http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–4 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1035641
ORIGINAL ARTICLE
Antenatal magnesium sulfate and neurodevelopmental outcome of preterm infants born to preeclamptic mothers Ozlem Bozkurt1, Zeynep Eras2, Fuat Emre Canpolat1, Serife Suna Oguz1, Nurdan Uras1, and Ugur Dilmen1 J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/27/15 For personal use only.
1
Department of Neonatology and 2Department of Developmental Behavioral Pediatrics, Zekai Tahir Burak Maternity Teahing Hospital, Ankara, Turkey Abstract
Keywords
Objective: Previous studies demonstrated that magnesium sulfate is associated with better neurological outcome and decreased cerebral palsy rates in preterm newborns. The aim of this study is to assess the effects of antenatal magnesium sulfate on neurodevelopmental outcomes of preterm infants. Methods: Preterm newborns with a gestational age of 532 weeks whose mothers were diagnosed with preeclampsia were extracted from the hospital records and files retrospectively. The neurodevelopmental assessment was performed at 2 years of age by developmental pediatrician. The results of the infants exposed to antenatal magnesium sulfate were compared with the control group. Results: Between the years 2010 and 2012, 387 preterm babies were born to preeclamptic mothers. Fifty-nine (15.2%) of them were exposed to antenatal magnesium sulfate. The main clinical characteristics did not differ between the groups. On the other hand, cerebral palsy was significantly lower in preterm infants exposed to magnesium sulfate compared to the control group (3.3% and 12.2%, respectively, p ¼ 0.004). On multinominal logistic regression analysis, magnesium sulfate was not an independent significant factor to reduce CP on its own. Conclusion: Antenatal magnesium sulfate can be used as a neuroprotective strategy especially for the prevention of cerebral palsy in preterm infants. Future studies should be designed to support the positive effect of antenatal magnesium sulfate on neurologic development.
Antenatal, magnesium sulfate, neurodevelopment, preeclampsia, preterm
Introduction Although the advances in medical care of preterm infants have increased the survival rates dramatically over the past few decades, neurodevelopmental impairment still remains an important issue to deal with. Cerebral palsy (CP) is the most common chronic motor disability in children [1]. It is a nonprogressive motor disorder which is believed to result secondary to insults in the early stages of brain development [2]. Preterm birth, low birth weight, hypoxia and infection are the major risk factors [3]. The risk of CP and adverse neurodevelopmental outcome increases inversely proportional to gestational age. It is 70 times more common in infants with gestational age of 28 weeks compared to term [4], and about one-third of cases of CP are associated with early preterm birth [5].
Address for correspondence: Ozlem Bozkurt, Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity Teaching Hospital, 06230 Ankara, Turkey. Tel: 0090 312 306 52 71. Fax: 0090 312 236 21 01. E-mail: [email protected]
History Received 2 February 2015 Revised 22 February 2015 Accepted 26 March 2015 Published online 20 April 2015
Depending on the observational studies in early 1990s suggesting that very low birth weight (VLBW) infants born to preeclamptic mothers had lower rates of cerebral hemorrhage, the relationship of magnesium sulfate administration, preeclampsia and cerebral palsy attracted attention [6,7]. Since then, clinical trials reporting that antenatal magnesium sulfate might reduce the risk of CP in preterm infants were published, but there is still disagreement regarding the effect of magnesium sulfate on neurodevelopmental outcome. We aimed to assess the neurodevelopmental outcome of preterm infants exposed to antenatal magnesium sulfate with a gestational age of 532 weeks and born to preeclamptic mothers in our institute between the years 2010 and 2012.
Methods This study was conducted at Zekai Tahir Burak Maternity Teaching Hospital. Preterm infants with a gestational age of 532 weeks born to preeclamptic mothers between the years 2010 and 2012 and survived to corrected 2 years of age were included. Data were collected retrospectively from hospital records and files. The infants were divided into two groups
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/27/15 For personal use only.
2
O. Bozkurt et al.
according to antenatal magnesium sulfate exposure. The first group included the infants whose mothers were treated with magnesium sulfate for preeclampsia, so had antenatal magnesium sulfate exposure and the second group (control group) included the infants with no antenatal magnesium sulfate exposure. In our institution magnesium sulfate was given as a loading dose of 6 g intravenous infusion in 20 min, followed by 2 g per hour maintenance infusion for 24 h for the treatment of preeclampsia. A comprehensive evaluation was done at 2 years of age. The neurological examinations were performed by a developmental pediatrician. Diagnosis of CP, including diplegia, quadriplegia, and hemiplegia, was based on the presence of hypertonicity, hyperreflexia, and dystonic or spastic movement in the involved extremities. The developmental assessment using the Bayley Scales of Infant Development II for subjects up to 42 months was performed in our developmental behavioral pediatrics unit by certified and experienced examiners who were blind to the groups [8]. The Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) were determined. Neurodevelopmental impairment (NDI) was defined as the presence of any one of the following: moderate or severe cerebral palsy, severe bilateral hearing loss or bilateral blindness, MDI or PDI score less than 70. MDI and PDI scores were deemed to be 49 when the child could not be tested because of severe developmental delay. Written informed consent was obtained from a parent or guardian of each infant. The study protocol was approved by the local ethics committee.
J Matern Fetal Neonatal Med, Early Online: 1–4
Table 1. The demographic features of the study population.
Birth weight, ga Gestational age, weeksa Male genderb Cesarean sectionb Apgar 5 minutec
Mg SO4 treatment n ¼ 59, n (%)
Control group n ¼ 328, n (%)
1155 ± 223 29.8 ± 2 32 (54) 42 (71) 6 (2–8)
1092 ± 245 28.7 ± 2 168 (51) 246 (75) 6 (1–8)
All of the p values are insignificant. Values are given as mean ± standard deviation. b Values are given as percentage. c Values are given as median (min–max). a
Table 2. The clinical features of the study population. Mg SO4 treatment n ¼ 59, n (%) Respiratory Distress Syndrome Bronchopulmonary Dysplasia Hypoglycemia Apnea Patent Ductus Arteriosus Grade 3-4 IVH + PVL PVL only Culture proven sepsis Necrotizing Enterocolitis Grade 2 Retinopathy of Prematurity Grade 43
37 10 7 27 37 7 3 7 4 4
(62) (17) (12) (45) (62) (12) (5) (12) (6.7) (6.7)
Control group n ¼ 328, n (%) 181 61 31 184 172 50 21 51 12 22
(55) (18) (9) (56) (52) (15.2) (6.4) (15.5) (4) (6)
All values are given as percentage. All of the p values are insignificant. IVH: Intraventricular Hemorrhage; PVL: Periventricular Leucomalasia.
Statistical analysis All statistics were done using the SPSS for windows software (SPSS Inc., Chicago, IL). Student’s t-test and chi-square test were used to evaluate differences between patient groups where appropriate. Multinominal logistic regression analysis was used to evaluate all the other risks and magnesium’s impact on CP. A p value 50.05 was considered significant.
Results A total of 387 preterm infants born to preeclamptic mothers between 2010 and 1012 were examined at two years of age. The number of preterm infants exposed to antenatal magnesium sulfate was 59 (15.2%) out of 387. The birth weights were similar between the groups (1155 ± 223 and 1092 ± 245 g, p40.05). There were no statisticaly significant differences between two groups regarding the gestational age (29.8 ± 1.8 and 28.7 ± 2, respectively, p40.05) (Table 1). We found no significant differences among clinical characteristics such as respiratory distress syndrome, bronchopulmonary dysplasia, hypoglycemia, apnea, patent ductus arteriosus, grade 3–4 intraventricular hemorrhage, periventricular leukomalacia, culture proven sepsis, necrotizing enterocolitis 2 and retinopathy of premature which might affect the neurodevelopmental outcomes adversly (Table 2). There were no significant differences in the number of patients with MDI and PDI scores570 between the two goups
Table 3. Neurodevelopmental evaluation of the patients.
MDI 570, n (%) PDI 570, n (%) MDI, mean ± SD PDI, mean ± SD Cerebral palsy, n (%) Hearing loss, n (%) Blindness
MgSO4 treatment n ¼ 59
Control group n ¼ 328
p value
9 (15) 6 (10) 88 ± 22 86 ± 21 2 (3.3) 1 (1.6) –
46 (14) 31 (9) 85 ± 23 76 ± 22 40 (12.2) 4 (1.2) –
0.82 0.781 0.703 0.085 0.004* 0.9 –
*Statistically significant.
(9 (15%) versus 46 (14%), p ¼ 0.82; 6 (10%) versus 31 (9%), p ¼ 0.781, respectively). Also no significant difference was found between the groups regarding median MDI and PDI scores (p ¼ 0.703 and p ¼ 0.085) (Table 3). There was no case of blindness and the percentage of hearing losses were similar in both of the groups. The rate of cerebral palsy was significantly lower in magnesium sulfate group when compared to the control group (3.3% and 12.2%, respectively, p ¼ 0.004).
Discussion There are many efforts to reduce the NDI in preterm infants. Antiinflammatory molecules, N-methyl D-aspartate receptor
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/27/15 For personal use only.
DOI: 10.3109/14767058.2015.1035641
antagonists, antenatal steroids, growth factors, melatonin, hypothermia, and antenatal magnesium sulfate are the neuroprotective strategies that are used experimentally and clinically in preterm newborns [9]. Among these strategies, antenatal magnesium sulfate shows promising results for neuroprotection. Magnesium sulfate acts as an antiinflammatory molecule and natural calcium antagonist [10,11]. It inhibits nuclear factor kapa B activation and membrane oxidation. In our present study, we found that the rate of cerebral palsy was significantly lower in infants of preeclamptic mothers with a gestational age of 532 weeks exposed to antenatal magnesium sulfate prior to birth. But on multinominal logistic regression analysis antenatal magnesium sulfate was not a significant factor to reduce CP solely. In the study by Crowther et al. [12], magnesium sulfate was given as a neuroprotective strategy and compared with placebo in women at imminent risk for delivery before 30 weeks of gestation. The pediatric mortality was not elevated in the magnesium group. The rates of cerebral palsy were similar, but the rate of substantial motor dysfunction was significantly lower in the magnesium sulfate group. The Beneficial Effects of Antenatal Magnesium Sulfate (BEAM) study with 2241 women at imminent risk of preterm delivery between 24 and 31 weeks of gestation demonstrated that magnesium sulfate compared to placebo significantly reduced the risk of moderate or severe cerebral palsy (1.9% versus 3.5%; RR ¼ 0.55; 95% CI ¼ 0.32–0.95) [13]. But the overall risk of cerebral palsy or death did not change between two groups (11.3% versus 11.7%; RR ¼ 0.97; 95% CI ¼ 0.77–1.23). In the randomized controlled trial of Magnesium Sulfate for Prevention of Eclapmsia (MAGPIE), the rates of cerebral palsy were lower than the other studies but not different between the magnesium and control groups [14]. Also, overall mortality rates were similar between two groups. Individually none of the studies presents reliable data to make change in clinical practice. The meta-analysis of five randomized controlled trials revealed that antenatal magnesium sulfate had no significant effect on pediatric mortality either used for neuroprotection or for other reasons such as tocolytic [15]. But there were significant effect of antenatal magnesium sulfate treatment to reduce cerebral palsy and substantial motor dysfunction both in the overall and neuroprotective intent groups. The Committee on Obstetric Practice and the Society for Maternal–Fetal Medicine concluded that magnesium sulfate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants and recommended that physicians should develop individual guidelines for treatment regimens [16]. In current obstetrical practice it is used as a tocolytic agent to prevent preterm labor and for seizure prophylaxis in preeclamptic pregnancies [17]. Although our study and the previous studies demonstrated promising effects of antenatal magnesium sulfate on cerebral palsy, still there is no routine use of magnesium sulfate for neuroprotective strategy in preterm births. Assuming the rate of CP as 3.5% in the placebo group of BEAM trial [13], to achieve 30% reduction in CP rate with
Antenatal magnesium sulfate and neurodevelopmental outcome
3
antenatal magnesium sulfate with 80% power and 2-tailed alpha and p50.05;48000 pregnant women with a gestational age of532 weeks should be taken to the study. The multicenter BEAM trial including 2241 pregnant women continued for 10 years and costed 25 million dolars. Therefore, we think that to analyse the data retrospectively with appropriate number of patients will be more cost-effective for our current practice. Additionally knowing that some tocolytic agents such as calcium channel blockers are more effective than Mg sulfate, it will not be ethical to design the study without giving medication to control group. In conclusion, since our study includes preterm newborns born to preeclamptic mothers, the results cannot be generalized to all preterm newborns. We think that antenatal magnesium sulfate can be used as a neuroprotective strategy, especially to prevent cerebral palsy in preterm newborns, but the effective and safe dosing regimens should be studied. To define and select the appropriate group of mothers for treatment will be more beneficial for maternal, fetal and neonatal outcome. New prospective studies are needed to demonstrate significant neuroprotective effects of magnesium sulfate, the appropriate group of patients for administration and the effective dose.
Decleration of interest The authors report no declerations of interest.
References 1. Centers for Disease Control and Prevention. Facts about cerebral palsy. 2012. Available from: http://www.cdc.gov/NCBDDD/cp/ facts.html [last accessed 1 Nov 2014]. 2. Colver A, Fairhurst C, Pharoah PO. Cerebral palsy. Lancet 2014; 383:1240–9. 3. Cummins SK, Nelson KB, Grether JK, Velie EM. Cerebral palsy in four northern California counties, births 1983 through 1985. J Pediatr 1993;123:230–7. 4. Doyle LW. Antenatal magnesium sulfate and neuroprotection. Curr Opin Pediatr 2012;24:154–9. 5. 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. 6. Leviton A, Kuban KC, Pagano M, et al. Maternal toxemia and neonatal germinal matrix hemorrhage in intubated infants less than 1751 g. Obstet Gynecol 1988;72:571–6. 7. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95: 263–9. 8. Bayley N. Bayley Scales of Infant Development II. San Antonio (TX): Psychological Corp.; 1993. 9. Salmeen KE, Jelin AC, Thiet MP. Perinatal neuroprotection. F1000Prime Rep 2014;6:6. 10. Mazur A, Maier JA, Rock E, et al. Magnesium and the inflammatory response: potential physiopathological implications. Arch Biochem Biophys 2007;458:48–56. 11. Sugimoto J, Romani AM, Valentin-Torres AM, et al. Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol 2012;188:6338–46. 12. Crowther CA, Hiller JE, Doyle LW, Haslam RR; Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:2669–76. 13. Rouse DJ, Hirtz DG, Thom E, et al.; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895–905.
4
O. Bozkurt et al.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/27/15 For personal use only.
14. The Magpie Trial Collaborative Group. Do women with preeclampsia, and their babies, benefit from magnesium suphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:1877–90. 15. Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;21(1):CD004661.
J Matern Fetal Neonatal Med, Early Online: 1–4
16. Patient safety checklist No. 7: magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol 2012;120:432–3. 17. Committee Opinion No. 573: magnesium sulfate use in obstetrics. American College of Obstetricians and Gynecologists Committee on Obstetric Practice Society for Maternal-Fetal Medicine. Obstet Gynecol 2013;122:727–72.
ORIGINAL ARTICLE
Antenatal magnesium sulfate and neurodevelopmental outcome of preterm infants born to preeclamptic mothers Ozlem Bozkurt1, Zeynep Eras2, Fuat Emre Canpolat1, Serife Suna Oguz1, Nurdan Uras1, and Ugur Dilmen1 J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/27/15 For personal use only.
1
Department of Neonatology and 2Department of Developmental Behavioral Pediatrics, Zekai Tahir Burak Maternity Teahing Hospital, Ankara, Turkey Abstract
Keywords
Objective: Previous studies demonstrated that magnesium sulfate is associated with better neurological outcome and decreased cerebral palsy rates in preterm newborns. The aim of this study is to assess the effects of antenatal magnesium sulfate on neurodevelopmental outcomes of preterm infants. Methods: Preterm newborns with a gestational age of 532 weeks whose mothers were diagnosed with preeclampsia were extracted from the hospital records and files retrospectively. The neurodevelopmental assessment was performed at 2 years of age by developmental pediatrician. The results of the infants exposed to antenatal magnesium sulfate were compared with the control group. Results: Between the years 2010 and 2012, 387 preterm babies were born to preeclamptic mothers. Fifty-nine (15.2%) of them were exposed to antenatal magnesium sulfate. The main clinical characteristics did not differ between the groups. On the other hand, cerebral palsy was significantly lower in preterm infants exposed to magnesium sulfate compared to the control group (3.3% and 12.2%, respectively, p ¼ 0.004). On multinominal logistic regression analysis, magnesium sulfate was not an independent significant factor to reduce CP on its own. Conclusion: Antenatal magnesium sulfate can be used as a neuroprotective strategy especially for the prevention of cerebral palsy in preterm infants. Future studies should be designed to support the positive effect of antenatal magnesium sulfate on neurologic development.
Antenatal, magnesium sulfate, neurodevelopment, preeclampsia, preterm
Introduction Although the advances in medical care of preterm infants have increased the survival rates dramatically over the past few decades, neurodevelopmental impairment still remains an important issue to deal with. Cerebral palsy (CP) is the most common chronic motor disability in children [1]. It is a nonprogressive motor disorder which is believed to result secondary to insults in the early stages of brain development [2]. Preterm birth, low birth weight, hypoxia and infection are the major risk factors [3]. The risk of CP and adverse neurodevelopmental outcome increases inversely proportional to gestational age. It is 70 times more common in infants with gestational age of 28 weeks compared to term [4], and about one-third of cases of CP are associated with early preterm birth [5].
Address for correspondence: Ozlem Bozkurt, Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity Teaching Hospital, 06230 Ankara, Turkey. Tel: 0090 312 306 52 71. Fax: 0090 312 236 21 01. E-mail: [email protected]
History Received 2 February 2015 Revised 22 February 2015 Accepted 26 March 2015 Published online 20 April 2015
Depending on the observational studies in early 1990s suggesting that very low birth weight (VLBW) infants born to preeclamptic mothers had lower rates of cerebral hemorrhage, the relationship of magnesium sulfate administration, preeclampsia and cerebral palsy attracted attention [6,7]. Since then, clinical trials reporting that antenatal magnesium sulfate might reduce the risk of CP in preterm infants were published, but there is still disagreement regarding the effect of magnesium sulfate on neurodevelopmental outcome. We aimed to assess the neurodevelopmental outcome of preterm infants exposed to antenatal magnesium sulfate with a gestational age of 532 weeks and born to preeclamptic mothers in our institute between the years 2010 and 2012.
Methods This study was conducted at Zekai Tahir Burak Maternity Teaching Hospital. Preterm infants with a gestational age of 532 weeks born to preeclamptic mothers between the years 2010 and 2012 and survived to corrected 2 years of age were included. Data were collected retrospectively from hospital records and files. The infants were divided into two groups
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/27/15 For personal use only.
2
O. Bozkurt et al.
according to antenatal magnesium sulfate exposure. The first group included the infants whose mothers were treated with magnesium sulfate for preeclampsia, so had antenatal magnesium sulfate exposure and the second group (control group) included the infants with no antenatal magnesium sulfate exposure. In our institution magnesium sulfate was given as a loading dose of 6 g intravenous infusion in 20 min, followed by 2 g per hour maintenance infusion for 24 h for the treatment of preeclampsia. A comprehensive evaluation was done at 2 years of age. The neurological examinations were performed by a developmental pediatrician. Diagnosis of CP, including diplegia, quadriplegia, and hemiplegia, was based on the presence of hypertonicity, hyperreflexia, and dystonic or spastic movement in the involved extremities. The developmental assessment using the Bayley Scales of Infant Development II for subjects up to 42 months was performed in our developmental behavioral pediatrics unit by certified and experienced examiners who were blind to the groups [8]. The Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) were determined. Neurodevelopmental impairment (NDI) was defined as the presence of any one of the following: moderate or severe cerebral palsy, severe bilateral hearing loss or bilateral blindness, MDI or PDI score less than 70. MDI and PDI scores were deemed to be 49 when the child could not be tested because of severe developmental delay. Written informed consent was obtained from a parent or guardian of each infant. The study protocol was approved by the local ethics committee.
J Matern Fetal Neonatal Med, Early Online: 1–4
Table 1. The demographic features of the study population.
Birth weight, ga Gestational age, weeksa Male genderb Cesarean sectionb Apgar 5 minutec
Mg SO4 treatment n ¼ 59, n (%)
Control group n ¼ 328, n (%)
1155 ± 223 29.8 ± 2 32 (54) 42 (71) 6 (2–8)
1092 ± 245 28.7 ± 2 168 (51) 246 (75) 6 (1–8)
All of the p values are insignificant. Values are given as mean ± standard deviation. b Values are given as percentage. c Values are given as median (min–max). a
Table 2. The clinical features of the study population. Mg SO4 treatment n ¼ 59, n (%) Respiratory Distress Syndrome Bronchopulmonary Dysplasia Hypoglycemia Apnea Patent Ductus Arteriosus Grade 3-4 IVH + PVL PVL only Culture proven sepsis Necrotizing Enterocolitis Grade 2 Retinopathy of Prematurity Grade 43
37 10 7 27 37 7 3 7 4 4
(62) (17) (12) (45) (62) (12) (5) (12) (6.7) (6.7)
Control group n ¼ 328, n (%) 181 61 31 184 172 50 21 51 12 22
(55) (18) (9) (56) (52) (15.2) (6.4) (15.5) (4) (6)
All values are given as percentage. All of the p values are insignificant. IVH: Intraventricular Hemorrhage; PVL: Periventricular Leucomalasia.
Statistical analysis All statistics were done using the SPSS for windows software (SPSS Inc., Chicago, IL). Student’s t-test and chi-square test were used to evaluate differences between patient groups where appropriate. Multinominal logistic regression analysis was used to evaluate all the other risks and magnesium’s impact on CP. A p value 50.05 was considered significant.
Results A total of 387 preterm infants born to preeclamptic mothers between 2010 and 1012 were examined at two years of age. The number of preterm infants exposed to antenatal magnesium sulfate was 59 (15.2%) out of 387. The birth weights were similar between the groups (1155 ± 223 and 1092 ± 245 g, p40.05). There were no statisticaly significant differences between two groups regarding the gestational age (29.8 ± 1.8 and 28.7 ± 2, respectively, p40.05) (Table 1). We found no significant differences among clinical characteristics such as respiratory distress syndrome, bronchopulmonary dysplasia, hypoglycemia, apnea, patent ductus arteriosus, grade 3–4 intraventricular hemorrhage, periventricular leukomalacia, culture proven sepsis, necrotizing enterocolitis 2 and retinopathy of premature which might affect the neurodevelopmental outcomes adversly (Table 2). There were no significant differences in the number of patients with MDI and PDI scores570 between the two goups
Table 3. Neurodevelopmental evaluation of the patients.
MDI 570, n (%) PDI 570, n (%) MDI, mean ± SD PDI, mean ± SD Cerebral palsy, n (%) Hearing loss, n (%) Blindness
MgSO4 treatment n ¼ 59
Control group n ¼ 328
p value
9 (15) 6 (10) 88 ± 22 86 ± 21 2 (3.3) 1 (1.6) –
46 (14) 31 (9) 85 ± 23 76 ± 22 40 (12.2) 4 (1.2) –
0.82 0.781 0.703 0.085 0.004* 0.9 –
*Statistically significant.
(9 (15%) versus 46 (14%), p ¼ 0.82; 6 (10%) versus 31 (9%), p ¼ 0.781, respectively). Also no significant difference was found between the groups regarding median MDI and PDI scores (p ¼ 0.703 and p ¼ 0.085) (Table 3). There was no case of blindness and the percentage of hearing losses were similar in both of the groups. The rate of cerebral palsy was significantly lower in magnesium sulfate group when compared to the control group (3.3% and 12.2%, respectively, p ¼ 0.004).
Discussion There are many efforts to reduce the NDI in preterm infants. Antiinflammatory molecules, N-methyl D-aspartate receptor
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/27/15 For personal use only.
DOI: 10.3109/14767058.2015.1035641
antagonists, antenatal steroids, growth factors, melatonin, hypothermia, and antenatal magnesium sulfate are the neuroprotective strategies that are used experimentally and clinically in preterm newborns [9]. Among these strategies, antenatal magnesium sulfate shows promising results for neuroprotection. Magnesium sulfate acts as an antiinflammatory molecule and natural calcium antagonist [10,11]. It inhibits nuclear factor kapa B activation and membrane oxidation. In our present study, we found that the rate of cerebral palsy was significantly lower in infants of preeclamptic mothers with a gestational age of 532 weeks exposed to antenatal magnesium sulfate prior to birth. But on multinominal logistic regression analysis antenatal magnesium sulfate was not a significant factor to reduce CP solely. In the study by Crowther et al. [12], magnesium sulfate was given as a neuroprotective strategy and compared with placebo in women at imminent risk for delivery before 30 weeks of gestation. The pediatric mortality was not elevated in the magnesium group. The rates of cerebral palsy were similar, but the rate of substantial motor dysfunction was significantly lower in the magnesium sulfate group. The Beneficial Effects of Antenatal Magnesium Sulfate (BEAM) study with 2241 women at imminent risk of preterm delivery between 24 and 31 weeks of gestation demonstrated that magnesium sulfate compared to placebo significantly reduced the risk of moderate or severe cerebral palsy (1.9% versus 3.5%; RR ¼ 0.55; 95% CI ¼ 0.32–0.95) [13]. But the overall risk of cerebral palsy or death did not change between two groups (11.3% versus 11.7%; RR ¼ 0.97; 95% CI ¼ 0.77–1.23). In the randomized controlled trial of Magnesium Sulfate for Prevention of Eclapmsia (MAGPIE), the rates of cerebral palsy were lower than the other studies but not different between the magnesium and control groups [14]. Also, overall mortality rates were similar between two groups. Individually none of the studies presents reliable data to make change in clinical practice. The meta-analysis of five randomized controlled trials revealed that antenatal magnesium sulfate had no significant effect on pediatric mortality either used for neuroprotection or for other reasons such as tocolytic [15]. But there were significant effect of antenatal magnesium sulfate treatment to reduce cerebral palsy and substantial motor dysfunction both in the overall and neuroprotective intent groups. The Committee on Obstetric Practice and the Society for Maternal–Fetal Medicine concluded that magnesium sulfate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants and recommended that physicians should develop individual guidelines for treatment regimens [16]. In current obstetrical practice it is used as a tocolytic agent to prevent preterm labor and for seizure prophylaxis in preeclamptic pregnancies [17]. Although our study and the previous studies demonstrated promising effects of antenatal magnesium sulfate on cerebral palsy, still there is no routine use of magnesium sulfate for neuroprotective strategy in preterm births. Assuming the rate of CP as 3.5% in the placebo group of BEAM trial [13], to achieve 30% reduction in CP rate with
Antenatal magnesium sulfate and neurodevelopmental outcome
3
antenatal magnesium sulfate with 80% power and 2-tailed alpha and p50.05;48000 pregnant women with a gestational age of532 weeks should be taken to the study. The multicenter BEAM trial including 2241 pregnant women continued for 10 years and costed 25 million dolars. Therefore, we think that to analyse the data retrospectively with appropriate number of patients will be more cost-effective for our current practice. Additionally knowing that some tocolytic agents such as calcium channel blockers are more effective than Mg sulfate, it will not be ethical to design the study without giving medication to control group. In conclusion, since our study includes preterm newborns born to preeclamptic mothers, the results cannot be generalized to all preterm newborns. We think that antenatal magnesium sulfate can be used as a neuroprotective strategy, especially to prevent cerebral palsy in preterm newborns, but the effective and safe dosing regimens should be studied. To define and select the appropriate group of mothers for treatment will be more beneficial for maternal, fetal and neonatal outcome. New prospective studies are needed to demonstrate significant neuroprotective effects of magnesium sulfate, the appropriate group of patients for administration and the effective dose.
Decleration of interest The authors report no declerations of interest.
References 1. Centers for Disease Control and Prevention. Facts about cerebral palsy. 2012. Available from: http://www.cdc.gov/NCBDDD/cp/ facts.html [last accessed 1 Nov 2014]. 2. Colver A, Fairhurst C, Pharoah PO. Cerebral palsy. Lancet 2014; 383:1240–9. 3. Cummins SK, Nelson KB, Grether JK, Velie EM. Cerebral palsy in four northern California counties, births 1983 through 1985. J Pediatr 1993;123:230–7. 4. Doyle LW. Antenatal magnesium sulfate and neuroprotection. Curr Opin Pediatr 2012;24:154–9. 5. 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. 6. Leviton A, Kuban KC, Pagano M, et al. Maternal toxemia and neonatal germinal matrix hemorrhage in intubated infants less than 1751 g. Obstet Gynecol 1988;72:571–6. 7. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95: 263–9. 8. Bayley N. Bayley Scales of Infant Development II. San Antonio (TX): Psychological Corp.; 1993. 9. Salmeen KE, Jelin AC, Thiet MP. Perinatal neuroprotection. F1000Prime Rep 2014;6:6. 10. Mazur A, Maier JA, Rock E, et al. Magnesium and the inflammatory response: potential physiopathological implications. Arch Biochem Biophys 2007;458:48–56. 11. Sugimoto J, Romani AM, Valentin-Torres AM, et al. Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol 2012;188:6338–46. 12. Crowther CA, Hiller JE, Doyle LW, Haslam RR; Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:2669–76. 13. Rouse DJ, Hirtz DG, Thom E, et al.; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895–905.
4
O. Bozkurt et al.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 04/27/15 For personal use only.
14. The Magpie Trial Collaborative Group. Do women with preeclampsia, and their babies, benefit from magnesium suphate? The Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:1877–90. 15. Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;21(1):CD004661.
J Matern Fetal Neonatal Med, Early Online: 1–4
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