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KEY WORDS
Intraventricular
hemorrhage
Preterm labor
Aminophylline
Corticosteroids
Magnesium sulfate
Preterm premature
rupture of
membranes
* Reprint requests: Gian Carlo Di Renzo, MD, PhD, Center of Perinatal and Reproductive Medicine, Department of Gynecologic, Obstetric and
Pediatric Sciences, University of Perugia, Policlinico Monteluce, 06122 Perugia, Italy.
E-mail: direnzo@unipg.it
0002-9378/$ - see front matter 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajog.2004.07.078
434
Di Renzo et al
Conclusion: Adjunctive maternal administration of aminophylline and magnesium sulfate was
associated with a significant reduction in the rate of intraventricular hemorrhage in neonates born
before 30 completed weeks.
2005 Elsevier Inc. All rights reserved.
Results
During the study period, there were 78 newborns in
group A and 68 in group B who met the inclusion
criteria. Maternal and neonatal characteristics and route
Di Renzo et al
Table I
435
Maternal characteristics*
Multiple pregnancy (twin-triplets)
PIH-Pre-eclampsia-HELLP
Severe IUGR (!3 centiles)
PPROM
Route of delivery
Vaginal delivery
Cesarean section
Mean Apgar
1 min (range)
5 min (range)
Birth weight (g)
Range
Mean G SD
Timing of delivery (from admission) and length of therapy
Range (d)
Mean G SD
Mean gestational age at delivery
Range (wks)
Mean G SD
Male/female ratio
13
14
10
32
12
10
9
27
27 (34.6%)
51 (65.4%)
21 (35.3%)
44 (64.7%)
NS
1-9
6-10
1-9
5-10
NS
565-1220
757 G 215
600-1260
821 G 275
NS
2-18
7.2 G 5.4
2-16
8.1 G 4.8
NS
23-30
26.8 G 2.7
34/44
24-30
27.2 G 2.5
31/37
NS
Significance
NS
NS
NS, Nonsignificant; PIH, pregnancy-induced hypertension; HELLP, hemolysis, elevated liver enzymes, low platelets; IUGR, intrauterine growth restriction;
PPROM, preterm premature rupture of membranes.
* More than one may have been present in the same pregnancy.
Comment
Principal findings of our study
The key observation of this study is that the combined
used of aminophylline and magnesium sulphate was
associated with a reduction in the rate of IVH (total
frequency as well as the rate of grade 3 and 4) in very
preterm infants (those born before the 30th week of
gestation). Adjunctive treatment with this combination
did not change the rate of other complications such as
RDS, PDA, and ROP. We think that our observation
justies further studies of the potential value of magnesium sulfate and aminophylline in the prevention of
neurologic injury.
436
Di Renzo et al
Table II
Significance
1
4
28
7
2
8
7
14
26
5
4
7
P ! .001
P ! .001
NS
NS
NS
NS
(1.3%)
(5.1%)
(35.9%)
(9.0%)
(2.6%)
(10.2%)
(10.3%)
(20.6%)
(38.2%)
(7.5%)
(5.9%)
(10.3%)
* Severe degree needing surfactant replacement and high-pressure positive ventilation (HPPV).
y
Within 28 days from delivery.
Di Renzo et al
toxicity when aminophylline is administered in the third
trimester of pregnancy.33 Thus, maternal aminophylline
administration may be a method to deliver this agent to
the fetus. Previous studies reported by our group34
documented that short-term maternal administration
of aminophylline to pregnant rabbits at 26 days improved the survival rate and the respiratory performance of the pups, which were delivered by hysterotomy
far from term (mean gestational duration in rabbits is 31
days). These observations were interpreted as indicating
that aminophylline administration induces maturation,
which is similar to that induced by steroids. Because the
mechanisms of action of steroids and aminophylline are
dierent, we proposed that a synergistic eect could occur
and hence the use of aminophylline in this study. Other
investigators have also demonstrated that short
treatment with aminophylline of preterm neonates is
associated with a signicant increase in oxyhemoglobin.35
In conclusion, we present the rst evidence that the
combined administration of magnesium sulfate and
aminophylline can reduce the rate of IVH in very
preterm neonates. This benet was observed in neonates
who had received steroids (both arms of the study), and
therefore the combination of magnesium sulfate and
aminophylline appears to oer additional advantages
over the current standard approach, which is limited to
steroid administration. The pharmacologic approach
reported herein is relatively simple and inexpensive,
and the doses utilized have a large margin of maternal
safety (8 g per day of magnesium sulfate and 480 mg/day
of aminophylline). Further studies are required to
dissect the precise contribution of magnesium sulfate
or aminophylline to improve neonatal outcome as well
as to conrm our ndings. This can be accomplished
only through a large multi-institutional, randomized
clinical trial.
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