Magnesium Sulfate Before Preterm Birth for Neuroprotection: An Updated Cochrane Systematic Review.

OBJECTIVE: To systematically review the evidence for the effectiveness and safety of magnesium sulfate as a fetal neuroprotective agent when given to individuals at risk of preterm birth. DATA SOURCES: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (through March 17, 2023), and reference lists of relevant studies. METHODS OF STUDY SELECTION: Randomized controlled trials (RCTs) assessing magnesium sulfate for fetal neuroprotection in pregnant participants at risk of imminent preterm birth were eligible. Two authors assessed RCTs for inclusion, extracted data, and evaluated risk of bias, trustworthiness, and evidence certainty (GRADE [Grading of Recommendations Assessment, Development and Evaluation]). TABULATION, INTEGRATION, AND RESULTS: We included six RCTs (5,917 pregnant participants and 6,759 fetuses at less than 34 weeks of gestation at randomization). They were conducted in high-income countries (two in the United States, two across Australia and New Zealand, and one each in Denmark and France) and commenced between 1995 and 2018. Primary outcomes: up to 2 years of corrected age, magnesium sulfate compared with placebo reduced the risk of cerebral palsy (risk ratio [RR] 0.71, 95% CI, 0.57-0.89; six RCTs, 6,107 children) and death or cerebral palsy (RR 0.87, 95% CI, 0.77-0.98; six RCTs, 6,481 children) (high-certainty evidence). Magnesium sulfate had little or no effect on death up to 2 years of corrected age (moderate-certainty evidence) or these outcomes at school age (low-certainty evidence). Although there was little or no effect on death or cardiac or respiratory arrest for pregnant individuals (low-certainty evidence), magnesium sulfate increased adverse effects severe enough to stop treatment (RR 3.21, 95% CI, 1.88-5.48; three RCTs, 4,736 participants; moderate-certainty evidence). Secondary outcome: magnesium sulfate reduced the risk of severe neonatal intraventricular hemorrhage (moderate-certainty evidence). CONCLUSION: Magnesium sulfate for preterm fetal neuroprotection reduces cerebral palsy and death or cerebral palsy for children. Further research is required on longer-term benefits and harms for children, effect variation by participant and treatment characteristics, and the generalizability of findings to low- and middle-income countries. SYSTEMATIC REVIEW REGISTRATION: The review protocol was based on a standard Cochrane Pregnancy and Childbirth template and our previous Cochrane Systematic Review (doi: 10.1002/14651858.CD004661.pub3; published before the introduction of PROSPERO).

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.

BACKGROUND: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version. OBJECTIVES: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies. SELECTION CRITERIA: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: Magnesium sulphate probably reduced severe intraventricular haemorrhage (grade 3 or 4) (RR 0.76, 95% CI 0.60 to 0.98; 5 RCTs, 5885 infants; NNTB 92, 95% CI 55 to 1102; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported. AUTHORS' CONCLUSIONS: The currently available evidence indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age, and probably reduces severe intraventricular haemorrhage for infants. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered.

Multivitamin use and adverse birth outcomes in high-income countries: a systematic review and meta-analysis.

BACKGROUND: In high-income countries, a healthy diet is widely accessible. However, a change toward a poor-quality diet with a low nutritional value in high-income countries has led to an inadequate vitamin intake during pregnancy. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the association between multivitamin use among women in high-income countries and the risk of adverse birth outcomes (preterm birth [primary outcome], low birthweight, small for gestational age, stillbirth, neonatal death, perinatal mortality, and congenital anomalies without further specification). STUDY DESIGN: We searched electronic databases (MEDLINE, Embase, Cochrane, Scopus, and CINAHL) from inception to June 17, 2016, using synonyms of pregnancy, study/trial type, and multivitamins. Eligible studies were all studies in high-income countries investigating the association between multivitamin use (3 or more vitamins or minerals in tablets or capsules) and adverse birth outcomes. We evaluated randomized, controlled trials using the Cochrane Collaboration tool. Observational studies were evaluated using the Newcastle-Ottawa Scale. Meta-analyses were applied on raw data for outcomes with data for at least 2 studies and were conducted using RevMan (version 5.3). Outcomes were pooled using the random-effect model. The quality of evidence was assessed using the Grades of Research, Assessment, Development and Evaluation approach. RESULTS: We identified 35 eligible studies including 98,926 women. None of the studies compared the use of folic acid and iron vs the use of multivitamins. The use of multivitamin did not change the risk of the primary outcome, preterm birth (relative risk, 0.84 [95% confidence interval, 0.69-1.03]). However, the risk of small for gestational age (relative risk, 0.77 [95% confidence interval, 0.63-0.93]), neural tube defects (relative risk, 0.67 [95% confidence interval, 0.52-0.87]), cardiovascular defects (relative risk, 0.83 [95% confidence interval, 0.70-0.98]), urine tract defects (relative risk, 0.60 [95% confidence interval, 0.46-0.78]), and limb deficiencies (relative risk, 0.68 [95% confidence interval, 0.52-0.89]) was decreased. Of the 35 identified studies, only 4 were randomized, controlled trials. The degree of clinical evidence according to the Grades of Research, Assessment, Development, and Evaluation system was low or very low for all outcomes except for recurrence of neural tube defects in which a moderate degree of clinical evidence was found. CONCLUSION: Routine multivitamin use in high-income countries can be recommended but with caution because of the low quality of evidence. Randomized, controlled trials or well-performed, large prospective cohort studies are needed.