Keywords
neonatology - pediatric cardiology - patent ductus arteriosus - MgSO
4
- NTproBNP
Magnesium is an abundant cation in the body that plays an important role in several
intracellular mechanisms.[1] Studies have suggested a neuroprotective effect of magnesium sulfate (MgSO4), with reductions in cerebral palsy rates in survivors.[2]
[3] The available evidence from various large randomized controlled trials suggests
that MgSO4 given before anticipated early preterm birth reduces the risk of cerebral palsy in
surviving infants.[4]
[5]
[6] The neuroprotective effects of MgSO4 for the fetus are due to various proposed mechanisms, such as effects on cellular
metabolism, decreased cell death by inhibition of calcium influx-mediated neuronal
apoptosis, decreased cell injury by reduction in proinflammatory cytokines, and regulation
of blood flow to the brain by inhibition of vascular voltage-depended calcium channels.[1] The Committee on Obstetric Practice and the Society for Maternal-Fetal Medicine
recommends that physicians electing to use MgSO4 for fetal neuroprotection should develop specific guidelines regarding inclusion
criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with
one of the larger trials. In our maternal-fetal medicine division, it is standard
of practice to administer MgSO4 for neuroprotection for preterm deliveries < 32 weeks. The incidence of MgSO4 exposure in preterm deliveries < 32 weeks is 99%. The usual duration of antenatal
MgSO4 for neuroprotection is the standard 12 hours with a loading dose of 4 g with a continuous
of 2 g/hr. After 12 hours, it is discontinued and the patient is managed expectantly.
MgSO4 may be restarted if patient makes cervical change is expected to deliver in the next
6 hours.
Patent ductus arteriosus (PDA) is commonly seen in premature infants (PI).[7] Patency of ductus arteriosus is mediated by smooth muscle relaxation from the activation
of G-protein coupled prostaglandin receptors (PGE2). The postnatal decline in the
levels of PGE2/prostacyclin (PCI) and increase in oxygen tension leads to calcium
influx mediated ductal constriction.[7] A large PDA with increased left to right shunting of blood has significant hemodynamic
consequences: compromised systemic perfusion, pulmonary overflow, and, eventually,
heart failure. A hemodynamically significant PDA (HsPDA) is associated with intraventricular
hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC),
congestive heart failure (CHF), and increased mortality.[8]
This study was based on the hypothesis that by antagonizing the influx of calcium
required for ductal constriction, the use of antenatal MgSO4 may increase the risk of HsPDA in PI.
Materials and Methods
This is a prospective cohort study conducted between 2011 and 2016. It was a part
of two larger studies that were conducted to evaluate a relationship between PDA and
cardiac biomarkers. After institutional review board's (IRB's) approval and parental
permission, PIs (< 32 weeks and < 1,500 g) born at the University of Texas Medical
Branch in Galveston, were recruited (n = 105). Infants with significant congenital or chromosomal anomalies and those born
at outside hospitals were excluded. Maternal and infant data were collected from electronic
medical records.
Echocardiograph (ECHO): all infants had ECHO done within first 3 days of life. ECHO
was performed by trained pediatric ECHO technician by using the Philips iE33 (Philips
North America Corporation, Andover, MA, USA) ultrasound machine. In each ECHO study,
we recorded and analyzed PDA diameter, left atrial to aortic root (LA/AO) ratio, and
ejection fraction using Simpson's biplane method. The diameter of PDA was determined
in the two-dimensional parasternal short-axis view. PDA diameter was measured at the
junction of PDA and the main pulmonary artery. The left to right ductal flow was confirmed
with the color Doppler ultrasound scanning. A two-dimensional parasternal long-axis
view was obtained for the assessment of the diameter of the LA in systole and AO diameter,
and LA/AO ratio was calculated. All ECHO data were saved and was analyzed by a pediatric
cardiologist. Both the ECHO technician and the pediatric cardiologist were blinded
to the study groups.
B-type natriuretic peptide (BNP) and N-terminal pro BNP (NTproBNP) measurement: in
the first study, we measured BNP levels on day 3 of life (n = 37) and in the second study, NTproBNP levels were measured (n = 68). Arterialized capillary by heel prick or umbilical arterial blood sample (0.5 mL)
was collected in chilled Ethylenediamine tetraacetic acid (EDTA) tubes within 3 hours
of ECHO. Blood sample was centrifuged at 3,000 rpm for 15 minutes at 4°C. Separated
plasma was stored at −80°C until BNP analysis of all collected samples. The BNP assay
was performed using the Triage BNP kit (Bio site Diagnostic, Sa Diego, CA), a fluorescence
immunoassay. The assay has a measurable range 5 to 5,000 pg/mL. The estimated coefficient
of variation for the assay is 9.2 to 11.4%. NTproBNP was measured in batch by routine
immune-assay analysis on the Cobas e601 platform (Roche Diagnostics, Indianapolis,
IN) at the department of Clinical Biochemistry, University of Texas Medical Branch
in Galveston. Electro chemiluminescent sandwich enzyme linked immunoabsorbant assay
were used. The Elecsys (Roche Diagnostics, Indianapolis, IN) proBNP II (a product
of Roche Diagnostics) quantitative assay has a lower and upper detection limit of
5 and 70,000 pg/mL.
Criteria for HsPDA: the definition of a HsPDA was based on previously established
criteria and was defined by the presence of PDA diameter > 1.5 mm[8] and BNP levels > 40 pg/dL (92% sensitivity and 46% specificity) or NTproBNP levels > 10,200
pg/dL (100% sensitivity and 91% specificity for diagnosis of HsPDA).[9]
Study groups: Magnesium (Mg) group (n = 95)—infants who were exposed to antenatal MgSO4 for neuroprotection, and control group (n = 10)—infants who were not exposed to antenatal MgSO4.
Clinical Data
Clinical medical data were collected from electronic medical records. We checked for
difference in antenatal steroid use in the two groups and used logistic regression
correcting for gestational age and birth weight. Other risk factors, including intraventricular
hemorrhage, evaluated at 7 days of life using the Papile's classification,[10] bronchopulmonary dysplasia (BPD) defined as persistent requirement of oxygen at
and beyond 36 weeks of life,[11] and necrotizing enterocolitis (NEC) with radiographic evidence of pneumatosis intestinalis[12] were also reviewed. Infants with PDA (any size) were followed to see how many ended
up requiring treatment (medical or surgical).
Selection of Subjects
Infants with no antenatal MgSO4 exposure (n = 10) were randomly matched with infants for gestational age, birth weight, and gender
with the same number of infants with antenatal MgSO4 exposure for further analysis. These infants were born within 6 months of each other.
Matching was performed by an investigator who was blinded to all other infant characteristics.
To compare the sickness in the groups, the clinical risk index for babies (CRIB II)
scores was calculated for all the matched infants.[13] The same outcome measures were studied again in the matched groups.
Statistical Analysis
Data were analyzed using IBM SPSS version 23 (International Business Machines Corporation,
Armonk, New York). Categorical variables were compared using X-test[2] or Fisher's exact test and variables with normal distribution were compared using
one-way analysis of variance (ANOVA). Collinearity was determined using Pearson's
correlation coefficient and a regression analysis was performed correcting for birth
weight, gestational age, gender, and antenatal steroid use. A p-value of < 0.05 was considered significant.
Results
[Table 1] shows the baseline characteristics of the two groups (n = 105). Pearson's correlation analysis demonstrates a negative correlation between
antenatal MgSO4 use and the occurrence of an HsPDA in neonates (p ≤ 0.05). There was no significant difference in the use of antenatal steroids between
the two groups (p = 0.062). Of note, the ejection fraction, mean PDA diameter, mean LA/AO ratio, and
requirement for medical versus surgical treatment were not significantly different
(p = 0.383, 0.063, and 0.103, respectively) in the two groups. Increasing gestational
age, birth weight, and male gender were all associated with a decreased likelihood
of HsPDA (p < 0.05). Antenatal steroid use not significantly associated with likelihood of HsPDA.
Table 1
Baseline characteristics
|
Characteristic
|
Antenatal MG (n = 95)
|
Control (n = 10)
|
p-Value
|
|
Birth weight (g)
|
1007 ± 271
|
1,030 ± 329
|
0.81
|
|
Sex (male) n (%)
|
48 (51)
|
5 (50)
|
0.61
|
|
Gestational age (wk)
|
27.8 ± 2.3
|
27.6 ± 2.5
|
0.79
|
|
Race n (%)
|
|
|
|
|
Hispanic
|
36 (38)
|
6 (60)
|
0.11
|
|
Caucasian
|
29 (30.5)
|
3 (30)
|
|
African American
|
29 (30.5)
|
1 (10)
|
|
Asian
|
1 (1)
|
0 (0)
|
|
Antenatal steroid use
|
74 (78)
|
5 (50)
|
0.12
|
|
BPD n (%)
|
24 (25)
|
3 (30)
|
0.7
|
|
NEC n (%)
|
9 (9.5)
|
1 (10)
|
1.0
|
|
IVH n (%)
|
7 (7.4)
|
2 (20)
|
0.2
|
|
HsPDA n (%)
|
12 (13)
|
4 (40)
|
0.04
|
|
PDA treatment n (%)
|
15 (16)
|
4 (40)
|
0.08
|
Abbreviations: BPD, bronchopulmonary dysplasia; HsPDA, hemodynamically significant
patent ductus arteriosus; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis;
MG, Magnesium sulfate.
Matched group analysis ([Table 2]) showed no significant association between antenatal MgSO4 use and the occurrence of an HsPDA (p = 0.50). Even though more infants in the control group (5/10) required treatment
for PDA compared with MG group (1/10), this difference was not significant (p = 0.07). There was no significant difference in the gestational age (GA), birth weight
(BW), gender, CRIB II scores, and antenatal steroid use in the two groups.
Table 2
Matched group analysis
|
Characteristic
|
Antenatal MG (n = 10)
|
Control (n = 10)
|
p-Value
|
|
Gestational age (wk) (mean ± SD)
|
27.6 ± 2.5
|
27.6 ± 2.5
|
1.00
|
|
Birth weight (g) (mean ± SD)
|
1,026 ± 360
|
1,030 ± 329
|
0.98
|
|
Sex, male n (%)
|
5 (50)
|
5 (50)
|
0.67
|
|
CRIB II score (mean ± SD)
|
8.1 ± 3.6
|
8.2 ± 3.2
|
0.94
|
|
HsPDA n (%)
|
3 (30)
|
4 (40)
|
0.5
|
|
PDA Treatment n (%)
|
1 (10)
|
5 (50)
|
0.07
|
|
Antenatal steroid use
|
3 (30)
|
5 (50)
|
0.32
|
|
BPD n (%)
|
2 (20)
|
4 (40)
|
0.31
|
|
NEC n (%)
|
1 (10)
|
1 (10)
|
0.76
|
|
IVH n (%)
|
2 (20)
|
2 (20)
|
0.71
|
Abbreviations: BPD, Bronchopulmonary dysplasia; CRIB, Clinical risk index for babies;
HsPDA, Hemodynamically significant patent ductus arteriosus; IVH, Intraventricular
hemorrhage; NEC, Necrotizing enterocolitis; SD, standard deviation; MG, Magniesum
sulfate.
Discussion
Contrary to our hypothesis that magnesium may increase the risk of an HsPDA by its
role as a calcium channel antagonist, the results of our study actually showed a decrease
in hemodynamically significant PDA in infants exposed to antenatal MgSO4. Even though this finding was not statistically significant upon conducting a matched
group analysis, the number of patients requiring treatment for PDA was lower in the
group exposed to magnesium versus control (1/10 vs. 5/10). To our knowledge, this
is the first reported association of antenatal MgSO4 exposure with HsPDA.
There are limited data in literature about the effects of antenatal MgSO4 on the neonatal cardiovascular system. James et al studied the effect of antenatal
MgSO4 use on the cardiovascular system in a cohort study using novel echocardiographic
parameters and found that infants who were exposed to antenatal MgSO4 had significantly lower systolic blood pressure (BP) and systemic vascular resistance
on day 1 of life but no significant difference on day 2.[14] Paradisis et al performed a randomized controlled trial to study whether the neuroprotective
effects of MgSO4 were secondary to cardiovascular changes.[15] They found significantly higher heart rate and higher incidence of low superior
vena cava flow at 10 to 12 hours of life but no significant difference was found at
24 hours of life. They reported an incidental finding of a significantly smaller PDA
(0.4 vs. 0.8 mm) in the MgSO4 group. This incidental finding, in conjunction to the findings of our study, may
point toward a role of magnesium in the closure of the ductus arteriosus. However,
given the difficulty in getting echocardiographic measurements of PDA size and the
large interobserver variability, it is difficult to make a definite conclusion based
on this incidental finding.
The previous studies point toward the role of magnesium in decreasing peripheral vascular
resistance via noncompetitive antagonism of inositol triphosphate gated calcium channels.[14] However, the results of our study could infer that magnesium does not antagonize
the calcium channels responsible for mediating ductal constriction. Similar to its
elusive mechanism of action in improving neurodevelopmental outcome, our results could
be explained by one or more of the many complex intracellular actions of magnesium.
It is a standard of practice at the University of Texas Medical Branch hospital in
Galveston to give antenatal MgSO4 for neuroprotection to all pregnant women who are at risk of delivering prior to
32 weeks of gestation. The incidence of MgSO4 exposure in women with preterm deliveries < 32 weeks is close to 99% at our institution.
These women also receive antenatal steroids for fetal lung maturity. The women who
did not receive MgSO4 are likely those who did not have enough time between presentation to the hospital
and delivery. To account for the limited sample size and the possible confounding
effect of antenatal steroid exposure, we performed a matched group analysis. We did
not see a significant difference in the incidence of HsPDA in the matched groups.
The main limitation of our study is the small sample size of the group that was not
exposed to antenatal MgSO4. Even though the first part of our study reports a statistically significant finding,
it was not significant upon adjusting for numbers and conducting a matched group analysis.
Conclusion
Exposure to antenatal MgSO4 in PI does not increase the likelihood of HsPDA. It may actually have a protective
role in helping with ductal closure, although we do not have sufficient evidence to
make that conclusion at this time. Further studies need to be performed to see if
these results are reproducible and to look into the association of magnesium with
HsPDA.
