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Promoting pulmonary
maturity
1 Introduction
2 Benefits of prenatal corticosteroid administration
2.1 Respiratory distress syndrome
2.2 Other neonatal morbidity and mortality
3 Potential risks of prenatal corticosteroid administration
3.1 Risks to the mother
3.2 Risks to the baby
4 Prenatal corticosteroid administration in special
situations
4.1 Hypertensive disease
4.2 Intra-uterine growth restriction
4.3 Diabetes mellitus
4.4 Rhesus iso-immunization
5 Other agents to promote pulmonary maturity
5.1 Ambroxol
5.2 Thyrotropin-releasing hormone
6 Conclusions
1 Introduction
Respiratory distress syndrome is the most common complication of
preterm birth, affecting over 50% of babies born before 32 weeks
gestation. It remains a significant cause of death and severe morbidity
in preterm infants.
A number of agents can promote fetal lung maturation and thereby
reduce the risk of respiratory distress syndrome in the newborn. Only
three of these have been evaluated in controlled trials: corticosteroids,
ambroxol, and thyrotropin-releasing hormone (TRH) administered in
combination with corticosteroids. Of these, corticosteroids and TRH
in combination with corticosteroids have been evaluated thoroughly,
and only prenatal corticosteroids are of benefit.
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SOURCE: Murray Enkin, Marc J.N.C. Keirse, James Neilson, Caroline Crowther, Lelia Duley, Ellen Hodnett, and
Justus Hofmeyr. A Guide to Effective Care in Pregnancy and Childbirth, 3rd ed. Oxford, UK: Oxford University
Press, 2000.
DOWNLOAD SOURCE: Maternity Wise website at www.maternitywise.org/prof/
Oxford University Press 2000
2 Benefits of prenatal corticosteroid
administration
2.1 Respiratory distress syndrome
Prenatal administration of corticosteroids that pass through the
placenta to the fetus results in a clinically important and statistically
significant decrease in the risk of respiratory distress syndrome.
Betamethasone (24 mg) and dexamethasone (24 mg) are both associ-
ated with an important and statistically significant reduction of respi-
ratory distress syndrome. The risk reduction is approximately 4060%.
Hydrocortisone has been evaluated in only a few small trials, without
sufficient power to demonstrate a statistically significant effect.
Maximum benefit is achieved for babies delivered more than 24
hours and less than 7 days after commencement of the medication. The
reductions in the incidence of respiratory distress seen for babies born
outside of this optimum period do not achieve statistical significance
in the trials conducted, although the trend suggests a benefit.
No beneficial treatment effect has been demonstrated from the trials
for babies born more than 7 days after the first course of prenatal
steroids. Because of this, it has become widespread practice to admin-
ister prenatal corticosteroids at weekly intervals to women who remain
undelivered and at risk of preterm birth. Whether or not prenatal
steroids should be repeated if the woman remains undelivered and at
risk of preterm birth 7 days or more after an initial course, is still
unknown and is currently being evaluated by randomized trials (see
also Section 3.2).
Corticosteroid administration to infants born at less than 28 weeks
gestation, produced similar reductions in the risk of respiratory distress
to that observed for preterm babies as a whole, although the numbers
available for analysis were not sufficient to demonstrate statistical
significance. Respiratory distress is uncommon among babies born
after 34 weeks gestation, so the beneficial effects will be less in absolute
terms, but the relative reduction of risk is similar to that found at earlier
gestational ages. Gender of the baby does not modify the effects of
prenatal corticosteroid administration.
2.2 Other neonatal morbidity and mortality
An important secondary benefit of corticosteroids has been a reduc-
tion in the duration and cost of neonatal hospital stay. The need for
use of surfactant is reduced. Corticosteroids reduce the risk, not only
of respiratory morbidity, but also of other serious forms of neonatal
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morbidity. The risk of periventricular hemorrhage is less than half that
seen without the use of corticosteroids. This effect is probably related
to the reduced risk of respiratory distress, although it might also reflect
an effect of corticosteroids on the periventricular vasculature. No
statistically significant effects have been observed on the risk of necro-
tizing enterocolitis or of chronic lung disease.
The marked reductions in risk of respiratory distress syndrome and
periventricular hemorrhage are reflected in a substantial reduction in
the risk of early neonatal mortality. As there is no concomitant increase
in the risk of fetal death with corticosteroid use, this represents a
decrease in overall perinatal mortality.
3 Potential risks of prenatal corticosteroid
administration
3.1 Risks to the mother
Instances of pulmonary edema have been reported in pregnant women
receiving a combination of corticosteroids and labor-inhibiting drugs.
It is difficult to estimate the magnitude of this risk, or to differentiate
the separate effects of corticosteroids and the labor-inhibiting drugs.
Infection is another potential risk of prenatal corticosteroid admin-
istration. Maternal infection is not increased overall, although infec-
tion is increased in women with rupture of the membranes for more
than 24 hours prior to birth.
Other pharmacological effects of corticosteroid administration in
adults relate to long-term treatment, and they provide few grounds for
concern when a single course of prenatal corticosteroids is used for a
period of 2448 hours to promote fetal maturation.
3.2 Risks to the baby
The immunosuppressive effects of corticosteroid therapy could, in
theory, result in an increased susceptibility to infection or to a delay
in its recognition. This concern has received a great deal of attention,
especially in pregnancies complicated by prelabor rupture of the
membranes. Data from the trials show no evidence that corticosteroid
therapy increases the risk of fetal or neonatal infection overall or in
cases of preterm prelabor rupture of the membranes.
A fetus may be exposed to corticosteroids throughout pregnancy if
the mother is receiving long-term steroid therapy for ulcerative colitis,
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asthma, rheumatoid arthritis, or other conditions. A review of the
literature shows no striking excess over expectation for any adverse
outcomes.
The most reliable evidence about the long-term effects of a single
course of prenatal corticosteroid therapy comes from follow-up of chil-
dren whose mothers had been treated in the randomized trials. None
of the studies indicate that prenatal corticosteroid therapy affects phys-
ical growth, lung growth, or development. Because of the reduced
neonatal mortality rate in corticosteroid-treated babies, survivors from
the corticosteroid groups had a lower mean gestational age at birth
than survivors from the control group. Despite this, the available
evidence suggests that prenatal corticosteroids may protect against the
long-term neurological sequelae of hemiparesis, diplegia, and quadri-
plegia. This is plausible in the light of the complications that some-
times accompany both respiratory distress and its treatment.
No controlled data are available on the risk of a repeat course of
prenatal corticosteroids on the baby, although poorly controlled data
suggest a reduction in birthweight. Animal studies have suggested other
concerns, such as an effect on the fetal adrenals, and prompt caution
against repeated use of prenatal corticosteroids until the results of trials
are available.
4 Prenatal corticosteroid administration in special
situations
Elective preterm delivery differs from spontaneous preterm birth in
at least four main ways. First, the timing of elective preterm delivery
can be controlled, thus securing the delay required to gain maximum
benefit from corticosteroid administration. Second, cesarean section,
which predisposes to respiratory distress, is a common route of delivery
in this group of babies. Third, elective preterm birth usually takes place
somewhat later in gestation than spontaneous preterm birth, so that
the absolute risk of respiratory distress is usually lower. Finally, elec-
tive preterm birth is often undertaken for conditions such as diabetes,
in which corticosteroid administration may have unwanted effects.
4.1 Hypertensive disease
Hypertensive disorders in pregnancy constitute one of the major indi-
cations for elective preterm birth. The initial concern about the use of
steroids in women with pre-eclampsia was based on the statistically
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significantly increased risk of fetal death associated with corticosteroid
use in the 90 women with pre-eclampsia studied in the first reported
trial. This early finding was not based on a plausible hypothesis, and
came from a subgroup analysis. All 12 deaths occurred in women with
proteinuria of more than 2 g per day for more than 14 days, a severity
of disease that was not found in any of the placebo-treated women.
There were no fetal deaths of babies of a similar number of hyperten-
sive women in the three other trials from which data are available to
address this issue. A consistent adverse effect of corticosteroids would
have resulted in an increased incidence of stillbirth overall, but this did
not occur. Thus, there is no good reason to deny women with pre-
eclampsia the benefits of steroid therapy.
Even in the absence of any adverse effect of corticosteroids in women
with pre-eclampsia, the clinician may be faced with the possible risks
of postponing delivery for the few hours required to achieve a useful
effect of corticosteroid administration. In some cases this delay may
constitute an unacceptably high risk of complications, such as
eclampsia or cerebral hemorrhage in the mother. Delivery should not
be delayed at the expense of maternal health, but even an incomplete
course of steroids may help the baby.
4.2 Intra-uterine growth restriction
Intra-uterine growth restriction, like hypertensive disease in preg-
nancy, is a common indication for elective preterm birth. Moreover,
the two conditions often co-exist. The lungs of fetuses with growth
restriction in the absence of maternal hypertension may have acceler-
ated maturation, but there might still be benefit from corticosteroid
administration.
A potential disadvantage of prenatal corticosteroid therapy with
intra-uterine growth restriction is the risk of neonatal hypoglycemia,
which is an important complication in growth restricted infants.
Although one trial reported more cases of neonatal hypoglycemia
among corticosteroid-treated babies compared with controls, without
information from other trials it is difficult to know whether this is
anything more than a chance difference.
4.3 Diabetes mellitus
Maternal diabetes mellitus may predispose to the development of respi-
ratory distress syndrome. The results of the randomized trials do not
clarify whether or not the use of corticosteroids is of benefit for diabetic
women who deliver preterm, as only 35 such women were included in
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the trials. Insufficient data are available to allow an evidence based
recommendation.
While the efficacy of prenatal corticosteroids to women with preg-
nancies complicated by diabetes mellitus is unknown, the potential
side-effects should be a source of concern. Fetal hyperinsulinism may
or may not cause cortisol resistance in the fetal lung. Administration
of corticosteroids causes insulin resistance in the diabetic. Loss of
diabetic control is to be expected with the doses of corticosteroids
administered to promote fetal pulmonary maturation. Therefore,
prenatal corticosteroid therapy in the diabetic woman would require
exceptionally close supervision, possibly with continuous intravenous
insulin and frequent blood glucose estimation. Failure to maintain
control of the mothers diabetes may result either in ketoacidosis,
which carries a high perinatal mortality rate, or in a state of fetal hyper-
insulinism, which may increase the likelihood of failure to respond to
corticosteroid therapy. Corticosteroid administration, if used at all in
diabetic women, should be used with great caution, as it is not certain
that it will do more good than harm.
4.4 Rhesus iso-immunization
Elective preterm delivery plays an important role in the management
of rhesus iso-immunization. Unlike other conditions associated with
chronic intra-uterine stress, rhesus disease is not thought to provoke
an acceleration of pulmonary maturation. While there is a trend
towards a reduction in perinatal mortality and in the incidence of
respiratory distress syndrome in steroid-treated infants compared with
controls, the numbers reported in the trials are too small to provide
any secure estimates of the likely effects. However, there are no specific
contra-indications to the administration of corticosteroids in women
with rhesus iso-immunization.
5 Other agents to promote pulmonary maturity
5.1 Ambroxol
Treatment with prenatal ambroxol compared with placebo shows a
tendency towards reducing the risk of respiratory distress syndrome,
but the results are not statistically significant. Direct comparisons
of ambroxol with corticosteroids show no clear differential effect,
although there were methodological weaknesses in the trials that exam-
ined this. The main disadvantage with ambroxol is the 5-day period
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required to complete therapy. Because the evidence in favor of prenatal
corticosteroids in anticipated preterm birth is so strong, they remain
the prophylactic strategy of choice.
5.2 Thyrotropin-releasing hormone
Prenatal administration of thyrotropin-releasing hormone (TRH) in
addition to corticosteroids, prior to very preterm birth, does not reduce
the risks of respiratory distress syndrome or of chronic lung disease,
and is associated with an increased risk of maternal side-effects of
nausea, vomiting, light headedness, and elevation of pulse and blood
pressure.
Systematic review of the randomized trials available shows not only
no benefit but an increase in the risk of respiratory distress syndrome,
need for ventilation, and death or need for oxygen by day 28 after birth,
in babies exposed to prenatal TRH who deliver 10 or more days later.
In view of this, prenatal TRH cannot be recommended.
6 Conclusions
Prenatal treatment with 24 mg betamethasone, or 24 mg dexametha-
sone, for lung maturation, is associated with a significant reduction in
the risk of respiratory distress syndrome in preterm infants. This
reduction is independent of gender, and applies to babies born at all
gestational ages at which respiratory distress syndrome may occur. It
is accompanied by reductions in the risk of periventricular hemor-
rhage, lower neonatal mortality rate, and in a reduced cost and dura-
tion of neonatal care.
These benefits are achieved without any detectable increase in the
risk of maternal, fetal, or neonatal infection. Although maternal infec-
tion is increased in women with rupture of membranes for more than
24 hours prior to birth, prenatal corticosteroid administration does not
increase the risk of stillbirth.
Every effort should be made to treat women with corticosteroids
prior to preterm birth, either as a result of preterm labor or planned
elective preterm birth. The only possible exception is for women with
diabetes. Treatment should commence at presentation in women
with any symptoms or signs that suggest the onset of preterm labor or
indicate a potential need for elective preterm birth in the near future.
Treatment should not be withheld because birth appears imminent.
There are no controlled data to recommend or refute the widespread
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use of repeat doses of prenatal corticosteroids for women who remain
at risk of preterm birth but undelivered after an initial course. Until
the results from the trials currently in progress are available, multiple
doses of prenatal corticosteroids should be avoided.
TRH should not be used for the promotion of pulmonary matura-
tion.
Sources
Effective care in pregnancy and childbirth
Crowley, P., Promoting pulmonary maturity.
Cochrane Library
Crowley, P., Prophylactic corticosteroids for preterm delivery.
Crowther, C.A., Alfirevic, Z. and Haslam, R. Prenatal thyrotropin-
releasing hormone (TRH) for preterm birth.
Pre-Cochrane reviews
Crowley, P. Ambroxol vs placebo prior to preterm delivery. Review no.
03276.
Ambroxol vs betamethasone prior to preterm delivery. Review no.
03852.
Ambroxol vs intralipid prior to preterm delivery. Review no. 03853.
Corticosteroids + induction of labour after PROM preterm. Review
no. 06871.
Corticosteroids prior to preterm delivery. Review no. 02955.
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