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Brief Reports

Indian Pediatrics 2000;37: 639-646

Effects of Antenatal Corticosteroids on Blood Pressure Support in Premature Neonates


Rajiv Aggarwal
Lynette Downe

From the Department of Pediatrics, St Johns Medical College and Hospital Bangalore, India and Neonatal Intensive Care Unit, Nepean Hospital, Penrith, NSW 2750, Australia.

Reprint requests: Dr. Rajiv Aggarwal, Assistant Professor, Department of Pediatrics, St. Johns Medical College and Hospital Bangalore 560 034, India.

Manuscript Received: June 1, 1999;
Initial review completed: July 26, 1999;
Revision Accepted: November 11, 1999

In 1972 Liggins and Howie(1) demonstrated that maternal administration of corticosteroids before preterm delivery resulted in a significant decrease in neonatal mortality and respiratory distress syndrome (RDS). Many studies have since then demonstrated a reduction in the incidence of adverse effects associated with premature birth such as mortality, RDS and intraventricular hemorrhage (IVH)(2-5). Studies have also shown a strong association between hypotension and IVH(6-8). The protective effect of steroids in the prevention of IVH may be related to its effect on the blood pressure of premature neonates. This retrospective cohort study was performed to evaluate the effect, if any, of antenatal steroids on blood pressure in the first 48 hours of life of babies born at less than 33 weeks gestation. We also examined the effect of antenatal steroids on mortality, requirement for ventilatory support, IVH and retinopathy of prematurity (ROP).

 Methods

All infants born at less than or equal to 32 weeks gestation and admitted to the Neonatal Intensive Care Unit (NICU) between July 1994 and June 1996 were eligible for this study. Babies needing early transfer to other NICU’s because of non availability of beds and babies with life threatening congenital malformations were excluded.

Medical records were reviewed to obtain maternal data including the incidence of pregnancy induced hypertension, antepartum hemorrhage, prolonged rupture of membranes, chorioamnionitis, mode of delivery and use of tocolytic agents. Gestational age was estimated by the date of the last menstrual period and if unavailable by antenatal ultrasound examina-tion. If both details were missing then the gestation was estimated by clinical examina-tion. Other infant details recorded were weight, sex, evidence of early onset infection or hemorrhage, perinatal asphyxia and whether sedation (fentanyl/morphine) was used after delivery.

For this study a complete course of antenatal steroids was defined as the period commencing 24 hours after beginning maternal steroid treatment and lasting 7 days. Two doses of steroids had to be repeated after 7 days to be considered as a complete course. An in-complete course was defined as delivery within 24 hours of starting therapy/or more than 7 days after completion of steroids. Women at risk of preterm delivery received steroids at the discretion of the treating obstetrician.

Data was collected on the total amount of colloid and inotrope infused in the first 48 hours for each infant as an indicator of the blood pressure support required. Colloid included all infusions of 5% albumin in normal saline, 20% concentrated albumin, fresh frozen plasma, packed red blood cells or platelets. The total amount of inotrope infused was assessed separately for dopamine and dobutamine. The inotrope score was calculated as described by Moise et al.(9). The score was obtained by summing the rate in micrograms per kg/min multiplied by the number of hours delivered during the first 48 hours after birth. For example if an infant received 5 mcg/kg per minute of dopamine every hour for 24 hours and then 3 mcg/kg per minute every hour for the next 24 hours then the dopamine score would be (5 ´ 24) + (3 ´ 24) = 192.

All babies had an initial recording of their heart rate, temperature, respiratory rate and blood pressure on admission to the NICU. If the baby was hypotensive, 10-20 ml/kg of colloid was infused. Hypotension was defined according to data from Versmold HT et al.(10). We aimed to maintain a MAP between 25-30 for babies weighing below 1000, 30-35 for babies weighing between 1000 to 1500 g and above 35 for babies weighing above 1500. Dopamine, Dobutamine or both were commenced if the MAP remained below the desired level. The choice of the inotrope depended on the attending neonatologist. Babies requiring ventilation had indwelling arterial catheters and had hourly recording of the systolic, diastolic and mean arterial blood pressures. Babies not requiring ventilatory support had their blood pressures monitored 4-6 hourly.

Data was collected on the ventilatory support required for each infant. The oxygenation index (mean airway pressure  ´  fraction of inspired oxygen  ´  100  ¸ PaO2) was used as a measure of amount of ventilatory support required. This was calculated at 24 and 48 hours for all ventilated infants. Surfactant (Exosurf) was administered within the first 4 hours and repeated after 12 hours if the initial chest X-ray was suggestive of Respiratory Distress Syndrome (RDS) and the baby required ventilation with a FiO2 greater than 0.4. Patients were evaluated for patent ductus arteriosus (PDA), retinopathy of prematurity (ROP) and intraventricular hemorrhage (IVH) using standard protocols and techniques.

Data were analyzed by using the Epi Info Version 6.1 software packages (CDC, Epi-demiology program office, Atlanta Georgia). Categoric data were analyzed by Chi square or Fisher exact probability test. Continuous data that were not normally distributed were analyzed with the Kruskal-Wallis test. Normally distributed numeric data were analyzed by unpaired ‘t’ test. Cornfield 95% confidence intervals were used for the odds ratios.

  Results

A total of 174 neonates with a gestation less than 33 completed weeks were admitted to the unit between July 1994 to June 1996. Nine babies were transferred to other Neonatal Intensive Care Units in New South Wales after their initial stabilization, due to non availability of beds (5 had received a complete antenatal steroid course, 2 incomplete and 2 none). These infants were not included in the analysis. Four more babies were excluded due to life threatening congenital malformations (2 with Trisomy 21 and congenital heart defects, 1 with myotonic dystrophy who died within 18 hours and 1 with multiple ileal and jejunal atresias). The remaining 161 babies were analyzed. Of these 161 infants, a total of 77 (48%) received a complete course of antenatal steroid. Forty two (26%) babies received an incomplete course and 42 (26%) did not receive steroids prior to delivery.

Clinical data of the 140 mothers and 161 infants are shown in Table I. There were 17 twin pregnancies and 2 triplet pregnancies in the study group. There was no significant difference found in the maternal characteristics between the 3 groups apart from the occurrence of prolonged rupture of membranes, being higher in the mothers receiving a complete course of steroids (p = 0.02). This difference could be expected as these would be mothers in whom there was sufficient time prior to delivery for the administration of steroids.

There were no significant differences in infant birth weight, gestation or sex between the 3 groups. The incidence of asphyxia, early infection and requirement for sedation with narcotics was not different between the groups. The group receiving no antenatal steroids did have a slightly higher incidence of blood loss during or immediately prior to delivery as determined by the need for urgent colloid or blood administration at the time of delivery or immediately after admission to the NICU (p = 0.05). However the initial volume replacement used for treating the early blood loss in these 4 patients was not included in the analysis for colloid volume.

Babies exposed to a complete course of steroid had a significantly lower mortality (4%) as compared to babies in the incomplete group (10%) and the no steroid group (19%). All deaths in the three groups occurred in ventilated infants and the beneficial effect of steroids on the mortality may be due to its effect on RDS in preterm neonates. Respiratory failure was not a cause of death in the complete steroid group and was responsible for seven deaths in the none/incomplete group. Babies receiving a complete course of steroid required less support to maintain their blood pressure in the first 48 hours after birth. A total of 65% of babies in this group required colloid infusions in the first 48 hours compared to 81% in the incomplete group and 83% in the no steroid group (p = 0.04). Also significantly fewer babies in the complete group required inotropic support as compared to the other two groups (complete 30%, incomplete 48%, none 52%; p = 0.03).

As the primary analysis showed no difference between babies in the no steroid and incomplete steroid groups with respect to their clinical outcomes, further analysis was done with these 2 groups combined together. These results are shown in Table II. Babies who had received a complete course of antenatal steroid were significantly more hemodynamically stable (Table II). Babies in this group were less likely to need colloid to maintain their blood pressure (p = 0.013) and if they did, they required a smaller volume (p = 0.0003). Despite the higher percentage of babies receiving larger volume of colloid in the none/incomplete group, more babies in this group required inotropic support as compared to the complete steroid group (p = 0.009). Since Dobutamine is associated with a higher failur rate in increasing the blood pressure, infants having received dopamine as the solitary inotrope in the two groups was also analyzed. Although, this comparison was also significant (p = 0.032), the difference between the two groups was narrower as compared to the difference with combined inotropic require-ment. There was no significant difference detected in the inotrope scores between the two groups. However, six babies in the none/incomplete group died within 24 hours and as these would have been the sickest babies with the highest inotrope requirements, this may have skewed these results away from statistical significance.

No differences were detected in the number of babies requiring any form of ventilatory support or oxygen therapy (Table II). However, significantly more babies in the none/incomplete group required surfactant (p 0.008). Also, babies in the complete group had significantly lower oxygenation and ventilation indices at 24 and 48 hours of age. Thus, although the proportion of babies in the two groups requiring ventilation was similar, babies in the none/incomplete group required more respiratory support in the form of higher ventilatory pressures and surfactant.

Only 9 of 157 (6%) babies developed severe IVH (grade III or IV IVH). Four babies died prior to head ultrasound examinations, 3 in the no steroid group and 1 in the incomplete group. However, the number of IVH’s in the study group is too small to show any significant difference. No significant difference was detected in the incidence of PDA or ROP in the three groups.

Table I: Clinical Dala

None (n = 42) Incomplete (n = 42) Complete (n = 77) p value
Maternal characteristics
PIH 6 (14) 9 (21) 19 (25) 0.41
APH 8 (19) 7 (17) 13 (17) 0.94
PROM 4 (10) 10 (24) 25 (32) 0.02
Chorioamnionitis 6 (14) 4 (10) 13 (17) 0.54
GBS 4 (10) 2 (5) 7 (9) 0.65
Tocolytics 4 (10) 8 (19) 20 (26) 0.15
LSCS 12 (28) 21 (50) 39 (50) 0.05
Infant characteristics
Gestation 28.6 ± 2.9 29.7 ± 1.9 29.6 ± 2.4 0.17
Weight 1269 ± 468 1453 ± 416 1379 ± 431 0.15
Sex M:F 22:20 23:19 39:38 0.91
IUGR 0 2 (5) 2 (3) 0.37
Birth asphyxia 2 (5) 2 (5) 2 (3) 0.76
Early infection 4 (10) 2 (5) 3 (4) 0.42
Blood loss 3 (7) 1 (2) 0 0.05
Morphine/Fentanyl 23 (55) 20 (48) 25 (32) 0.10

APH–antepartum hemorrhage, LSCS–lower segment Caesarian section, PIH–pregnancy induced hypertension, IUGR–intra uterine growth retardation PROM–prolonged rupture of membranes, GBS–Group B hemolytic streptococci isolated from high vaginal swab.
Values for weight and gestation are mean ± SD.
Figures in parantheses represent percentages.

Table II: Outcomes: Blood Pressure and Respiratory Support

None/Incomplete 
(n = 84)
Complete 
(n = 77)
Odds ratio (95% confidence interval)
Mortality 12 3 0.24 (0.04 to 0.96)
Blood pressure      
Colloid (n) 69 (82%) 50 (65%) 0.40 (0.18 to 0.88)
Inotrope (n) 42 (50%) 23 (30%) 0.43 (0.21 to 0.86)
Only dopamine (n) 21 (33) 11 (17) 0.41 (0.16 to 0.96)
Volume of colloid* 39 ± 26 23 ± 15 0.0003**
Amount of inotrope* 521 ± 363 382 ± 424 0.05**
Ventilation (n) 68 (81%) 56 (73%) 0.58 (0.27 to 1.21)
Surfactant (n) 48 (57%) 28 (36%) 0.43 (0.22 to 0.85)
OI (24)* 6.6 ± 5.0 4.4 ± 3.6 0.015**
OI (48)* 7.0 ± 7.7 3.6 ± 2.4 0.001**
Days of ventilation 18 ± 18 21 ± 22 0.61**

* 78 patients in the none/incomplete group as 6 died before 48 hours.
** = p value.
Values are mean ± SD.
Volume of colloid calculated as ml/kg in 48 hours.
Inotrope score: sum of the dose in mcg/kg/m ´ no. of hours received in first 48 hours.
n = no of patients.

 Discussion

This study found that a complete course of antenatal steroids was associated with a better neonatal outcome. Babies exposed to steroids had less need for colloid or infusion of inotropes to maintain blood pressure, a lower mortality rate and decreased ventilatory requirements.

Maintenance of blood pressure has become an issue in the management of newborns because of its predicted association with IVH. Miall-Allen et al.(6) using computerized continuous measurement of mean arterial blood pressure and serial cranial ultrasounds in 3 infants of less than 31 weeks gestation found that a mean blood pressure of less than 30 mm Hg for more than 1 hour was significantly associated with severe hemorrhage or ischemic cerebral lesions or death within 48 hours. They found no severe lesions if the mean blood pressure remained greater than 30 mm Hg. Bada et al.(7) studied the changes in mean arterial pressure (MAP) in the first 48 hours of life and its association with IVH in 100 preterm babies weighing less than 1500 grams using minute-to-minute computerized arterial monitoring. They found that babies with grade II-IV IVH had consistently lower MAP values during the study period as compared to the babies with grade I or no IVH. Low et al.(8) showed that abnormal outcome increased from 8% in newborns with no hypotension or hypoxemia to 53% in infants with both hypotension and hypoxemia. The results of these studies support the hypothesis that systemic hypotension and cerebral hypo-perfusion are important factors leading to IVH in low birth weight (LBW) infants. If this hypothesis is correct, preventing hypotension in preterm babies should help reduce the incidence of IVH in LBW infants. However normative data regarding MAP values in preterm babies is lacking. Additionally Zubrow et al.(11) in their study involving 608 infants demonstrated that both the systolic and diastolic blood pressures progressively rise during the first 5 days irrespective of the gestational age or weight. These factors compound the difficulty of choosing a "normal range" in which to maintain MAP in LBW infants.

Antenatal steroids have been found to reduce the incidence and severity of IVH in preterm babies(5). It is possible that this protective effect of steroids for IVH is mediated via better hemodynamic stability. Segar et al.(12) have evaluated the role of antenatal steroids on blood pressure in preterm lambs and found that antenatal steroids were associated with better hemodynamic stability. Arnold et al.(13) have evaluated the pulsatile secretion of steroids in preterm infants exposed to antenatal steroids. They found that the postnatal pulsatile surge of cortisol after exposure to antenatal steroids was blunted. However the frequency of these pulses were unaffected. Also they found that mean arterial blood pressure had a positive correlation with the frequency of pulses as well as the production rate of cortisol. Moise et al.(9) have shown that babies exposed to any dose of antenatal steroid had significantly less hypotension as compared to no dose.

In our study the effect of a complete course of steroid on blood pressure was better than either an incomplete or no exposure. However, some babies in the incomplete group received a single dose 4-6 hours prior to delivery which may have been insufficient for steroid to have effect. The possible impact of prolonged rupture of membranes (PROM), mode of delivery (LSCS vs vaginal) and perinatal blood loss on blood pressure support required was also evaluated in stratified analysis. All the three factors were found to be non confounding and the summary chi square p values for inotropic use in the two groups remained significant (PROM = 0.020, mode of delivery = 0.01, and blood loss = 0.016). However antenatal steroids and the choice of inotrope used were at the discretion of the attending physician and results of such a retrospective analysis need to be confirmed in a prospective manner.

The protective effect of antenatal steroid on occurrence of IVH should have been reflected as a lower incidence of this complication in the steroid group. However, the incidence of IVH in the study population was so low that the beneficial effect of the antenatal therapy could not be seen. One reason for the comparable incidence of IVH in the no steroid group may be the active management of hypotension. Prevention of systemic hypotension and cerebral hypoperfusion with the use of colloid and inotropes may have reduced the incidence of severe IVH. Nevertheless a favourable trend towards the steroid group was still present. It is possible that steroids in addition to preventing hypotension have a direct maturational effect on the germinal matrix thereby preventing IVH.

Antenatal steroids have been shown to be effective in reducing both the incidence and severity of RDS(1-4). This effect was also seen in our study. Babies not receiving antenatal steroid required more ventilatory support compared to the steroid group. The magnitude of this difference may have been decreased by the use of postnatal surfactant. However, although surfactant may have been successful in reducing the amount of ventilatory support, its use did not prevent RDS related mortality in the no steroid or incomplete groups. Therefore despite the benefits of surfactant in the management of preterm newborns it cannot replace the use of antenatal steroids.

Our results demonstrate that the use of antenatal steroids is associated with less need for blood pressure support in the first 48 hours after birth. They are also effective in reducing newborn mortality and ventilatory requirements in the initial 48 hours in preterm neonates and may have a protective effect on prevention of IVH. Consequently routine use of antenatal steroids whenever possible for threatened preterm delivery would not only improve survival and long term neurological outcome, but may also have significant cost benefit implications for the NICU by reducing the intensity and complexity of support required.

Contributors: RA coordinated the study (particularly its design, data collection and interpretation) and drafted the paper; he will act as the guarantor for the paper. LD helped in designing the study and drafting the paper.
Funding
: None.
Competing interests
: None stated.

 References

  1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for preven-tion of the respiratory distress syndrome in premature infants. Pediatrics 1972; 50: 515-525.

  2. Collaborative Group on Antenatal Steroid Therapy. Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome. Am J Obstet Gynecol 1981; 141: 276-287.

  3. Gamsu HR, Mullinger BM, Donnai P, Dash CH. Antenatal administration of betamethasone to prevent respiratory distress syndrome in preterm infants. report of a UK multicentre trial. Br J Obstet Gynecol 1989; 96: 401-410.

  4. Papageorgiou AN, Desgranges MF, Masson M, Colle R, Shatz R, Gelfand MM. The antenatal use of betamethasone in the prevention of respiratory distress syndrome: A controlled double blind study. Pediatrics 1979; 63: 73-79.

  5. Crowley P, Chalmers I, Keirse MJN. The effect of corticosteroid administration before preterm delivery: An overview of the evidence from controlled trials. Br J Obstet Gynecol 1990; 97: 11-25.

  6. Miall-Allen VM, De Vries LS, Whitelaw AGL. Mean arterial blood pressure and neonatal cerebral lesions. Arch Dis Child 1987; 62: 1068-1069.

  7. Bada HS, Korones SB, Perry EH, Arheart KL, Ray JD, Pourcyrous M, et al. Mean arterial blood pressure changes in premature infants and those at risk of intraventricular hemorrhage. J Pediatr 1990; 117: 607-614.

  8. Low JA, Froese AB, Galbraith RS, Smith JT, Sauerbrei EE, Derrick EJ. The association between preterm newborn hypotension and hypoxemia and outcome during the first year. Acta Paediatr 1993; 82: 433-437.

  9. Moise AA, Wearden ME, Kozinetz CA, Gest AL, Welty SE, Hansen TN. Antenatal steroids are associated with less need for blood pressure support in extremely premature infants. Pediatrics 1995; 95: 845-850.

  10. Versmold HT, Kitterman JA, Phibbs RH, Gregory GA, Tooley WH. Aortic blood pressure during the first 12 hours of life in infants with birth weight 610 to 4220 grams. Pediatrics 1981; 67: 607-613.

  11. Zubrow AB, Hulman S, Kushner H, Falkner B. Determinants of blood pressure in infants admitted to neonatal intensive care units: A prospective multicenter study. J Perinatol 1995; 15: 470-478.

  12. Segar JL, Eugenie RL, Nuyt AM, Smith OJ, Robillard JE. Effect of antenatal glucocorticoids on sympathetic nerve activity at birth in preterm sheep. Am J Physiol 1998; 274 (1pt2): R160-R167.

  13. Arnold JD, Bonacruz G, Leslie GI, Veldhuis JD, Milmlow D, Silink M. Antenatal glucocorticoids modulate the amplitude of pulsatile cortisol secretion in premature neonates. Pediatr Res 1998; 44: 876-881.

Key Messages

  • Hypotension and Respiratory Distress Syndrome (RDS) are common morbidities in preterm babies below 33 weeks.

  • Use of antenatal steroids (AS) is associated with a beneficial effect on both these morbidities.

  • Babies exposed to AS are hemodynamically more stable and require lesser colloid and inotrope infusions for maintaining normal blood pressure.

  • Use of AS is associated with lesser need for surfactant, ventilatory support and a reduction in mortality.

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