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Gates and Brocklehurst (1) provide a careful re-analysis of the published evidence on the use of
powerful drugs which can affect the newborn baby. The safety of single doses of corticosteroids
is not established. Dalziel et al (2,3) followed up the Auckland data (4) after 30 years to check
the long term safety of antenatal corticosteroids for the survivors. They found that "there were
similar numbers of neonatal survivors with much the same perinatal morbidity in both treatment
groups." So re-analysis of the Auckland data showed that there was no benefit from the steroids
in terms of either survival or morbidity but that the treatment did not cause any adverse effects
in the survivors. If this dataset shows safety it must also put efficacy in question. If efficacy
is considered to be valid as a result of other studies then safety remains in question.
The Auckland study (4) formed a major part of the Cochrane review on antenatal steroids to
accelerate lung maturity, yet the data from the follow-up reports (2,3) differed from those in
the Cochrane review.(6) There are also discrepancies between different versions of the Cochrane
review. The version published in Effective care in Pregnancy and Childbirth Table 45.12 (6,7)
contains 12 trials reporting the effect of corticosteroids on early neonatal death (0-7 days).
Some of these 12 are in the analysis presented later for the outcome neonatal death (0-28 days).
However, for Liggins 1972a, Block 1977, Gamsu 1989, and Morales 1989 the data remained unchanged
between the two reviews. Did this mean there were no deaths from 8-28 days? We now know this is
not true for Liggins 1972a. There is also something peculiar about the randomisation in Schmidt
1984. Between appearing in Effective Care in Pregnancy and Childbirth and inclusion in the
Cochrane review 15 women were added to this study, all in the treatment group and with no change
in the number of deaths.
The authors of the latest Cochrane review implied that the differences in the results were due to
intention to treat analysis however data was not available to support this. In the paragraph
entitled "Effects of antenatal corticosteroids for preterm birth" the third sentence referring
to the 1990 review by Crowley et al (4) is not strictly correct. "This
review showed that corticosteroids ... are effective in preventing respiratory
distress syndrome and neonatal mortality." In fact that analysis was for
early neonatal deaths (deaths in the first seven days) only. Subsequently the
Cochrane review used neonatal deaths (deaths in the first 28 days) and data from some of the
trials (Liggins 1972a, Block 1977, Gamsu 1989, and Morales 1989) are still the same as the
previous data reported as early neonatal deaths. Therefore, to be correct, the above
sentence should end "...preventing respiratory distress and early neonatal
mortality. Confusion remains regarding the results of three trials. Differences
in the data for neonatal death between this update and the previous version
(Table 1) are unexplained. For Block 1977 and Gamsu 1989 the differences are
minor, but for Morales 1986 they are larger. These changes merit some explanation.
Table 1
Differences in the data for neonatal mortality
Original data
Recent data
Trial ID
Treatment
Control
Treatment
Control
n/N
n/N
n/N
n/N
Block 1977
1/69
5/61
1/57
5/53
Gamsu 199
14/131
20/137
14/130
17/134
Morales 1986
7/121
13/124
7/87
8/78
It is interesting to postulate what might have happened if the true results of the Auckland trial
showing similar numbers of neonatal survivors with much the same perinatal morbidity in both
treatment and control groups had been available in the late eighties. How many trials of steroids
might never have been started and would other ways of improving preterm survival and morbidity
have been explored. Dunn (8) published preliminary data showing a marked improvement in mortality
at preterm caesarean delivery using a slow delivery technique which delayed cord clamping,
mimicking the effect of a natural vaginal delivery. Unfortunately this approach was never
subjected to a randomised controlled trial although Kimmond et al showed a similar benefit for
simple delayed cord clamping at vaginal delivery. The ease of a simple steroid injection which
appeared to have a similar benefit led to the technique being lost in the mass of literature.
Is it not time to explore this approach once more? The beneficial effect of delayed cord clamping
could be additive to the effect of corticosteroids.
References
1. Gates S, Brocklehurst P. Decline in effectiveness of antenatal corticosteroids with time to
birth: real or artefact? BMJ 2007;335:77-79
2. Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A et al. Cardiovascular risk
factors after exposure to antenatal betamethasone: 30-year follow-up of a randomised controlled
trial. Lancet 2005;365:1856-62.
3. Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A et al. Antenatal exposure to
betamethasone: psychological functioning and health related quality of life 31 years after
inclusion in a randomised controlled trial. BMJ 2005;331:665-8.
4. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention
of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515-25.
5. Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane database Syst Rev 2000:2
CD000065
6. In: Chalmers I, Enkin M, Keirse MJNC, eds. Effective care in pregnancy and childbirth. Oxford:
Oxford University Press, 1989:754.
7. Crowley P, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before
preterm delivery: an overview of the evidence from controlled trials. British
Journal of Obstetrics and Gynaecology 1990; 97:11-25
8. Dunn P M, Caesarean Section and the prevention of respiratory distress syndrome of the
newborn. In: Bossart, H et al (eds) Perinatal Medicine. 3rd Europ. Congr. Perinatal Medicine,
Single dose steroids not be without risk
Gates and Brocklehurst (1) provide a careful re-analysis of the published evidence on the use of
powerful drugs which can affect the newborn baby. The safety of single doses of corticosteroids
is not established. Dalziel et al (2,3) followed up the Auckland data (4) after 30 years to check
the long term safety of antenatal corticosteroids for the survivors. They found that "there were
similar numbers of neonatal survivors with much the same perinatal morbidity in both treatment
groups." So re-analysis of the Auckland data showed that there was no benefit from the steroids
in terms of either survival or morbidity but that the treatment did not cause any adverse effects
in the survivors. If this dataset shows safety it must also put efficacy in question. If efficacy
is considered to be valid as a result of other studies then safety remains in question.
The Auckland study (4) formed a major part of the Cochrane review on antenatal steroids to
accelerate lung maturity, yet the data from the follow-up reports (2,3) differed from those in
the Cochrane review.(6) There are also discrepancies between different versions of the Cochrane
review. The version published in Effective care in Pregnancy and Childbirth Table 45.12 (6,7)
contains 12 trials reporting the effect of corticosteroids on early neonatal death (0-7 days).
Some of these 12 are in the analysis presented later for the outcome neonatal death (0-28 days).
However, for Liggins 1972a, Block 1977, Gamsu 1989, and Morales 1989 the data remained unchanged
between the two reviews. Did this mean there were no deaths from 8-28 days? We now know this is
not true for Liggins 1972a. There is also something peculiar about the randomisation in Schmidt
1984. Between appearing in Effective Care in Pregnancy and Childbirth and inclusion in the
Cochrane review 15 women were added to this study, all in the treatment group and with no change
in the number of deaths.
The authors of the latest Cochrane review implied that the differences in the results were due to
intention to treat analysis however data was not available to support this. In the paragraph
entitled "Effects of antenatal corticosteroids for preterm birth" the third sentence referring
to the 1990 review by Crowley et al (4) is not strictly correct. "This
review showed that corticosteroids ... are effective in preventing respiratory
distress syndrome and neonatal mortality." In fact that analysis was for
early neonatal deaths (deaths in the first seven days) only. Subsequently the
Cochrane review used neonatal deaths (deaths in the first 28 days) and data from some of the
trials (Liggins 1972a, Block 1977, Gamsu 1989, and Morales 1989) are still the same as the
previous data reported as early neonatal deaths. Therefore, to be correct, the above
sentence should end "...preventing respiratory distress and early neonatal
mortality. Confusion remains regarding the results of three trials. Differences
in the data for neonatal death between this update and the previous version
(Table 1) are unexplained. For Block 1977 and Gamsu 1989 the differences are
minor, but for Morales 1986 they are larger. These changes merit some explanation.
Table 1
Control
It is interesting to postulate what might have happened if the true results of the Auckland trial
showing similar numbers of neonatal survivors with much the same perinatal morbidity in both
treatment and control groups had been available in the late eighties. How many trials of steroids
might never have been started and would other ways of improving preterm survival and morbidity
have been explored. Dunn (8) published preliminary data showing a marked improvement in mortality
at preterm caesarean delivery using a slow delivery technique which delayed cord clamping,
mimicking the effect of a natural vaginal delivery. Unfortunately this approach was never
subjected to a randomised controlled trial although Kimmond et al showed a similar benefit for
simple delayed cord clamping at vaginal delivery. The ease of a simple steroid injection which
appeared to have a similar benefit led to the technique being lost in the mass of literature.
Is it not time to explore this approach once more? The beneficial effect of delayed cord clamping
could be additive to the effect of corticosteroids.
References
1. Gates S, Brocklehurst P. Decline in effectiveness of antenatal corticosteroids with time to
birth: real or artefact? BMJ 2007;335:77-79
2. Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A et al. Cardiovascular risk
factors after exposure to antenatal betamethasone: 30-year follow-up of a randomised controlled
trial. Lancet 2005;365:1856-62.
3. Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A et al. Antenatal exposure to
betamethasone: psychological functioning and health related quality of life 31 years after
inclusion in a randomised controlled trial. BMJ 2005;331:665-8.
4. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention
of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515-25.
5. Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane database Syst Rev 2000:2
CD000065
6. In: Chalmers I, Enkin M, Keirse MJNC, eds. Effective care in pregnancy and childbirth. Oxford:
Oxford University Press, 1989:754.
7. Crowley P, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before
preterm delivery: an overview of the evidence from controlled trials. British
Journal of Obstetrics and Gynaecology 1990; 97:11-25
8. Dunn P M, Caesarean Section and the prevention of respiratory distress syndrome of the
newborn. In: Bossart, H et al (eds) Perinatal Medicine. 3rd Europ. Congr. Perinatal Medicine,
Lausanne, 1972,135-45. Bern, Hans Huber
Competing interests:
None declared
Competing interests: No competing interests