Persistent ductus arteriosus
The ductus arteriosus is a blood vessel which links the pulmonary artery with the aorta during the foetal period. During the foetal period, the vessel is kept open by prostaglandins because circulation through the lungs is then not necessary. After the birth, the blood vessel closes quickly, usually during the first day, but the closure is often delayed in premature children. In Sweden, approx. 60 per cent of the extremely premature infants are treated for persistent ductus arteriosus (PDA) and the shorter the length of the pregnancy, the more common it is [4, 26].
When the flow resistance in the pulmonary circulation is reduced, with PDA there is a leakage of blood from the aorta to the pulmonary artery (known as a left-right shunt). If the shunt blood flow becomes significant, symptoms appear in the form of greater breathing and heart rates, a greater need for oxygen and sometimes respirator-dependent. The child can also suffer heart failure, apnoea (interrupted breathing), a drop in blood pressure, kidney failure and digestion problems. PDA has been associated with intra-ventricular brain haemorrhage (IVH), necrotising enterocolitis (NEC, inflammation of the bowel) and chronic lung disease (bronchopulmonary dysplasia, BPD) [64].
Although PDA is common and can have significant consequences for the child, the scientific support is unclear when it comes to the most suitable diagnostics and treatment [65]. As a rule, the diagnostics are based on ultrasound examinations of the heart (echocardiography) but there are no uniform criteria for when PDA becomes significant and must be treated [66, 67]. PDA can be closed pharmacologically or surgically, but the treatment has been questioned because spontaneous, delayed closure of PDA is common [64, 68]. Pharmacological treatment is also less effective among the extremely premature infants than in the more mature children [69].
Preventative measures
The Swedish National Board of Health and Welfare’s assessment
o The preventative measures for persistent ductus arteriosus (PDA) ought to include the treatment of pregnant women threatened with premature birth with corticosteroids because, as well as effects on lung immaturity, it also reduces the occurrence of significant PDA.
o Prophylactic closure of ductus arteriosus (with medicines or surgery) is not recommended.
The assessment is based on systematic charting.
In order to prevent significant PDA, intervention ought to begin before the birth or during the first day of life. Treatment with antenatal (administered
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before the birth) corticosteroids is recommended for pregnant women threatened with premature birth because it has been shown to reduce the occurrence of significant PDA in children who are born prematurely, even if not all scientific studies have been able to show this effect [11, 70, 71]. Corticosteroids reduce the sensitivity to prostaglandins which otherwise keep the ductus arteriosus open [72-74].
Where extremely premature infants are concerned, prophylactic treatment with medicines has been shown to reduce the occurrence of significant PDA as well as reduce the need for surgical duct closure. However, there is a risk of side effects and unclear safety aspects. Nor has it been shown that prophylactic treatment lowers the mortality rate or improves the psychomotor development in the long term [75-78]. The treatment cannot therefore be recommended at the moment.
Prophylactic duct ligation (within 24 hours of the birth) in children with an extremely low birth weight (less than 1 000 g) has not been well studied. Studies have shown that with the operation there was no difference in mortality, severe pre-maturity retinopathy (ROP) or serious IVH compared with the standard treatment. The occurrence of NEC did fall on the other hand. The scientific support as to whether prophylactic duct surgery is linked to the development of BPD is not unequivocal [79-82].
Not cutting the umbilical cord until 30-120 seconds after the birth and early CPAP treatment (continuous positive airway pressure) facilitate the circulation adaptation at the birth and both of these interventions have been shown to reduce such ill-health which is also linked with PDA [14].
PDA diagnostics
The Swedish National Board of Health and Welfare’s assessment
o PDA diagnostics ought to take place using echocardiography where the first examination is done within one to three days.
The assessment is based on consensus between the chairpersons of the expert groups.
Echocardiography is the crucial diagnostic tool and all extremely premature infants ought to undergo an ultrasound of the heart to assess PDA, the first time within one to three days of the birth. The clinical picture and x-ray finds can also be important in terms of diagnosing and assessing PDA. Low diastolic blood pressure can be a sign of PDA, as can heart murmurs at the time of auscultation and brisk peripheral pulses, particularly early on in the course of events.
The echocardiographic assessment is a qualified task requiring knowledge and experience. The size of the ductal shunt depends on the duct width as well as the pressure and resistance conditions in both the pulmonary and systemic circulation, which complicates the assessment. The examination conditions are also often difficult with very limited echocardiographic windows. An important
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aspect of the diagnostics is also that a ductus-dependent heart defect needs to have been precluded before with any duct-closing treatment can be relevant.
Despite a large number of studies within the field, both strong scientific support for or consensus surrounding the diagnostic criteria are absent [2, 4, 8]. However, the following echocardiographic criteria can be used as signs of haemodynamically significant PDA:
•Duct width exceeds 1.5 mm.
•Left atrium is enlarged, which can be measured using the diameter of the left atrium (LA = left atrial) and the aortic root (Ao = aortic). An LA/Ao quota greater than 1.5 is a sign of a significant shunt and values exceeding 2 indicate a severe shunt.
•The child has low or reversed diastolic blood flows in the descending aorta, mesenteric artery or cerebral artery (a strong indication).
•There is a diastolic forward flow in the pulmonary artery branches. An end-diastolic velocity exceeding 0.2 m/sec is a sign of a significant PDA, and a velocity exceeding 0.5 m/sec indicates a severe shunt.
A duct examination usually also includes an assessment of the size of the left chamber. However, for the extremely premature infants, there is currently no information on the reliable normal values.
In recent times, bio markers such as pro-BNP, a peptide that is excreted from the myocardium when loaded, have started to be used in the assessment [83]. However, experiences and the scientific support are currently insufficient to give any recommendation.
Treatment of PDA
The Swedish National Board of Health and Welfare’s assessment
• Early treatment of PDA ought to be considered for the occurrence of one or more echocardiographic criteria and clinical symptoms of significant PDA. If there is intervention,
o pharmacological treatment with Ibuprofen should be used as a first choice for haemodynamically significant PDA;
o surgical treatment (ligation of PDA) should be used restrictively, but can be considered if therapy fails, there is a late recurrence or if there is a contraindication for pharmacological treatment.
The assessment is based on systematic charting and consensus between the chairpersons of the expert groups.
PDA treatment means an intervention that usually begins 1-14 days after the birth and which aims to put an end to symptomatic PDA. Pharmacological or surgical closure of the ductus constitutes the basis of the treatment arsenal. The proportion of those who do not respond to pharmacological treatment is higher among children with a lower gestational age (level of maturity). The spontaneous PDA closure rate is also at its lowest in this group.
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As well as pharmacological and surgical treatment, other interventions can also have an effect. CPAP treatment has low scientific support when it comes to closure of the PDA, but is supported by physiological knowledge and tried and tested experience. Fluid restriction has some support in observational studies and can be considered if it is possible to ensure adequate nutrition. Loop diuretics can impair ductus closure and these medicines ought therefore to be used only for children with clear clinical signs of over-circulation in the lungs and other signs of acute heart failure [84-87]. Blood transfusion also does not facilitate the closure of the PDA and therefore cannot be recommended [88].
Pharmacological treatment with cyclo-oxygenase inhibitors
Pharmacological treatment of PDA currently takes place using non-selective cyclo-oxygenase inhibitors. Ibuprofen is recommended as the first choice preparation for PDA before Indomethacin, even if the preparation is comparable as regards the effect on the PDA (three out of four children respond with closure of the PDA), treatment failure, recurrence and PDA requiring surgery (approx. 10 per cent) [89]. The recommendation is based on Ibuprofen’s more favourable side effects profile (lower risk of NEC, oliguria and kidney impairment) [89-91].
Ibuprofen is given intravenously, usually for three days (one dose per day) [92, 93] and after this treatment, another round of treatment may be appropriate. There is some scientific support for a second round of treatment leading to the closure of the ductus arteriosus [94-96]. The clearance of Ibuprofen increases relatively rapidly with the child’s age and a higher dose may then be more effective [97-99]. Enteral (through the gastrointestinal tract Ibuprofen treatment appear to be just as effective as intravenous [89], but enteral administration can increase the risk of gastrointestinal haemorrhage [76].
Early pharmacological treatment of PDA (during the first day of life) has not been shown to be able to reduce serious neonatal morbidity such as BPD, NEC or ROP compared with later treatment (at five to seven days of age) [100].
Surgical treatment
One in four children who were part of the EXPRESS study (extremely preterm infants in Sweden study) was operated on for PDA. The operation took place at a median age of 18 days after the birth, and the reason in 65 per cent of the cases was that pharmacological duct closure had failed. The remaining proportion of the children was operated on as the primary option. An examination of all children in EXPRESS who were treated surgically for PDA showed that the nutrition was inadequate at the time of the operation [101].
Surgical treatment of PDA can be considered if therapy fails or there is a recurrence following pharmacological treatment. Surgical treatment may also be appropriate if the child shows symptoms which mean that pharmacological treatment may be considered to be relatively or fully contraindicated (greater tendency to haemorrhage and recent or ongoing internal haemorrhage in the brain or the gastrointestinal tract) [64]. Where there is IVH grade I (milder haemorrhage), repeating the ultrasound examination of brain after one day is recommended and, if the haemorrhage remains unchanged, it is not considered to constitute a contraindication for pharmacological treatment. If blood is shown in the ventricular system, the assessment ought to be assessed more cautiously as regards
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starting pharmacological treatment. A grade IV haemorrhage (larger haemorrhage) is judged to be a contraindication for pharmacological treatment.
An impaired neurosensory capacity has been reported among children who have had an operation for PDA [102, 103]. However, available data is not sufficient to determine whether the link is due to the fact that the group who had operations were particularly ill and vulnerable, or due to the fact that there are risk factors that are specifically associated with the surgical intervention. Paralysis of the vocal cords (caused by damage to recurrent nerve) [104] and postoperative blood pressure drop [105] have also been shown to be common complications, and ductus surgery therefore ought to be carried out on a restrictive basis on extremely premature infants.
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The immature brain
The immature brains of extremely premature infants have a greater risk of being affected by damage and deviating development. During the neonatal care period, several factors can affect and disrupt the brain’s growth because it is in a dynamic development phase. This means that the children have a greater risk of being affected by neurological and cognitive function impairments as well as by neuropsychiatric condition such as ADHD and autism. These conditions are associated with complications that arise during the pregnancy and the neonatal period [106-108].
It has been shown that improved neonatal care reduces the brain injuries [3] and it is therefore extremely important for the initial care of these children to take place at hospitals that have substantial experience of and competence in neonatal specialist care.
The Swedish National Board of Health and Welfare’s assessment
•The care is of substantial significance to the risk of developing brain haemorrhages and damage in the brain’s white matter. It is therefore extremely important for the care to take place at units that have substantial experience of extremely premature infants.
•The brain ought to be continuously assessed to diagnose injuries and deviations as well as to inform the parents of the child’s condition and prognosis. The assessment ought to take place with the help of
o clinical examinations;
valid examination methods to detect brain injury, such as ultrasound, electroencephalography and magnetic resonance tomography.
•The businesses ought to draw up procedures to reduce risk factors that are linked to the development of brain injuries.
•Neurological and cognitive follow-ups ought to take place until school age in accordance with the national follow-up programme.
The assessment is based on systematic charting and consensus between the chairpersons of the expert groups.
Brain injuries
The immature brains of extremely premature infants develop milder injuries such as haemorrhages and matter loss. The brain injuries which are diagnosed in the neonatal period in the first instance are known as intraventricular haemorrhages (IVH), which arise in an area from which nerve cells migrate [109-111]. In 90 per cent of the cases, IVH occur during the first week and usually already during the three first day of life. The size of the haemorrhage affects the prognosis where milder haemorrhages (IVH grades I-II) often do not lead to a great risk of a later impact, while larger haemorrhages
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(IVH grades III-IV) involve a high risk of development of subsequent function impairments.
Approx. 10-15 per cent of the extremely premature infants are also affected by haemorrhages in the cerebellum. The haemorrhages increase the risk of subsequent cognitive and motor function impairment.
The risk of injuries in the brain’s white matter is also higher for these children. Cystic periventricular leukomalacia (cPVL) leads to a loss of matter in the brain which is linked to the development of motor and perceptual (the ability to perceive) function impairments. More diffuse white matter injury is also relatively common.
Improved neonatal care, which is adapted to the very smallest children, has led to a fall in the occurrence of IVH grades III-IV and cPVL (and thereby also the risk of cerebral palsy), but 15-20 per cent of the extremely premature children [3] are still affected.
Methods of detecting brain injuries
Neurological assessment can be difficult to do on extremely premature infants. The child’s neurological function (such as muscle tone, activity, spasms, sleep and alertness) ought to be clinically assessed.
Ultrasound examinations of the brain can give direct information on morphological injury. Both IVH and PVL can be detected, while substantial experience of haemorrhages in the cerebellum is required for them to be visible [109, 111, 112]. Ultrasound examinations ought to be performed on all of these children as a matter of routine within the first 3 days, after 3-7 days and after 14-21 days when the child has reached the estimated full term as well as in addition to that where necessary Where there is an increasing accumulation of cerebrospinal fluid (post-haemorrhagic ventricular dilation, PHVD) and the development of hydrocephalus (water on the brain), more frequent ultrasounds ought to take place and early contact be established with a neurosurgeon. The circumference of the child’s head ought to be routinely measured each week or more often if necessary.
More diffuse white matter injury can be diagnosed using with magnetic resonance tomography (MR). After just one day, the brain activity registered with EEG (electroencephalography) or amplitude-integrated EEG (aEEG, a modified EEG), has been shown to predict a later prognosis. It shows the importance of the early brain injury’s role in the child’s future prognosis. EEG and aEEG examinations have also shown that subclinical (not fully developed) epileptic attacks are relatively common, primarily in children with IVH [109, 111, 112].
An ultrasound or MR of the brain ought to take place at full term or in the weeks before this. The injuries that can be seen at this time are often predictors of later problems but unfortunately, a normal examination does not always predict normal development. The examinations show that extremely premature infants, irrespective of whether or not there is a brain injury, have a lower brain volume when they have reached the full estimated term compared with full-term children. However, the scientific support for whether ultrasound [113, 114] or MR [115] gives the most suitable predictive information is not unequivocal.
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Prevent brain injuries - risk factors
There are no specific interventions to treat brain injuries that have arisen without focus being primarily on running the care in such a way that the children’s exposure to risk factors that are linked to brain injuries is minimised as far as possible. These risk factors include: