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To identify intrapartum predictors of newborn encephalopathy in term infants.
Population based, unmatched case-control study.
Metropolitan area of Western Australia, June 1993 to September 1995.
All 164 term infants with moderate or severe newborn encephalopathy; 400 randomly selected controls.
Adjusted odds ratio estimates.
The birth prevalence of moderate or severe newborn encephalopathy was 3.8/1000 term live births. The neonatal fatality was 9.1%. Maternal pyrexia (odds ratio 3.82), a persistent occipitoposterior position (4.29), and an acute intrapartum event (4.44) were all risk factors for newborn encephalopathy. More case infants than control infants were induced (41.5% and 30.5%, respectively) and fewer case infants were delivered by caesarean section without labour (3.7% and 14.5%, respectively). Operative vaginal delivery (2.34) and emergency caesarean section (2.17) were both associated with an increased risk. There was an inverse relation between elective caesarean section (0.17) and newborn encephalopathy. After application of a set of consensus criteria for elective caesarean section only three (7%) eligible case mothers compared with 33 (65%) eligible control mothers were sectioned electively. Of all the case infants, 113 (69%) had only antepartum risk factors for newborn encephalopathy identified; 39 (24%) had antepartum and intrapartum factors; eight (5%) had only intrapartum factors; and four (2%) had no recognised antepartum or intrapartum factors.
The causes of newborn encephalopathy are heterogeneous and many relate to the antepartum period. Elective caesarean section has an inverse association with newborn encephalopathy. Intrapartum hypoxia alone accounts for only a small proportion of newborn encephalopathy. These results question the view that most risk factors for newborn encephalopathy lie in the intrapartum period.
Previous studies of newborn encephalopathy have focused almost exclusively on the intrapartum causes of “hypoxic ischaemic encephalopathy.”1–7 The contribution of intrapartum events to newborn encephalopathy remains unclear. We report the intrapartum findings from the Western Australian case-control study of newborn encephalopathy.8
The subjects and methods are as reported in the accompanying paper.8
Maternal pyrexia, a persistent occipitoposterior position, and an acute intrapartum event were all labour related events associated with a significantly increased risk of newborn encephalopathy (table (table1).1). Only nine of the 18 affected infants and none of the nine control infants whose mothers had experienced pyrexia had a pathogenic organism isolated from mother or baby. A prolonged interval from rupture of membranes to delivery, abnormalities in blood pressure, a nuchal cord, cord prolapse, and shoulder dystocia were associated with a non-significantly increased risk.
The final mode of delivery is determined by the delivery plan and response to intrapartum events. As the delivery plan could not be determined onset of labour was investigated as a surrogate (table (table1).1). The same proportion of cases and controls had spontaneous onset of labour. More case infants than control infants, however, were induced and fewer case infants were delivered by caesarean sections without labour.
Overall, a similar proportion of case and control infants were delivered by caesarean sections (23% (38) and 24% (96), respectively). Relative to spontaneous vaginal delivery, instrumental vaginal delivery and emergency section were associated with over a twofold increased risk of encephalopathy. Only 2.4% (four) affected infants compared with 14.5% (58) of control infants were delivered by elective section, defined as one planned at least 24 hours before the procedure (adjusted odds ratio relative to spontaneous vaginal delivery 0.17; 95% confidence interval 0.05 to 0.56). This inverse relation was not explained by social factors, including health insurance status, as these had been adjusted for. The documented indications for elective sections among case and control infants are shown in table table2;2; previous caesarean section was the most common.
To ascertain whether different risk factor profiles explained the differences in proportion of emergency and elective caesarean sections, 14 practising consultant obstetricians from Perth were asked to develop a set of criteria which would lead them to recommend an elective section at term in the interest of the baby. The consensus, which was developed without knowledge of the study results, comprised intrauterine growth restriction, malpresentation, abnormal antepartum cardiotocography, two previous sections, macrosomia with diabetes or gestational diabetes, active herpes, and a previous difficult labour. When we applied these consensus criteria to mothers of case and control infants (table (table3)3) eligible mothers of case infants were 24 times less likely (unadjusted odds ratio relative to spontaneous vaginal delivery 24.2; 6.61 to 90.1) than eligible mothers of control infants to have been sectioned electively. Nearly 40% of the eligible case infants were eventually delivered by an emergency section and nearly 20% were delivered instrumentally or by vaginal breech delivery. The consensus criteria met by eligible mothers are summarised in table table4.4. This shows that even in the group that met the consensus criteria there was a difference in antepartum risk factor profiles between cases and controls.
The presence of an abnormal intrapartum cardiotocogram, meconium stained liquor, and fetal distress are usually considered to reflect intrapartum hypoxia and were not included in the adjusted analyses as they were likely to be along a causal pathway for, or the first signs of, newborn encephalopathy or were markers of encephalopathy. Inclusion of these variables in the adjusted analysis would have masked the effects of other variables that were working through them. Half the affected infants had intrapartum cardiotocography performed compared with 30% of control infants. The cardiotocogram was described as abnormal in 61% of affected infants compared with 37% of control infants (unadjusted odds ratio 4.43; 1.81 to 10.85). Meconium was described more commonly in case infants than control infants (33% v 12%; 3.72; 2.33 to 5.95) and grade III meconium in particular was much more common in case infants (13% v 1.0%; 16.7; 5.76 to 50.0). Finally, fetal distress during labour was recorded by the midwife more often in case infants than control infants (21% v 8%; 3.16; 1.84 to 5.43). For the same reason we did not include immediate characteristics of the newborn (table (table5)5) in the adjusted analysis.
In an attempt to estimate the proportion of infants who had been exposed to possible intrapartum hypoxia we used the following modified criteria: presence of an abnormal intrapartum cardiotocogram or abnormal fetal heart rate on auscultation or fresh meconium in labour, or both, together with a 1 minute Apgar score of less than 3 and a 5 minute Apgar score of less than 7.9 Cord pH measurements were not included because they were performed so infrequently. Thirty one affected infants (19%) and two control infants (0.5%) fulfilled these criteria. A further 16 cases did not strictly fulfil the definition, but there was evidence that they had experienced a significant intrapartum event which may have been associated with intrapartum hypoxia (for example, breech presentation, birth before arrival at hospital, head stuck, Apgar scores not measured). Therefore, a total of 47 case infants (29%) had evidence of having experienced intrapartum hypoxia. Only seven of these (4% of all cases), however, fulfilled the criteria of possible intrapartum hypoxia in the absence of preconceptional or antepartum abnormalities. Four case infants (2%) had no recognised antepartum risk factors or evidence of intrapartum hypoxia and 113 (69%) had only antepartum factors identified (figure (figure1).1). Only 15 of these 47 case infants met the consensus eligibility criteria for an elective caesarean section.
Our results indicate that intrapartum hypoxia alone accounts for only a small proportion of cases of newborn encephalopathy, and elective caesarean section had an unexpected inverse association with newborn encephalopathy.
Although 29% of affected infants experienced events traditionally indicative of birth asphyxia, it does not necessarily follow that asphyxia was the primary cause of the encephalopathy. While some intrapartum factors may be single causes—that is, a previously normal baby who becomes encephalopathic in labour (fig (fig2,2, pathway 1)—this was an uncommon scenario in our study (see fig fig1).1). Other factors may be on a causal pathway that starts before birth but which includes intrapartum hypoxia as a contributor (figure (figure2,2, pathway 2). For example, growth restriction alone is associated with newborn encephalopathy8 and exposure to labour may compound that damage.10 A further possibility is that the intrapartum factors are merely markers of damage associated with adverse events before birth (fig (fig2,2, pathway 3). Abnormality on a cardiotocogram, meconium stained liquor, low Apgar scores, or the need for active resuscitation may simply reflect previous neurological compromise.11
A very small proportion of infants had no recognised antepartum risk factors nor evidence of intrapartum hypoxia, and it remains unclear as to when their encephalopathy started and what caused it. Over two thirds of affected infants had only antepartum factors identified. Together these two groups represent over 70% of cases among which there was no evidence of adverse intrapartum events. This points to the antepartum period being of prime aetiological importance in most cases of newborn encephalopathy.
Maternal pyrexia in labour was a significant risk factor, confirming our previous finding.12 Prolonged interval between rupture of membranes and delivery, a risk factor for ascending infection, was more common in cases compared with controls but not significantly so. Chorioamnionitis is of current interest as a cause of cerebral palsy in both term13 and preterm14 infants. The mechanisms of fetal damage, however, are not known but could include cerebral sepsis, hyperthermia, or action via inflammatory mediators.15
The most striking finding relates to mode of delivery. These data suggest an important inverse association between elective caesarean section and newborn encephalopathy. There are several possible explanations for this finding. Chance alone is an unlikely explanation, as shown by the 95% confidence interval, although mode of delivery was not one of the initial study hypotheses.12 The results are also unlikely to be due to biased selection of control subjects. The control subjects were randomly selected and their final mode of delivery and all 21 other characteristics of pregnancy, labour, and infant available for comparison were the same as for all term live births in Western Australia during the study period.16 There was no evidence of case selection bias as all affected infants were included and none died before transfer.8 We therefore conclude that our findings are real.
A vital distinction, not made in most other studies, is the differentiation between elective and non-elective sections.2,12,17,18 Had we failed to make this distinction we would have concluded that caesarean section had no effect on the risk of newborn encephalopathy. When we applied the eligibility criteria for elective sections we found that eligible case infants were more than 20 times less likely to be delivered by elective section than eligible control infants. The reasons for the apparent differences in the management of labour in the cases and controls are undoubtedly complex and may reflect genuine differences (see table table4).4). Unrecognised high risk features, alternatives to the consensus view, women’s choice of vaginal delivery, or perhaps some undefined factors which led a pregnancy to result in a baby with encephalopathy may also have operated to affect the management of delivery. As the definition of an elective caesarean section was one in which there were 24 hours between the decision and delivery, it is also possible that some of these women had been booked for an elective section which they did not receive because they went into labour. On close review of the eligible cases, however, a maximum of only 20% could possibly fall into this category.
It is of note that even in those women not meeting the consensus criteria for elective section, mothers of control infants were electively sectioned much more commonly than mothers of case infants. Furthermore, eligible mothers of case infants did not avoid operative and instrumental delivery but had emergency rather than elective procedures. Non-elective sections involve inherently more operative and postoperative risk, reflected in the lower maternal morbidity after elective sections.19 In addition, the baby delivered by a non-elective section has usually been exposed to the stresses of labour, and this may have an independent impact on outcome.
Elective caesarean sections may exert their apparent beneficial effects by avoiding some of the intrapartum risk factors for encephalopathy. For example, elective sections prevent exposure to post-maturity, persistent occipitoposterior position, intrapartum maternal pyrexia, and catastrophic events in labour. It may be the avoidance of these factors other than caesarean section per se which contributes to its apparent benefit.
We readily recognise that there is no “correct rate” of elective caesarean sections, but it is pertinent to ask whether women who would benefit most are being identified and given access to this method of delivery. It is not possible to say from this observational study whether elective section would have actually changed the outcome in any of the cases, but it is an obvious question and one worthy of further investigation. As a trial to answer this question is unlikely ever to be performed,20 however, observational studies such as this would probably be our only source of information. It is, however, pertinent to note that our findings cannot be used to argue on a very wide basis that disability can be prevented by elective caesarean section.
Increasingly, the debate about the aetiology of perinatal brain injury emphasises the relatively small contribution of the intrapartum period. The presence of antepartum events does not mean that the intrapartum course did not contribute to the final outcome. Nevertheless, even with the best care not all potentially damaging intrapartum events are avoidable. It seems likely, however, that many babies already have encephalopathy before labour and others, whose reserve is diminished at the onset of labour, may have less capacity to cope with hypoxia when it occurs during labour. Elucidating these multiple pathways will be the only way we can go forward in the prevention of newborn encephalopathy.
For acknowledgements and details of contributors, funding, and competing interests please see the accompanying paper.8
Editorial by Edwards
Dr Alessandri died in August 1997