- Email: [email protected]
Vitamin K deficiency bleeding: Early history and recent trends in the United Kingdom
Early Human Development 86 (2010) S63–S65
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Vitamin K deficiency bleeding: Early history and recent trends in the United Kingdom Andrew McNinch Royal Devon and Exeter Foundation NHS Trust, Barrack Road, Exeter EX2 5DW, United Kingdom
a r t i c l e
i n f o
Keywords: Haemorrhagic disease of the newborn Vitamin K Vitamin K deficiency bleeding Vitamin K prophylaxis
a b s t r a c t At the start of the 20th century the mechanisms of haemostasis were virtually unknown. Townsend had coined the term ‘Haemorrhagic disease of the newborn’ in 1894 but it was not until the discovery of vitamin K (‘Koagulation vitamin’) by Dam and others in the 1930s that the condition became understood, allowing treatment and prophylaxis. Methods of prophylaxis (preparations used, doses and routes of administration), still widely debated, have varied with time and from one country to another. The formation of the British Paediatric Surveillance Unit in the 1980s has allowed a series of prospective population studies of Vitamin K deficiency bleeding (VKDB) in the United Kingdom (UK) and Ireland which, together with contemporaneous surveys of practices of vitamin K prophylaxis, have greatly improved our understanding of the condition and informed practices of prophylaxis. In the UK prophylaxis (by injection or by mouth) is now offered to every newborn baby and VKDB is very rare, most cases occurring in breastfed babies whose parents have refused prophylaxis; by contrast, in developing countries most babies do not receive prophylaxis and VKDB is probably a common (but poorly documented) cause of death and handicap in the early months of life. Vitamin K prophylaxis should be available to all newborn babies. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Early history Whilst the properties and functions of blood were the subjects of fascination and debate even in the times of Hippocrates (c460 BC), the mechanisms of haemostasis became gradually understood only in the 19th and (particularly) 20th centuries [1]. The fibrin in clots was described in 1832 by Johannes Müller; its postulated soluble precursor in the plasma was named fibrinogen by Rudolf Virchow and isolated in 1856 by Prosper Sylvain Denis; platelets were not described until 1865 and the earliest understanding of their function had to wait another 15 years [2]. The plight of congenital ‘bleeders’ (whom we now say to have ‘haemophilia’) was recognised in antiquity and became widely known after Prince Leopold (b.1853), son of Great Britain's Queen Victoria, died in 1884 after a fall [3,4] — but the haemophilias A and B were not properly understood or effectively treatable until the 1950s. The ‘four factor’ theory of blood clotting (the ‘factors’ being thromboplastin, prothrombin, calcium and fibrinogen) was not developed until the early 1900s; huge progress has subsequently been made, particularly since 1940 [1], but some details of the clotting mechanism are still to be elucidated. It is therefore understandable that at the end of the 19th century the common (and often fatal) occurrence of spontaneous bleeding in newborn babies was not understood and that an early edition of the American Textbook of Paediatrics stated, boldly but wrongly, that, ‘ …
E-mail address: [email protected]. 0378-3782/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2010.01.017
trauma at birth is by far the commonest cause’. This view was challenged in 1894 by Charles Townsend, a Boston physician, who reported a personal series of 50 cases [5]. He stressed that they were not caused by either trauma (the births had not been difficult and the bleeding was generalised rather than localised) or haemophilia (girls were affected as often as boys, there was no family history of ‘bleeders’ and, in the survivors, there was no later recurrence of bleeding). In all of his cases the bleeding began in the first few days after birth; 31 (62%) of the babies died, half of them within 24 h of the onset of bleeding and all within a week, whilst in all the survivors it stopped by day nine. Townsend could not explain the condition but, as some of the affected babies had fever, he felt infection might be involved; perhaps those cases had what we would now recognise as disseminated intravascular coagulation rather than vitamin K deficiency bleeding. His major contributions were to draw attention to the condition, state its incidence (1 in 150) and to give it a name, Haemorrhagic Disease of the Newborn, thereby ensuring that it did not sink back into obscurity. Nearly a century later it was recognised that the name had served its purpose well but had important limitations, describing what was seen without explaining the cause and often being confused with Haemolytic Disease of the Newborn, which describes a completely unrelated condition. For these reasons, and because the old term may, in the past, have been used in babies suffering from conditions other than vitamin K deficiency, the term ‘vitamin K deficiency bleeding’ (VKDB) is now much preferred and has become widely accepted since the 1990s. The work of Henrik Dam, a biochemist from Copenhagen who was working in Freiburg, Germany, brought new understanding to the
S64
A. McNinch / Early Human Development 86 (2010) S63–S65
condition. In the course of his studies into cholesterol metabolism, Dam fed chicks a fat-free diet; when they developed spontaneous bleeding he inferred that the fat of their normal diet must contain a substance essential for normal blood coagulation — in his paper of 1929 he coined the term ‘koagulation factor’ (spelt with a K in both Danish and German) for the mystery substance and, when he and co-workers isolated it in 1935 [6], it was named vitamin K (VK). Today it may be helpful to think of it as the ‘Karboxylation vitamin’ (The Danish/German spelling still serves) as a reminder of VK's essential function as a co-factor in the carboxylation of glutamate (Glu) to γ carboxyglutamate (Gla) residues, allowing calcium binding and so activating the ‘vitamin K dependent proteins’ (now known to include clotting factors II, VII, IX, X, proteins C and S in the blood; osteocalcin and matrix GLA proteins in bone; and Gla-containing proteins in a variety of other tissues). In the 1940s other important facts were established: giving just 90 ml of cow's milk to neonates in the first 2 days of life seemed to eliminate the risk of bleeding in a unit previously having an incidence of 0.84% [7]; oral vitamin K3 (menadione 1 mg) given prophylactically at birth reduced the incidence of neonatal deaths from bleeding from 2% to 0.45% [8]; and it was suggested earlier feeding, rather than the practice ‘in most civilised countries’ of delaying even until the second day, might also be protective [7]. By the 1950s the practice of giving VK prophylaxis at birth was becoming common (how common is not established), using synthetic preparations of VK in ever-increasing doses — presumably on the assumption that if tiny doses were beneficial (well-established), bigger doses might be better (conjecture). It is salutary to recall that in this post-war era science was often applied with great enthusiasm and apparently without due regard to possible consequences — numerous examples include the cavalier use of x-rays (eg to treat trival conditions such as tinea capitis and even to check the fit of new shoes on childrens' feet in high street shops); the giving of high concentrations of oxygen to premature babies, later found to cause retinopathy and blindness in many; indiscriminate use of insecticides wreaking havoc in the natural world. So it was with VK prophylaxis — a decade after a 1mg oral dose was shown to be dramatically effective in protecting term babies, in the UK doses of 60 mg or more of synthetic vitamin K3 (Synkavit, Roche) were given to premature babies before a rising incidence of kernicterus was noted and linked to the increasing doses of VK being routinely used [9–11]. A return to a standard 1mg dose was recommended as being both effective and safe in not causing haemolysis; Roche withdrew Synkavit and substituted Konakion containing the natural form of vitamin K1, which did not carry the same risk of causing haemolysis. Nevertheless this episode must have shaken confidence in VK prophylaxis (as would the ‘possible cancer link’ 30 years later [12]) and severely limited its widespread adoption – it is recorded that amongst 16,193 infants born in one week in Great Britain in 1970 (and followed up throughout childhood) only about 20% received VK at birth [13]. Whilst it is easy, with the benefit of hindsight, to be critical of some practices in those times we must also remember what different times they were; medical research, comprehensive surveillance and collaboration were so much more difficult to perform when travel was so slow and expensive, telephone communication (especially internationally) so poor and such invaluable aids as fax, the internet and personal computers were not dreamed of. We should admire what was learned and achieved; above all, we must remember (and pass on) the hard-learned lessons: significant changes in practice must be introduced with care, surveillance for short- and long-term side effects (as well as benefits) is essential and, as ever, ‘first do no harm’. 2. More recent experience in the United Kingdom Exeter (established on a Celtic foundation by the Roman 2nd Augustan Legion in 50AD) is a city of 110,000 people in the county of
Devon, southwest England. In the 1980s its neonatal unit served a birth population of some 5000 babies/year. VK prophylaxis used Konakion (Roche) 1 mg given intramuscularly — but, as was then common practice, it was given only to the babies considered most at risk of ‘haemorrhagic disease’: those born pre-term or by traumatic delivery, those who were sick in any way or born to mothers taking anticonvulsants; sole breast-feeding was not a criterion for VK prophylaxis. This selective practice seemed to work, a retrospective review finding no documented case in Exeter of what we would now call VKDB in the 10 years before 1980 — but we then saw 6 cases in 18 months (∼1 in 1200 births). All involved term babies who were solely breast fed from birth; none had been selected to have VK (one in error, the mother having been treated with phenobarbital in pregnancy); 3 of the babies died [14]. This experience demanded that we change our policy to giving VK prophylaxis to every baby and made us wonder whether other neonatal units in the country were also experiencing a resurgence of ‘haemorrhagic disease’. The British Paediatric Surveillance Unit had recently been formed and was the perfect tool to allow national prospective surveillance of the condition [15]; a concurrent national survey of VK prophylaxis policies was also conducted, by postal questionnaire [16]. This pair of surveys in the late 1980s established baseline data, some of the most important of which were: – 27 cases of ‘haemorrhagic disease of the newborn’(25 confirmed, 2 ‘probable’) in 2 years, incidence 1.62/100,000 births – 24 of the affected babies had been solely breast fed – 57% of all babies at the time were born in units recommending intramuscular (IM) VK for all babies; some ‘high risk’ babies born in units recommending oral VK or none routinely would also have received it IM — yet no baby receiving IM prophylaxis was reported to develop bleeding – 30% of all babies were born in units recommending a single oral dose of VK as routine (IM recommended selectively for ‘high risk’ babies). 7/27 cases bled after oral prophylaxis – Only 13% of all babies were born in units recommending no VK prophylaxis routinely (IM recommended selectively for ‘high risk’ babies) — but 20/27 cases who bled came from this small subgroup – The 7 babies who bled after a single oral dose of VK presented significantly later than the 20 who had had no VK, suggesting that repeated oral doses might ‘repeatedly delay’ bleeding and so give secure protection – 6/27 babies were found, after presenting with bleeding, to have previously- unsuspected underlying liver disease. Better screening for prolonged jaundice or failure to thrive might have allowed earlier detection of the liver diseases and treatment before bleeding occurred – 14/27 cases had delayed presentation of 1–14 days after the onset of apparently trivial bleeding such as oozing from the umbilicus or after the ‘Guthrie’ screening heel-prick, or bruising or nose-bleeds; had the significance of these ‘warning bleeds’ been recognised immediately, later devastating bleeds could have been avoided (For example, intracranial haemorrhage (ICH) occurred after ‘warning bleeds’ in 7 cases) – 10/27 suffered ICH; 2 of them died and there was concern about future development in all the survivors The paired studies have since been repeated 3 times [17–19] (full data from the fourth studies await publication) and have shown the following data and trends in the United Kingdom: – VK prophylaxis is now routinely offered to virtually every newborn baby – In 2003 some 60% of babies were offered IM as routine, 40% an oral regimen (of which there was a variety) – Oral prophylaxis now routinely involves at least 2 doses and extends beyond 1 week of age in breast fed babies
A. McNinch / Early Human Development 86 (2010) S63–S65
– The incidence, mortality and morbidity of VKDB have all declined significantly but the condition is not eliminated. In the most recent published study there were 7 cases in 2 years; fortunately all affected babies survived without sequelae – In most cases of VKDB the babies have been solely breast fed and have received no VK prophylaxis — now most commonly because parents have refused the offered prophylaxis – IM prophylaxis using Konakion (Roche) 1 mg almost guaranteed protection against VKDB (3 exceptions notified to the first three BPSU studies), even in babies with underlying liver disease — but the preparation has now been withdrawn in Europe. The substitute, Konakion MM (Roche), is currently the only preparation licensed for IM, IV and oral prophylaxis in the UK but there are no large studies published to document its effectiveness; the fourth pair of UK studies, carried out since Konakion (Roche) was withdrawn, will address that deficiency. 3. Tasks for the future The effectiveness of VK prophylaxis in preventing VKDB is established but its expense means that most babies do not receive it in developing countries, where VKDB is known to be more common but is poorly documented; prophylaxis should be available to all newborns worldwide in safe, practical and affordable form. In the United Kingdom there is an urgent need for a licensed oral preparation which parents can administer to their babies, preferably as drops given daily; issues of dose, formulation and bioavailability must be addressed. IM prophylaxis is certainly necessary in the most vulnerable babies, but some parents refuse it outright and others rightly question the recommendation that apparently-well babies be injected with a vitamin which can be absorbed orally (Formula feeding, which gives a small dose of oral VK prophylaxis with every feed, gives effective protection against VKDB even in babies with liver disease). Parents, as well as primary care staff, need education to be alert to signs suggesting particular vulnerability to VK deficiency (poor weight gain, jaundice persisting beyond 2 weeks of age, pale stools or persistently-dark urine). Any unexplained bruising or bleeding, however apparently trivial, should be regarded as a medical emergency — whether caused by VK deficiency, some other bleeding disorder or non-accidental injury, it may be the first and only warning of imminent disaster. Last but not least, we must continue to promote breast-feeding. Conflict of interest statement Roche pharmaceuticals contributed funding to the early vitamin K studies in Exeter and sponsored the author to present work at two international conferences.
S65
Acknowledgements All of the Exeter work on vitamin K and VKDB has been done in collaboration with colleagues, particularly Drs John Tripp and Alison Busfield. The surveillance studies would not have been possible without the organisation of the British Paediatric Surveillance Unit and the generosity of the many paediatricians who notified cases to us. References [1] Hougie C. Thrombosis and bleeding: an era of discovery. Trafford Publishing1412032407; 2004. [2] Brewer D.B., Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol 2006; 133 (3): 251–8 [3] Anonymous. The haemorrhagic diathesis. BMJ 1884;1:686. [4] Anonymous. The death of the Duke of Albany. BMJ 1884;1:690. [5] Townsend CW. The haemorrhagic disease of the newborn. Arch Paediatr 1894;11: 559–65. [6] Dam H, Shonheyder. The antihaemorrhagic vitamin of the chick. Nature 1935;133: 652–3. [7] Salomonsen L. On the prevention of haemorrhagic disease of the newborn by the administration of cow's milk during the first 2 days of life. Acta Paediatr 1940;28:1–7. [8] Lehman J. Vitamin K as prophylaxis in 13,000 infants. Lancet 1944;i:493–4. [9] Laurance B. Danger of vitamin-K analogues to newborn. Lancet 1955;265:819. [10] Bound JP, Telfer TP. Effect of vitamin-K dosage on plasma–bilirubin levels in premature infants. Lancet 1956;1:720–2. [11] Meyer TC, Angus J. The effect of large doses of ‘Synkavit’ in the newborn. Arch Dis Child 1956;31:212–5. [12] Fear NT, Roman E, Ansell E, Simpson J, Day N, Eden OB. United Kingdom Childhood Cancer Study Investigators. Vitamin K and childhood cancer: a report from the United Kingdom childhood cancer study. Br J Cancer 2003;89:1228–31. [13] Chamberlain R, Chamberlain G, Howlett B, Claireaux A. British births. Obstetric Care, vol. 2. London: Heinemann Medical Publications; 1975. [14] McNinch AW, Orme RL'E, Tripp JH. Haemorrhagic disease of the newborn returns. Lancet 1983;1:1089–90. [15] McNinch AW, Tripp JH. Haemorrhagic disease of the newborn in the British Isles: two year prospective study. BMJ 1991;303:1105–9. [16] Handel J, Tripp JH. Vitamin K prophylaxis against haemorrhagic disease of the newborn in the United Kingdom. BMJ 1991;303:1109. [17] Barton J., Tripp J.H., McNinch A.W. Neonatal vitamin K prophylaxis in the British Isles: current practice and trends. BMJ 1995;310:632–3. [18] McNinch A, Busfield A, Tripp J. Vitamin K deficiency bleeding in Great Britain and Ireland: British Paediatric Surveillance Unit Surveys, 1993–1994 and 2001–2002. Arch Dis Child 2007;92:759–66. [19] Busfield A, McNinch A, Tripp J. Neonatal vitamin K prophylaxis in Great Britain and Ireland: the impact of perceived risk and product licensing on effectiveness. Arch Dis Child 2007;92:754–8.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Vitamin K deficiency bleeding: Early history and recent trends in the United Kingdom Andrew McNinch Royal Devon and Exeter Foundation NHS Trust, Barrack Road, Exeter EX2 5DW, United Kingdom
a r t i c l e
i n f o
Keywords: Haemorrhagic disease of the newborn Vitamin K Vitamin K deficiency bleeding Vitamin K prophylaxis
a b s t r a c t At the start of the 20th century the mechanisms of haemostasis were virtually unknown. Townsend had coined the term ‘Haemorrhagic disease of the newborn’ in 1894 but it was not until the discovery of vitamin K (‘Koagulation vitamin’) by Dam and others in the 1930s that the condition became understood, allowing treatment and prophylaxis. Methods of prophylaxis (preparations used, doses and routes of administration), still widely debated, have varied with time and from one country to another. The formation of the British Paediatric Surveillance Unit in the 1980s has allowed a series of prospective population studies of Vitamin K deficiency bleeding (VKDB) in the United Kingdom (UK) and Ireland which, together with contemporaneous surveys of practices of vitamin K prophylaxis, have greatly improved our understanding of the condition and informed practices of prophylaxis. In the UK prophylaxis (by injection or by mouth) is now offered to every newborn baby and VKDB is very rare, most cases occurring in breastfed babies whose parents have refused prophylaxis; by contrast, in developing countries most babies do not receive prophylaxis and VKDB is probably a common (but poorly documented) cause of death and handicap in the early months of life. Vitamin K prophylaxis should be available to all newborn babies. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Early history Whilst the properties and functions of blood were the subjects of fascination and debate even in the times of Hippocrates (c460 BC), the mechanisms of haemostasis became gradually understood only in the 19th and (particularly) 20th centuries [1]. The fibrin in clots was described in 1832 by Johannes Müller; its postulated soluble precursor in the plasma was named fibrinogen by Rudolf Virchow and isolated in 1856 by Prosper Sylvain Denis; platelets were not described until 1865 and the earliest understanding of their function had to wait another 15 years [2]. The plight of congenital ‘bleeders’ (whom we now say to have ‘haemophilia’) was recognised in antiquity and became widely known after Prince Leopold (b.1853), son of Great Britain's Queen Victoria, died in 1884 after a fall [3,4] — but the haemophilias A and B were not properly understood or effectively treatable until the 1950s. The ‘four factor’ theory of blood clotting (the ‘factors’ being thromboplastin, prothrombin, calcium and fibrinogen) was not developed until the early 1900s; huge progress has subsequently been made, particularly since 1940 [1], but some details of the clotting mechanism are still to be elucidated. It is therefore understandable that at the end of the 19th century the common (and often fatal) occurrence of spontaneous bleeding in newborn babies was not understood and that an early edition of the American Textbook of Paediatrics stated, boldly but wrongly, that, ‘ …
E-mail address: [email protected]. 0378-3782/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2010.01.017
trauma at birth is by far the commonest cause’. This view was challenged in 1894 by Charles Townsend, a Boston physician, who reported a personal series of 50 cases [5]. He stressed that they were not caused by either trauma (the births had not been difficult and the bleeding was generalised rather than localised) or haemophilia (girls were affected as often as boys, there was no family history of ‘bleeders’ and, in the survivors, there was no later recurrence of bleeding). In all of his cases the bleeding began in the first few days after birth; 31 (62%) of the babies died, half of them within 24 h of the onset of bleeding and all within a week, whilst in all the survivors it stopped by day nine. Townsend could not explain the condition but, as some of the affected babies had fever, he felt infection might be involved; perhaps those cases had what we would now recognise as disseminated intravascular coagulation rather than vitamin K deficiency bleeding. His major contributions were to draw attention to the condition, state its incidence (1 in 150) and to give it a name, Haemorrhagic Disease of the Newborn, thereby ensuring that it did not sink back into obscurity. Nearly a century later it was recognised that the name had served its purpose well but had important limitations, describing what was seen without explaining the cause and often being confused with Haemolytic Disease of the Newborn, which describes a completely unrelated condition. For these reasons, and because the old term may, in the past, have been used in babies suffering from conditions other than vitamin K deficiency, the term ‘vitamin K deficiency bleeding’ (VKDB) is now much preferred and has become widely accepted since the 1990s. The work of Henrik Dam, a biochemist from Copenhagen who was working in Freiburg, Germany, brought new understanding to the
S64
A. McNinch / Early Human Development 86 (2010) S63–S65
condition. In the course of his studies into cholesterol metabolism, Dam fed chicks a fat-free diet; when they developed spontaneous bleeding he inferred that the fat of their normal diet must contain a substance essential for normal blood coagulation — in his paper of 1929 he coined the term ‘koagulation factor’ (spelt with a K in both Danish and German) for the mystery substance and, when he and co-workers isolated it in 1935 [6], it was named vitamin K (VK). Today it may be helpful to think of it as the ‘Karboxylation vitamin’ (The Danish/German spelling still serves) as a reminder of VK's essential function as a co-factor in the carboxylation of glutamate (Glu) to γ carboxyglutamate (Gla) residues, allowing calcium binding and so activating the ‘vitamin K dependent proteins’ (now known to include clotting factors II, VII, IX, X, proteins C and S in the blood; osteocalcin and matrix GLA proteins in bone; and Gla-containing proteins in a variety of other tissues). In the 1940s other important facts were established: giving just 90 ml of cow's milk to neonates in the first 2 days of life seemed to eliminate the risk of bleeding in a unit previously having an incidence of 0.84% [7]; oral vitamin K3 (menadione 1 mg) given prophylactically at birth reduced the incidence of neonatal deaths from bleeding from 2% to 0.45% [8]; and it was suggested earlier feeding, rather than the practice ‘in most civilised countries’ of delaying even until the second day, might also be protective [7]. By the 1950s the practice of giving VK prophylaxis at birth was becoming common (how common is not established), using synthetic preparations of VK in ever-increasing doses — presumably on the assumption that if tiny doses were beneficial (well-established), bigger doses might be better (conjecture). It is salutary to recall that in this post-war era science was often applied with great enthusiasm and apparently without due regard to possible consequences — numerous examples include the cavalier use of x-rays (eg to treat trival conditions such as tinea capitis and even to check the fit of new shoes on childrens' feet in high street shops); the giving of high concentrations of oxygen to premature babies, later found to cause retinopathy and blindness in many; indiscriminate use of insecticides wreaking havoc in the natural world. So it was with VK prophylaxis — a decade after a 1mg oral dose was shown to be dramatically effective in protecting term babies, in the UK doses of 60 mg or more of synthetic vitamin K3 (Synkavit, Roche) were given to premature babies before a rising incidence of kernicterus was noted and linked to the increasing doses of VK being routinely used [9–11]. A return to a standard 1mg dose was recommended as being both effective and safe in not causing haemolysis; Roche withdrew Synkavit and substituted Konakion containing the natural form of vitamin K1, which did not carry the same risk of causing haemolysis. Nevertheless this episode must have shaken confidence in VK prophylaxis (as would the ‘possible cancer link’ 30 years later [12]) and severely limited its widespread adoption – it is recorded that amongst 16,193 infants born in one week in Great Britain in 1970 (and followed up throughout childhood) only about 20% received VK at birth [13]. Whilst it is easy, with the benefit of hindsight, to be critical of some practices in those times we must also remember what different times they were; medical research, comprehensive surveillance and collaboration were so much more difficult to perform when travel was so slow and expensive, telephone communication (especially internationally) so poor and such invaluable aids as fax, the internet and personal computers were not dreamed of. We should admire what was learned and achieved; above all, we must remember (and pass on) the hard-learned lessons: significant changes in practice must be introduced with care, surveillance for short- and long-term side effects (as well as benefits) is essential and, as ever, ‘first do no harm’. 2. More recent experience in the United Kingdom Exeter (established on a Celtic foundation by the Roman 2nd Augustan Legion in 50AD) is a city of 110,000 people in the county of
Devon, southwest England. In the 1980s its neonatal unit served a birth population of some 5000 babies/year. VK prophylaxis used Konakion (Roche) 1 mg given intramuscularly — but, as was then common practice, it was given only to the babies considered most at risk of ‘haemorrhagic disease’: those born pre-term or by traumatic delivery, those who were sick in any way or born to mothers taking anticonvulsants; sole breast-feeding was not a criterion for VK prophylaxis. This selective practice seemed to work, a retrospective review finding no documented case in Exeter of what we would now call VKDB in the 10 years before 1980 — but we then saw 6 cases in 18 months (∼1 in 1200 births). All involved term babies who were solely breast fed from birth; none had been selected to have VK (one in error, the mother having been treated with phenobarbital in pregnancy); 3 of the babies died [14]. This experience demanded that we change our policy to giving VK prophylaxis to every baby and made us wonder whether other neonatal units in the country were also experiencing a resurgence of ‘haemorrhagic disease’. The British Paediatric Surveillance Unit had recently been formed and was the perfect tool to allow national prospective surveillance of the condition [15]; a concurrent national survey of VK prophylaxis policies was also conducted, by postal questionnaire [16]. This pair of surveys in the late 1980s established baseline data, some of the most important of which were: – 27 cases of ‘haemorrhagic disease of the newborn’(25 confirmed, 2 ‘probable’) in 2 years, incidence 1.62/100,000 births – 24 of the affected babies had been solely breast fed – 57% of all babies at the time were born in units recommending intramuscular (IM) VK for all babies; some ‘high risk’ babies born in units recommending oral VK or none routinely would also have received it IM — yet no baby receiving IM prophylaxis was reported to develop bleeding – 30% of all babies were born in units recommending a single oral dose of VK as routine (IM recommended selectively for ‘high risk’ babies). 7/27 cases bled after oral prophylaxis – Only 13% of all babies were born in units recommending no VK prophylaxis routinely (IM recommended selectively for ‘high risk’ babies) — but 20/27 cases who bled came from this small subgroup – The 7 babies who bled after a single oral dose of VK presented significantly later than the 20 who had had no VK, suggesting that repeated oral doses might ‘repeatedly delay’ bleeding and so give secure protection – 6/27 babies were found, after presenting with bleeding, to have previously- unsuspected underlying liver disease. Better screening for prolonged jaundice or failure to thrive might have allowed earlier detection of the liver diseases and treatment before bleeding occurred – 14/27 cases had delayed presentation of 1–14 days after the onset of apparently trivial bleeding such as oozing from the umbilicus or after the ‘Guthrie’ screening heel-prick, or bruising or nose-bleeds; had the significance of these ‘warning bleeds’ been recognised immediately, later devastating bleeds could have been avoided (For example, intracranial haemorrhage (ICH) occurred after ‘warning bleeds’ in 7 cases) – 10/27 suffered ICH; 2 of them died and there was concern about future development in all the survivors The paired studies have since been repeated 3 times [17–19] (full data from the fourth studies await publication) and have shown the following data and trends in the United Kingdom: – VK prophylaxis is now routinely offered to virtually every newborn baby – In 2003 some 60% of babies were offered IM as routine, 40% an oral regimen (of which there was a variety) – Oral prophylaxis now routinely involves at least 2 doses and extends beyond 1 week of age in breast fed babies
A. McNinch / Early Human Development 86 (2010) S63–S65
– The incidence, mortality and morbidity of VKDB have all declined significantly but the condition is not eliminated. In the most recent published study there were 7 cases in 2 years; fortunately all affected babies survived without sequelae – In most cases of VKDB the babies have been solely breast fed and have received no VK prophylaxis — now most commonly because parents have refused the offered prophylaxis – IM prophylaxis using Konakion (Roche) 1 mg almost guaranteed protection against VKDB (3 exceptions notified to the first three BPSU studies), even in babies with underlying liver disease — but the preparation has now been withdrawn in Europe. The substitute, Konakion MM (Roche), is currently the only preparation licensed for IM, IV and oral prophylaxis in the UK but there are no large studies published to document its effectiveness; the fourth pair of UK studies, carried out since Konakion (Roche) was withdrawn, will address that deficiency. 3. Tasks for the future The effectiveness of VK prophylaxis in preventing VKDB is established but its expense means that most babies do not receive it in developing countries, where VKDB is known to be more common but is poorly documented; prophylaxis should be available to all newborns worldwide in safe, practical and affordable form. In the United Kingdom there is an urgent need for a licensed oral preparation which parents can administer to their babies, preferably as drops given daily; issues of dose, formulation and bioavailability must be addressed. IM prophylaxis is certainly necessary in the most vulnerable babies, but some parents refuse it outright and others rightly question the recommendation that apparently-well babies be injected with a vitamin which can be absorbed orally (Formula feeding, which gives a small dose of oral VK prophylaxis with every feed, gives effective protection against VKDB even in babies with liver disease). Parents, as well as primary care staff, need education to be alert to signs suggesting particular vulnerability to VK deficiency (poor weight gain, jaundice persisting beyond 2 weeks of age, pale stools or persistently-dark urine). Any unexplained bruising or bleeding, however apparently trivial, should be regarded as a medical emergency — whether caused by VK deficiency, some other bleeding disorder or non-accidental injury, it may be the first and only warning of imminent disaster. Last but not least, we must continue to promote breast-feeding. Conflict of interest statement Roche pharmaceuticals contributed funding to the early vitamin K studies in Exeter and sponsored the author to present work at two international conferences.
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Acknowledgements All of the Exeter work on vitamin K and VKDB has been done in collaboration with colleagues, particularly Drs John Tripp and Alison Busfield. The surveillance studies would not have been possible without the organisation of the British Paediatric Surveillance Unit and the generosity of the many paediatricians who notified cases to us. References [1] Hougie C. Thrombosis and bleeding: an era of discovery. Trafford Publishing1412032407; 2004. [2] Brewer D.B., Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol 2006; 133 (3): 251–8 [3] Anonymous. The haemorrhagic diathesis. BMJ 1884;1:686. [4] Anonymous. The death of the Duke of Albany. BMJ 1884;1:690. [5] Townsend CW. The haemorrhagic disease of the newborn. Arch Paediatr 1894;11: 559–65. [6] Dam H, Shonheyder. The antihaemorrhagic vitamin of the chick. Nature 1935;133: 652–3. [7] Salomonsen L. On the prevention of haemorrhagic disease of the newborn by the administration of cow's milk during the first 2 days of life. Acta Paediatr 1940;28:1–7. [8] Lehman J. Vitamin K as prophylaxis in 13,000 infants. Lancet 1944;i:493–4. [9] Laurance B. Danger of vitamin-K analogues to newborn. Lancet 1955;265:819. [10] Bound JP, Telfer TP. Effect of vitamin-K dosage on plasma–bilirubin levels in premature infants. Lancet 1956;1:720–2. [11] Meyer TC, Angus J. The effect of large doses of ‘Synkavit’ in the newborn. Arch Dis Child 1956;31:212–5. [12] Fear NT, Roman E, Ansell E, Simpson J, Day N, Eden OB. United Kingdom Childhood Cancer Study Investigators. Vitamin K and childhood cancer: a report from the United Kingdom childhood cancer study. Br J Cancer 2003;89:1228–31. [13] Chamberlain R, Chamberlain G, Howlett B, Claireaux A. British births. Obstetric Care, vol. 2. London: Heinemann Medical Publications; 1975. [14] McNinch AW, Orme RL'E, Tripp JH. Haemorrhagic disease of the newborn returns. Lancet 1983;1:1089–90. [15] McNinch AW, Tripp JH. Haemorrhagic disease of the newborn in the British Isles: two year prospective study. BMJ 1991;303:1105–9. [16] Handel J, Tripp JH. Vitamin K prophylaxis against haemorrhagic disease of the newborn in the United Kingdom. BMJ 1991;303:1109. [17] Barton J., Tripp J.H., McNinch A.W. Neonatal vitamin K prophylaxis in the British Isles: current practice and trends. BMJ 1995;310:632–3. [18] McNinch A, Busfield A, Tripp J. Vitamin K deficiency bleeding in Great Britain and Ireland: British Paediatric Surveillance Unit Surveys, 1993–1994 and 2001–2002. Arch Dis Child 2007;92:759–66. [19] Busfield A, McNinch A, Tripp J. Neonatal vitamin K prophylaxis in Great Britain and Ireland: the impact of perceived risk and product licensing on effectiveness. Arch Dis Child 2007;92:754–8.