Effect of maternal glucocorticoid exposure on risk of severe intraventricular hemorrhage in surfactant-treated preterm infants

FETAL AND NEONATAL MEDICINE

Effect of maternal glucocorticoid exposure on risk of severe intraventricular hemorrhage in surfactant-treated preterm infants Jeffery S. G a r l a n d , MD, SM,° Rosanne Buck, MSN, CNNP, a n d Alan Leviton, MD, SM From the Joint Program in Neonatology and the Department of Neurology, Harvard Medical School, and Children's Hospital, Boston, Massachusetts

Objective: To determine whether the r e d u c e d risk of severe intraventricular hemorrhage (SIVH) that follows antenatal maternal g l u c o c o r t i c o i d (AMG) receipt is m e d i a t e d by an AMG effect on b l o o d pressure or improved respiratory function in infants who receive artificial surfactant as rescue therapy. Design: Retrospective cohort study. Setting: Two level III neonatal intensive care units, Boston, Mass. Participants: Two hundred twenty-five infants _<32 weeks of gestational a g e and ___1.7 kg birth weight, treated with surfactant. Main findings: SIVH occurred in 10% (10/102) of infants who were e x p o s e d to AMG, c o m p a r e d with 23% (25/111) of infants not e x p o s e d (odds ratio, 0.4; 95% c o n f i d e n c e interval, 0.2 to 0.8). Hypotension and need for colloid or d o p a m i n e were associated with both SIVH and the a b s e n c e of AMG exposure (p _<0.03). Logistic regression models of SIVH risk and AMG exposure, with adjustment for antenatal potential confounders, were altered by the addition of measures of hypotension. Most clinical measures of pulmonary function, both before and after surfactant receipt, were not associated with r e d u c e d risk of SIVH and did not a p p e a r to a c c o u n t for the increased risk of SIVH in babies not e x p o s e d to AMG. Conclusion: The r e d u c e d risk of SIVH in preterm newborn infants whose mothers received AMG was associated with normal b l o o d pressures. The association b e t w e e n AMG and SIVH was not consistently e n h a n c e d by respiratory function improvement after surfactant therapy. (J PEDIATR1995;126:272-9)

Antenatal maternal glucocorticosteroid treatment before the delivery of high-risk preterm infants decreases the incidence and severity of respiratory distress syndrome and also

Supported in part by a grant from the Medical Foundation, Boston, Massachusetts. Submitted for publication Dec. 20, 1993; accepted Aug. 12, 1994. Reprint requests: Jeffery S. Garland, MD, SM, 5000 West Chambers St., Milwaukee, WI 53210. aNow at St. Joseph's Hospital, Milwaukee, Wis. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/23/59940

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appears to reduce the incidence of periventricular-intraventricular hemorrhage. 1-9 Some authors have postulated that the risk of PIVH can be reduced by reducing the risk of RDS. 1° In this observational study, we wanted to identify how AMG reduced the risk of severe intraventricular hemorrhage, defined as intraventricular hemorrhage filling much of the lateral ventricle or intraventricular hemorrhage, with acute dilation. We considered two possible mechanisms. One was through improvement in lung function and lowered likelihood of increased intrathoracic pressure (i.e., less grunting or "bucking the respirator") and, consequently, a

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See related article, p. 317.

a/A AMG OI PIVH RDS SIVH VEI

Arterial/alveolar [ratio] Antenatal maternal glucocorticoidsteroid Oxygenation index Periventricular-intraventricular hemorrhage Respiratory distress syndrome Severe intraventricular hemorrhage Ventilatory efficiency index

lowered probability of increased cerebral venous pressure. Another was by reducing the risk of hypotension and the need for volume expanders, both of which have been associated with PIVH. A third mechanism, which could not be evaluated in this sample, was that A M G enhanced the maturation of intracranial vessels traversing areas of the germinal matrix. METHODS

Subjects. The population for this retrospective cohort study included all infants who were --<32 weeks of gestational age ( ~ 1700 gm), had received rescue artificial surfactant (Exosurf [Burroughs Wellcome]) therapy for RDS within the first 24 hours of life, had no major congenital anomalies, and had been cared for at one of two special care nurseries between November 1989 and April 1992. The study population was further limited to infants who had at least one cranial ultrasound study during the first 14 days of life. Care at both nurseries was provided by the same group of neonatology fellows and attending physicians. Between November 1989 and August 1990, rescue surfactant therapy was administered in two doses, 12 hours apart, to infants who had radiographs compatible with respiratory distress syndrome, required mechanical ventilation, and had arterial/alveolar ratios of -<0.22 before the first dose of artificial surfactant. After U.S. Food and Drug Administration approval of Exosurf in August 1990, criteria for surfactant therapy were liberalized and infants with RDS were eligible for Exosurf if they required a mean airway pressure of -->7 cm H20 and a fractional inspiratory oxygen concentration of at least 0.40 to maintain acceptable arterial blood gas values. Exposures. Data were collected from infant and maternal records by two of us (R.B. and J.S.G.). The gestational age of 63% of babies was determined by a first-trimester sonogram. Maternal dates (13%) or Ballard evaluation 11 (23%) was used to determine gestational age when early sonograms were not available. Glucocorticoids were given to women in preterm labor at the discretion of attending obstetricians; A M G treatment Consisted of either two doses of betamethasone separated by 24 hours or four doses of

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dexamethasone 12 hours apart. A course was considered complete if there was at least a 24-hour, but not more than a 7-day, delay between the last dose and delivery. A second complete course was defined in a similar fashion. A partial course of AMGs was defined by at least one dose of glucocorticoids before delivery but less than a complete course. Data collected from each record included demographics and information pertaining to the pregnancy, delivery room events, and the clinical course before artificial surfactant treatment and for the subsequent 24 hours. Data on ventilator settings, clinical measures of pulmonary function, and changes with time in these measures were also collected from each record. These clinical measures of severity of pulmonary disease included oxygenation index 12, 13 (mean airway pressure x fraction of inspired oxygen/arterial oxygen tension), a / A oxygen tension ratio, 12-16 and ventilatory efficiency index 17 [3800/(positive inspiratory pressure - positive expiratory pressure) x respiratory rate X arterial carbon dioxide tension]. Because most PIVHs occur during the first 48 hours of life, 18-21we limited our study to the interval between birth and 24 hours after the first dose of artificial surfactant, which was invariably given between 1 and 24 hours of life. Whenever possible, exposures were dichotomized into clinically relevant strata that have been used in past studies.3, 13 For clinical measures of pulmonary function improvement, we compared infants in the upper quartile of improvement with those in the lower three quartiles. Outcomes. Cranial sonograms were obtained at the discretion of the clinicians; in 60% of infants (134/225) the first scan was obtained within the first 24 hours of life. Subsequent scans were obtained most often on postnatal days 3, 7, 14, and 28. Cranial sonograms were obtained with a DS-30 Diasonics real-time unit (Diasonics Inc., Milpitas, Calif.) with either a 5, 6, or 7.5 M H z transducer (Children's Hospital) or a Mark-100 unit (Advanced Technology Laboratories, Inc., Bothell, Wash.) with a 5 or 7.5 MHz transducer (Brigham and Women's Hospital). These scans were evaluated by ultrasonographers at each institution who had no knowledge of each child's A M G exposure. Severe intraventricular hemorrhage was defined as an intraventricular hemorrhage filling much of a lateral ventricle, or intraventricular hemorrhage with acute ventricular dilation. Parenchymal hemorrhages unaccompanied by SIVH were excluded from the analysis. Data analysis. Three hypotheses were evaluated: 1. Among babies who require rescue surfactant, those exposed to A M G are at lower risk of having SIVH than those not so exposed. 2. The reduced risk of SIVH associated with A M G in babies who require rescue surfactant is accompanied by reduced risk of hypotension and reducedneed of

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Table I. Percentage of infants with (n = 35) and those without (n = 178) S I V H who had each maternal or neonatal characteristic

SIVH (+)

(-)

P

20 6 9 3 54 37 29

10 25 19 8 72 46 52

0.08 0.01 0.1 0.5

66 49 71 20

56 47 57 8

0.3 0.8 0.1 0.06

14 74 31 46 50 66 59 13 40

4 54 18 25 36 52 31 7 27

0.03 0.03 0.08

38 29 46 26 47

40 25 39 24 23

57

58

0.02 0.04

77 66 93 88

71 76 88 78

0.2 0.2 0.7 0.2

Maternal factors Outborn Pregnancy-induced hypertension Rupture of membranes >_24 hr Chorioamnionitis Cesarean section Cesarean section for fetal distress Any maternal glucocorticoids

0.04

0.5 0.01

Infant characteristics' Male Birth weight _<1.0 kg Gestational age --<28 wk Apgar score (at 5 min) <5 Nursery course/treatment before surfactant Sodium bicarbonate for acidosis Mean arterial blood pressure <30 mm Hg Dopamine for hypotension Albumin >_10 ml/kg for hypotension Mean airway pressure at ->10 cm H20 a/A ratio -<0.15 VEI -<0.15 OI -->0.25 Positive inspiratory pressure >-25 cm H20 Nursery course/treatment after surfactant receipt Average mean blood pressure <30 mm Hg At 0-12 hr At 12-24 hr Albumin requirements for hypotension >- 10 ml/kg Dopamine for hypotension Mean airway pressure >-10 cm H20* Positive inspiratory pressure >_25 cm H20* Pulmonary function improvements from baseline* VEI: _<77% a/A ratio: -<150% OI: -<65% PIP: no improvement

0.02

0.1 0.07 0.002

0.03 0.1

0.9 0.6 0.4 0.8

PIP, Positive inspiratory pressure. *Assessed 24 hours after surfactant.

colloid or dopamine infusion before rescue receipt of surfactant. 3. The reduced risk of S I V H associated with A M G is not appreciably influenced by the magnitude of pulmonary function improvement after surfactant therapy. After correlates of S I V H were identified (Table I), correlates of A M G were considered (Table II). Rate ratios were then evaluated among infants exposed and those not exposed to A M G , stratified by the presence or absence of measures of physiologic characteristics associated with both S I V H and A M G (Table III). These stratified analyses were examined to determine to what extent the A M G effect on S I V H risk might have been influenced by covariates. Only

covariates associated with both S I V H and A M G at a p level of --<0.25 were evaluated. In another attempt to identify variables that might explain how A M G reduces S I V H risk, we first modeled S I V H risk with logistic regression analysis, adjusting for five maternal or infant variables unalterable by subsequent nursery therapies (i.e., pregnancy-induced hypertension, cesarean delivery, rupture of membranes >--24 hours before delivery, delivery in a hospital without a level III nursery, and gestational age --<28 weeks). W e then compared the A M G regression coefficient (an index of A M G effect on S I V H risk) in this model with the coefficient in models that also included selected, individual postnatal measures of

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Garland, Buck, and Leviton

275

T a b l e II. Percentage of infants exposed (n = 102) and those not exposed (n = 111) to A M G who had each maternal and neonatal characteristic to surfactant

AMG* (+)

(-)

P

Maternal factors Outborn Rupture of membranes -->24 hr Chorioamnionitis Cesarean section Cesarean section for fetal distress Pregnancy-induced hypertension

1

22

30 9 65 37 25

6 6 73 46 19

0.001 0.001

60 49 63 7

56 45 57 14

0.6 0.6 0.4 0.1

9 46 15 4 27 44 30 25 5

32 68 41 7 48 64 41 33 11

0,001

35 25 27 20 20

44 27 51 29 39

0.2 0.6 0.001 0.1

30

5l

71 82 85 83

72 66 92 76

0.5 0.2 0.4 0.3

Infant characteristics Male Birth weight _<1.0 kg Gestational age -<28 wk Apgar score at 5 rain: <5 Nursery course/treatment before surfactant Dopamine for hypotension Mean arterial blood pressure <30 mm Hg Albumin for hypotension -> 10 cc/kg Sodium bicarbonate for metabolic acidosis Mean airway pressure __.10 cm a/A ratio _<0.15 VEI -<0.15 Positive inspiratory pressure ->25 cm H20 OI ->0.25 Nursery course/treatment after surfaetant receipt Average mean blood pressure <30 mm Hg At 0-12 hr At 12-24 hr Albumin requirement for hypotension: -> 10 ml/kg Dopamine for hypotension Mean airway pressure >_ 10 cm H20 Positive inspiratory pressure ->25 cm H20 Pulmonary function improvements from baseline* VEI: _<75% a/A: -<150% 0I: -<65% PIP: no improvement

0.001

0.001 0.3 0.003 0.004

0.1 0.2 0.2

0.004 0.002

0.9 0.009

0.1 0.2

PIP, Positiveinspiratory pressure. *Assessed 24 hours after surfactant therapy.

respiratory function and blood pressure. We separately evaluated eight characteristics identified before surfactant receipt and nine characteristics after receipt of surfactant. Finally we added groups of those postnatal variables that individually most changed the A M G coefficient. RESULTS Of 280 infants who received artificial surfactant from November 1989 to April 1992, a total of 241 received rescue artificial surfactant during the first 24 hours of life; 225 of these infants had at least one cranial sonogram during the first 14 days of life. We excluded 12 infants who had a parenchymal hemorrhage but did not satisfy the study criteria for S I V H , leaving 213 infants for the final analysis.

Timing of the first cranial sonogram in relation to the first dose of artificial surfactant or birth time was not associated with A M G exposure, birth weight, or final S I V H status. Infants --<28 weeks of gestational age were more likely than older infants to have ultrasonographic examination of the head during the first 24 postnatal hours (p = 0.01). No measure of pulmonary function before or improvement after surfactant therapy was associated with the timing of the first cranial sonogram. Seventeen percent (36/213) of infants died, 12 during the first week of life. We obtained at least two cranial sonograms of 8 of these infants before their death. Of the 12 infants who died during the first week of life, 6 had been exposed to A M G .

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T a b l e Ill. Percentage of infants who had SIVH

(n = 35), presented separately for strata of sample classified by both A M G exposure and selected characteristics AMG Potential effect modifier Gestational age Age -<28 wk Age >28 wk Apgar score (at 5 min) <5 >--5

(+)

(-)

Odds ratio (95% Cl)

13 5

27 17

0.4 (0.2-0.98) 0.3 (0.06-1.4)

29

33

0.8 (0.1-5.7)

8

21

0.4 (0.1-0.8)

Dopamine before surfactant 22 26 No dopamine before surfactant 9 21 VEI at time of surfactant* _<0.15 17 34 >0.15 7 14 a/A ratio at time of surfactant _<0.15 14 26 >0.15 7 18 a/A ratio improvement -<150% improvement 13 19 >150% improvement 0 36 Positive inspiratory pressure improvement No improvement 10 26 Any improvement 6 12 Positive inspiratory pressure at 24 hr >-25 cm H20 13 29 <25 cm H20 9 17 Percentagesare specificfor each row and column. CI, Confidenceinterval. *Newborn infants with missingvalue not included. tConfidenceintervalcannot be calculated.

0.8 (0.1-4.8) 0.4 (0.1-0.9) 0.4 (0.1-1.3) 0.5 (0.2-1.5) 0.5 (0.2-1.3) 0.4 (0.1-1.3) 0.6 (0.3-1.6) 0.0t 0.3 (0.1-0.8) 0.5 (0;05-5.2) 0.4 (0.1-1.3) 0.5 (0.2-1.4)

Severe intraventricular hemorrhage developed in 16% (35/213) of the infants. Because SIVH risk was similar for infants who exposted to a complete or partial course of glucocorticoids (10% [6/59] vs 9% [4/43]), the groups were combined. Ten percent (10/102) of infants who were exposed to any A M G had SIVH, compared with 23% (25/ 111) of infants who were not (odds ratio, 0.4; 95% confidence interval, 0.2 to 0.8). Physiologic characteristics and their correlates before artificial surfactant that were associated with increased SIVH riskincluded sodium bicarbonate infusion (p = 0.03), hypotension (defined as a mean arterial blood pressure <30 mm Hg) (p = 0.03), hypotension treated with more than 10 ml/kg of colloid (/9 = 0.02), VEI --<0.15 (p = 0.002), and OI >0.25 (p = 0.03) (Table I). Of nine potential risk factors for SIVH during the 24 hours after surfactant therapy, only a high mean airway pressure (-> 10 cm H20) and a high positive inspiratory pressure (defined as ->25 cm H20) were associated with an increased risk of SIVH (p <0.04). Pulmonary function improvement (i.e., percentage change in OI, VEI, or a / A ratio) was not associated with

SIVH (Table I). When the a / A ratio improvement was stratified by the level of a / A ratio before surfactant, infants with low a / A ratios (<0.15) had similar (20% vs 23%; p = 0.7) rates of SIVH whether or not their a / A ratio improved after surfactant. Infants with a / A ratios >0.15 before surfactant whose a / A ratios improved >150% after surfactant were more likely to have SIVH than were infants showing less improvement (38% [3/8] vs 9% [8/85]; p = 0.05). Before surfactant therapy, infants exposed to any A M G were less likely than infants not so exposed to become by. potensive (p = 0.001) or to receive dopamine (p = 0.001) or colloid infusions (p = 0.001) for blood pressure support (Table II). Infants exposed to any A M G were also less likely to require a high mean airway pressure (p = 0.003) and have a low a / A ratio (p = 0.004). After artificial surfactant therapy, infants exposed to any A M G required less colloid support (p <0.04) and were less likely to require a high positive inspiratory pressure (-->25 cm H20; p = 0.002) or mean airway pressure (>_10 cm H20; p = 0.004). Infants exposed to A M G were also less likely to show a great improvement (i.e., >150% improvement from baseline) in their a / A ratios after artificial surfactant therapy (p <0.009). The reduced risk of SIVH in infants exposed to A M G was most prominent among babies with 5-minute Apgar scores -->5 and for babies who did not receive dopamine before surfactant therapy (Table III). Hypotensive episodes and colloid infusion appeared to influenced the A M G / S I V H relation in a fashion similar to dopamine infusion (data not shown). SIVH risk differences between neonates exposed to A M G and those not exposed were not consistently influenced by pulmonary function improvement after surfactant therapy. Reduction in SIVH associated with A M G was greatest among infants showing the greatest improvement (> 150%) in a / A ratio after surfactant therapy. On the other hand, SIVH risk reduction associated with A M G was more apparent in infants showing no improvement with respect to positive inspiratory pressure after surfactant therapy than in infants who showed any improvement in positive inspiratory pressures (Table III). Measures of pulmonary function improvement after surfactant that were determined primarily by the level of ventilatory support, such as percentage of change in OI or VEI, were not analyzed because they were not associated with either A M G (change in VEI) or SIVH (change in OI). Analyses limited to infants <28 weeks of gestational age (data not shown) demonstrated similar findings. In logistic regression models that adjusted for five maternal or infant characteristics evident by the time of birth (gestational age, pregnancy-induced hypertension, birth in hospital without level III nursery, cesarean birth,

The Journal of Pediatrics Volume 126, Number 2

rupture of membranes >24 hours), the use of AMG was associated with a reduced risk of SIVH (odds ratio, 0.5; 95% confidence interval, 0.2 to 1.1). The regression coefficient for AMG was altered most by the addition of individual or groups of postnatal correlates of low blood pressure and less by individual or groups of clinical measures of respiratory illness before surfactant therapy (Table IV). Adding correlates for hypotension occurring after surfactant therapy to the regression model did not reduce the association between AMG and SIVH (data not shown). Adding individual or groups of measures of pulmonary function that exhibited little change after surfactant therapy accentuated the apparent protective effect of AMG on SIVH risk (regression coefficient for AMG increased by up to 28%; data not shown). DISCUSSION This study had four main findings. First, in agreement with prior studies, AMG receipt is associated with a reduced risk of SIVH. Second, a partial course of AMG administration appears to be as effective as a full course. Third, the SIVH protective effects of AMG appear to be explained by or correlated with avoidance of hypotension. Fourth, marked improvement in clinical measures of pulmonary function after surfactant therapy did not appear to enhance the beneficial effects of AMG on SIVH risk. If AMG produced much of its SIVH reduction via improved pulmonary function during the first hours of life, thereby reducing the need for surfactant, the babies who most prominently responded to AMG would be excluded from this sample. Thus our finding of an AMG effect on SIVH risk even in babies with significant respiratory distress treated with surfactant therapy adds to the evidence that much of the SIVH risk reduction caused by AMG is not a consequence of improved pulmonary function. Some have found, as did we, that hypotension is associated with increased risk of intracranial hemorrhage, 22-25 whereas others have not. 26, 27 Receipt of volume expanders also appears to be associated with increased risk of intracranial hemorrhage. 28, 29 In the beagle puppy, both hypotension and subsequent volume expansion appear to be required to induce intraventricular hemorrhage. 3° As we did, Moise et al. 21 found that "antenatal steroids reduce the need for blood pressure support in extremely premature infants." In addition, mean blood pressure in preterm sheep appears to be stabilized by exposure to AMG. 31 In our data set, some of the SIVH risk information conveyed by hypotension and volume expansion is appropriated by the AMG variable. This suggests that some of the SIVH reduction by AMG might be achieved through reduced risk of hypotension and the need for volume expansion.

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Table IV. Risk of SIVH among newborn infants exposed tO AMG as a function of the risk among newborn infants not so exposed Postnatal variable before surfactant therapy Apgar score at 5 min: <5 Sodium bicarbonate for acidosis Dopamine infusion Mean arterial blood pressure <30 mm Hg Albumin >-I0 ml/kg a/A ratio --<0.15 VEI -<0.15 Positive inspiratory pressure >--25 cm H20 Sets of variables Correlates of hypotension: Albumin _>10 ml/kg, Sodium bicarbonate for acidosis Measures of respiratory illness severity: a/A ratio _<0.15, VEI --<0.15 Both sets of variables

Odds ratio* (95% Cl)

Percentage change in AMG

0.5 0.5 0.5 0.5

(0.2, (0.2, (0.2, (0.2,

1.3) 1.3) 1.2) 1.2)

-18 -12 -3 -11

0.5 0.5 0.5 0.5

(0.2, 1.3) (0.2, 1.2) (0.2, 1.2) (0.2, 1.2)

-11 -8 -6 -6

0.5 (0.2, 1.3)

-17

0.5 (0.2, 1.3)

-9

0.5 (0.2, 1.4)

-15

All valuesare adjustedfor fiveantenatalvariables(pregnancy-inducedhypertension,abdominaldelivery,rupture of membranes~24 hours, gestationalage,birthin hospitalwithoutlevelIII nursery).Additionaladjustment wasmadefor the postnatalvariablelistedon the left. Tilepercentagechange in the AMG coefficientcompareslogisticregressionmodelswith and without the variableon the left. *Point estimate(95%confidenceinterval).

In stratified analyses, the SIVH reduction capability of AMG was more obvious in babies who had good Apgar scores and in those who did not receive dopamine or albumin before surfactant therapy. Thus, although AMG was associated with less dopamine or albumin use for hypotension and may thereby contribute to reducing the risk of SIVH, the SIVH risk reduction in those who did not receive dopamine suggests that another mechanism might be involved. For example, it is possible that AMG enhances maturation of blood vessels within the ganglionic eminence,32 thereby improving their capacity to withstand transmural pressures and other influences thought to contribute to PIVH. 33 We were unable to evaluate this hypothesis. This study has several limitations. First is the method of ascertaining gestational age. Although 63% of babies had gestational age determined by a first-trimester sonogram, Ballard evaluations served as the measure of gestational age in approximately 23% of infants. Second, as in other studies, 5 we do not know when many of the hemorrhages occurred. Thus we cannot establish an exact temporal relation between SIVH and receipt of surfactant. Others have reported that low birth weight infants who

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receive A M G are at reduced risk of having intracranial hemorrhage,2, 3, 5-8, 34, 35 even after partial courses. 1, 4, 5 This, however, has not always been the case. 34 The apparent effectiveness of partial courses has been evident only since the availability of surfactants. Many other changes in the care of women at risk of undergoing preterm delivery have also been made since then. Although others have suggested that surfactant may potentiate some of the intracranial beneficial effects of A M G , 5 we were unable to demonstrate that a marked improvement in pulmonary function after surfactant therapy enhanced the association between A M G and SIVH. Our findings may differ from those recently reported because of differences in study design, studypopulations, definition of outcomes, or surfactant preparations. The evidence that A M G reduces the risk of P I V H satisfies all the epidemiologic criteria of causation. 36 The strength criterion is met by the finding that in most studies the odds ratio is close to 0.5. Because A M G receipt antedates the vast majority of PIVH, the temporal order criterion is also satisfied. An expanding literature about the effects of corticosteroids on fetal lung, heart, and cerebral blood vessels provides support for the biologic plausibility criterion.31, 37, 38 Most impressive, however, is support for the experiment criterion. Five of six randomized clinical trials demonstrated that preterm newborn infants whose mothers received A M G had a prominently reduced risk of PIVH. 39 Our data support the hypothesis that some of the S I V H protection provided by A M G is mediated by the reduced occurrence of hypotension, reduced need for blood pressure support (including volume expansion), or closely related phenomena. W e conclude that A M G exposure reduces S I V H risk in newborn infants who require artificial surfactant therapy. This appears to be true for both gestationally younger and gestationally older infants. Although A M G was associated with the reduced occurrence of hypotension, the beneficial effects of A M G on S I V H were evident even among preterm infants with acceptable blood pressure levels. Measures of pulmonary function improvement after surfactant therapy, especially those related to ventilatory requirements, did not appear to enhance the protective effect that A M G had on S I V H risk. REFERENCES

1. Jobe AH, Mitchell BR, Gunkel JH. Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol 1993;168:50813. 2. Garite T J, Rumney P, Briggs GG, et al. A randomized, placebo-controlled trial of betarnethasone for prevention of respiratory distress syndrome at 24 to 48 weeks' gestation. Am J Obstet Gynecol 1993;166:646-51.

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3. Leviton A, Kuban KC, Pagano M, et al. Antenatal corticosteroids appear to reduce the risk of postnatal germinal matrix hemorrhage in intubated low birth weight babies. Pediatrics 1993;91:1083-8. 4. Andrews EB, White AD, Weinberg JM, et al. Antenatal steroids and neonatal outcomes in infants receiving surfactants in Exosurftreatment IND [Abstract]. Pediatr Res 1992;31:241A. 5. Kari M, Hallman M, Eronen M, et al. Prenatal dexamethasone treatment in conjunction with rescue therapy of human surfactant: a randomized, placebo-controlled, multicenter study. Pediatrics 1994;93:730-6. 6. Doran TA, Sawyer P, MacMurray B, et al. Results of a double-blind controlled Study on the use of betamethasone in prevention of respiratory distress syndrome. Am J Obstet Gynecol 1980;136:313-20. 7. Morales W J, Diebel D, Lazar A, Zadrozny D. The effect of antenatal dexamethasone administration the prevention of respiratory distress syndrome in preterm gestations with premature rupture of membranes. Am J Obstet Gynecol 1986; 154:591-5. 8. Gamsu HR, Mullinger BM, Donnai P, Dash CH. Antenatal administration of betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicenter trial. Br J Obstet Gynaecol 1989;96:401-10. 9. O'Shea M, Savitz DA, Hage ML, Feinstein KA. Prenatal events and the risk of subependyrnal/intraventricular hemorrhage in very low birth weight neonates. Paediatr Perinat Epidemiol 1992;6:352-62. 10. Volpe JJ. Intraventricular hemorrhage in the premature infant: current concepts. Part I. Ann Neurol 1989;25:3-11. 11. Ballard JL, Novack KK, Driver A. A simplified score assessment of fetal maturation of newly born infants. J PEDIATR 1979;95:769-84. 12. Fnjiwara T, Kouishi M, Chida S, et al. Surfactant replacernent therapy with a single postventilatory dose of a reconstituted bovine surfactant in preterm neonate with respiratory distress syndrome: final analysis of a rnulticenter, double-blind, randomized trial and comparison with similar trials. Pediatrics 1990;86:753-64. 13. Hallman M, Merritt TA, Jarvenpaa AL, et al. Exogenous human surfactant for treatment of severe respiratory distress syndrome: a randomized prospective clinical trial. J PEDIATR 1985;106:963-9. 14. Hallman M, Merritt TA, Kristina B, Berry C. Association between neonatal care practices and efficacy of exogenous human surfactant: results of a bicenter randomized trial. Pediatrics 1993;91:552-60. 15. Horbar JD, Soll RF, Schachinger H, et al. A European multicenter randomized controlled trial of single-dose surfactant therapy for idiopathic respiratory distress syndrome. Eur J Pediatr 1990;149:416-23. 16. Horbar JD, Soll RF, Sutherland JM, et al. A rnulticenter randomized placebo-controlled trial of surfactant therapy for respiratory distress syndrome. N Engl J Med 1989;320:959-65. 17. Kwong MS, Egan EA, Notter RH, Shapiro DL. Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pediatrics 1985;76:585-91. 18. Paneth N, Pinto-Martin J, Gardiner J, et al. Incidence and timing of germinal matrix/intraventricular hemorrhage in low birth weight infants. Am J Epidemiol 1993;137:1167-76. 19. Ment LR, Duncan CC, Ehrenbranz RA, et al. Intraventricu-

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20.

21.

22.

23.

24.

25.

26.

27.

28.

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