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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.

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

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    



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 40–60%.

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 24–48 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



  

1

significantly increased risk of fetal death associated with corticosteroid

2

use in the 90 women with pre-eclampsia studied in the first reported

3

trial. This early finding was not based on a plausible hypothesis, and

4

came from a subgroup analysis. All 12 deaths occurred in women with

5

proteinuria of more than 2 g per day for more than 14 days, a severity

6

of disease that was not found in any of the placebo-treated women.

7

There were no fetal deaths of babies of a similar number of hyperten-

8

sive women in the three other trials from which data are available to

9

address this issue. A consistent adverse effect of corticosteroids would

10

have resulted in an increased incidence of stillbirth overall, but this did

1

not occur. Thus, there is no good reason to deny women with pre-

2

eclampsia the benefits of steroid therapy.

3

Even in the absence of any adverse effect of corticosteroids in women

4

with pre-eclampsia, the clinician may be faced with the possible risks

5

of postponing delivery for the few hours required to achieve a useful

6

effect of corticosteroid administration. In some cases this delay may

7

constitute an unacceptably high risk of complications, such as

8

eclampsia or cerebral hemorrhage in the mother. Delivery should not

9

be delayed at the expense of maternal health, but even an incomplete

20

course of steroids may help the baby.

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2

4.2

Intra-uterine growth restriction

3

Intra-uterine growth restriction, like hypertensive disease in preg-

4

nancy, is a common indication for elective preterm birth. Moreover,

5

the two conditions often co-exist. The lungs of fetuses with growth

6

restriction in the absence of maternal hypertension may have acceler-

7

ated maturation, but there might still be benefit from corticosteroid

8

administration.

9

A potential disadvantage of prenatal corticosteroid therapy with

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intra-uterine growth restriction is the risk of neonatal hypoglycemia,

1

which is an important complication in growth restricted infants.

2

Although one trial reported more cases of neonatal hypoglycemia

3

among corticosteroid-treated babies compared with controls, without

4

information from other trials it is difficult to know whether this is

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anything more than a chance difference.

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4.3

Diabetes mellitus

8

Maternal diabetes mellitus may predispose to the development of respi-

9

ratory distress syndrome. The results of the randomized trials do not

40

clarify whether or not the use of corticosteroids is of benefit for diabetic

41

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

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recommendation.

3

While the efficacy of prenatal corticosteroids to women with preg-

4

nancies complicated by diabetes mellitus is unknown, the potential

5

side-effects should be a source of concern. Fetal hyperinsulinism may

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or may not cause cortisol resistance in the fetal lung. Administration

7

of corticosteroids causes insulin resistance in the diabetic. Loss of

8

diabetic control is to be expected with the doses of corticosteroids

9

administered to promote fetal pulmonary maturation. Therefore,

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prenatal corticosteroid therapy in the diabetic woman would require

1

exceptionally close supervision, possibly with continuous intravenous

2

insulin and frequent blood glucose estimation. Failure to maintain

3

control of the mother’s diabetes may result either in ketoacidosis,

4

which carries a high perinatal mortality rate, or in a state of fetal hyper-

5

insulinism, which may increase the likelihood of failure to respond to

6

corticosteroid therapy. Corticosteroid administration, if used at all in

7

diabetic women, should be used with great caution, as it is not certain

8

that it will do more good than harm.

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4.4

Rhesus iso-immunization

1

Elective preterm delivery plays an important role in the management

2

of rhesus iso-immunization. Unlike other conditions associated with

3

chronic intra-uterine stress, rhesus disease is not thought to provoke

4

an acceleration of pulmonary maturation. While there is a trend

5

towards a reduction in perinatal mortality and in the incidence of

6

respiratory distress syndrome in steroid-treated infants compared with

7

controls, the numbers reported in the trials are too small to provide

8

any secure estimates of the likely effects. However, there are no specific

9

contra-indications to the administration of corticosteroids in women

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with rhesus iso-immunization.

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5 Other agents to promote pulmonary maturity

4

5

5.1

Ambroxol

6

Treatment with prenatal ambroxol compared with placebo shows a

7

tendency towards reducing the risk of respiratory distress syndrome,

8

but the results are not statistically significant. Direct comparisons

9

of ambroxol with corticosteroids show no clear differential effect,

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although there were methodological weaknesses in the trials that exam-

41

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.