Can long term neonatal outcome be predicted by antenatal surveillance?
S. Škrablin, D. Kalafatić, E. Juretić, G. Zlopaša, T. Goluža, I. Kuvačić
INTRODUCTION
A growing body of evidence strongly suggests that the majority of longterm developmental handicaps, especially neurologic, originate from fetal
asphyxial insults during intrauterine life, rather than during labor (1,2).
Intrauterine growth retardation (IUGR) is a well-recognized risk factor for
permanent neurologic damage (3). Significantly higher incidence of minor motor
and cognitive deficits, such as hyperactivity, short attention span or learning
difficulties, are observed in those cases, especially when preterm birth or postnatal
complications supervene (3,4). Furthermore, major neurologic deficits, such as
infantile cerebral palsy, can be attributable to insults occuring in early pregnancy
(5).
Various parameters of fetal circulation, registered by Doppler
ultrasonography, are able to predict IUGR and adverse perinatal outcome. The
earliest and most sensitive detectors of IUGR and fetal hypoxia are the cerebralumbilical and cerebral-aortic ratios of blood flow pulsatility indices (6). Fetuses
with IUGR and dramatic circulatory disturbances of the umbilical artery (absent
or reverse end-diastolic flow) had a three-fold increase in the risk for neurologic
damage compared with fetuses with IUGR only (7). On the other hand, most
studies (8,9), although not all (10), failed to confirm that increased cerebral blood
flow was an additional risk factor for intracranial haemorrhagic and ischemic
lesions, as well as for permanent neurologic disabilities. Recent longitudinal study
of Ley and co-workers was the first one to reveal the significance of abnormal
blood flow pattern in fetal aorta in prediction of minor neurological deficits at
seven years of age (11). Therefore, it seems obvious that changes in fetal
hemodynamics, both independently and in combination with well-known
obstetrical risk factors, play an important role in the postnatal neurodevelopment.
The aim of our study was to reveal the most significant perinatal predictors of
neurologic abnormalities in children at 3 to 5 years of age.
MATERIALS AND METHODS
We performed fetal blood flow velocity examinations in 132 high-risk
pregnancies, over a three year period, at the Department of Obstetrics and
Gynecology in Zagreb. Ultrasonographic biometry and Doppler blood flow
measurements were performed using 3,5 MHz transabdominal transducer and 50
Hz wall filter. Doppler flow analysis was carried out during episodes of fetal
apnea. Peak systolic (PSV) and end-diastolic velocity (EDV), as well as resistance
indices (RI) were obtained for fetal middle cerebral artery, umbilical artery and
fetal descending aorta. The results of the last set of measurements (median: 6 days
before delivery) was used for the analysis.
Pregnancy and newborn characteristics that were collected and analyzed
regarding neurodevelopmental outcome included: gestational age at delivery, birth
weight, body weight ratio (neonatal birth weight divided by expected birth weight
at the 50th centile for the corresponding gestational age), 1- and 5- minute Apgar
scores, fetal heart rate pattern, neonatal acid-base status, clinical signs of neonatal
hypoxic-ischemic encephalopathy, other early neonatal complications: infection,
additional oxygenation or artificial ventilation, if needed, emergency caesarean
section rate and neonatal intensive care unit (NICU) admission.
The diagnosis of IUGR was made when birthweight was below the 5th
centile according to reference growth curves for our population (12). Thirty-eight
out of 132 children (28,8%) met that criterion and were considered as being small
for gestational age. Six of them died in utero and 3 infants died during the early
neonatal period. The blood velocity waveforms in the umbilical artery and fetal
aorta were converted into blood flow classes: BFC I (normal, positive blood flow
during the whole cycle), BFC II (no end-diastolic velocity) and BFC III (no
positive flow throughout diastole or reverse diastolic flow). Cerebral-umbilical
ratio was calculated by dividing middle cerebral artery RI with umbilical artery
RI. Values below one were considered abnormal.
RESULTS
One hundred and twenty-eight singleton pregnancies were included in the
analysis. Eight children died in utero and 6 subsequently died during the early
neonatal period. Asphyxia was the principal cause of perinatal death, being
responsible for death in 9 out of 14 children (64,3%). At three years of age 19
infants suffered neurologic illness: 4 of them major neurologic impairment and 15
minor or mild form of the disease. Three out of 4 children with major neurologic
illness had fully expressed cerebral palsy with spastic diplegia; the remaining
child suffered mental retardation with severe generalized convulsions.
Analysis of variance revealed that the mean gestational age at birth of
healthy children was significantly higher in comparison to any of the remaining
groups. In comparison to all other groups, children that died had significantly
lower Apgar indices and were significantly more often in need for artificial
respiration. In comparison to healthy children, those who suffered minor or mild
neurologic disease had significantly lower Apgar score values; they were
significantly more often growth retarded, their mean birth weight was lower and
newborn encephalopathy observed more frequently. They spent significantly
longer period in neonatal intensive care unit and they needed additional
oxygenation and artificial respiration more frequently. Children from both groups,
those that died and those with mild/minor neurological handicap were, in
comparison to healthy children, significantly more often growth retarded, their
birth weight was significanlty lower and they suffered signs of perinatal hypoxia
more often.
No differences in Apgar score values, pH, base deficit, birth weight and
body weight ratio were observed between healthy children and children who
suffered major neurologic impairment. No one was growth retarded, and in only
one antenatal FHR showed alterations suggestive of hypoxia. In comparison to
healthy children, gestational age at birth in children with major disabilities was,
however, significantly lower. Their NICU admission was more frequent, as was
their need for additional oxygenation significantly longer than in healthy children.
In l out of 4 newborn encephalopathy was diagnosed.
Caesarean section rate, umbilical arterial, fetal aortic and middle cerebral
artery PSV and EDV were equally distributed between the groups.
In two out of 96 healthy newborns positive neonatal neurosonography
was encountered in a form of mild subependimal haemorrhagic lesions in two
growth- retarded infants. Positive neonatal neurosonography was more frequent in
neurologically disabled children: in three out of four (75%) with major neurologic
deficit third degree periventricular leucomalatia (PVL) eventually occured after a
period of periventricular echodensities. Intraventricular haemorrhage was
observed in two, third degree PVL in one, second degree PVL in two,
subependimal haemorrhage in two and diffuse edema in one out of 14 newborns
with milder neurologic handicap.
There was no difference in C/U ratio between children with mild/minor
abnormalities or those with major abnormalities and healthy ones and no
difference in middle cerebral artery RI between any of the groups. Umbilical
artery RI was significanlty higher and C/U ratio significantly lower in children
that died than in those remaining healthy and in those suffering major difficulties.
Importantly, mean aortic RI was significantly higher in the group of children with
minor form of neurologic disease, compared to the healthy and major abnormality
group.
Converting blood velocity waveforms in fetal aorta and umbilical artery
into semi-quantitative blood flow classes (BFC), it turned out that 111 out of 132
children (84,1%) had positive blood flow in the umbilical artery throughout the
heart cycle. Twenty children (15,2%) had no end-diastolic velocity (BFC II) and
only 1 child (0,7%) had reversed diastolic flow (BFC III). Eleven out of 104
liveborns with umbilical arterial BFC I (10,3%) and 4 out of 17 liveborns with
umbilical arterial BFC II (23,5%), showed positive neonatal neurosonography,
(p=NS). One hundred and six out of 132 children (80,3%) had BFC I in the aorta,
23 (17,4%) had no end-diastolic blood flow, and 1 child (0,7%), who had reverse
end-diastolic flow in the umbilical artery, also had reverse diastolic flow in the
aorta. That child subsequently died from asphyxia in the 32nd week of gestation,
complicated by severe IUGR and oligohydramnios. Positive neonatal
neurosonography was observed in 9 out of 103 liveborn children with aortic BFC
I (8,7%) and in 6 out of 20 (30%) liveborns showing aortic BFC II (p<0,01).
Absent or reversed aortic flow shows danger of either dying during the perinatal
period or suffering intracranial pathology during the early neonatal period,
although most of the newborns with subsequent sequellae showed umbilical
arterial and aortal BFC I.
Univariate analysis revealed significant association between aortic RI,
gestational age at birth, IUGR, 1’ and 5’ Apgar score, FHR tracing, birth weight,
body weight ratio, newborn hypoxic-ischemic encephalopathy, the need for
arteficial oxygenation, positive neonatal neurosonography and minor neurologic
dysfunction. The results of the univariate analysis are summarized in Table 1.
The results of the multivariate analysis are presented in Table 2. It is
important to notice that only positive cranial ultrasonography and aortic BFC II
showed significant independent predictive value regarding postnatal
neurodevelopment. Multivariate analysis of the risk of selected factors on the
occurence of major neurologic sequellae (stepwise logistic regression) did not
reveal significance of any of the factors tested.
Table 1. Summary of univariate analysis of significantly different variables between
healthy children and children with minor/mild neurologic impairment
Healthy
Minor/mild
children
impairment
p
(N=99)
(N=15)
Gestational age (weeks)
37,9
35,3
<0,01
Birthweight (g) (mean)
IUGR (N,%)
2722
2099
<0,01
22 (22,2)
7 (46,7)
<0,001
Body weight ratio
0,91
0,86
<0,05
Aortic RI (mean)
0,86
0,92
<0,05
Aortic BFC II (N,%)
Neonatal USG
(N, % positive findings)
Suspected perinatal
hypoxia (FHR) (N,%)
Apgar 1' (median)
15 (15,2)
6 (40,0)
<0,05
2 (2,0)
8 (53,3)
<0,001
20 (20,2)
7 (46,7)
<0,05
10
7
<0,05
Apgar 5' (median)
10
9
<0,05
Neonatal encephalopathy
(N,%)
Neonatal infection (N,%)
Arteficial oxygenation
(N,%)
4 (4,0)
5 (33,3)
<0,001
9 (9,1)
5 (33,3)
<0,05
1 (1,0)
2 (13,3)
<0,01
Table 2. Multivariate analysis of risk to minor/mild neurologic impairment (logistic
regression)
95% confidence
Odds ratio
p
interval
Preterm birth
0,79
0,51-1,05
0,4597
Birthweight
1,01
0,90-1,21
0,3233
IUGR
1,76
1,08-2,67
0,0775
Body weight ratio
0,24
0,15-0,45
0,7717
Aortic RI > mean + 2 S.D.
1,46
1,21-1,85
0,1154
Cranial USG
3,12
2,15-7,59
0,0082
Aortic BFC II
2,03
1,25-5,36
0,0105
Positive FHR
0,61
0,42-0,91
0,1132
Apgar 1' (<7)
0,88
0,78-1,01
0,2748
Apgar 5' (<7)
0,59
0,41-0,95
0,8894
Newborn encephaloptahy
1,28
1,15-1,44
0,7443
Newborn infection
0,74
0,66-0,88
0,8691
Arteficial oxygentaion
1,31
0,85-2,21
0,2101
CONCLUSION
As pathological patterns of fetal blood flow distribution are often
associated with various obstetrical complications per se, it is difficult to
distinguish permanent neurologic disability independently predicted by various
complications of pregnancy and/or early neonatal period and those somehow
predicted by some circulatory abnormality.
Positive neonatal cranial ultrasonography showed significant predictive
value regarding both major and minor neurologic impairment later in life. Blood
circulation in fetal aorta could be an important milestone in detection of fetuses at
increased risk, perhaps irrespective of their gestational age at birth. We therefore
recommend cranial ultrasonography examination to all neonates with absent or
reversed blood flow in descending aorta. The combination of both positive
findings, regardless of gestational age at birth, carries a significantly increased
risk of permanent neurologic damage.
REFERENCES
1. Godfrey KM. Maternal regulation of fetal development and health in adult life. Eur J
Obstet Gynecol Reprod Biol 1998;78:141-50.
2. Garaizar C, Prats-Vinas JM. Brain lesions of perinatal and late prenatal origin in a
neuropediatric context. Rev Neurol 1998;26:934-50.
3. Calame A, Fawer CL, Claeys V, Arrazola L, Ducret S, Jaunin L. Neurodevelopmental
outcome and school performance of very low birthweight infants at 8 years of age. Eur J
Pediatr 1986;145:461-6.
4. Michelsson K, Noronen M. Neurological, psychological and articulary impairment in
five-year-old children with a birthweight of 2000 g or less. Eur J Pediatr 1983;141:96100.
5. Michaelis R, Rooschz B, Dopfer R. Prenatal origin of congenital spastic hemiparesis.
Early Hum Dev 1980;4:243-55.
6. Arbeille P. Fetal arterial Doppler-IUGR and hypoxia. Eur J Obstet Gynecol Reprod
Biol 1997;75:51-3.
7. Valcamonico A, Danti L, Frusca T, et al. Absent end-diastolic velocity in umbilical
artery: Risk of neonatal morbidity and brain damage. Am J Obstet Gynecol 1994; 170:
796-801.
8. Scherjon SA, Smolders-de Haas H, Kok JH, Zondervan HA. The "brain-sparing
effect": antenatal cerebral Doppler findings in relation to neurologic outcome in very
preterm infants. Am J Obstet Gynecol 1993;169:169-75.
9. Arias F. Accuracy of the middlecerebral-to-umbilical-artery resistance index ratio in
the prediction of neonatal outcome in patients at high risk for fetal and neonatal
complications. Am J Obstet Gynecol 1994;171:1541-5.
10. Scherjon S, Briet J, Oosting H, Kok J. The discrepancy between maturation of visualevoked potentials and cognitive outcome at five years in very preterm infants with and
without hemodynamic signs of fetal brain-sparing. Pediatrics 2000;105:385-91.
11. Ley D, Laurin J, Bjerre I, Marsal K. Abnormal fetal aortic waveform and minor
neurologic disfunction at 7 years of age. Ultrasound Obstet Gynecol 1996;8:152-9.
12. Dražančić A, Pevec-Stupar R, Kern J. Fetal growth in Zagreb. Jugoslav Ginekol
Perinatol 1988;1-2:13-20.