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Intrapartum magnesium sulfate is associated with neuroprotection in growth-restricted fetuses

Published:September 18, 2018DOI:https://doi.org/10.1016/j.ajog.2018.09.010

      Background

      Intrapartum magnesium sulfate administration is recommended for fetal neuroprotection in women with imminent very preterm birth. However, previous studies have not included or separately analyzed the outcomes of pregnancies with fetal growth restriction that were treated with intrapartum magnesium sulfate.

      Objective

      We sought to evaluate the neonatal and neurodevelopmental outcomes of growth-restricted fetuses born <29 weeks’ gestation and exposed to maternal intrapartum magnesium sulfate.

      Study Design

      We conducted a retrospective cohort study of infants born <29 weeks’ gestation from 2010 through 2011, admitted to participating Canadian Neonatal Network units, and followed by the Canadian Neonatal Follow-up Network centers. Growth restriction was defined either as estimated fetal or actual neonatal birthweight <10th percentile according to fetal or neonatal growth standards for gestational age and sex, respectively. Infants exposed to intrapartum magnesium sulfate were compared with unexposed infants. The primary outcome was composite of death or significant neurodevelopmental impairment at 18–36 months’ corrected age. Secondary outcomes were death or any neurodevelopmental impairment at 18–36 months’ corrected age. Neonatal morbidities were also compared.

      Results

      Of the 336 growth-restricted fetuses, 112 (33%) received magnesium sulfate and of the 177 growth-restricted infants, 61 (34%) received magnesium sulfate. Administration of magnesium sulfate was at the discretion of the treating physician. Intrapartum magnesium sulfate was associated with reduced odds of composite of death or significant neurodevelopmental impairment for infants classified according to both fetal standards (adjusted odds ratio, 0.42; 95% confidence interval, 0.22–0.80) and neonatal standards (adjusted odds ratio, 0.44; 95% confidence interval, 0.20–0.98).

      Conclusion

      Intrapartum administration of magnesium sulfate to women with growth-restricted fetuses born <29 weeks’ gestation was associated with reduced odds of composite of death or significant neurodevelopmental impairment.

      Key words

      Click Supplemental Materials under article title in Contents at ajog.org

      Introduction

      Administration of intrapartum magnesium sulfate is recommended for fetal neuroprotection in women presenting with imminent preterm birth at <32 weeks’ gestation.
      • Magee L.
      • Sawchuck D.
      • Synnes A.
      • Von Dadelszen P.
      Magnesium Sulfate for Fetal Neuroprotection Consensus Committee, Maternal Fetal Medicine Committee
      SOGC clinical practice guideline. Magnesium sulfate for fetal neuroprotection.
      This practice is supported by meta-analyses that showed administration of intrapartum magnesium sulfate was associated with a reduced risk of cerebral palsy (CP) in preterm infants.
      • 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.
      • Costantine M.M.
      • Weiner S.J.
      Eunice Kennedy Shriver National Institute of Child Health and Human Development, Maternal-Fetal Medicine Units Network
      Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis.
      • Doyle L.W.
      • Crowther C.A.
      • Middleton P.
      • Marret S.
      • Rouse D.
      Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus.
      However, previous clinical trials did not include or analyze the outcomes of pregnancies with fetal growth restriction.
      • Crowther C.A.
      • Hiller J.E.
      • Doyle L.W.
      • Haslam R.R.
      Australasian Collaborative Trial of Magnesium Sulfate Collaborative Group
      Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial.
      Magpie Trial Follow-up Study Collaborative Group
      The Magpie Trial: a randomized trial comparing magnesium sulfate with placebo for pre-eclampsia. Outcome for children at 18 months.
      • Marret S.
      • Marpeau L.
      • Zupan-Simunek V.
      • et al.
      Magnesium sulfate given before very-preterm birth to protect infant brain: the randomized controlled PREMAG trial*.
      • Mittendorf R.
      • Dambrosia J.
      • Pryde P.G.
      • et al.
      Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants.
      • Rouse D.J.
      • Hirtz D.G.
      • Thom E.
      • et al.
      A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy.
      It is unclear whether administration of magnesium sulfate to pregnancies with fetal growth restriction can reverse the consequences of adverse brain growth associated with fetal growth restriction as some of the processes for neuronal injury may have been established already in such fetuses.
      • Mallard C.
      • Loeliger M.
      • Copolov D.
      • Rees S.
      Reduced number of neurons in the hippocampus and the cerebellum in the postnatal guinea-pig following intrauterine growth-restriction.
      • Sasaki J.
      • Fukami E.
      • Mimura S.
      • Hayakawa M.
      • Kitoh J.
      • Watanabe K.
      Abnormal cerebral neuronal migration in a rat model of intrauterine growth retardation induced by synthetic thromboxane A(2).
      • Ting J.Y.
      • Kingdom J.C.
      • Shah P.S.
      Antenatal glucocorticoids, magnesium sulfate, and mode of birth in preterm fetal small for gestational age.
      Moreover, borderline high ionized magnesium levels in cord blood were observed in growth-restricted fetuses when compared to healthy term newborns, though neither group was exposed to intrapartum magnesium sulfate.
      • Barbosa N.O.
      • Okay T.S.
      • Leone C.R.
      Magnesium and intrauterine growth restriction.
      Thus, intrapartum magnesium sulfate could lead to levels of magnesium that are neurotoxic in growth-restricted fetuses. To our knowledge, there are no published studies evaluating the safety and long-term effects of intrapartum magnesium sulfate in growth-restricted fetuses.
      • Ting J.Y.
      • Kingdom J.C.
      • Shah P.S.
      Antenatal glucocorticoids, magnesium sulfate, and mode of birth in preterm fetal small for gestational age.
      Thus, our objective was to compare the neonatal and neurodevelopmental outcomes of growth-restricted fetuses born <29 weeks’ gestation who received intrapartum magnesium sulfate for neuroprotection with those who did not receive magnesium sulfate.

      Why was this study conducted?

      This study was conducted to evaluate the neuroprotective effects and safety of intrapartum magnesium sulfate in growth-restricted fetuses.

      Key findings

      We found that intrapartum magnesium sulfate given to mothers of growth-restricted infants of <29 weeks’ gestation was associated with reduced odds of death or significant neurodevelopmental impairment at 18–36 months’ corrected age.

      What does this add to what is known?

      This study furthers our knowledge of the beneficial effects of intrapartum magnesium sulfate for neuroprotection in growth-restricted extremely preterm infants of <29 weeks’ gestation.

      Materials and Methods

      Design and participants

      We conducted a retrospective cohort study using data collected for the Canadian Neonatal Network (CNN) and the Canadian Neonatal Follow-up Network (CNFUN) as part of our wider initiative, the Canadian Preterm Birth Network.
      • Shah P.S.
      • McDonald S.D.
      • Barrett J.
      • et al.
      The Canadian Preterm Birth Network: a study protocol for improving outcomes for preterm infants and their families.
      Growth-restricted infants of <29 weeks’ gestation born from Jan. 1, 2010, through Sept. 30, 2011, who were admitted to one of the tertiary neonatal intensive care units (NICUs) participating in the CNN and were assessed in neurodevelopmental follow-up clinics at 18–36 months’ corrected age were included. We have included only infants <29 weeks' gestation as these infants are at very high risk of neurodevelopmental impairment (NDI) so we have targeted to have standardized follow-up of such infants in a national cohort in Canada.
      Growth restriction was defined in 2 ways: estimated fetal weight and actual birthweight <10th percentile according to fetal
      • Salomon L.J.
      • Bernard J.P.
      • Ville Y.
      Estimation of fetal weight: reference range at 20-36 weeks' gestation and comparison with actual birth-weight reference range.
      and neonatal
      • Kramer M.S.
      • Platt R.W.
      • Wen S.W.
      • et al.
      A new and improved population-based Canadian reference for birth weight for gestational age.
      growth standards, respectively. We assumed that actual birthweight was the same as estimated fetal weight because when magnesium sulfate is administered the maternal care provider is only aware of the estimated fetal weight. We also analyzed data using neonatal classification of small for gestational age as this included the correct birthweight information. Infants were subdivided into 2 groups: infants exposed to intrapartum magnesium sulfate and infants not exposed to intrapartum magnesium sulfate. Infants with major congenital or chromosomal anomalies, planned palliative care prior to birth, or missing data were excluded. Mount Sinai Hospital’s Research Ethics Board and the steering committees of CNN and CNFUN approved data collection and analyses.

      Outcomes

      The primary outcome was composite of death or significant NDI (sNDI) defined as any of the CP with Gross Motor Function Classification System (GMFCS)
      • Palisano R.
      • Rosenbaum P.
      • Walter S.
      • Russell D.
      • Wood E.
      • Galuppi B.
      Development and reliability of a system to classify gross motor function in children with cerebral palsy.
      score ≥III; or Bayley Scales of Infant and Toddler Development-third edition (BSID-III)

      Bayley N. Manual for Bayley Scale of Infant and Toddler Development. Available at: http://www.pearsonclinical.com/childhood/products/100000123/bayley-scales-of-infant-and-toddler-development-third-edition-bayley-iii.html. Accessed Nov. 1, 2017.

      motor, language, cognitive, or general adaptive composite scores of <70; or severe developmental delay that precluded the use of BSID-III for assessment at 18–36 months’ corrected age. Secondary outcomes were death or any NDI defined as any of the CP with GMFCS score ≥I or any BSID-III component score of <85 in any domain.
      • Synnes A.
      • Luu T.M.
      • Moddemann D.
      • et al.
      Determinants of developmental outcomes in a very preterm Canadian cohort.
      Sensory impairments were unlikely affected by magnesium sulfate; thus, vision and hearing impairments were not included in the definition of NDI. Target neurodevelopmental assessment age was 18–21 months’ corrected age. A few difficult-to-track participants were seen >21 months; median assessment age was 18 months’ corrected age. Common neonatal morbidities defined below were also compared.

      Data collection

      Patient data were collected by the CNN and CNFUN across all centers using standard manuals of operations and definitions.

      Canadian Neonatal Network. The Canadian Neonatal Network abstractor manual, version 1.3.4. Available at: http://www.canadianneonatalnetwork.org/Portal/LinkClick.aspx?fileticket=U4anCYsSN20%3D&tabid. Accessed Nov. 1, 2017.

      Canadian Neonatal Follow-up Network. Canadian Neonatal Follow-up Network 18-month corrected age assessment manual. Available at: http://www.cnfun.ca/LinkClick.aspx?fileticket=d4p7mZoXWDU%3d&tabid=68Canadian. Accessed Nov. 1, 2017.

      The CNN database was shown to have high consistency and reliability.
      • Shah P.S.
      • Seidlitz W.
      • Chan P.
      • et al.
      Internal audit of the Canadian Neonatal Network data collection system.
      Eligible infants were identified within the CNN database and linked to the CNFUN database using a unique identifier. The CNN covered 28 NICUs and CNFUN all 26 follow-up clinics during the study period encompassing ∼90% of eligible infants born during the study period in Canada.
      Variables obtained from the CNN database were: (1) growth restriction, defined as both estimated and actual weight <10th percentile for gestational age and sex according to fetal and neonatal growth standards as described above; (2) exposure of intrapartum magnesium sulfate; (3) maternal and neonatal characteristics; (4) common neonatal morbidities; and (5) mortality, both in the NICU and postdischarge. Administration of magnesium sulfate was at the discretion of the treating physician. Admission severity of illness was characterized by the Score for Neonatal Acute Physiology-II.
      • Richardson D.K.
      • Corcoran J.D.
      • Escobar G.J.
      • Lee S.K.
      SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores.
      Neonatal morbidities evaluated were intraventricular hemorrhage defined according to Papile classification;
      • Papile L.A.
      • 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.
      nosocomial infection, defined as the presence of a pathogenic organism in blood or cerebrospinal fluid in a symptomatic infant >2 days of age; bronchopulmonary dysplasia, defined as receipt of oxygen or respiratory support at 36 weeks’ postmenstrual age or at discharge; necrotizing enterocolitis, defined according to the Bell criteria;
      • Bell M.J.
      • Ternberg J.L.
      • Feigin R.D.
      • et al.
      Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging.
      and severe retinopathy of prematurity (ROP), defined as stage ≥3 or ROP requiring treatment with laser or antivascular endothelial growth factor.
      International Committee for the Classification of Retinopathy of Prematurity
      The International Classification of Retinopathy of Prematurity revisited.
      At 18–36 months’ corrected age, children were assessed at affiliated CNFUN sites by specialized clinicians whenever possible, and 6% of assessments were by community health care professionals. The assessment included a standardized history, physical and neurological examinations, and administration of the BSID-III test to obtain cognitive, language, and motor scores. In cases where the child could not be tested, the BSID-III Adaptive Behavior questionnaires were administered. A diagnosis of CP was made using standard definitions
      • Rosenbaum P.
      • Paneth N.
      • Leviton A.
      • et al.
      A report: the definition and classification of cerebral palsy April 2006.
      and if CP was present, the degree of functional impairment was classified using the GMFCS.

      Statistical analysis

      Maternal and infant characteristics, as well as the primary and secondary outcomes, were compared among infants exposed and unexposed to intrapartum magnesium sulfate. Frequency (percentage), mean (SD), or median (interquartile range) were reported. Differences were assessed by Pearson χ2 for categorical variables, and Student t test or Wilcoxon rank test for continuous variables. Multivariable logistic analyses were applied for primary and secondary outcomes. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated. Confounding factors included the following: maternal hypertension, cesarean delivery, multiple gestations, gestational age, male sex, and Score for Neonatal Acute Physiology-II score >20. All analyses were conducted using software (SAS 9.3; SAS Institute Inc, Cary, NC) with 2-sided significance level .05.

      Results

      Of the 2777 infants admitted to one of the participating CNN NICUs from January 1, 2010, through September 30, 2011, 447 infants were growth-restricted fetuses according to fetal growth standards and 227 infants were growth restricted according to neonatal growth standards. After applying exclusion criteria, 336 suspected growth-restricted fetuses remained, of which 112 (33%) were exposed to magnesium sulfate and 177 infants were growth restricted by birthweight standards, of whom 61 (34%) were exposed to magnesium sulfate (Figure). All infants identified as growth restricted by birthweight were classified as growth-restricted fetuses using fetal growth standards.
      Figure thumbnail gr1
      FigureFlow diagram of the study population
      Flow diagram of study population.
      MgSO4, magnesium sulfate; NICU, neonatal intensive care unit.
      Stockley et al. Magnesium sulfate for neuroprotection of growth-restricted fetuses. Am J Obstet Gynecol 2018.
      The maternal and neonatal characteristics varied between growth-restricted infants exposed and not exposed to intrapartum magnesium sulfate (Table 1). Significantly more growth-restricted infants exposed to magnesium sulfate had mothers with hypertension, as well as fewer multiple gestations in exposed infants, in both growth restriction categories. Gestational age, prolonged rupture of membrane, and cesarean deliveries were also variable in growth-restricted fetuses as defined by the fetal growth standard.
      Table 1Maternal and neonatal characteristics
      CharacteristicsGrowth-restricted fetuses
      Fetal growth standards define growth restriction as estimated birthweight <10th percentile
      Growth-restricted infants
      Neonatal growth standards define growth restriction as birthweight <10th percentile.
      Intrapartum MgSO4 exposed, N = 112Intrapartum MgSO4 unexposed, N = 224P valueIntrapartum MgSO4 exposed, N = 61Intrapartum MgSO4 unexposed, N = 116P value
      Maternal characteristics
      Maternal age, y, mean (SD)31.6 (5.8)30.6 (5.7).1431.6 (6.1)30.9 (6.1).47
      Hypertension, n (%)97 (86.6)79 (35.6)<.0154 (88.5)48 (41.7)<.01
      Prolonged rupture of membrane >24 h, n (%)6 (5.5)41 (18.8)<.015 (8.3)13 (11.6).50
      Antenatal steroids, n (%)107 (96.4)209 (94.1).3857 (95.0)110 (96.5).63
      Cesarean delivery, n (%)103 (92.0)178 (79.5)<.0157 (93.4)98 (84.5).09
      Neonatal characteristics
      Gestational age, wk, mean (SD)26.8 (1.1)26.5 (1.4).0426.5 (1.1)26.6 (1.3).83
      Birthweight, g, mean (SD)703 (143)684 (139).23617 (1.6)619 (108).91
      Male sex, n (%)51 (45.5)127 (56.7).0532 (52.5)57 (49.1).67
      Multiple gestations, n (%)16 (14.3)65 (29.0)<.019 (14.8)32 (27.6).05
      Apgar score <7, n (%)45 (40.2)95 (42.8).6527 (44.3)49 (42.6).83
      SNAP-II score >20, n (%)35 (32.1)82 (37.3).3620 (34.5)44 (38.6).60
      Receipt of chest compression or epinephrine, n (%)12 (10.7)21 (9.4).706 (9.8)8 (6.9).49
      MgSO4, magnesium sulfate; N, number in category; n, number in group; SNAP-II, score for neonatal acute physiology.
      Stockley et al. Magnesium sulfate for neuroprotection of growth-restricted fetuses. Am J Obstet Gynecol 2018.
      a Fetal growth standards define growth restriction as estimated birthweight <10th percentile
      b Neonatal growth standards define growth restriction as birthweight <10th percentile.
      Table 2 shows aORs of common neonatal morbidities. Intrapartum magnesium sulfate was associated with reduced odds of mortality, both in the NICU and postdischarge. However, the odds of intraventricular hemorrhage, late-onset sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, and severe ROP were not statistically significantly different between the infants exposed and unexposed to magnesium sulfate.
      Table 2Neonatal outcomes of infants exposed to magnesium sulfate vs unexposed to magnesium sulfate
      OutcomesGrowth-restricted fetuses
      Fetal growth standards define growth restriction as estimated birthweight <10th percentile
      Growth-restricted infants
      Neonatal growth standards define growth restriction as birthweight <10th percentile
      Intrapartum MgSO4 exposed [N = 112], n (%)Intrapartum MgSO4 unexposed [N = 224], n (%)Adjusted OR
      Adjusted for gestational age, sex, type of delivery, multiple births, SNAP-II>20, and maternal hypertension.
      (95% CI)
      Intrapartum MgSO4 exposed [N = 61], n (%)Intrapartum MgSO4 unexposed [N = 116], n (%)Adjusted OR
      Adjusted for gestational age, sex, type of delivery, multiple births, SNAP-II>20, and maternal hypertension.
      (95% CI)
      Grade 1 or 2 IVH27 (24.1)55 (24.6)1.02 (0.53–1.94)10 (16.4)22 (19.0)0.54 (0.20–1.42)
      Grade 3 or 4 IVH8 (7.1)26 (11.6)0.55 (0.20–1.51)6 (9.8)14 (12.1)0.68 (0.20–2.34)
      Late-onset sepsis30 (26.8)72 (32.1)0.89 (0.49–1.61)16 (26.2)45 (38.8)0.71 (0.32–1.56)
      BPD53 (53.0)100 (59.9)0.84 (0.46–1.52)32 (62.8)55 (68.8)1.10 (0.47–2.61)
      NEC7 (6.2)32 (14.3)0.38 (0.15–1.00)5 (8.2)11 (9.5)0.57 (0.16–2.00)
      Stage 3/4/5 ROP or treated ROP13 (11.6)33 (14.7)0.80 (0.34–1.88)9 (14.8)17 (14.7)0.96 (0.34–2.73)
      Mortality, both NICU and postdischarge15 (13.4)65 (29.0)0.42 (0.19–0.95)13 (21.3)39 (33.6)0.37 (0.15–0.95)
      BPD, bronchopulmonary dysplasia; CI, confidence interval; IVH, intraventricular hemorrhage; MgSO4, magnesium sulfate; N, number in category; n, number in group; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; OR, odds ratio; ROP, retinopathy of prematurity.
      Stockley et al. Magnesium sulfate for neuroprotection of growth-restricted fetuses. Am J Obstet Gynecol 2018.
      a Fetal growth standards define growth restriction as estimated birthweight <10th percentile
      b Neonatal growth standards define growth restriction as birthweight <10th percentile
      c Adjusted for gestational age, sex, type of delivery, multiple births, SNAP-II>20, and maternal hypertension.
      Table 3 presents aORs for the primary and secondary outcomes. Intrapartum magnesium sulfate was associated with significantly reduced odds of death or sNDI in growth-restricted infants. Odds of death or any NDI were not different between groups. Rates of CP were lower in growth-restricted fetuses exposed to intrapartum magnesium sulfate; however, the adjusted odds were not different between groups. BSID-III composite motor scores were significantly higher in magnesium sulfate–exposed group than the unexposed group in both growth restriction categories. No significant differences were seen in the adjusted difference in mean of BSID-III composite scores in cognitive and language skills between those exposed and unexposed to intrapartum magnesium sulfate.
      Table 3Neurodevelopmental outcomes of infants exposed vs unexposed to magnesium sulfate
      Neurodevelopmental outcomesGrowth-restricted fetuses
      Fetal growth standards define growth restriction as estimated birthweight <10th percentile
      Growth-restricted infants
      Neonatal growth standards define growth restriction as birthweight <10th percentile
      Intrapartum MgSO4 exposed [N = 112], n (%)Intrapartum MgSO4 unexposed [N = 224], n (%)Adjusted OR
      Adjusted for gestational age, sex, type of delivery, multiple births, SNAP-II>20, and maternal hypertension
      (95% CI)
      Intrapartum MgSO4 exposed [N = 61], n (%)Intrapartum MgSO4 unexposed [N = 116], n (%)Adjusted OR
      Adjusted for gestational age, sex, type of delivery, multiple births, SNAP-II>20, and maternal hypertension
      (95% CI)
      Death or sNDI27 (24.1)96 (42.9)0.42 (0.22–0.80)21 (34.4)53 (45.7)0.44 (0.20–0.98)
      Death or any NDI59 (52.7)145 (64.7)0.70 (0.40–1.24)38 (62.3)77 (66.4)0.69 (0.32–1.50)
      sNDI
      Only infants who received neurodevelopmental follow-up assessment
      12 (12.4)31 (19.5)0.46 (0.20–1.07)8 (16.7)14 (18.2)0.53 (0.16–1.69)
      Any NDI
      Only infants who received neurodevelopmental follow-up assessment
      44 (45.4)80 (50.3)0.84 (0.46–1.53)25 (52.1)38 (49.4)0.87 (0.37–2.03)
      Cerebral palsy
      Only infants who received neurodevelopmental follow-up assessment
      6 (6.4)11 (7.0)1.67 (0.47–5.99)NR
      Count in cell <5–therefore, results are not reported to avoid identification of individuals according to network policy
      NR
      Count in cell <5–therefore, results are not reported to avoid identification of individuals according to network policy
      NR
      Count in cell <5–therefore, results are not reported to avoid identification of individuals according to network policy
      BSID-III motor
      Only infants who received neurodevelopmental follow-up assessment
      <85
      19 (20.7)33 (23.4)0.63 (0.29–1.39)12 (26.1)16 (22.5)0.75 (0.25–2.24)
      BSID-III cognitive
      Only infants who received neurodevelopmental follow-up assessment
      <85
      14 (15.2)23 (15.7)0.59 (0.25–1.38)10 (21.7)15 (20.8)0.66 (0.22–1.95)
      BSID-III language
      Only infants who received neurodevelopmental follow-up assessment
      <85
      32 (34.8)54 (38.6)0.81 (0.42–1.56)20 (43.5)26 (38.2)0.92 (0.38–2.24)
      BSID-III cognitive score
      Only infants who received neurodevelopmental follow-up assessment
      95 (90–100)
      median score (interquartile range)
      95 (85–100)
      median score (interquartile range)
      2.4 (–2.2 to 7.1)
      mean difference as calculated by linear regression (95% CI).
      95 (85–100)
      median score (interquartile range)
      90 (85–100)
      median score (interquartile range)
      3.8 (–3.1 to 10.6)
      mean difference as calculated by linear regression (95% CI).
      BSID-III motor score
      Only infants who received neurodevelopmental follow-up assessment
      94 (85–100)
      median score (interquartile range)
      94 (85–97)
      median score (interquartile range)
      4.7 (0.7–8.7)
      mean difference as calculated by linear regression (95% CI).
      94 (82–100)
      median score (interquartile range)
      91 (85–97)
      median score (interquartile range)
      4.9 (0.2–9.6)
      mean difference as calculated by linear regression (95% CI).
      BSID-III, Bayley Scales of Infant and Toddler Development-third edition; CI, confidence interval; MgSO4, magnesium sulfate; N, number in category; n, number in group; NDI, neurodevelopmental impairment; NR, not recorded; OR, odds ratio; sNDI, significant neurodevelopmental impairment.
      Stockley et al. Magnesium sulfate for neuroprotection of growth-restricted fetuses. Am J Obstet Gynecol 2018.
      a Fetal growth standards define growth restriction as estimated birthweight <10th percentile
      b Neonatal growth standards define growth restriction as birthweight <10th percentile
      c Adjusted for gestational age, sex, type of delivery, multiple births, SNAP-II>20, and maternal hypertension
      d Only infants who received neurodevelopmental follow-up assessment
      e Count in cell <5–therefore, results are not reported to avoid identification of individuals according to network policy
      f median score (interquartile range)
      g mean difference as calculated by linear regression (95% CI).

      Comment

      Principal findings

      In this population-based cohort study, we identified that death or sNDI at 18–36 months’ corrected age was significantly lower in growth-restricted fetuses exposed to intrapartum magnesium sulfate. The results were similar whether we used fetal growth standards or neonatal birthweight standards to classify growth restriction. Correspondingly, we identified higher composite motor scores among magnesium sulfate–exposed infants than unexposed infants. Mortality during NICU admission and postdischarge was also significantly lower in magnesium-exposed infants than unexposed infants. Finally, the majority of outcome rates were lower in magnesium sulfate–exposed growth-restricted fetuses than unexposed; however, in adjusted analyses there were no differences between the groups.

      Results in context

      Our study is the first to specifically evaluate the effects of intrapartum magnesium sulfate in growth-restricted fetuses. There have been 5 randomized controlled trials evaluating the use of intrapartum magnesium sulfate for antenatal neuroprotection, but none of them have specifically examined a subgroup of growth-restricted fetuses. Crowther et al
      • Crowther C.A.
      • Hiller J.E.
      • Doyle L.W.
      • Haslam R.R.
      Australasian Collaborative Trial of Magnesium Sulfate Collaborative Group
      Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial.
      evaluated the use of intrapartum magnesium sulfate when delivery was imminent in infants born at <30 weeks’ gestation. They found a statistically significant reduction in substantial gross motor dysfunction and death or substantial gross motor dysfunction but not in mortality, CP, and combined death or CP at 24 months’ corrected age in infants exposed to magnesium sulfate. The PREMAG trial
      • Marret S.
      • Marpeau L.
      • Zupan-Simunek V.
      • et al.
      Magnesium sulfate given before very-preterm birth to protect infant brain: the randomized controlled PREMAG trial*.
      assessed the effectiveness of intrapartum magnesium sulfate in preventing mortality, white-matter injury, or both in infants born <33 weeks’ gestation. They also reported a nonstatistically significant reduction in neonatal mortality, severe white-matter injury, and combined outcome of severe white-matter injury and/or mortality at discharge in infants who received magnesium sulfate. Rouse et al
      • Rouse D.J.
      • Hirtz D.G.
      • Thom E.
      • et al.
      A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy.
      investigated the effects of intrapartum magnesium sulfate by rates of death at 12 months’ corrected age or moderate-severe CP at ≥24 months’ corrected age in infants born between 24–31 weeks’ gestation. They found that moderate or severe CP occurred less frequently in infants exposed to magnesium sulfate, but unlike our study, the risk of death was similar in infants exposed or unexposed to magnesium sulfate. The Magpie trial
      Magpie Trial Follow-up Study Collaborative Group
      The Magpie Trial: a randomized trial comparing magnesium sulfate with placebo for pre-eclampsia. Outcome for children at 18 months.
      was primarily designed to determine the maternal effects of magnesium sulfate, but also reported on neonatal outcomes. They noted a lower risk of death or CP at 24 months’ corrected age in infants exposed to magnesium sulfate, but again the difference did not reach statistical significance. Last, the findings of Mittendorf et al
      • Mittendorf R.
      • Dambrosia J.
      • Pryde P.G.
      • et al.
      Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants.
      • Mittendorf R.
      • Covert R.
      • Boman J.
      • Khoshnood B.
      • Lee K.S.
      • Siegler M.
      Is tocolytic magnesium sulfate associated with increased total pediatric mortality?.
      are in contrast to both our study and others. They reported significantly higher pediatric mortality rates, as well as adverse outcomes (a composite of neonatal intraventricular hemorrhage, periventricular leukomalacia, CP, or death) in infants exposed than unexposed to intrapartum magnesium sulfate at 18 months’ corrected age. In 2009, 3 meta-analyses
      • 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.
      • Costantine M.M.
      • Weiner S.J.
      Eunice Kennedy Shriver National Institute of Child Health and Human Development, Maternal-Fetal Medicine Units Network
      Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis.
      • Doyle L.W.
      • Crowther C.A.
      • Middleton P.
      • Marret S.
      • Rouse D.
      Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus.
      concluded that magnesium sulfate given for fetal neuroprotection reduced the risk of CP. Our data add to the evidence showing that intrapartum magnesium sulfate could be safe and beneficial, even in growth-restricted fetuses.
      Our choice to use both fetal and neonatal standards for growth restriction highlights the difference in cut-offs used by obstetricians and neonatologists. This has been investigated previously in detail with incidence of growth restriction diagnosis approximately 20–25% by fetal standards and 10% by neonatal standards.
      • Martin L.J.
      • Sjors G.
      • Reichman B.
      • et al.
      Country-specific vs common birthweight-for-gestational age references to identify small for gestational age infants born at 24-28 weeks: an international study.
      Results from both cut-offs in our study pointed to similar results in outcomes; however, it adds to ongoing debate regarding the use of numerical cut-off, outcome-based cut-off, local population-based cut-off, universal cut-off, or combined criteria
      • Beune I.M.
      • Bloomfield F.H.
      • Ganzevoort W.
      • et al.
      Consensus based definition of growth restriction in the newborn.
      • Odibo A.O.
      • Francis A.
      • Cahill A.G.
      • Macones G.A.
      • Crane J.P.
      • Gardosi J.
      Association between pregnancy complications and small-for-gestational-age birth weight defined by customized fetal growth standard versus a population-based standard.
      • Hua X.
      • Shen M.
      • Reddy U.M.
      • et al.
      Comparison of the INTERGROWTH-21st, National Institute of Child Health and Human Development, and WHO fetal growth standards.
      • Francis A.
      • Hugh O.
      • Gardosi J.
      Customized vs INTERGROWTH-21(st) standards for the assessment of birthweight and stillbirth risk at term.
      for diagnosis of fetal/neonatal growth restriction.

      Potential mechanism of action

      The association of magnesium sulfate with reduced sNDI fits with magnesium sulfate’s role as a key mediator in molecular pathways that regulate apoptosis secondary to inflammation and hypoxic-ischemic injury.
      • Oddie S.
      • Tuffnell D.J.
      • Mcguire W.
      Antenatal magnesium sulfate: neuro-protection for preterm infants.
      Although the exact mechanism of magnesium sulfate has yet to be elucidated, hypotheses include blocking the N-methyl-D-aspartate receptor, competitively reducing entry of intracellular calcium, modulating the actions of proinflammatory cytokines and oxygen-free radicals, and reducing vascular instability thereby stabilizing blood pressure and cerebral arterial perfusion.
      • Oddie S.
      • Tuffnell D.J.
      • Mcguire W.
      Antenatal magnesium sulfate: neuro-protection for preterm infants.
      • Beloosesky R.
      • Khatib N.
      • Ginsberg Y.
      • et al.
      Maternal magnesium sulfate fetal neuroprotective effects to the fetus: inhibition of neuronal nitric oxide synthase and nuclear factor kappa-light-chain-enhancer of activated B cells activation in a rodent model.
      • Mami A.G.
      • Ballesteros J.
      • Mishra O.P.
      • Delivoria-Papadopoulos M.
      Effects of magnesium sulfate administration during hypoxia on Ca(2+) influx and IP(3) receptor modification in cerebral cortical neuronal nuclei of newborn piglets.
      Our study evaluated intrapartum magnesium sulfate use given for any indication. Our cohort was born in 2010 and 2011 after the meta-analyses
      • 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.
      • Costantine M.M.
      • Weiner S.J.
      Eunice Kennedy Shriver National Institute of Child Health and Human Development, Maternal-Fetal Medicine Units Network
      Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis.
      • Doyle L.W.
      • Crowther C.A.
      • Middleton P.
      • Marret S.
      • Rouse D.
      Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus.
      were published, and during the period the Canadian guidelines
      • Magee L.
      • Sawchuck D.
      • Synnes A.
      • Von Dadelszen P.
      Magnesium Sulfate for Fetal Neuroprotection Consensus Committee, Maternal Fetal Medicine Committee
      SOGC clinical practice guideline. Magnesium sulfate for fetal neuroprotection.
      were published in 2011. Following professional guidelines, it is not uncommon for clinicians to administer the intervention to all comers rather than exclusively patients who were eligible in the original clinical trials. Thus, it is imperative to evaluate the impact of practices in vulnerable subgroups to ensure the practice does not lead to adverse consequences. However, De Silva et al
      • De Silva D.A.
      • Synnes A.R.
      • Von Dadelszen P.
      • et al.
      Magnesium sulfate for fetal neuroprotection to prevent cerebral palsy (MAG-CP)–implementation of a national guideline in Canada.
      showed that overuse of magnesium sulfate for fetal neuroprotection to prevent CP was not a significant problem.

      Clinical implications

      The fact that one third of our cohort received magnesium sulfate indicates that there was some awareness; however, there is a need for improved knowledge translation. From our previous reports we know that the rates of intrapartum magnesium sulfate administration have increased slowly from 40–65% over the last 6 years.

      Shah PS, Yoon EW, Chan P; Members of the Annual Report Review Committee. The Canadian Neonatal Network annual report. Available at: http://www.canadianneonatalnetwork.org/Portal/LinkClick.aspx?fileticket=PJSDwNECsMI%3d&tabid=39. Accessed Aug. 14, 2018.

      Our study supports the use of intrapartum magnesium sulfate for growth-restricted fetuses and suggests that intrapartum magnesium sulfate use can be reliably adopted for growth-restricted fetuses; however, our sample size is small and additional evaluation is required.

      Research implications

      Our results need to be confirmed in further studies as our numbers are relatively small. This is also evident from the results of many of the secondary outcomes, which indicate point estimate of odds ratio being <1 but confidence interval crossing 1. In addition, we also need to study longer term neurodevelopmental outcomes at school age to assess the safety of magnesium sulfate. The majority of trials have evaluated infants <32 weeks' gestation and it may be worthwhile to evaluate infants 29–32 weeks' gestation in future studies.

      Strengths and limitations

      The strengths of this study include the population-based cohort, robust data collection, and detailed analysis of the association of intrapartum magnesium sulfate on neonatal morbidities and neurodevelopment. We also analyzed data by both pragmatic fetal standards and stricter neonatal growth standards. However, we acknowledge that our study has several limitations. First, this was retrospective observational study with a relatively small sample size. However, looking at the challenges of such trials, we do not expect another large-scale trial focused only on growth-restricted fetuses. Second, we have ∼20% loss to follow-up in our cohort. In our previous reports we identified that those lost to follow-up were somewhat larger and more mature infants; however, it is possible that attrition could have impacted our results. However, there was no differential loss of follow-up in 2 groups. Third, our database only contains birthweight and does not collect data on estimated fetal weight. We used fetal growth standards and applied those values to actual birthweight assuming that if clinicians had estimated fetal weight data they will correspond with actual birthweight data. This assumption could be challenged; however, we believe that at population level our assumption will hold true on average. Forth, we do not have data on dose and duration of magnesium sulfate in our database and were therefore unable to quantify exposure amount and duration. Fifth, we did not collect reasons for lack of administration of magnesium sulfate, which may include extenuating circumstances, imminent birth, or lack of knowledge of the evidence for intrapartum magnesium sulfate use for growth-restricted fetuses. Similarly, we also do not have indications for administration of magnesium sulfate to mothers and could not distinguish between the effect of magnesium sulfate given for preeclampsia, antenatal neuroprotection, or other reasons. Finally, although we adjusted analyses for confounding variables, we cannot rule out unmeasured or residual confounding.

      Conclusion

      In conclusion, the administration of magnesium sulfate to women with growth-restricted fetuses immediately prior to preterm birth was associated with a reduced odds of death or sNDI at 18–36 months’ corrected age for infants born at <29 weeks’ gestation.

      Acknowledgment

      The authors gratefully acknowledge all site investigators of the Canadian Neonatal Network (CNN), Canadian Neonatal Follow-up Network (CNFUN), and Canadian Preterm Birth Network. We would also like to extend our thanks to the data abstractors of the CNN and CNFUN. Finally, from the Maternal-Infant Care Research Center at Mount Sinai Hospital, Toronto, Ontario, we thank Junmin Yang, MSc, for statistical support; Sarah Hutchinson, PhD, for editorial support; and other staff for organizational support.

      Supplementary Data

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