly known as Haemorrhagic Disease of the Newborn (HDN) (Lewis, 2015). Although the incidence of this disease is rare, the neurological consequences can be catastrophic to the infant (MacDonald & Seshia, 2016). This is a preventable condition and it is for this reason that all parents in the UK are offered VK prophylaxis for their baby (NICE, 2006).
VKDB……. This essay will use this term instead of hemmorrhagic …
This essay will……..
The role and responsibility of the midwife in the care of baby Paige will be discussed throughout in addition to the support of the parents.
Pathophysiology of Vitamin K Deficiency
In order to explore the pathophysiology related to vitamin K deficiency in the neonate and the impact this has on the health of baby Paige, it is necessary to give an overview of the structure, storage and function of VK in the neonate. This will allow for further in depth analysis on how Vitamin K Deficiency Bleeding (VKDB) can potentially arise in the newborn. Different timeframes by which the disorder is categorised into will also be reviewed below.
Vitamin K
VK is a fat-soluble substance stored in the liver, which is needed for the complex process of blood clotting (Soltani & Fair, 2017). If there is a severe deficiency of VK , there is the risk that bruising and bleeding can arise due to prolonged clotting time and VKDB may occur (Soltani & Fair, 2017), which will be discussed in more detail later in this section. There are essentially two forms of naturally occurring VK , including Vitamin K1 and Vitamin K2 (Lippi & Francini, 2011). Vitamin K1 (also known as phytomenadione, phytonadione or phylloquinone) is the dietary form found in foods such as green leafy vegetables (Greig, 2014), liver and some vegetable oils (Waugh & Grant, 2014). It is the only form of VK used therapeutically in humans (Mihatsch et al., 2016). It has been known for a number of years that Vitamin K1 is poorly transferred through the placenta from mother to fetus, with plasma Vitamin K1 concentrations being significantly lower than adults as well as fetal liver stores being detected as significantly lower than adults (Shearer et al, 1982; Shearer, 1990; Shearer, 1992 & Greig, 2014). Vitamin K2 (menaquinone) is mainly produced by gastrointestinal bacterial flora (Soltani & Fair, 2017; Woods, Woods & Cederholm, 2015) and it is suggested that it may assist with converting proteins to active clotting factors (Greig, 2014). In order for fat soluble vitamins (which include vitamins A,D,E and K) to be absorbed in the small intestine, bile is required (Waugh & Grant, 2014). However, when the neonate is born, it’s bowel has not been colonised yet and is in a sterile state, thus it does not have enough bacteria present in the gut to create vitamin K in the body (Greig, 2014).The aforementioned factors of neonates having significantly lower levels of VK and fetal liver stores than adults along with the fact their intestine not being colonised, makes the neonate particularly vulnerable VKDB (Greig, 2014; Waugh & Grant, 2014). Neonates need to have a constant supply of VK and therefore milk feeding colonises the neonate’s sterile gastrointestinal tract by bacteria, which is responsible for synthesising it (McEwan, 2017). Now that VK has been explained in detail, this leads the essay onto coagulation factors and the relationship VK deficiency along with these factors are connected with VKDB.
Coagulation system
Blood clotting, also referred to as coagulation, is a complex process involving a positive feedback system involving multiple clotting factors (Waugh & Grant, 2014). Several proteins require VK in order to convert into clotting factors (Greig, 2014). These include coagulation factors II, VII, IX and X and natural anticoagulants proteins C, S and Z, which are initially synthesized as inactive precursors, requiring post translational chemical modification (carboxylation), which is essential to haemostatic function of these proteins (MacDonald & Seshia, 2016). Haemostasis is dependent on the interaction between injured vessels, platelets and the aforementioned coagulation system, however neonates are at particular risk of spontaneous bleeding due to the relative deficiency of vitamin K, which is essential for the synthesis of these clotting factors within the liver (McEwan, 2017). Deficiency in VK therefore prevents normal physiological process of blood coagulation (Waugh & Grant, 2014). Term infants are born with half the serum levels of factors II, VII, IX, and X and preterm infants like Paige have even less , putting them more at risk of VK deficiency (Pilcher, 2008). Deficiency in VK, leading to VKDB will now be reviewed.
Vitamin K Deficiency Bleeding (VKDB)
VKDB, formerly known as Haemorrhagic Disease of the Newborn (HDN), was described Townsend in 1984 as a spontaneous bleeding syndrome (Townsend, 1984). He reported over 50 cases of generalised bleeding in neonates, recognising the distinction in presentation between this disorder and haemophilia and also the fact that there was no family history connected to the bleeding unlike haemophilic diseases (Jinghe, Mizuta & Ozaki, 2015). In the 1940s a Danish biochemist, Henrik Dam, discovered the link between this disease and lack of VK in the newborn and his work earned him a noble prize in the 1950s when he was able to prove that a vitamin K prophylaxis worked in preventing bleeding in the newborn (Tripp & McNish, 1987; Zipursky, 1999). A large study published in 1944 involving 13,000 infants, revealed a fivefold reduction in death from haemorrhage in those infants who were given 1mg of vitamin K3 (menadione) at delivery (Lehmann, 1944). As research developed, the American Academy of Paediatrics recommended in 1961 that all neonates should be given a single dose of VK (either 0.5-1 mg intramuscular (IM) or 1-2 mg oral) shortly after birth (American Academy of Paediatrics, 1961). This is still common practice in the UK (NICE, 2006). The name HDN was changed to VKDV in 1999, reflecting that the condition is due to a VK deficiency and that that some infants begin bleeding after the four-week newborn period is over (Shearer, 2009).
VKDB is currently defined by MacDonald and Seshia (2016) as the “bleeding that is triggered by a decreased in VK-dependent factors below the haemostatic level”, which can be corrected with the administration of VK (MacDonald & Seshia, 2016, pp.908). Neonates are relatively deficient in vitamin K at birth due to insufficient placental transfer (Pacifici, 2016; Shearer,1992), the relatively short half-life of the vitamin K liver stores (Schulte et al., 2014) and the aforementioned immature gastrointestinal absorption (Jinghe, Mizuta & Ozaki, 2015). These factors compounded by deficient vitamin K content in breast milk compared with fortified cow’s milk–based formula, make newborn infants at higher risk of developing VKDB (Schulte et al., 2014). Breastfeeding will be discussed in detail at a later stage. It is important to note that the maternal use of antiepileptic drugs, antitubercular drugs, or anticoagulants also put the infant at higher risk of VKDB (Woods, Woods & Cederholm, 2015). In addition to these factors, any treatment for the neonate which involves using broad-spread antimicrobials puts the infant at risk of VKDB as it can destroy essential VK producing bacteria (McEwan, 2017).
VKDB can be identified as either idiopathic, which is where the cause is unknown but seen in infants who are exclusively breastfed or secondary VKDV, which is caused by an underlying disorder such as gallbladder disease or cystic fibrosis. Like idiopathic CKDB, most babies who have secondary VKDB are also exclusively breastfed (Shearer 2009). VKDB can be classified as early, classic or late depending on the age of the infant appears symptomatic (MacDonald & Seshia, 2016; Woods, Woods & Cederholm, 2015). Early VKDB, which occurs in the first 24 hours of life and presents with bleeding is very rare and is normally seen in women who have been using anticonvulsants (e.g. phenytoin) or anticoagulant medications (e.g. warfarin) during pregnancy (Greig, 2014). The newborn with early VKDB will present with bleeding, with cephalohematomas and intracranial haemorrhages being most common (Pitchler & Pitchler, 2008). Because these drugs can interfere with the metabolism of VK, a lot of the literature suggests avoidance of these drugs during pregnancy to reduce the risk of early VKDB (Greig, 2014; Nulman, Laslo & Koren, 2009). However, there was a systematic review of the evidence in 2009 looking at the use of anti-epileptic drugs (AEDs) in pregnancy (Harden et al., 2009). Even though this study looked at evidence published over a 22 year period, only 10 articles were identified in the literature search with the authors concluding that there is inadequate evidence to determine if newborns of women with epilepsy taking AEDs in pregnancy have a substantially increased risk of haemorrhagic complications. The first epidemiologic study assessing the occurrence of bleeding complications in newborns exposed to maternal enzyme‐inducing AEDs in utero was published in 2003 which also does not support the hypothesis that maternal enzyme‐inducing AEDs increase the risk of bleeding in the neonate (Morrow & Graig, 2003). Further research is needed in this area and it is important to note that although there may not be high quality evidence available connecting AED use in pregnancy and VKDB, there may be other associated risks for the newborn including congenital malformations, therefore women must be counselled about the teratogenic risks to the newborn (Veroniki et al., 2017). Classic VKDB can occur between day one and seven of life. Babies who are more susceptible include preterm babies with a low birth weight and babies subjected to birth trauma (England, 2014). Classic VKDV can also be a consequence of inadequate or delayed feeding of the newborn (MacDonald & Seshia, 2016). These babies are more likely to bleed spontaneously (England, 2014), have bleeding under the skin, in the gut, from the nose or from a circumcision wound (Puckett and Offringa, 2000). Late onset VKDB refers to bleeding between 1 and 4 months of age (Schulte et al., 2014) and is seen in exclusively breastfed infants and also children with syndromes associated with Vitamin K malabsorption (MacDonald & Seshia, 2016). It is associated with higher mortality and morbidity, with blood tests revealing prolonged prothrombin time (PT) and partial thromboplastin time (PTT), with a normal platelet count (Nimavat, 2012). Both classic and late onset of VKDB could be a cause of concern for Paige, given she is a breastfed baby, born preterm. It is essential that midwives, are aware of the clinical symptoms of VKDB as well as explaining and educating the parents regarding signs and signs and symptoms of VKDB (NICE, 2006). Now that the pathophysiology of VKDB has been outlined, a critical analysis of the literature with regards to management and prevention will now follow.
Evidence Based Management
Vitamin K prophylactic treatment has always been a topic of debate, with some parents opting out giving it to their children. Historical research topics include the link between VK injections and leukaemia, which involved several decades of research and debate, concluding that there is no supporting a relationship between Vitamin K and leukaemia or other childhood cancers (Shearer, 2009). There has also been great debate around whether or not neonates are born deficient in VK for a reason (Wickham, 2017; Kay, 2000; Iraels et al., 1997) An article published in 2014 in a paediatric journal, shared details of infants admitted to a Tennessee hospital in the USA who were diagnosed with late VKDB (Schulte et al., 2014). This brought the topic back to the limelight again and further research was undertaken as a consequence. Despite this, there are evident gaps in the research with regards to safe dosages of VK in particular relating to pre-term infants, which will be discussed further. Due to word limitations, this essay will critique solely on the topics of breastmilk, dosages and routes of VK with a focus on the preterm neonate.
Association with breastfeeding and VKDB
Paige was born at 30 weeks gestation, which is defined by The World Health Organisation (WHO) (2018) as very preterm (born between 28 and 32 weeks) (WHO, 2018). Her mother intends to breastfeed. It is widely accepted that human breastmilk is the most appropriate nutrient for the preterm neonate as opposed to formula and other substances (WHO, 2018; Zukowsky, 2016; UNICEF, 2018). The association of breastfeeding and VKDB will now be explored further. Preterm babies are more susceptible to infection due to the immaturity of the gastrointestinal, which makes it more permeable and thus at more risk of infection (Pollard, 2018), therefore it is important they are breastfed or receive breastmilk to protect against infection (Wambach & Riordan, 2016). However, breastfeeding the preterm infant can be particularly challenging and can be associated with delayed feeding (Pollard, 2018). The suck and swallow mechanism, essential for milk transfer, does not start to co-ordinate in the infant until 32-36 weeks gestation (Jones & Spencer, 2005), putting Paige at particular risk of delayed feeding. Breastmilk also contains low concentrations of VK (McEwan, 2017; Schulte et al., 2014) compared with formula and there are few reports to date which show VKDB occurring in infants who have been fed artificial milk (Shearer, 2009). Evidence reports babies who are fed artificial milk as opposed to human breastmilk receive nearly 100 times more Vitamin K1 and blood levels of Vitamin K1 in 6-week old breastfed babies are about 0.13 micrograms per litre, compared to 6.0 micrograms per litter in formula-fed babies (von Kries, Shearer et al. 1987; Greer, Marshall et al. 1991; Shearer 2009). Some researchers have challenged the theory that breastmilk is low in vitamin K as it is too often compared with formula which as discussed above can supplement infants up to 100 times more than breast milk (Wickham, 2017). Wickham (2017) notes that not only has our knowledge on breastmilk increased, but a lot of the research carried out on breastmilk levels were done during a generation in which there were strict feeding time regimes, potentially making them irrelevant. Greer (2004) provided evidence supporting this claim by reporting that levels of VK were nearly double than what was reported as the norm in breastfed infants. Although such revelations came to light, Greer (2004) along with other researchers maintained that VK levels were still not high enough for babies (Wickham, 2017). We now know that colostrum and hind milk contain higher concentrations of VK (McEwan, 2017) and as lactation mature and the infant’s gut is colonised with bacteria, vitamin K levels will in turn increase (Pollard, 2018).
It is evident that breastmilk is vital for preterm neonates, however premature birth can be associated with delayed feeding, which is associated with VK deficiency. This highlights the importance of prophylactic treatment for the neonate, particularly in the preterm. As our knowledge increases throughout time, so should our practise, which should be challenged and evidence given as to why we do things. This leads the essay on to critically evaluate the correct dosages of prophylaxis for the newborn, another topic of great debate.
Dosage and Route of Vitamin K Administration
In the UK, all parents are offered a single dose of 1 mg vitamin K prophylaxis for their infants, which should be given intramuscularly (IM) as this is the most clinically and cost-effective method of administration (NICE, 2006). As Paige was born pre-term, a lower dose may be considered (McEwan, 2017) and oral VK can be offered but as a second-line option (NICE, 2006). Dosage and administration of VK will be critically discussed further and due to word count restraints there will be a focus on the pre-term infant, linked to evidence based research.
Pacifini (2016), highlighted that although the recommended 1mg VK dose does prevent VKDB in the term infant, it may be too high a dose for a very preterm infant, causing liver overload. A recent Systematic Review in 2016 identified a gap in the research with regards to the optimal dose of VK in preterm neonates with the authors recommending the need to evaluate the efficacy of using smaller doses (between 100 and 1000 mcg) of IM vitamin K in preterm infants (Sankar et al., 2016). Although this was an important finding, the main objectives of the review were two-fold and not related to preterm dosages. The objectives were to evaluate the burden of VKDB by estimating the incidence of late VKDB in infants who did not receive vitamin K prophylaxis at birth and to establish the effect of vitamin K prophylaxis on the incidence of classical and late VKDB in neonates and infants up to 1 year of age (Sankar et al., 2016). Only 5 citations were eligible for inclusion in the review, out of a significant 883 retrieved, highlighting the small scale of evidence available on VK dosages. Another recent Cochrane Systematic Review was undertaken to determine the effect of vitamin K prophylaxis in the prevention of vitamin K deficiency bleeding (VKDB) in preterm infants (Ardell et al., 2018). No eligible studies were found that compared vitamin K to no treatment even though pre-term infants are at more risk of VKDB compared to term infants due to delays in feeding and intestine colonisation as well as immaturity of liver and clotting functions (Ardell et al., 2018). Only one study by Clarke et al. (2008) was found in the review that compared dosage and route of vitamin K administration in preterm infants (Ardell et al., 2018) which assessed vitamin K status and metabolism in preterm infants after 3 regimens of prophylaxis. Because no other studies had compared VK regimes in preterm infants, the researchers chose an arbitrary sample size based on anticipated number of eligible infants admitted over an 18 month period. 98 out of 152 eligible infants all under 32 weeks’ gestation were randomised and 80 completed the study by receiving one of three vitamin K regimens: the control dose of 0.5 mg IM (intramuscularly), 0.2 mg of vitamin K1 IM, or 0.2 mg IV (intravenously) after birth (Clarke et al., 2008). PIVKA II protein levels and Vitamin K1 levels were measured by taking cord gas, blood on day 5 and 25. This allowed measurement of uptake, tissue stores and how well the liver metabolised VK. Concentration of the epoxide metabolite of vitamin K1 was also used to determine how much the premature liver could metabolise VK. Their data revealed those infants who were given the 0.2 mg IM prophylaxis maintained adequate vitamin K status of preterm infants and this dose did not cause an early significant build-up of vitamin K1 2,3-epoxide. However the 0.2 mg IV and 0.5 mg IM prophylaxis did the opposite, leading to vitamin K1 2,3-epoxide accumulation, which may be an indication that these methods are too much for the immature liver of the preterm infant to handle (Clarke et al., 2008). They recommended breastfed preterm are given 0.2-mg dose of prophylaxis and only when feeding has been well established, they should receive additional supplementation to prevent late onset VKDB. Although this study was of good quality as it as a randomised control study, the final sample size was only from 80 infants. Given the little research available regarding prophylactic dosages for the preterm infant, and relatively small scale sample size in the research available, further evidence is required with a larger sample size in order to draw any concrete conclusions. It has also been nearly a decade since this data was published, which is also a reason to welcome future, evidence based research.
Oral versus injectable – what is the evidence?