Acta Paediatr 81: 655-7. 1992
Vitamin K prophylaxis and vitamin K deficiency bleeding (VKDB) in early infancy Riidiger von Kries and Ulrich Gobel' Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, London. U K and Children's Hospital'. Heinrich Heine Universitat, Diisseldorf. Department Paediatric Haematology and Oncology, Uiisseldorf. Germany
von Kries R, Gobel U. Vitamin K prophylaxis and vitamin K deficiency bleeding (VKDB) in early infancy. Acta Psdiatr 1992;81:655-7. Stockholm. ISSN 0803-5253 The efficacy of vitamin K prophylaxis (1 mg im or sc, or 1-2 mg orally both given as a single dose at birth) in the prevention of vitamin K deficiency bleeding in early infancy was estimated in Germany during a 15-month period between 1988 i n d 1989. Cases were identified by a survey bf all paediatric hospitals and population denominators by a survey of all obstetric hospitals. Response rates were 85% and 68%, respectively. Thirteen cases of vitamin K deficiency bleeding in early infancy with confirmed prophylactic states were confirmed, seven of whom had intracranial haemorrhage. The estimated efficacy of single parenteral administration of vitamin K versus no prophylaxis was 96.7% (95% confidence interval: 74-99.6%) and for single oral administration versus no prophylaxis 80.4% (9.195.6Y0). Single parenteral vitamin K prophylaxis gave substantial protection against vitamin K deficiency bleeding in early infancy. Single oral prophylaxis appeared to be less effective, dthough the difference was not significant, as indicated by the wide overlap of the respective 95% confidence intervals. 0 Infancy, vitamin K deficiency bleeding. vitamin K prophylaxis R. von Kries. Children$ Hospital, Heinrich Heine University, Diisseldorf, Moorenstr. 5,4000 Diisseldorf I , Germany
Classical haemorrhagic disease of newborn (HDN) is caused by vitamin K deficiency and accounts for gastrointestinal, nasal, skin and circumcision bleeding in the first week of life (I). Vitamin K deficiency bleeding (VKDB) in early infancy has only recently been recognized as a bleeding disorder due to vitamin K deficiency in early infancy with a distinct clinical picture. Most cases occur in three to six-week-old, fully breast-fed infants and intracranial haemorrhage, accounting for death and serious neurologic and mental handicap, occurs in about 50% of the cases (I). Vitamin K prophylaxis is considered safe and effective in preventing classical H D N and has been a common practice in the USA since 1961 (1). Whether vitamin K prophylaxis, administered within the first hours of life, can prevent VKDB in early infancy also, has been questioned (2,3). Analysis of cumulated cases of VKDB in early infancy from different countries showed that the vast majority of cases had not received vitamin K prophylaxis (1). Studies assessing both vitamin K prophylaxis and cases of VKDB in early infancy in a population are needed. We performed such a study in Germany.
Patients and methods The use of vitamin K prophylaxis in all obstetric hospitals in West Germany (n= 1141) in March 1988 was assessed by a questionnaire which asked whether or not vitamin K prophylaxis was given, to whom and by what route. The number of cases of VKDB in early
infancy from January I , 1988 to March 31, 1989 and exposure to vitamin K prophylaxis were collected by a questionnaire sent to all paediatric hospitals in West Germany (n=225) in March 1989. For all reported cases, we asked for an anonymous hospital discharge letter and validated the diagnosis of VKDB in early infancy with respect to our case definition: bleeding at any site in an infant older than 1 week and less than 16 weeks, associated with decreased Quicks's prothrombin index to less than 10%of normal adult values, returning to normal within 24 h after vitamin K administration. Risk ratios, confidence intervals and significance tests were calculated using Epi Info, a computer package released by the Centers for DBease Control, Atlanta Georgia, USA.
Results The response rate to the questionnaire for the paediatric hospitals was 85%. Seventeen hospitals reported and sent hospital discharge letters for 19 cases. The initial diagnosis proved wrong in 5 cases: 14 cases fulfilled the criteria of the case definition. In all of these cases, Quick's prothrombin time was well below lo%, as clot formation was not observed within 2 min. The aPTT was greater than 60 s in all and above 3 min in 1 1 of 14 cases. The bleeding sites were: CNS (n = 7), gastrointestinal ( n =4), skin (n=2) and epistaxis (n= 1). Three of the cases with intracranial haemorrhage had been preceded
656
R von Kries and U Gobel
ACTA PRDIATR 81 (1992)
by skin or mucosal bleeding 1 to 3 days before the event leading to diagnosis. The sequelae of CNS haemorrhage, detectable by the time of reporting were: death (n = l), epilepsy (n = 2), hemiparesis (n = 1) and hydrocephalus (n= 1). The age spectrum for all cases of VKDB in early infancy was 2 to 7 weeks (median 4 weeks). Information on feeding was given for 10 cases, all of whom had been exclusively breast fed except for one who had soy milk based formula. Direct bilirubin was determined in 3 of 14 cases. Values greater than agerelated normal ranges were found in 2 of 3 cases. Ten of the 14 cases had not received prophylactic vitamin K at birth, 1 had been given vitamin K I 1 mg im, 2 had been given a single oral dose of 2 mg and in 1 case the history of prophylaxis remained unclear. The response rate to the questionnaire sent to the obstetric hospitals was 68%. The proportion of replies was: large community hospitals (loo%), university hospitals (61 %) and small hospitals (58%). The distribution of vitamin K prophylaxis policy was very similar among different types of hospital. Thus the assumption was made that vitamin K prophylaxis distribution in all births was identical to that in hospitals. As the number of babies born in individual hospitals was not available, a figure for babies exposed to either form of vitamin K prophylaxis from January 1988 to March 1989 was estimated from the number of births (750000) and the reported proportions of different practices for vitamin K prophylaxis in the hospitals that replied (Table I ) . Single parenteral vitamin K prophylaxis (1 mg im or sc) was given to all babies in 55.8% of the hospitals, whereas 37.2% of the hospitals had a “risk-guided’’ policy. Preterm, small-for-dates, non-vaginally delivered babies and babies with neonatal disease were considered at risk. “Non-risk” babies received single oral prophylaxis in 5% and no prophylaxis in the other 50% of these hospitals. “At-risk’’ babies were always given single parenteral vitamin K prophylaxis. Very few hospitals gave no prophylaxis or single oral prophylaxis only. The group “unclassified” comprises hospitals that gave either repeated doses or whose reports were inconclusive. As the proportion of babies considered at risk is not known exactly, the figure quoted for babies given single parenteral vitamin K is a minimum. Similarly, the figure quoted for babies in the other two specified groups (Table 2) is a maximum.
-
The incidence of VKDB in early infancy suggested from these data are I in 14000 for no prophylaxis, 1 in 70 000 for single oral prophylaxis and 1 in 42 0000 for single parenteral vitamin K prophylaxis. As VKDB in early infancy presents with intracranial haemorrhage in approximately 50% of cases, death or neurological sequelae would be expected in approximately 1 in 30 000 infants (accounting for 20 cases per year in West Germany), if no vitamin K prophylaxis were given. The respective relative risk (RR)of VKDB in early infancy for babies not given vitamin K compared to those given single parenteral vitamin K prophylaxis is 30.3 (95% confidence interval 3.9-235.6) (Table 2). As this RR calculation is based on the minimum number of babies receiving single parenteral administration and the maximum number of babies receiving no vitamin K prophylaxis, the true RR is likely to be even higher. Expressed in terms of vaccine efficacy (4), this relative risk represents an efficacy of 96.7% (74-99.6%). The protective effect of single oral vitamin K prophylaxis was less impressive (Table 2). The RR was 5.1 Yo (1.1-23.1 %). Expressed in terms of vaccine efficacy (4), this RR represents an efficacy of 80.4% (9. I-95.6%). The difference in the efficacy of a single oral dose and parenteral prophylaxis was not significant (p = 0.157; Fisher’s exact test). The risk ratio of single oral to parenteral prophylaxis was 5.97. The confidence intervals, however, were wide ranging; from twofold reduction of the risk for oral prophylaxis to an increase in the risk by a factor of 66.
Discussion A review of cases of VKDB in early infancy, reported in the literature, suggested that vitamin K prophylaxis administered at birth might be protective against VKDB in early infancy (1). This was also suggested from surveillance data for VKDB in early infancy in West
Table 2. VKDB in early infancy in West Germany in patients given no prophylaxis compared with single parenteral or oral vitamin K prophylaxis.
VKDB in early infancy Present
Table 1. Vitamin K prophylaxis in West Germany, calculated from questionnaire response (response rate 68%) from all obstetric hospitals in March 1988, relative proportions of different vitamin K prophylactic practices and estimated number of babies exposed from January I, 1988 to March 30, 1989.
of hospitals
Estimated No. exposed
55.8 18.7 18.5
418 500 140 250 138 150 52 500
%
Prophylaxis Single parenteral for all All oral-“at-risk” single parenteral None or “at-risk” single parenteral only Unclassified
7
Absent
No prophylaxis vs single parenteral No prophylaxis 10 Single parenteral prophylaxis I Risk ratio: 30.3; 95% Confidence interval: 3.9-235.6%
138 750 418500
N o prophylaxis vs single oral No prophylaxis 10 Single oral prophylaxis 2 Risk ratio: 5.1; 95% confidence interval: 1.1-23.1%
138 750 I40 250
Single oral vs single parenteral Single oral prophylaxis 2 Single parenteral prophylaxis 1 Risk ratio: 5.97; 95% confidence interval: 0.5-65.8%”
140 250 418500
Neonatal vitamin K prophylaxis
ACTA PEDIATR 81 (1992)
Germany published by Sutor & Scharbau (9, who demonstrated a decrease in incident cases of VKDB in early infancy following the recommendation of vitamin K prophylaxis in Germany. In order to substantiate this view further, by means of appropriate epidemiological methods, an analytical study was performed on a subset of cases. These had been collected with an active surveillance scheme for a time period during which the practice of vitamin K prophylaxis could be estimated from survey data. The response rate for paediatric hospitals for active surveillance of VKDB in early infancy was 85%, suggesting that most suspected cases of VKDB in early infancy had been reported. The numbers of babies exposed to either form of vitamin K prophylaxis are potentially subject to bias as a result of misclassification and non-response. The numbers of babies exposed to either form of vitamin K prophylaxis was estimated from the proportion of different practices in the hospitals that replied. This procedure is justified as the relative proportions of different forms of vitamin K prophylaxis was independent of the hospital size. As hospital policies for nursing procedures tend to be followed, random misclassification on an individual level should be negligible. Nonrandom misclassification is a possibility, in that obstetric hospital response probability may have been influenced by their prophylaxis policy. This would tend to overestimate the total proportion of babies receiving vitamin K prophylaxis. Even assuming the most extreme casethat all non-responding hospitals gave no vitamin K prophylaxis at all-a significant protective effect of single parenteral vitamin K prophylaxis on VKDB in early infancy would be retained ( p =0.013). These data, therefore, give substantial evidence for a protective effect of single parenteral vitamin K prophylaxis in VKDB in early infancy. This finding is in agreement with the results of a recent study in the UK (6). There is good evidence that single oral and single parenteral vitamin K prophylaxis are equivalent with respect to classical VKDB in early infancy (7). Our data suggest that single parenteral vitamin K prophylaxis is more effective than single oral vitamin K prophylaxis in preventing VKDB in early infancy although there was no significant difference between the two treatments. Similar findings have been reported from the UK (6), Switzerland (8) and Sweden (9), with significance levels just less than p
Vitamin K prophylaxis and vitamin K deficiency bleeding (VKDB) in early infancy Riidiger von Kries and Ulrich Gobel' Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, London. U K and Children's Hospital'. Heinrich Heine Universitat, Diisseldorf. Department Paediatric Haematology and Oncology, Uiisseldorf. Germany
von Kries R, Gobel U. Vitamin K prophylaxis and vitamin K deficiency bleeding (VKDB) in early infancy. Acta Psdiatr 1992;81:655-7. Stockholm. ISSN 0803-5253 The efficacy of vitamin K prophylaxis (1 mg im or sc, or 1-2 mg orally both given as a single dose at birth) in the prevention of vitamin K deficiency bleeding in early infancy was estimated in Germany during a 15-month period between 1988 i n d 1989. Cases were identified by a survey bf all paediatric hospitals and population denominators by a survey of all obstetric hospitals. Response rates were 85% and 68%, respectively. Thirteen cases of vitamin K deficiency bleeding in early infancy with confirmed prophylactic states were confirmed, seven of whom had intracranial haemorrhage. The estimated efficacy of single parenteral administration of vitamin K versus no prophylaxis was 96.7% (95% confidence interval: 74-99.6%) and for single oral administration versus no prophylaxis 80.4% (9.195.6Y0). Single parenteral vitamin K prophylaxis gave substantial protection against vitamin K deficiency bleeding in early infancy. Single oral prophylaxis appeared to be less effective, dthough the difference was not significant, as indicated by the wide overlap of the respective 95% confidence intervals. 0 Infancy, vitamin K deficiency bleeding. vitamin K prophylaxis R. von Kries. Children$ Hospital, Heinrich Heine University, Diisseldorf, Moorenstr. 5,4000 Diisseldorf I , Germany
Classical haemorrhagic disease of newborn (HDN) is caused by vitamin K deficiency and accounts for gastrointestinal, nasal, skin and circumcision bleeding in the first week of life (I). Vitamin K deficiency bleeding (VKDB) in early infancy has only recently been recognized as a bleeding disorder due to vitamin K deficiency in early infancy with a distinct clinical picture. Most cases occur in three to six-week-old, fully breast-fed infants and intracranial haemorrhage, accounting for death and serious neurologic and mental handicap, occurs in about 50% of the cases (I). Vitamin K prophylaxis is considered safe and effective in preventing classical H D N and has been a common practice in the USA since 1961 (1). Whether vitamin K prophylaxis, administered within the first hours of life, can prevent VKDB in early infancy also, has been questioned (2,3). Analysis of cumulated cases of VKDB in early infancy from different countries showed that the vast majority of cases had not received vitamin K prophylaxis (1). Studies assessing both vitamin K prophylaxis and cases of VKDB in early infancy in a population are needed. We performed such a study in Germany.
Patients and methods The use of vitamin K prophylaxis in all obstetric hospitals in West Germany (n= 1141) in March 1988 was assessed by a questionnaire which asked whether or not vitamin K prophylaxis was given, to whom and by what route. The number of cases of VKDB in early
infancy from January I , 1988 to March 31, 1989 and exposure to vitamin K prophylaxis were collected by a questionnaire sent to all paediatric hospitals in West Germany (n=225) in March 1989. For all reported cases, we asked for an anonymous hospital discharge letter and validated the diagnosis of VKDB in early infancy with respect to our case definition: bleeding at any site in an infant older than 1 week and less than 16 weeks, associated with decreased Quicks's prothrombin index to less than 10%of normal adult values, returning to normal within 24 h after vitamin K administration. Risk ratios, confidence intervals and significance tests were calculated using Epi Info, a computer package released by the Centers for DBease Control, Atlanta Georgia, USA.
Results The response rate to the questionnaire for the paediatric hospitals was 85%. Seventeen hospitals reported and sent hospital discharge letters for 19 cases. The initial diagnosis proved wrong in 5 cases: 14 cases fulfilled the criteria of the case definition. In all of these cases, Quick's prothrombin time was well below lo%, as clot formation was not observed within 2 min. The aPTT was greater than 60 s in all and above 3 min in 1 1 of 14 cases. The bleeding sites were: CNS (n = 7), gastrointestinal ( n =4), skin (n=2) and epistaxis (n= 1). Three of the cases with intracranial haemorrhage had been preceded
656
R von Kries and U Gobel
ACTA PRDIATR 81 (1992)
by skin or mucosal bleeding 1 to 3 days before the event leading to diagnosis. The sequelae of CNS haemorrhage, detectable by the time of reporting were: death (n = l), epilepsy (n = 2), hemiparesis (n = 1) and hydrocephalus (n= 1). The age spectrum for all cases of VKDB in early infancy was 2 to 7 weeks (median 4 weeks). Information on feeding was given for 10 cases, all of whom had been exclusively breast fed except for one who had soy milk based formula. Direct bilirubin was determined in 3 of 14 cases. Values greater than agerelated normal ranges were found in 2 of 3 cases. Ten of the 14 cases had not received prophylactic vitamin K at birth, 1 had been given vitamin K I 1 mg im, 2 had been given a single oral dose of 2 mg and in 1 case the history of prophylaxis remained unclear. The response rate to the questionnaire sent to the obstetric hospitals was 68%. The proportion of replies was: large community hospitals (loo%), university hospitals (61 %) and small hospitals (58%). The distribution of vitamin K prophylaxis policy was very similar among different types of hospital. Thus the assumption was made that vitamin K prophylaxis distribution in all births was identical to that in hospitals. As the number of babies born in individual hospitals was not available, a figure for babies exposed to either form of vitamin K prophylaxis from January 1988 to March 1989 was estimated from the number of births (750000) and the reported proportions of different practices for vitamin K prophylaxis in the hospitals that replied (Table I ) . Single parenteral vitamin K prophylaxis (1 mg im or sc) was given to all babies in 55.8% of the hospitals, whereas 37.2% of the hospitals had a “risk-guided’’ policy. Preterm, small-for-dates, non-vaginally delivered babies and babies with neonatal disease were considered at risk. “Non-risk” babies received single oral prophylaxis in 5% and no prophylaxis in the other 50% of these hospitals. “At-risk’’ babies were always given single parenteral vitamin K prophylaxis. Very few hospitals gave no prophylaxis or single oral prophylaxis only. The group “unclassified” comprises hospitals that gave either repeated doses or whose reports were inconclusive. As the proportion of babies considered at risk is not known exactly, the figure quoted for babies given single parenteral vitamin K is a minimum. Similarly, the figure quoted for babies in the other two specified groups (Table 2) is a maximum.
-
The incidence of VKDB in early infancy suggested from these data are I in 14000 for no prophylaxis, 1 in 70 000 for single oral prophylaxis and 1 in 42 0000 for single parenteral vitamin K prophylaxis. As VKDB in early infancy presents with intracranial haemorrhage in approximately 50% of cases, death or neurological sequelae would be expected in approximately 1 in 30 000 infants (accounting for 20 cases per year in West Germany), if no vitamin K prophylaxis were given. The respective relative risk (RR)of VKDB in early infancy for babies not given vitamin K compared to those given single parenteral vitamin K prophylaxis is 30.3 (95% confidence interval 3.9-235.6) (Table 2). As this RR calculation is based on the minimum number of babies receiving single parenteral administration and the maximum number of babies receiving no vitamin K prophylaxis, the true RR is likely to be even higher. Expressed in terms of vaccine efficacy (4), this relative risk represents an efficacy of 96.7% (74-99.6%). The protective effect of single oral vitamin K prophylaxis was less impressive (Table 2). The RR was 5.1 Yo (1.1-23.1 %). Expressed in terms of vaccine efficacy (4), this RR represents an efficacy of 80.4% (9. I-95.6%). The difference in the efficacy of a single oral dose and parenteral prophylaxis was not significant (p = 0.157; Fisher’s exact test). The risk ratio of single oral to parenteral prophylaxis was 5.97. The confidence intervals, however, were wide ranging; from twofold reduction of the risk for oral prophylaxis to an increase in the risk by a factor of 66.
Discussion A review of cases of VKDB in early infancy, reported in the literature, suggested that vitamin K prophylaxis administered at birth might be protective against VKDB in early infancy (1). This was also suggested from surveillance data for VKDB in early infancy in West
Table 2. VKDB in early infancy in West Germany in patients given no prophylaxis compared with single parenteral or oral vitamin K prophylaxis.
VKDB in early infancy Present
Table 1. Vitamin K prophylaxis in West Germany, calculated from questionnaire response (response rate 68%) from all obstetric hospitals in March 1988, relative proportions of different vitamin K prophylactic practices and estimated number of babies exposed from January I, 1988 to March 30, 1989.
of hospitals
Estimated No. exposed
55.8 18.7 18.5
418 500 140 250 138 150 52 500
%
Prophylaxis Single parenteral for all All oral-“at-risk” single parenteral None or “at-risk” single parenteral only Unclassified
7
Absent
No prophylaxis vs single parenteral No prophylaxis 10 Single parenteral prophylaxis I Risk ratio: 30.3; 95% Confidence interval: 3.9-235.6%
138 750 418500
N o prophylaxis vs single oral No prophylaxis 10 Single oral prophylaxis 2 Risk ratio: 5.1; 95% confidence interval: 1.1-23.1%
138 750 I40 250
Single oral vs single parenteral Single oral prophylaxis 2 Single parenteral prophylaxis 1 Risk ratio: 5.97; 95% confidence interval: 0.5-65.8%”
140 250 418500
Neonatal vitamin K prophylaxis
ACTA PEDIATR 81 (1992)
Germany published by Sutor & Scharbau (9, who demonstrated a decrease in incident cases of VKDB in early infancy following the recommendation of vitamin K prophylaxis in Germany. In order to substantiate this view further, by means of appropriate epidemiological methods, an analytical study was performed on a subset of cases. These had been collected with an active surveillance scheme for a time period during which the practice of vitamin K prophylaxis could be estimated from survey data. The response rate for paediatric hospitals for active surveillance of VKDB in early infancy was 85%, suggesting that most suspected cases of VKDB in early infancy had been reported. The numbers of babies exposed to either form of vitamin K prophylaxis are potentially subject to bias as a result of misclassification and non-response. The numbers of babies exposed to either form of vitamin K prophylaxis was estimated from the proportion of different practices in the hospitals that replied. This procedure is justified as the relative proportions of different forms of vitamin K prophylaxis was independent of the hospital size. As hospital policies for nursing procedures tend to be followed, random misclassification on an individual level should be negligible. Nonrandom misclassification is a possibility, in that obstetric hospital response probability may have been influenced by their prophylaxis policy. This would tend to overestimate the total proportion of babies receiving vitamin K prophylaxis. Even assuming the most extreme casethat all non-responding hospitals gave no vitamin K prophylaxis at all-a significant protective effect of single parenteral vitamin K prophylaxis on VKDB in early infancy would be retained ( p =0.013). These data, therefore, give substantial evidence for a protective effect of single parenteral vitamin K prophylaxis in VKDB in early infancy. This finding is in agreement with the results of a recent study in the UK (6). There is good evidence that single oral and single parenteral vitamin K prophylaxis are equivalent with respect to classical VKDB in early infancy (7). Our data suggest that single parenteral vitamin K prophylaxis is more effective than single oral vitamin K prophylaxis in preventing VKDB in early infancy although there was no significant difference between the two treatments. Similar findings have been reported from the UK (6), Switzerland (8) and Sweden (9), with significance levels just less than p
