Fetal Neuroprotection Research Articles

Neuroprotective effects of antenatal magnesium sulfate under inflammatory conditions in a Sprague–Dawley pregnant rat model*

Objective: Antenatal magnesium sulfate (MgSO4) is recommended for fetal neuroprotection. The aim of this animal study was to assess the neuroprotective effect of in utero exposure to MgSO4, under inflammatory conditions.Methods: Timed pregnant Sprague–Dawley (SD) rats (n = 29) received four intra-peritoneal (IP) injections of lipopolysaccharides (LPS; 200 μg/kg), combined with increasing concentrations of MgSO4 (25, 50 or 100 mg/kg, n = 19) or saline solution (SS; n = 10). In the second set of experiments, animals (n = 8) received a single IP injection of i) LPS (500 μg/kg), MgSO4 (50 mg/kg) and SS (n = 4) or ii) LPS (500 μg/kg), MgSO4 (50 mg/kg) and IL-6 (12 μg/kg) (n = 4). Neurodevelopmental outcomes of surviving pups (n = 212) were assessed by the open field and the rotarod tests.Results: Pups’ average weight at postnatal day (P) 25 was 75.77 g and 89.08 g in MgSO4 and control groups, respectively (p = 0.02). Pups in MgSO4 group have traveled a shorter distance and have shown reduced motor balance and coordination (p < 0.01). Average weight of pups receiving (LPS + MgSO4+ IL-6) was 92.26 g at P25, compared to 75.86 g in (LPS + MgSO4+SS) group (p < 0.05).Conclusions: In our model, MgSO4 induces pup’s growth retardation and motor deficits, which may partly be related to a lower IL-6 circulating concentration.

Magnesium Sulfate for Fetal Neuroprotection: Correlation between Maternal and Infant Serum Magnesium Concentrations

Magnesium Sulfate for Fetal Neuroprotection: Correlation between Maternal and Infant Serum Magnesium Concentrations

Melatonin for women in pregnancy for neuroprotection of the fetus.

Melatonin is an antioxidant with anti-inflammatory and anti-apoptotic effects. Animal studies have supported a fetal neuroprotective role for melatonin when administered maternally. It is important to assess whether melatonin, given to the mother, can reduce the risk of neurosensory disabilities (including cerebral palsy) and death, associated with fetal brain injury, for the preterm or term compromised fetus. To assess the effects of melatonin when used for neuroprotection of the fetus. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2016). We planned to include randomised controlled trials and quasi-randomised controlled trials comparing melatonin given to women in pregnancy (regardless of the route, timing, dose and duration of administration) for fetal neuroprotection with placebo, no treatment, or with an alternative agent aimed at providing fetal neuroprotection. We also planned to include comparisons of different regimens for administration of melatonin. Two review authors planned to independently assess trial eligibility, trial quality and extract the data. We found no randomised trials for inclusion in this review. One study is ongoing. As we did not identify any randomised trials for inclusion in this review, we are unable to comment on implications for practice at this stage.Although evidence from animals studies has supported a fetal neuroprotective role for melatonin when administered to the mother during pregnancy, no trials assessing melatonin for fetal neuroprotection in pregnant women have been completed to date. However, there is currently one ongoing randomised controlled trial (with an estimated enrolment target of 60 pregnant women) which examines the dose of melatonin, administered to women at risk of imminent very preterm birth (less than 28 weeks' gestation) required to reduce brain damage in the white matter of the babies that were born very preterm.Further high-quality research is needed and research efforts should directed towards trials comparing melatonin with either no intervention (no treatment or placebo), or with alternative agents aimed at providing fetal neuroprotection (such as magnesium sulphate for the very preterm infant). Such trials should evaluate maternal and infant short- and longer-term outcomes (including neurosensory disabilities such as cerebral palsy), and consider the costs of care.

Tocolysis for Acute Preterm Labor: Where Have We Been, Where Are We Now, and Where are We Going?

Tocolytics have been used for over 60 years for women with preterm labor, which ultimately can lead to preterm birth (PTB). Diagnosing preterm labor is challenging, but use of objective tests such as transvaginal ultrasound of cervical length assists in the identification of women at the highest risk for PTB. Once preterm labor has been diagnosed, clinicians can choose from a variety of drug classes (cyclooxygenase inhibitors, calcium channel blockers, and betamimetics) to achieve the primary goal of delaying delivery by 48 hours, thereby allowing time for administration of corticosteroids for fetal lung maturity, and if appropriate, starting magnesium sulfate for fetal neuroprotection. Cyclooxygenase inhibitors are the only class of tocolytics proven to decrease PTB < 37 weeks. Knowledge of the safety and effectiveness of these medications is paramount. Several additional agents (e.g., oxytocin receptor antagonists) have significant promise, but further studies are required before these medications can be approved for tocolysis in the United States. As we look into the future of tocolysis, we anticipate that deeper understanding of the complex physiology of preterm labor will allow us to uniquely target different etiologies that lead to the final path resulting in spontaneous preterm delivery.

Committee Opinion No 652

The U.S. Food and Drug Administration advises against the use of magnesium sulfate injections for more than 5-7 days to stop preterm labor in pregnant women. Based on this, the drug classification was changed from Category A to Category D, and the labeling was changed to include this new warning information. However, the U.S. Food and Drug Administration's change in classification addresses an unindicated and nonstandard use of magnesium sulfate in obstetric care. The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine continue to support the short-term (usually less than 48 hours) use of magnesium sulfate in obstetric care for appropriate conditions and for appropriate durations of treatment, which includes the prevention and treatment of seizures in women with preeclampsia or eclampsia, fetal neuroprotection before anticipated early preterm (less than 32 weeks of gestation) delivery, and short-term prolongation of pregnancy (up to 48 hours) to allow for the administration of antenatal corticosteroids in pregnant women who are at risk of preterm delivery within 7 days.

702: Optimization of maternal magnesium sulfate administration for fetal neuroprotection and cerebral palsy prevention

702: Optimization of maternal magnesium sulfate administration for fetal neuroprotection and cerebral palsy prevention

Barriers and enablers to implementing antenatal magnesium sulphate for fetal neuroprotection guidelines: a study using the theoretical domains framework.

BackgroundStrong evidence supports administration of magnesium sulphate prior to birth at less than 30 weeks’ gestation to prevent very preterm babies dying or developing cerebral palsy. This study was undertaken as part of The WISH (Working to Improve Survival and Health for babies born very preterm) Project, to assess health professionals’ self-reported use of antenatal magnesium sulphate, and barriers and enablers to implementation of 2010 Australian and New Zealand clinical practice guidelines.MethodsSemi-structured, one-to-one interviews were conducted with obstetric and neonatal consultants and trainees, and midwives in 2011 (n = 24) and 2012–2013 (n = 21) at the Women’s and Children’s Hospital, South Australia. Transcribed interview data were coded using the Theoretical Domains Framework (describing 14 domains related to behaviour change) for analysis of barriers and enablers.ResultsIn 2012–13, health professionals more often reported ‘routinely’ or ‘sometimes’ administering or advising their colleagues to administer magnesium sulphate for fetal neuroprotection (86 % in 2012–13 vs. 46 % in 2011). ‘Knowledge and skills’, ‘memory, attention and decision processes’, ‘environmental context and resources’, ‘beliefs about consequences’ and ‘social influences’ were key domains identified in the barrier and enabler analysis. Perceived barriers were the complex administration processes, time pressures, and the unpredictability of preterm birth. Enablers included education for staff and women at risk of very preterm birth, reminders and ‘prompts’, simplified processes for administration, and influential colleagues.ConclusionsThis study has provided valuable data on barriers and enablers to implementing magnesium sulphate for fetal neuroprotection, with implications for designing and modifying future behaviour change strategies, to ensure optimal uptake of this neuroprotective therapy for very preterm infants.Electronic supplementary materialThe online version of this article (doi:10.1186/s12884-015-0618-9) contains supplementary material, which is available to authorized users.

Update on the use of magnesium sulphate for fetal neuroprotection in preterm birth.

The administration of magnesium sulphate to mothers at risk for preterm birth for fetal neuroprotection has demonstrated to reduce the risk of cerebral palsy and gross motor dysfunction by 30-40%. Although there is controversy regarding the regimen of administration of magnesium sulphate, the gestational age limit, the extent of its potential benefit or even if it provides any benefit, current evidence is enough to support the use of magnesium sulphate in women at imminent risk for preterm delivery before 32 weeks of gestation. The objective of this study is to describe available evidence and current recommendations regarding neuroprotection with magnesium sulphate.

Actualización sobre el uso de sulfato de magnesio como neuroprotector en el parto prematuro

The administration of magnesium sulphate to mothers at risk for preterm birth for fetal neuroprotection has demonstrated to reduce the risk of cerebral palsy and gross motor dysfunction by 30-40%. Although there is controversy regarding the regimen of administration of magnesium sulphate, the gestational age limit, the extent of its potential benefit or even if it provides any benefit, current evidence is enough to support the use of magnesium sulphate in women at imminent risk for preterm delivery before 32 weeks of gestation. The objective of this study is to describe available evidence and current recommendations regarding neuroprotection with magnesium sulphate.

NKCC1 downregulation induces hyperpolarizing shift of GABA responsiveness at near term fetal stages in rat cultured dorsal root ganglion neurons.

BackgroundGABAA receptor-mediated neurotransmission is greatly influenced by cation-chloride cotransporter activity during developmental stages. In embryonic neurons Na–K–2Cl (NKCC1) cotransporters mediate active chloride uptake, thus increasing the intracellular chloride concentration associated with GABA-induced depolarization. At fetal stages near term, oxytocin-induced NKCC1 downregulation has been implicated in the developmental shift from depolarizing to hyperpolarizing GABA action. Mature dorsal root ganglion neurons (DRGN), however, express high NKCC1 levels and maintain high intracellular chloride levels with consequent GABA-induced depolarization.ResultsGramicidin-perforated patch-clamp recordings were used to assess the developmental change in chloride homeostasis in rat cultured small DRGN at the embryonic day 16 (E16) and 19 (E19). The results were compared to data previously obtained in fetal DRGN at E14 and in mature cells. A significant NKCC1 downregulation, leading to reduction in excitatory GABAergic transmission, was observed at E16 and E19.ConclusionThese results indicate that NKCC1 activity transiently decreases in DRGN at fetal stages near term. This developmental shift in GABAergic transmission may contribute to fetal analgesia and neuroprotection at birth.

O12. Analysis of the molecular and cellular mechanisms regulated by magnesium sulphate in an in vitro model of the human placenta

Introduction Pre-eclampsia is a multi-systemic pregnancy disorder and characterised as a hypertensive condition which consists of symptoms such as high blood pressure and proteinuria in women in their second trimester (around 20weeks gestation). It globally affects 2–8% of all pregnancies and remains the leading pregnancy disorder. Magnesium sulphate (MgSO 4 ) is commonly administered for the prevention and treatment of life-threatening seizures in women with preeclampsia and fetal neuroprotection before anticipated preterm birth. Despite this the mechanisms of action of MgSO 4 are poorly understood, partly due to a lack of good cellular models. We have developed an in vitro placental model to investigate the effects of MgSO 4 on (1) cytotrophoblast differentiation (syncytialisation) and (2) on preventing placental inflammation. Objectives To investigate the effects of MgSO 4 on (1) cytotrophoblast differentiation (syncytialisation) and (2) on preventing placental inflammation. Methods Cytotrophoblast viability was examined at 24h and 48h post treatment with Lipopolysaccharide (LPS) (10–1000ng/ml) and MgSO 4 (100nM–1mM) by MTT assay. Pyknotic nuclei morphology was identified by immunofluorescence. Syncytial formation was assessed by β -HCG production via ELISA methodology and assessed by desmoplakin architectural staining of cells treated with MgSO 4 (1mM), LPS (200ng) and Forksolin (25 μ M) for 72h. Quantitative real-time PCR was used to evaluated ACVR2A mRNA and TNF- α mRNA expression. Results MgSO 4 has a dose dependent effect on cytotrophoblast viability. BeWo cells treated with 200ng/ml LPS had a statistically significant effect on cell viability (30% viable cells) after 48h. 1mM MgSO 4 pre-treatment of cells resulted in an increase in viability to 57% compared to controls. Similarly, 1mM MgSO 4 pre-treatment reduced development of pyknotic nuclei compared to controls. MgSO 4 reduced the mRNA expression of ACVR2A and TNF- α . Finally MgSO 4 may have the potential to alter cytotrophoblast differentiation. Conclusion MgSO 4 provides protection against LPS-induced inflammation by modulating syncytialisation and reducing pro-inflammatory cytokine expression in vitro .

Nonreceipt of antenatal magnesium sulphate for fetal neuroprotection at the Women's and Children's Hospital, Adelaide 2010-2013.

Australian and New Zealand clinical practice guidelines, endorsed by the NHMRC in 2010, recommend administration of antenatal magnesium sulphate to women at risk of imminent preterm birth at less than 30 weeks' gestation to reduce the risk of their very preterm babies dying or having cerebral palsy. The purpose of the ongoing Working to Improve Survival and Health for babies born very preterm (WISH) implementation project is to monitor and improve the uptake of this neuroprotective therapy across Australia and New Zealand. To quantify and explore reasons for nonreceipt of antenatal magnesium sulphate at the Women's and Children's Hospital, in Adelaide, South Australia. Data from the case records of women who gave birth between 23(+0) and 29(+6) weeks' gestation from 2010 to mid-2013 were reviewed to determine the proportion of eligible mothers not receiving antenatal magnesium sulphate and to explore reason(s) for nonreceipt over this time period. There was a reduction in the proportion of eligible mothers not receiving antenatal magnesium sulphate from 2010 (69.7%) to 2011 (26.9%), which was maintained in 2012 and 2013 (22.5%). In 2012-2013, nonreceipt was predominantly associated with immediately imminent (advanced labour, rapid progression of labour) or indicated emergent birth (actual or suspected maternal or fetal compromise). Use of antenatal magnesium sulphate at the Women's and Children's Hospital is now predominantly in-line with the binational guideline recommendations. Ongoing education and enhanced familiarity with procedures may facilitate timely administration in the context of some precipitous or immediately imminent births.

Use and attitudes of obstetricians toward 3 high-risk interventions in MFMU Network hospitals

We sought to evaluate the frequency of, and factors associated with, the use of 3 evidence-based interventions: antenatal corticosteroids for fetal lung maturity, progesterone for prevention of recurrent preterm birth, and magnesium sulfate for fetal neuroprotection. A self-administered survey was conducted from January through May 2011 among obstetricians from 21 hospitals that included 30 questions regarding their knowledge, attitudes, and practice of the 3 evidence-based interventions and the 14-item short version of the Team Climate for Innovation survey. Frequency of use of each intervention was ascertained from an obstetrical cohort of women between January 2010 and February 2011. A total of 329 obstetricians (74% response rate) who managed 16,946 deliveries within the obstetrical cohort participated in the survey. More than 90% of obstetricians reported that they incorporated each intervention into routine practice. Actual frequency of administration in women eligible for the treatments was 93% for corticosteroids, 39% for progesterone, and 71% for magnesium sulfate. Provider satisfaction with quality of treatment evidence was 97% for corticosteroids, 82% for progesterone, and 57% for magnesium sulfate. Obstetricians perceived that barriers to treatment were most frequent for progesterone (76%), 30% for magnesium sulfate, and 17% for corticosteroids. Progesterone use was more frequent among patients whose provider reported the quality of the evidence was above average to excellent compared with poor to average (42% vs 25%, respectively; P < .001), and they were satisfied with their knowledge of the intervention (41% vs 28%; P = .02), and was less common among patients whose provider reported barriers to hospital or pharmacy drug delivery (31% vs 42%; P = .01). Corticosteroid administration was more common among patients who delivered at hospitals with 24 hours a day-7 days a week maternal-fetal medicine specialist coverage (93% vs 84%; P = .046), CONCLUSION: Obstetricians in Maternal-Fetal Medicine Units Network hospitals frequently use these evidence-based interventions; however, progesterone use was found to be related to their assessment of evidence quality. Neither progesterone nor the other interventions were associated with overall climate of innovation within a hospital as measured by the Team Climate for Innovation. National Institutes of Health Consensus Conference Statements may also have an impact on use; there is such a statement for antenatal corticosteroids but not for progesterone for preterm prevention or magnesium sulfate for fetal neuroprotection.

School-Age Outcomes of Very Preterm Infants After Antenatal Treatment With Magnesium Sulfate vs Placebo

Survival rates for infants born at less than 28 weeks’ gestation have increased, but rates of adverse long-term neurodevelopmental outcomes remain high compared with outcomes for term infants. The ACTOMgSO4 (Australasian Collaborative Trial of Magnesium Sulphate) study was designed to determine whether antenatal magnesium sulfate given to women at risk of preterm birth at less than 30 weeks’ gestation was related to mortality and neurosensory morbidity, particularly cerebral palsy (CP), in early childhood. The aim of the present study was to determine outcomes into school age from antenatal magnesium sulfate compared with placebo. Of 1062 parturients at less than 30 weeks’ gestation with birth planned or expected within 24 hours, 535 were randomized to receive intravenously administered magnesium sulfate and 527 to receive normal saline placebo. These women had a total of 1255 fetuses alive at randomization, and 1066 survived to hospital discharge (n = 544 exposed, n = 522 placebo). The outcomes for the school-age follow-up were CP, motor function, general intellectual ability, academic skills, attention, executive function, behavior, growth, functional and other neurosensory outcomes, and mortality. The severity of gross motor dysfunction in children with CP was classified according to the Gross Motor Function Classification System or by the Movement Assessment Battery for Children (MABC). General cognitive ability was assessed using the Wechsler Intelligence Scale for Children. Academic skills were assessed using the Wide Range Achievement Test. Attention and executive function were assessed with tests sensitive to specific attentional and executive processes. Attention-deficit/hyperactivity disorder symptoms were evaluated with parent and teacher versions of the Conners’ ADHD/DSM-IV Scales. Of the 1255 fetuses alive at randomization, the known mortality rate to school age was 14.0% in the magnesium sulfate group (88/629) compared with 17.6% in the placebo group (110/626), not a statistically significant difference. The final analysis included 867 children (443 magnesium sulfate and 424 placebo) for follow-up at school age; outcomes were determined for 669 (77%). Both groups were assessed at a mean age of 8.4 ±1.0 years, corrected for prematurity. The groups were similar for important perinatal, sociodemographic, and 2-year outcome variables. The 2 groups had no statistically significant differences in proportions with CP or in its severity (8% vs 7%; odds ratio, 1.26; 95% confidence interval [CI], 0.84–1.91). A 96% agreement was found between a diagnosis or not of CP at age 6 to 11 years with that at age 2 years in children assessed at both ages; 11 children with CP at age 2 years no longer had the diagnosis at age 6 to 11 years, and 16 children with no CP at age 2 years had the diagnosis at 8 years. Motor function on the Gross Motor Function Classification System and distribution on the MABC centiles (29 vs 32 centile; mean difference, −2.8; 95% CI, −9.1 to 3.5) were similar between groups. The proportions with abnormal motor function based on the MABC and definite motor dysfunction were similar (27% vs 27%; odds ratio, 1.16; 95% CI, 0.88–1.52). The groups did not differ in cognitive, academic, attention, executive function, or behavioral outcomes or in any of the growth, functional, or other neurosensory outcomes. Potentially confounding social variables and sex of the child had little effect and changed no conclusions. In this study, antenatal magnesium sulfate was not associated with any long-term benefits or harms compared with placebo. Magnesium sulfate given to mothers just before preterm birth for fetal neuroprotection has been one of the few measures available to possibly improve neurologic outcome for preterm survivors. Other adequately powered studies are needed to evaluate long-term benefit of magnesium for fetal neuroprotection.

Creatine for women in pregnancy for neuroprotection of the fetus.

Creatine is an amino acid derivative and, when phosphorylated (phosphocreatine), is involved in replenishing adenosine triphosphate (ATP) via the creatine kinase reaction. Cells obtain creatine from a diet rich in fish, meat, or dairy and by endogenous synthesis from the amino acids arginine, glycine, and methionine in an approximate 50:50 ratio. Animal studies have shown that creatine may provide fetal neuroprotection when given to the mother through her diet in pregnancy. It is important to assess whether maternally administered creatine in human pregnancy (at times of known, suspected, or potential fetal compromise) may offer neuroprotection to the fetus and may accordingly reduce the risk of adverse neurodevelopmental outcomes, such as cerebral palsy and associated impairments and disabilities arising from fetal brain injury. To assess the effects of creatine when used for neuroprotection of the fetus. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2014). We planned to include all published, unpublished, and ongoing randomised trials and quasi-randomised trials. We planned to include studies reported as abstracts only as well as full-text manuscripts. Trials using a cross-over or cluster-randomised design were not eligible for inclusion.We planned to include trials comparing creatine given to women in pregnancy for fetal neuroprotection (regardless of the route, timing, dose, or duration of administration) with placebo, no treatment, or with an alternative agent aimed at providing fetal neuroprotection. We also planned to include comparisons of different regimens for administration of creatine. We identified no completed or ongoing randomised controlled trials. We found no randomised controlled trials for inclusion in this review. As we did not identify any randomised controlled trials for inclusion in this review, we are unable to comment on implications for practice. Although evidence from animal studies has supported a fetal neuroprotective role for creatine when administered to the mother during pregnancy, no trials assessing creatine in pregnant women for fetal neuroprotection have been published to date. If creatine is established as safe for the mother and her fetus, research efforts should first be directed towards randomised trials comparing creatine with either no intervention (ideally using a placebo), or with alternative agents aimed at providing fetal neuroprotection (including magnesium sulphate for the very preterm infant). If appropriate, these trials should then be followed by studies comparing different creatine regimens (dosage and duration of exposure). Such trials should be high quality and adequately powered to evaluate maternal and infant short and longer-term outcomes (including neurodevelopmental disabilities such as cerebral palsy), and should consider utilisation/costs of health care.

Effect of Magnesium Sulphate on Fetal Heart Rate Parameters: A Systematic Review

ObjectiveTo examine the potential effects of intravenous magnesium sulphate (MgSO4) administration on antepartum and intrapartum fetal heart rate (FHR) parameters measured by cardiotocography (CTG) or electronic fetal monitoring (EFM). MethodsWe undertook a systematic review of randomized controlled trials, observational studies, and case series. Studies were reviewed independently by two reviewers and qualitatively analyzed with regard to CTG/EFM parameters (baseline FHR, variability and acceleration-deceleration patterns), types of participants, interventions offered, and outcomes reported. ResultsOf 18 included studies, two were RCTs (72 women); 12 were prospective observational studies (269 women), 10 of which were of a pre- and post-intervention design; one was a prospective cohort study (36 women) and three were retrospective cohort studies (555 women). Lower baseline FHR was associated with MgSO4 exposure in seven of nine relevant studies. Decreased FHR variability was reported in nine of 12 relevant studies. Reductions in reactivity or acceleration pattern were seen in four of six relevant studies without an increase in decelerative patterns. All changes were small and not associated with adverse clinical outcomes. ConclusionMaternal administration of MgSO4 for eclampsia prophylaxis/treatment, tocolysis or fetal neuroprotection appears to have a small negative effect on FHR, variability, and accelerative pattern, but is not sufficient clinically to warrant medical intervention.

Intrapartum magnesium sulfate and need for intensive delivery room resuscitation

ObjectiveTo evaluate the association of intrapartum magnesium sulfate for fetal neuroprotection (MgSO4-FN) with the delivery room resuscitation and neonatal outcomes of preterm infants in an era of minimisation of invasive...

Magnesium sulphate for preventing preterm birth in threatened preterm labour.

Magnesium sulphate has been used in some settings as a tocolytic agent to inhibit uterine activity in women in preterm labour with the aim of preventing preterm birth. To assess the effects of magnesium sulphate therapy given to women in threatened preterm labour with the aim of preventing preterm birth and its sequelae. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (last searched 31 January 2014). Randomised controlled trials of magnesium sulphate as the only tocolytic, administered by any route, compared with either placebo, no treatment or alternative tocolytic therapy (not magnesium sulphate) to women considered to be in preterm labour. At least two review authors assessed trial eligibility and risk of bias and undertook data extraction independently. The 37 included trials (total of 3571 women and over 3600 babies) were generally of moderate to high risk of bias. Antenatal magnesium sulphate was compared with either placebo, no treatment, or a range of alternative tocolytic agents.For the primary outcome of giving birth within 48 hours after trial entry, no significant differences were seen between women who received magnesium sulphate and women who did not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cox inhibitors, prostaglandin inhibitors, or human chorionic gonadotropin) (19 trials, 1913 women). Similarly for the primary outcome of serious infant outcome, there were no significant differences between the infants exposed to magnesium sulphate and those not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cox inhibitors, prostaglandin inhibitors, human chorionic gonadotropin or various tocolytic drugs) (18 trials; 2187 babies). No trials reported the outcome of extremely preterm birth. In the seven trials that reported serious maternal outcomes, no events were recorded.In the group treated with magnesium sulphate compared with women receiving antenatal placebo or no alternative tocolytic drug, a borderline increased risk of total death (fetal, neonatal, infant) was seen (risk ratio (RR) 4.56, 95% confidence interval (CI) 1.00 to 20.86; two trials, 257 babies); none of the comparisons between magnesium sulphate and other classes of tocolytic drugs showed differences for this outcome (10 trials, 991 babies). The outcomes of neonatal and/or infant deaths and of fetal deaths did not show differences between magnesium sulphate and no magnesium sulphate, whether compared with placebo/no alternative tocolytic drug, or any specific class of tocolytic drug. For most of the other secondary outcomes, there were no significant differences between magnesium sulphate and the control groups for risk of preterm birth (except for a significantly lower risk with magnesium sulphate when compared with barbiturates in one trial of 65 women), gestational age at birth, interval between trial entry and birth, other neonatal morbidities, or neurodevelopmental outcomes. Duration of neonatal intensive care unit stay was significantly increased in the magnesium sulphate group compared with the calcium channel blocker group, but not when compared with cox inhibitors or prostaglandin inhibitors. No maternal deaths were reported in the four trials reporting this outcome. Significant differences between magnesium sulphate and controls were not seen for maternal adverse events severe enough to stop treatment, except for a significant benefit of magnesium sulphate compared with betamimetics in a single trial. Magnesium sulphate is ineffective at delaying birth or preventing preterm birth, has no apparent advantages for a range of neonatal and maternal outcomes as a tocolytic agent and its use for this indication may be associated with an increased risk of total fetal, neonatal or infant mortality (in contrast to its use in appropriate groups of women for maternal, fetal, neonatal and infant neuroprotection where beneficial effects have been demonstrated).

Antenatal magnesium sulfate exposure and acute cardiorespiratory events in preterm infants

Antenatal magnesium (anteMg) is used for various obstetric indications including fetal neuroprotection. Infants exposed to anteMg may be at risk for respiratory depression and delivery room (DR) resuscitation. The study objective was to compare the risk of acute cardiorespiratory events among preterm infants who were and were not exposed to anteMg. This was a retrospective analysis of prospective data collected in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Generic Database from April 1, 2011, through March 31, 2012. The primary outcome was DR intubation or respiratory support at birth or on day 1 of life. Secondary outcomes were invasive mechanical ventilation, hypotension treatment, neonatal morbidities, and mortality. Logistic regression analysis evaluated the risk of primary outcome after adjustment for covariates. We evaluated 1544 infants <29 weeks' gestational age (1091 in anteMg group and 453 in nonexposed group). Mothers in the anteMg group were more likely to have higher education, pregnancy-induced hypertension, and antenatal corticosteroids, while their infants were younger in gestation and weighed less (P < .05). The primary outcome (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.88-1.65) was similar between groups. Hypotension treatment (OR, 0.70; 95% CI, 0.51-0.97) and invasive mechanical ventilation (OR, 0.54; 95% CI, 0.41-0.72) were significantly less in the anteMg group. Among preterm infants age <29 weeks' gestation, anteMg exposure was not associated with an increase in cardiorespiratory events in the early newborn period. The safety of anteMg as measured by the need for DR intubation or respiratory support on day 1 of life was comparable between groups.

Treatment of poor placentation and the prevention of associated adverse outcomes--what does the future hold?

ABSTRACTPoor placentation, which manifests as pre-eclampsia and fetal growth restriction, is a major pregnancy complication. The underlying cause is a deficiency in normal trophoblast invasion of the spiral arteries, associated with placental inflammation, oxidative stress, and an antiangiogenic state. Peripartum therapies, such as prenatal maternal corticosteroids and magnesium sulphate, can prevent some of the adverse neonatal outcomes, but there is currently no treatment for poor placentation itself. Instead, management relies on identifying the consequences of poor placentation in the mother and fetus, with iatrogenic preterm delivery to minimise mortality and morbidity. Several promising therapies are currently under development to treat poor placentation, to improve fetal growth, and to prevent adverse neonatal outcomes. Interventions such as maternal nitric oxide donors, sildenafil citrate, vascular endothelial growth factor gene therapy, hydrogen sulphide donors, and statins address the underlying pathology, while maternal melatonin administration may provide fetal neuroprotection. In the future, these may provide a range of synergistic therapies for pre-eclampsia and fetal growth restriction, depending on the severity and gestation of onset.