Obstet Gynecol Sci.  2020 Jul;63(4):395-406. 10.5468/ogs.19210.

The effect of antenatal magnesium sulfate on intraventricular hemorrhage in premature infants: a systematic review and meta-analysis

• Moradi Y
• Khateri R
• Haghighi L
• Dehghani S
• Hanis SM
• Valipour M
• Najmi Z
• Fathollahy Z
• Allahmoradi M
• Mansori K

• KMID: 2505029
• DOI: http://doi.org/10.5468/ogs.19210

Abstract

Objective
The aim of this systematic review and meta-analysis study was to determine the pooled estimate of the effect of antenatal magnesium sulfate (MgSO₄) on intraventricular hemorrhage (IVH) in premature infants.
Methods
Two review authors independently searched all randomized clinical trials from international databases, including Medline (PubMed), Web of Sciences, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Research Registers of ongoing trials (ClinicalTrials.gov), from January 1989 to August 2017. Two independent review authors were responsible for data collection. After extracting the necessary information from the evaluated articles, metaanalysis of the data was performed using Stata version 14. Also, sources of heterogeneity among studies were determined by Meta regression.
Results
In this study, among 126 articles that were extracted from primary studies, 7 papers that evaluated the effect of MgSO₄ on IVH were eligible for inclusion in the meta-analysis. The results of the meta-analysis showed that pooled relative risk (95% confidence interval [CI]) was 0.80 (95% CI, 0.63 to 1.03) for the effect of MgSO₄ on IVH.
Conclusion
Results of this study showed that although MgSO₄ had a protective effect on IVH in premature infants, this effect was not statistically significant. Further studies are needed to determine the best dosage, timing, and gestational age to achieve the optimum effect of MgSO₄ on IVH. Systematic Review Registration International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42019119610

Keyword

Magnesium Sulfate; IVH; Premature infants; Systematic review; Meta-analysis

Figure

• 

  Fig. 1. Flow diagram of the literature search and study selection.

• 

  Fig. 2. Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.

• 

  Fig. 3. Risk of bias summary (review authors’ judgments about each risk of bias item for each included study).

• 

  Fig. 4. Frost plot for relative risk (RR) and 95% confidence interval (CI) of magnesium sulfate (MgSO4) on intraventricular hemorrhage (IVH).

Reference

References

1. Delbos F, Bertrand G, Croisille L, Ansart-Pirenne H, Bierling P, Kaplan C. Fetal and neonatal alloimmune thrombocytopenia: predictive factors of intracranial hemorrhage. Transfusion. 2016; 56:59–66.

2. Ancel PY, Livinec F, Larroque B, Marret S, Arnaud C, Pierrat V, EPIPAGE Study Group, et al. Cerebral palsy among very preterm children in relation to gestational age and neonatal ultrasound abnormalities: the EPIPAGE cohort study. Pediatrics. 2006; 117:828–35.

3. Ibishi VA, Isjanovska RD. Prelabour rupture of membranes: mode of delivery and outcome. Open Access Maced J Med Sci. 2015; 3:237–40.

4. Perlman JM, Goodman S, Kreusser KL, Volpe JJ. Reduction in intraventricular hemorrhage by elimination of fluctuating cerebral blood-flow velocity in preterm infants with respiratory distress syndrome. N Engl J Med. 1985; 312:1353–7.

5. Ahmann PA, Lazzara A, Dykes FD, Brann AW Jr, Schwartz JF. Intraventricular hemorrhage in the high-risk preterm infant: incidence and outcome. Ann Neurol. 1980; 7:118–24.

6. 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 for intraventricular hemorrhage. J Pediatr. 1990; 117:607–14.

7. Papile LA, Munsick-Bruno G, Schaefer A. Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr. 1983; 103:273–7.

8. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978; 92:529–34.

9. Stark MJ, Hodyl NA, Andersen CC. Effects of antenatal magnesium sulfate treatment for neonatal neuro-protection on cerebral oxygen kinetics. Pediatr Res. 2015; 78:310–4.

10. Crowther CA, Hiller JE, Doyle LW, Haslam RR; Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4). Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA. 2003; 290:2669–76.

11. Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks' gestation: a systematic review and metaanalysis. Am J Obstet Gynecol. 2009; 200:595–609.

12. Killion MM. Magnesium sulfate for neuroprotection. MCN Am J Matern Child Nurs. 2015; 40:394.

13. Bozkurt O, Eras Z, Canpolat FE, Oguz SS, Uras N, Dilmen U. Antenatal magnesium sulfate and neurodevelopmental outcome of preterm infants born to preeclamptic mothers. J Matern Fetal Neonatal Med. 2016; 29:1101–4.

14. Bano S, Chaudhary V, Garga UC, Yadav S, Singh SK. Chapter 1. Intracranial hemorrhage in the newborn. In : Chaudhary V, editor. Intracerebral Hemorrhage. London: IntechOpen Limited;2014.

15. Kimberlin DF, Hauth JC, Goldenberg RL, Bottoms SF, Iams JD, Mercer B, et al. The effect of maternal magnesium sulfate treatment on neonatal morbidity in < or = 1000-gram infants. Am J Perinatol. 1998; 15:635–41.

16. Paneth N, Jetton J, Pinto-Martin J, Susser M; The Neonatal Brain Hemorrhage Study Analysis Group. Magnesium sulfate in labor and risk of neonatal brain lesions and cerebral palsy in low birth weight infants. Pediatrics. 1997; 99:E1.

17. Grether JK, Hoogstrate J, Walsh-Greene E, Nelson KB. Magnesium sulfate for tocolysis and risk of spastic cerebral palsy in premature children born to women without preeclampsia. Am J Obstet Gynecol. 2000; 183:717–25.

18. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009; 6:e1000100.

19. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. Version 5.0.1. London: The Cochrane Collaboration;2008.

20. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987; 9:1–30.

21. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177–88.

22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21:1539–58.

23. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629–34.

24. Hirtz DG, Weiner SJ, Bulas D, DiPietro M, Seibert J, Rouse DJ, et al. Antenatal MAGNESIUM AND CEREBRAL PALSY IN PRETERM INFANTS. J Pediatr. 2015; 167:834–839. e3.

25. Horton AL, Lai Y, Rouse DJ, Spong CY, Leveno KJ, Varner MW, et al. Effect of magnesium sulfate administration for neuroprotection on latency in women with preterm premature rupture of membranes. Am J Perinatol. 2015; 32:387–92.

26. Marret S, Marpeau L, Follet-Bouhamed C, Cambonie G, Astruc D, Delaporte B, et al. Effect of magnesium sulphate on mortality and neurologic morbidity of the very-preterm newborn (of less than 33 weeks) with two-year neurological outcome: results of the prospective PREMAG trial. Gynecol Obstet Fertil. 2008; 36:278–88.

27. Mirzamoradi M, Behnam M, Jahed T, Saleh-Gargari S, Bakhtiyari M. Does magnesium sulfate delay the active phase of labor in women with premature rupture of membranes? A randomized controlled trial. Taiwan J Obstet Gynecol. 2014; 53:309–12.

28. Mittendorf R, Dambrosia J, Dammann O, Pryde PG, Lee KS, Ben-Ami TE, et al. Association between maternal serum ionized magnesium levels at delivery and neonatal intraventricular hemorrhage. J Pediatr. 2002; 140:540–6.

29. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med. 2008; 359:895–905.

30. Mittendorf R, Dammann O, Lee KS. Brain lesions in newborns exposed to high-dose magnesium sulfate during preterm labor. J Perinatol. 2006; 26:57–63.

31. Pinto Cardoso G, Houivet E, Marchand-Martin L, Kayem G, Sentilhes L, Ancel PY, et al. Association of intraventricular hemorrhage and death with tocolytic exposure in preterm infants. JAMA Netw Open. 2018; 1:e182355–182355.

32. Braun A, Xu H, Hu F, Kocherlakota P, Siegel D, Chander P, et al. Paucity of pericytes in germinal matrix vasculature of premature infants. J Neurosci. 2007; 27:12012–24.

33. McCrea HJ, Ment LR. The diagnosis, management, and postnatal prevention of intraventricular hemorrhage in the preterm neonate. Clin Perinatol. 2008; 35:777–92.

34. Folkerth RD, Haynes RL, Borenstein NS, Belliveau RA, Trachtenberg F, Rosenberg PA, et al. Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter. J Neuropathol Exp Neurol. 2004; 63:990–9.

35. Ma S, Li X, Fang Q, Ross MG, Chao CR. Influence of fetal to neonatal transition on nitric oxide synthase expression in the nucleus tractus solitarius in sheep. Brain Res Dev Brain Res. 1999; 118:119–27.

36. Winter S, Autry A, Boyle C, Yeargin-Allsopp M. Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics. 2002; 110:1220–5.

37. Fox NS, Gelber SE, Kalish RB, Chasen ST. Contemporary practice patterns and beliefs regarding tocolysis among U.S. maternal-fetal medicine specialists. Obstet Gynecol. 2008; 112:42–7.

38. Lewis DF. Magnesium sulfate: the first-line tocolytic. Obstet Gynecol Clin North Am. 2005; 32:485–500.

39. Mittendorf R, Pryde PG. A review of the role for magnesium sulphate in preterm labour. BJOG. 2005; 112(Suppl1):84–8.

40. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. N Engl J Med. 2020; 382:1199–207.

41. Mittendorf R, Besinger R, Santillan M, Gianopoulos J. When used in the circumstance of preterm labor, is there a paradoxical effect of varying exposures to magnesium sulfate (MgSO4) on the developing human brain? Am J Obstet Gynecol. 2005; 193:S65.

42. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics. 1995; 95:263–9.

43. You C, Deng Y, Hu W, Sun J, Lin Q, Zhou F, et al. Estimation of the time-varying reproduction number of COVID-19 outbreak in China. Lancet. 2020 Feb 20 [Epub]. https://doi.org/10.2139/ssrn.3539694.

44. Schendel DE, Berg CJ, Yeargin-Allsopp M, Boyle CA, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA. 1996; 276:1805–10.

45. Doyle LW, Crowther CA, Middleton P, Marret S. Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol. 2009; 113:1327–33.

46. Golan H, Kashtuzki I, Hallak M, Sorokin Y, Huleihel M. Maternal hypoxia during pregnancy induces fetal neurodevelopmental brain damage: partial protection by magnesium sulfate. J Neurosci Res. 2004; 78:430–41.

47. Gulczynska E, Gadzinowski J, Wilczynski J, Zylinska L. Prenatal MgSO4 treatment modifies the erythrocyte band 3 in preterm neonates. Pharmacol Res. 2006; 53:347–52.

48. Sameshima H, Ikenoue T. Long-term magnesium sulfate treatment as protection against hypoxic-ischemic brain injury in seven-day-old rats. Am J Obstet Gynecol. 2001; 184:185–90.

49. Thordstein M, Bågenholm R, Thiringer K, Kjellmer I. Scavengers of free oxygen radicals in combination with magnesium ameliorate perinatal hypoxic-ischemic brain damage in the rat. Pediatr Res. 1993; 34:23–6.

50. Türkyilmaz C, Türkyilmaz Z, Atalay Y, Söylemezoglu F, Celasun B. Magnesium pre-treatment reduces neuronal apoptosis in newborn rats in hypoxia-ischemia. Brain Res. 2002; 955:133–7.

51. Mittendorf R, Pryde PG. An overview of the possible relationship between antenatal pharmacologic magnesium and cerebral palsy. J Perinat Med. 2000; 28:286–93.

52. Garnier Y, Middelanis J, Jensen A, Berger R. Neuroprotective effects of magnesium on metabolic disturbances in fetal hippocampal slices after oxygen-glucose deprivation: mediation by nitric oxide system. J Soc Gynecol Investig. 2002; 9:86–92.

53. Elimian A, Verma R, Ogburn P, Wiencek V, Spitzer A, Quirk JG. Magnesium sulfate and neonatal outcomes of preterm neonates. J Matern Fetal Neonatal Med. 2002; 12:118–22.

54. Petrova A, Mehta R. Magnesium sulfate tocolysis and intraventricular hemorrhage in very preterm infants. Indian J Pediatr. 2012; 79:43–7.