Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage
Antenatal administration of vitamin K to women at imminent risk of preterm delivery was not found to prevent significantly periventricular haemorrhage in preterm infants. There was also no improvement with regard to other neurodevelopmental outcomes in childhood.
RHL Commentary by Pileggi C
1. INTRODUCTION
A significant number of preterm babies develop neurodevelopmental disorders. Periventricular haemorrhage (PVH) is the major cause of cerebral injury in babies born before 34 weeks of gestation. In preterm babies born at less than 30 weeks of gestation, the risk of having PVH is higher than in those born after 30 weeks, as is the risk of severe outcomes such as cerebral palsy (1, 2). The highest chance of occurrence of PVH is before 72 hours of life, which is the period when the preterm baby is exposed to a variety of support procedures in the intensive care unit. While the etiology of PVH is still unclear, variation in blood pressure and cerebral perfusion, genetic factors, hypoxia and acidosis are associated with increased risk of PVH (3). The major goal in preterm babies is to prevent PVH, using either pre- or postnatal interventions (4). PVH is a common complication in preterm babies, particularly in those with coagulation disorders, and coagulopathies are frequently associated with deficiency of vitamin K, which is essential for producing coagulation factors. Hence, this Cochrane review (5) aimed to investigate the effectiveness (in term of prevention of PVH) and safety of the antenatal administration of vitamin K in mothers at high-risk of preterm deliveries.
2. METHODS OF THE REVIEW
The systematic review includes all relevant published, unpublished and ongoing randomized or quasi-randomized trials that have compared outcomes for women at imminent risk of preterm birth who were given vitamin K therapy, placebo or no treatment. The primary outcomes of interest were neonatal mortality, neonatal neurological morbidity (as measured by the presence of PVH using ultrasound during the first week of life) and long-term neurodevelopment. Any maternal side-effects or other neonatal morbidities were included as secondary outcomes. The search was conducted on 20 December 2010 using the Cochrane Pregnancy and Childbirth Group’s Trials Register. The search strategies used were in line with those recommended by the Cochrane Pregnancy and Childbirth Group and no language restrictions were applied. Two reviewers independently matched the identified studies with the inclusion criteria. The assessment of the methodological quality did not consider the results and followed the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.
The statistical analysis was conducted with the Review Manager software (RevMan 2008). Fixed-effect meta-analysis was used to combine data in the absence of significant heterogeneity if trials were sufficiently similar. To combine data with significant heterogeneity, a sensitivity analysis using random-effects was performed. For dichotomous data, the results were presented as summary risk ratios (RR) with 95% confidence intervals (CI). For continuous data, standardized mean difference (SMD) was used to compare outcomes if measured in the same way between trials.
3. RESULTS OF THE REVIEW
Seven out of nine identified studies met the inclusion criteria. One study was included in the review, but data from it were not included in the analysis. Details of each study are included in the appropriate tables in the complete version of the systematic review. The interventions in the included trials varied in terms of dosages used, routes of administration, number of doses, interval before delivery and use of other drugs (with which vitamin K could have interacted). Four trials were not placebo-blinded and the use of antenatal corticosteroids (an established antenatal intervention which is associated with reduced severe neonatal morbidity) was imbalanced in two trials. Five out of seven trials used formal randomization, but allocation concealment was also unclear in all of them. One study suggested bias in treatment allocation. A detailed description of the quality assessment of the studies is included in the review. Although GRADE tables have not been included in the review, the overall quality of the evidence would be low or low-to-moderate as assessed by contrast assessment.
The combined analysis did not show differences between the risks of perinatal mortality in the intervention and control groups (RR 1.92, 95%CI 0.18–21.06). For all grades of PVH, a non-significant trend in favour of the intervention was found (RR 0.76, 95% CI 0.54–1.06; seven trials; 851 infants). A significant reduction in risk was found in severe PVH (grades 3 and 4) (RR 0.58, 95% CI 0.37–0.91; seven trials; 851 infants) in infants receiving prenatal vitamin K compared with control babies. With regard to secondary outcomes, only one trial reported pruritic rash and another reported one case of rash. However, when the pooled analysis included only high-quality studies, maternal side-effects were not seen (RR 2.96, 95%CI 0.12–72.18). In three trials, the researchers did not find any maternal side-effects and the analysis of high-quality studies did not show a trend in favour of the intervention. Only one study reported long-term adverse neurodevelopmental disorders, the incidence of which at 2 years and 7 years did not show differences in outcomes for babies born to mothers in both groups. The outcome, Bayley Mental Developmental Index at 2 years, presents increased risk of neurodevelopmental disorders in the treatment group, as per lowest score achieved in the assessment (SMD –9.00, 95% CI –16.66 to –1.34).
4. DISCUSSION
4.1 APPLICABILITY OF THE RESULTS
Antenatal administration of vitamin K to women at imminent risk of preterm delivery was not found to prevent significantly PVH in preterm infants. There was also no improvement with regard to other neurodevelopmental outcomes in childhood. Antenatal use of vitamin K in women at risk of preterm delivery was expected to be a simple, inexpensive and safe intervention for the prevention of PVH, which, if found effective, would have been especially relevant to under-resourced settings.
4.2. IMPLEMENTATION OF THE INTERVETNION
Although vitamin K was not shown to be effective in this review, other antenatal preventive therapies are emerging and have been found to have different levels of effectiveness depending on the study population (3, 4).
4.3. FURTHER RESEARCH
Further research on prenatal prevention of PVH should be encouraged. Future trials on antenatal use of vitamin K to reduce the risk of PVH in preterm babies should be better designed to reduce the problems of bias and reporting. The potential severity of the complications of PVH justifies the effort to search for methods to prevent pre-term births and its complications. Long-term follow-up of preterm babies must be given priority in trials in order to allow the assessment of neurodevelopment outcomes.
References
- Volpe JJ. Intraventricular hemorrhage in the premature infant--current concepts. Part II. Annals of Neurology 1989;25:109-116.
- McCrea JH. Ment LR. The diagnosis, management and postnatal prevention of intraventricular hemorrhage in the preterm neonate. Clinics in Perinatology 2008; 35: 777–792.
- Crowther CA, Crosby DD, Henderson-Smart DJ. Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000164.
- Volpe JJ. Intraventricular hemorrhage in the premature infant – current concepts. Part I. Annals of Neurology 1989;25:3-11.
- Crowther CA, Crosby DD. Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage. Cochrane Database of Systematic Reviews 2010; Issue 1. Art. No.: CD000229; DOI: 10.1002/14651858.CD000229.pub2.
- Mwansa-Kambafwile J, Cousens S, Hansen T, Lawn JE. Antenatal steroids in preterm labour for the prevention of neonatal deaths due to complications of preterm birth. International Journal of Epidemiology 2010; 39 Suppl 1: i122- i133.
This document should be cited as: Pileggi C. Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage: RHL commentary (last revised: 1 January 2012). The WHO Reproductive Health Library; Geneva: World Health Organization.