Abstract
Background
Recent studies reported conflicting results on the relationship between antenatal magnesium sulfate (MgSO4) exposure and neonatal intestinal injury. Most studies have not assessed MgSO4 exposure quantitively and none reported the exposure timing.
Objectives
To assess whether there is a temporal or dose dependent relationship between antenatal MgSO4 exposure and intestinal injury in extremely preterm neonates.
Methods
Retrospective study of inborn neonates with gestational age ≤ 28 weeks and/or birth weights ≤ 1000 g. Primary outcomes included necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP) and/or death prior to discharge or in the first 2 weeks of life. Outcomes comparisons were made based on timing of MgSO4 exposure; within 7 days (Mg7D) or within 3 days (Mg3D) of birth. Total cumulative doses for the Mg3D group were also computed.
Results
302 neonates were included, 210 in the Mg7D group, out of whom 179 (85.2%) constituted the Mg3D group. There were no differences noted when comparing MgSO4 exposure timing and the likelihood of NEC, SIP and/or death. This remained the same for subgroup analysis of neonates <26 weeks’ gestation. Each 10 g increase in MgSO4 cumulative dose correlated with decrease in SIP/NEC/death by 18.9% prior to discharge and by 21.9% in the first 2 weeks of life. Small for gestational age (SGA) was a potential effect modifier by a Likelihood Ratio test with P = 0.07.
Conclusions
Antenatal MgSO4 exposure in extremely preterm neonate was not associated with an increased risk of intestinal injury or death and might have reduced these complications in a dose dependent manner in our study. This protective effect was more noticeable in SGA neonates.
Keywords: Magnesium sulfate, necrotizing enterocolitis, spontaneous intestinal perforation
Introduction
Magnesium sulfate (MgSO4) has been used in obstetric practice for tocolysis, management of preeclampsia, and for fetal neuroprotection in women with threatened preterm delivery (1). The latter practice has been widely adopted after the American College of Obstetricians and Gynecologists (ACOG) released a Committee Opinion in 2010 encouraging MgSO4 administration before anticipated early preterm birth to reduce the risk of cerebral palsy (2). The recommendation was based on the results of three clinical trials included 4,184 participants (3–5) and a Cochrane systematic review by Doyle et al in 2009 (6). The systematic review concluded that the number of women needed to be treated to benefit one neonate by avoiding cerebral palsy is 63, without an increase in neonatal mortality or morbidities(6). The ACOG however stated that comparison between the three major randomized clinical trials (3–5) was made difficult by differences in inclusion criteria, populations studied, MgSO4 regimens, and outcomes studied between the trials (2).
Subsequently, a number of groups have investigated the relationship between antenatal MgSO4 exposure and intestinal injury in premature neonates. In 2014, Rattray et al reported their experience with implementation of a protocol using MgSO4 for neuroprotection (7). They found a higher incidence of death or spontaneous intestinal perforation (SIP) during protocol implementation as compared to prior to implementation and after discontinuation (30.4% vs. 20.5%, P=0.28), with a stronger correlation for higher MgSO4 dose and smaller neonates (7). In a secondary analysis of the NICHD Maternal Fetal Medicine Units Network study (5), the authors reported there was a significantly elevated risk for death or severe necrotizing enterocolitis (NEC) in neonates with gestational age (GA) <26 weeks who were randomized to receive antenatal MgSO4, odds ratio (OR) = 1.9 (95% confidence interval (CI): 1.12–3.22, P = 0.017) (8). In these two studies MgSO4 for neuroprotection regimens were in accordance with NICHD Maternal Fetal Medicine Units Network study (5). However, two larger reports by the Pediatrix Medical Group and the Canadian Neonatal Network showed no increase in neonatal adverse outcomes in relationship to any antenatal MgSO4 exposure (9, 10).
While MgSO4 infusion protocols vary among institutions in dose, duration and criteria for re-loading, most studies have assessed MgSO4 exposure in a dichotomous fashion only: exposed or not (7–10). Moreover, no previous study has reported on timing of antenatal MgSO4 exposure in relation to birth or the onset of intestinal injury. Hence it is difficult to arrive at a definitive conclusion regarding the association between antenatal MgSO4 exposure and neonatal intestinal injury. We aimed to explore these variables to determine if there is a temporal or dose dependent relationship between antenatal MgSO4 exposure and neonatal intestinal injury in extremely preterm neonates.
Methods
Study Population
This was a retrospective study of neonates who were admitted to Pomona Valley Hospital Medical Center neonatal intensive care unit (NICU), Pomona, CA, from January 2010 through December 2016. This is a tertiary level NICU with an annual average of 8,000 deliveries and 800 NICU admissions. Subjects included inborn neonates with birth weight ≤ 1,000 g and/or GA ≤ 28 weeks with no congenital gastrointestinal anomalies. The study was approved by the hospital institutional review board (IRB).
MgS04 Protocol
In October 2012 MgSO4 for neuroprotection protocol was implemented in our center. Women with threatened preterm delivery at 24 to 32 weeks’ gestation receive a MgSO4 loading dose of 4 g over 30 min followed by an infusion of 2 g/h for 12 h or until delivery. If delivery does not occur by 12 h, the infusion is stopped and resumed if delivery is thought to be imminent. Also, a repeat loading dose is administered if > 6 h passed after discontinuation of the infusion.
MgSO4 Exposure
The following exposure groups were chosen to describe the different times of antenatal MgSO4 exposure in relation to birth: neonates who received MgSO4 within 7 days (Mg7D) or within 3 days (Mg3D) prior to birth. Among patients who delivered within 3 days, the number of MgSO4 loading doses and cumulative doses were also compared to delineate any potential dose dependent effect.
Outcomes of Interest
Primary outcomes included SIP (diagnosed intraoperatively or radiologically), NEC (Bell’s staging criteria II or greater)(11) and death, either individually or combined. We analyzed these outcomes prior to hospital discharge or within 2 weeks of life. Also examined the likelihood of NEC, SIP or death before and after MgSO4 for neuroprotection protocol implementation
Statistical Methods
For baseline characteristics, t-test was used for continuous variables and Chi-square test for categorical variables. For the univariate analysis, chi-square test was used to compare both individual and combined outcomes between exposure groups. The univariate association was examined for the entire cohort as well as the sub-cohort with GA < 26 weeks. MgSO4 exposure effect was further examined with a multivariate logistic regression analysis after adjusting for significantly different baseline characteristics. Logistic regression modeling was used to examine the effect of MgSO4 loads and cumulative doses on the outcomes among neonates who were exposed to antenatal MgSO4 within 3 days prior to birth. Additionally, effect modification for all baseline characteristics was assessed with Likelihood Ratio tests.
Results
Baseline Characteristics
302 neonates met inclusion criteria. 210 (69.5%) were exposed to antenatal MgSO4 within 7 days prior to birth, out of whom 179 (85.2%) were exposed within 3 days prior to birth (Figure 1).
Figure 1.
Study population
Subjects’ maternal, perinatal and neonatal characteristics (Table 1) were compared between the Mg7D group and the group of neonates whom were not exposed to antenatal MgSO4 within 7 days prior to birth (No-Mg7D). The Mg7D group had significantly higher likelihood of maternal hypertension, exposure to antenatal steroids and antenatal indomethacin. Also, higher neonatal first serum magnesium level (when measured within 72h of life) was detected in the Mg7D group. There were no other significant differences in perinatal or neonatal characteristics between Mg7D and No-Mg7D groups that might contribute to intestinal injury (Table 1).
Table 1.
Subjects maternal, perinatal and neonatal characteristics comparison
| Mg7D (N = 210) | No-Mg7D (N = 92) | P Value | ||
|---|---|---|---|---|
| Maternal Characteristics | ||||
| Age, years | 28.1 ± 6.4 | 27.5 ± 6.5 | 0.43 | |
| Body mass index, kg/m2 | 31.3 ± 6.6 | 29.9 ± 7.8 | 0.14 | |
| Race | 0.58 | |||
| White | 40 (19) | 14 (15.2) | ||
| Black | 28 (13.3) | 16 (17.4) | ||
| Hispanic | 112 (53.3) | 52 (56.5) | ||
| Other | 30 (14.2) | 10 (10.9) | ||
| Illicit drug abuse | 21 (10) | 10 (10.9) | 0.82 | |
| Maternal hypertension | 62 (29.5) | 13 (14.1) | 0.004 | |
| Perinatal Characteristics | ||||
| Prolonged rupture of membranes | 54 (25.7) | 24 (26.1) | 0.95 | |
| Cesarean delivery | 146 (69.5) | 67 (72.8) | 0.56 | |
| Antenatal steroids | 200 (95.2) | 59 (64.1) | < 0.0001 | |
| Antenatal indomethacin | 43 (20.5) | 8 (8.7) | 0.012 | |
| Multiple gestations | 31 (14.8) | 20 (21.7) | 0.14 | |
| Neonatal Characteristics | ||||
| Gestational age, weeks | 26.2 ± 1.9 | 26.1 ± 2.1 | 0.6 | |
| Birth weight, g | 804 ± 212 | 812 ± 231 | 0.8 | |
| Male sex | 101 (48.1) | 48 (52.2) | 0.5 | |
| 5-minutes Apgar score* | 7(6–8) | 7(5–8) | 0.078 | |
| Small for gestational age | 36 (17.1) | 14 (15.2) | 0.68 | |
| Postnatal steroids | 79 (37.6) | 37 (40.2) | 0.67 | |
| Postnatal NSAIDs treatment for PDA | 73 (34.76) | 40 (43.48) | 0.15 | |
| First serum magnesium level within 72h, mg/dl | 2.7 ± 0.9 | 2.1 ± 0.4 | < 0.0001 | |
| Intraventricular hemorrhage grade III or higher | 19 (9) | 11 (12) | 0.4 | |
| Late onset sepsis | 42 (20) | 27 (29.3) | 0.075 |
NSAIDs - non-steroidal anti-inflammatory drugs; PDA - patent ductus arteriosus.
Data are means ± SD. Data are number of neonates with a presenting variable, and values in parentheses are percent of each group.
Data are medians and IQR
MgSO4 Time of Exposure and Outcomes
There were no differences noted between different MgSO4 exposure timing and the likelihood of SIP, NEC or death prior to hospital discharge or in the first 2 weeks of life (early). Combined outcomes also did not show significant differences. This was true for the entire cohort (Table 2A) and in a subgroup analysis of neonates <26 weeks’ gestation (Table 2B).
Table 2.
Outcomes comparison among different exposure groups for all neonates (A) and neonates with GA < 26 weeks (B)
| (A) All neonates | |||||||||
| Mg7D (N = 210) | No-Mg7D (N= 92) | P Value | Mg3D (N = 179) | No-Mg7D + No-Mg3D (N =123) | P Value | Mg3D (N = 179) | No-Mg3D (N = 31) | P Value | |
| SIP | 20 (9.5) | 8 (8.7) | 0.82 | 18 (10.1) | 10 (8.1) | 0.57 | 18 (10.1) | 2 (6.4) | 0.53 |
| Early SIP | 19 (9.1) | 7 (7.6) | 0.68 | 17 (9.5) | 9 (7.3) | 0.54 | 17 (9.5) | 2 (6.5) | 0.75 |
| NEC | 15 (7.1) | 7 (7.6) | 0.89 | 13 (7.3) | 9 (7.3) | 0.98 | 13 (7.3) | 2 (6.5) | 0.87 |
| Early NEC | 4 (1.9) | 1 (1.1) | 0.61 | 3 (1.7) | 2 (1.6) | 0.97 | 3 (1.7) | 1 (3.2) | 0.56 |
| Death | 24 (11.4) | 12(13) | 0.69 | 18 (10.1) | 18 (14.6) | 0.23 | 18 (10.1) | 6 (19.4) | 0.13 |
| Early Death | 15 (7.1) | 10 (10.9) | 0.28 | 13 (7.3) | 12 (9.8) | 0.44 | 13 (7.3) | 2 (6.5) | 0.87 |
| SIP/NEC/Death | 52 (24.8) | 24 (26.1) | 0.81 | 43 (24) | 33 (26.8) | 0.58 | 43 (24) | 9 (29) | 0.55 |
| Early SIP/NEC/Death | 34 (16.2) | 16 (17.4) | 0.79 | 29 (16.2) | 21(17.1) | 0.8412 | 29 (16.2) | 5 (16.1) | 0.99 |
| (B) Neonates with GA < 26 weeks | |||||||||
| Mg7D (N = 90) | No-Mg7D (N= 45) | P Value | Mg3D (N = 75) | No-Mg7D + No-Mg3D (N = 60) | P Value | Mg3D (N = 75) | No-Mg3D (N = 15) | P Value | |
| SIP | 14 (15.6) | 6 (13.3) | 0.73 | 13 (17.3) | 7 (11.7) | 0.36 | 13 (17.3) | 1 (6.7) | 0.3 |
| Early SIP | 13 (14.4) | 5(11.1) | 0.79 | 12 (16) | 6 (10) | 0.44 | 12 (16) | 1 (6.7) | 0.69 |
| NEC | 8 (8.9) | 6 (13.3) | 0.42 | 6 (8) | 8 (13) | 0.31 | 6 (8) | 2(13.3) | 0.51 |
| Early NEC | 4 (4.4) | 1 (2.2) | 0.52 | 3 (4) | 2 (3.3) | 0.84 | 3 (4) | 1 (6.7) | 0.65 |
| Death | 18 (20) | 10 (22.2) | 0.76 | 13 (17.3) | 15(25) | 0.27 | 13 (17.3) | 5 (33.3) | 0.16 |
| Early Death | 12 (13.3) | 9 (20) | 0.31 | 10 (13.3) | 11 (18.3) | 0.43 | 10 (13.3) | 2(13.3) | 1.0 |
| SIP/NEC/Death | 34 (37.8) | 20 (44.4) | 0.46 | 27 (36) | 27 (45) | 0.29 | 27 (36) | 7 (46.7) | 0.44 |
| Early SIP/NEC/Death | 26 (28.9) | 13 (28.9) | 1.0 | 22 (29.3) | 17 (28.3) | 0.9 | 22 (29.3) | 4 (26.7) | 0.83 |
Data are number of neonates with a presenting variable, and values in parentheses are percent of each group.
Multivariate Analysis on Combined Outcomes
Maternal hypertension, antenatal steroids and antenatal indomethacin were adjusted in the multivariate logistic regression (Table 3) on the combined outcome of SIP/NEC/death due to the differences observed in baseline characteristics comparisons (Table 1). After controlling for potential confounding variables there were no significant differences in the odds of SIP/NEC/death between Mg7D and No-Mg7D groups prior to discharge, OR = 0.69 (95% CI: 0.35–1.38, P = 0.29). This remained similar for early SIP/NEC/death as well with OR = 1.7 (95% CI: 0.73–3.75, P = 0.22) (Table 3).
Table 3.
Results of multivariate logistic regression
| (A) Effect on SIP/NEC/death prior to discharge | |||||
| Variable | Category | Parameter | SE | OR (95% CI) | P Value |
| Mg7D | Yes | −0.3664 | 0.3494 | 0.69 (0.35–1.38) | 0.29 |
| No | (Reference) | ||||
| Maternal Hypertension | −0.8426 | 0.3879 | 0.43 (0.2–0.92) | 0.03 | |
| Antenatal Steroids | −1.2559 | 0.4061 | 0.28 (0.13–0.63) | 0.002 | |
| Antenatal Indomethacin | 0.8936 | 0.3441 | 2.44 (1.24–4.8) | 0.009 | |
| (B) Effect on SIP/NEC/death in the first 2 weeks of life | |||||
| Variable | Category | Parameter | SE | OR (95% CI) | P Value |
| Mg7D | Yes | 0.5067 | 0.4159 | 1.7 (0.73–3.75) | 0.22 |
| No | (Reference) | ||||
| Maternal Hypertension | −0.7547 | 0.4532 | 0.47 (0.19–1.14) | 0.096 | |
| Antenatal Steroids | −1.4523 | 0.4500 | 0.23 (0.10–0.57) | 0.0012 | |
| Antenatal Indomethacin | 0.5568 | 0.4010 | 1.75 (0.80–3.83) | 0.16 | |
Before and After MgSO4 for Neuroprotection Protocol Implementation Analysis
Included in the study there were 112 neonates born pre and 190 post protocol implementations. Subjects’ maternal, perinatal and neonatal characteristics showed no significant differences except the higher rate of exposure to antenatal MgSO4 within 7 days of birth in the post protocol group (pre vs. post, 58.9% vs. 75.8%, P = 0.003). There was no difference in rate of exposure to antenatal MgSO4 within 3 days of birth (pre vs. post, 53.5% vs. 62.6%, P = 0.15).
The likelihood of intestinal injury and death were similar in the pre vs. post protocol groups; SIP (10.7% vs. 8.4%, P = 0.6), NEC (8.9% vs. 6.3%, P = 0.5) or death (8.9% vs. 13.7%, P = 0.3). Among the 135 neonates with GA <26 weeks, 49 were born pre and 86 post protocol implementation. The likelihood of adverse outcomes was not significantly different in the pre vs. post protocol groups; SIP (22.4% vs. 10.4%, P = 0.1), NEC (12.2% vs. 9.3%, P = 0.8) or death (16.3% vs. 23.2%, P = 0.4).
MgSO4 Dose Dependent Effect
We examined the effect of MgSO4 cumulative dose on the combined outcomes of SIP/NEC/death among the 179 neonates exposed to antenatal MgSO4 within 3 days prior to birth (Mg3D). Based on logistic regression modeling, each 10 g increase in MgSO4 cumulative dose correlated with an 18.9% decrease in SIP/NEC/death prior to discharge (95% CI: 2.2%−32.8%, P = 0.028) and a 21.9% decrease in early SIP/NEC/death (95% CI: 1.4%−38.1%, P = 0.037).
There was no significant association however between the number of MgSO4 loading doses and SIP/NEC/death prior to discharge, OR= 1.07 (95% CI: 0.53–2.1, P = 0.86) or early SIP/NEC/death, OR: 1.08 (95% CI: 0.48–2.4, P = 0.86).
Assessment on Effect Modification
Small for gestational age (SGA) status; defined as neonates with birth weight less than the 10th percentile for gestational age using Fenton et al growth curves (12), was found to be correlated with a reduction in SIP/NEC/ death in the Mg7D group by a Likelihood Ratio test with P = 0.07. The odds ratio of early SIP/NEC/death for Mg7D vs. No-Mg7D in SGA neonates was 0.23 (95% CI: 0.04–1.19, P = 0.079). There was no difference demonstrated in the non-SGA neonates with OR = 1.19 (95% CI: 0.58–2.47, P = 0.63) (Figure 2). The significance level of treatment effect in the SGA group was around boundary (P < 0.1).
Figure 2.
Comparison of early SIP/NEC/death Odds Ratios for Mg7D vs. No-Mg7D among all, SGA and non-SGA neonates
Discussion
Recent studies (7, 8) have raised concerns regarding the association between antenatal MgSO4 exposure and intestinal injury or death in preterm neonates. In our cohort of 302 neonates with birth weight ≤ 1,000 g and/or GA ≤ 28 weeks, we found no relationship between antenatal MgSO4 exposure and the individual or combined outcomes of SIP, NEC or death. This remained true for the subset of neonates < 26 weeks GA. Our results complement data from the studies by the Pediatrix Medical Group (9) and the Canadian Neonatal Network (10). Similarly, the original randomized controlled trials investigating antenatal MgSO4 for neuroprotection (3–5) showed no increase in neonatal and pediatrics adverse outcomes.
This is the first study to examine the temporal relationship between antenatal MgSO4 exposure and adverse neonatal outcomes. MgSO4 decreases intestinal peristalsis (13), can possibly alter mesenteric blood flow (14, 15) and is associated with feeding intolerance in neonates (16). It also crosses the placenta freely with a linear relationship between maternal and neonatal levels (17–19). However neonatal intestinal injury and death can be caused by many contributing factors. Therefore, it was compelling for us to investigate if there is a temporal relationship between antenatal MgSO4 exposure and the onset of intestinal injury or death. We found no association between different timing of antenatal MgSO4 exposure (Mg7D and Mg3D) and the likelihood of adverse outcome either prior to hospital discharge or in the first 2 weeks of life.
In contrast to the study by Rattray et al (7), we observed no increase in the likelihood of SIP or death after implementation of MgSO4 for neuroprotection protocol at our hospital. Moreover, we found that increased MgSO4 cumulative dose correlated with a reduction in SIP/NEC/death both early and prior to discharge. Our study included a larger population with longer post protocol duration and a similar rate of exposure to antenatal MgSO4 post protocol.
Noteworthy, the post protocol group had a higher rate of exposure to antenatal MgSO4 within 7 days of birth (pre vs. post, 58.95 vs. 75.8%, P = 0.003) but not within 3 days of birth (pre vs. post, 53.5% vs. 62.6%, P = 0.15), probably as the indication for 7 days exposure was primarily for fetal neuroprotection.
Downey et al (9) reported less SIP/NEC/death in neonates exposed to any antenatal MgSO4 with OR = 0.84 (95% CI: 0.77–0.9), which our results did not reproduce. However, we did find that each 10 g increase in MgSO4 cumulative dose correlated with an 18.9% decrease in SIP/NEC/death prior to discharge (95% CI: 2.2%−32.8%, P = 0.028) and a 21.9% decrease in early SIP/NEC/death (95% CI: 1.4%−38.1%, P = 0.037). Their results were primarily driven by reduction in death among neonates exposed to MgSO4 OR= 0.76 (0.70, 0.83) (9). This differs from the Cochrane review by Doyle et al (6) which reported no difference in neonatal death during primary hospitalization OR =1.04 (0.84, 1.29). However Downey et al (9) study had a significantly larger population (28,035 vs. 5,980) with average lower birth weight, including only neonates less than 1,000 g.
Small for gestational age (SGA) is a high risk population for neonatal mortality and morbidities including intestinal injury (20–22). A possible protective effect of antenatal MgSO4 in SGA neonates (Figure 2) was an unexpected finding which is not previously reported in the literature. Marrs et al (23) recently performed a secondary analysis of the NICHD Maternal Fetal Medicine Units Network randomized controlled trial of MgSO4 for the prevention of cerebral palsy (5). In their report, SGA neonates had similar rates of neonatal morbidities and mortality in comparison to non-SGA neonates. Noteworthy, 54% of SGA neonates were randomized to receive antenatal MgSO4 in this study (23). We speculate that MgSO4 exposure could have contributed to better neonatal outcomes in comparison to earlier studies (20–22).
The study’s limitations include being a retrospective study performed at single center. The chosen exposure timing of within 3 or 7 days of birth were exploratory, as previous studies did not report on temporal relationship of MgSO4 exposure and neonatal outcomes. Future studies might focus on narrower exposure timing such as less than 24 h. Another limitation is the relatively small number of SGA neonates included in the analysis.
However, our report has unique strengths, including analyzing the cumulative dose and exposure timing of MgSO4 in relation to birth, reporting on contemporary cohort of neonates with no other practices changes that might have affected neonatal outcomes and complete outcome data without missing endpoints.
The present study supports the likelihood that antenatal MgSO4 exposure in preterm neonates does not increase risk of intestinal injury or death and may in fact reduce these complications at higher doses. This protective effect was more noticeable in small for gestational age neonates. Future studies might clarify the treatment effects in this subgroup.
Acknowledgments
Funding Sources
This work was partially supported by grant UL1 TR001414 from the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through the Biostatistics, Epidemiology and Research Design Unit. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Abbreviations
- GA
gestational age
- MgSO4
magnesium sulfate
- Mg3D
neonates who received MgSO4 within 3 days prior to birth
- Mg7D
neonates who received MgSO4 within 7 days prior to birth
- NEC
necrotizing enterocolitis
- SIP
spontaneous intestinal perforation
Footnotes
Disclosure Statement
The authors have no conflicts of interest to declare.
Statement of Ethics
The study was approved by Pomona Valley Hospital Medical Center, Pomona, CA, institutional review board (IRB). Informed consents were not required since it is a retrospective study.
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