DOI 10.1515/jpm-2013-0340 J. Perinat. Med. 2014; 42(5): 585–589
ChengWei Xiao, Mihnea Gangal and Haim A. Abenhaim*
Effect of magnesium sulfate and nifedipine on the risk of developing pulmonary edema in preterm births Abstract Objective: To evaluate the risk of developing pulmonary edema in women exposed to nifedipine, magnesium sulfate (MgSO4), or both in a preterm setting. Study design: We carried out a retrospective case-control study at a large tertiary care center from 2007 to 2012. Cases of pulmonary edema were age, and gestational age matched to controls at a ratio of 1 case to 4 controls. Logistic regression analysis was used to estimate the effect of nifedipine and/or MgSO4 on the development of pulmonary edema while controlling for predetermined confounding variables. Stepwise logistic regression analysis was used to evaluate additional risk factors of pulmonary edema. Results: A total of 150 charts were reviewed (28 cases and 122 controls). Nifedipine did not increase the odds of developing pulmonary edema [adjusted odds ratio (OR) = 1.22 (confidence interval (CI) 0.50, 3.01), P = 0.67], whereas exposure to MgSO4, or both MgSO4 and nifedipine, significantly increased the risk of developing pulmonary edema [adjusted OR = 3.91 (CI 1.44, 10.65), P = 0.008 and adjusted OR = 4.75 (CI 1.15, 19.71), P = 0.032, respectively]. In the stratified analysis, this association persisted even in nonpreeclamptic women [nifedipine: adjusted OR = 0.91 (CI 0.33, 2.52), P = 0.852; MgSO4: adjusted OR = 3.51 (CI 1.26, 9.76), P = 0.016; both: adjusted OR = 3.39 (0.76, 15.07), P = 0.108]. Other independent risk factors for pulmonary edema were multi-fetal pregnancy, azithromycin, and erythromycin administration. Conclusion: MgSO4 treatment is strongly associated with the development of pulmonary edema when used either as a tocolytic agent or for seizure prophylaxis. In light of the availability of safer alternatives, MgSO4 should be used for tocolysis only in cases whereby the benefits clearly outweigh the risks. Keywords: Preterm birth; pulmonary edema; tocolytics. *Corresponding author: Haim A. Abenhaim, MD, MPH, Department of Obstetrics and Gynecology, Jewish General Hospital, 5790 Cote-des-Neiges, H412, Montreal, QC, H3T 1E2 Canada, Tel.: +(514) 340-8222x5488, Fax: +(514) 340-7941, E-mail: [email protected]
ChengWei Xiao and Mihnea Gangal: Department of Obstetrics and Gynecology, Jewish General Hospital, McGill University, Montreal, QC, Canada Haim A. Abenhaim: Department of Obstetrics and Gynecology, Jewish General Hospital, McGill University; and Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, Montreal, QC, Canada
Introduction Preterm birth is the leading cause of neonatal morbidity and mortality worldwide, with an estimated incidence of 11.54% in North America [11]. Tocolytics have been used to delay preterm labor, allowing sufficient time to transfer patients to tertiary care facilities and to administer antenatal corticosteroids, which have shown to improve neonatal outcomes [2, 22]. Clinical indications for magnesium sulfate (MgSO4) and calcium channel blockers (CCBs) now include tocolysis in addition to treatment of gestational hypertensive disorders [5, 24]. Rare and severe side effects such as pulmonary edema, associated with the use of MgSO4 and CCBs, have emerged as the number of patients taking these medications has increased. The first case series to report pulmonary edema following administration of CCBs for tocolysis dates back to 2004. Several case reports suggesting the same association have been published [1, 3, 10, 13, 17, 19, 28] since. More recent reviews conducted on the safety profile of CCBs have also reported pulmonary edema as a serious adverse event, with an incidence of approximately 1% in patients treated with CCBs [8, 14]. The literature on MgSO4 as a cause of pulmonary edema is, however, conflicting [6, 15, 23, 25]. A 2006 case-control study assessing risk factors for pulmonary edema during pregnancy demonstrated an odds ratio (OR) of 4.3 for tocolytic administration, particularly for MgSO4 and nifedipine [21]. The Montreal Jewish General Hospital is a tertiary level referral center where an estimated 4200 deliveries occur per year among which 10% are preterm births. In our institution, CCBs have emerged as first-line tocolytic agents; however, MgSO4 is still commonly used. To evaluate the safety of these medications on the risk of pulmonary edema, we carried out a retrospective case-control study evaluating the effect of these agents on the development of pulmonary edema.
586 Xiao et al., Effect of magnesium sulfate and nifedipine on risk of pulmonary edema
Materials and methods We carried out a retrospective case-control study within the Department of Obstetrics and Gynecology of the Jewish General Hospital, an associate teaching hospital of McGill University, Montreal, Quebec, Canada. The study was approved by the Research Ethics Committee of the Jewish General Hospital. The main study inclusion criteria were development of labor and/or delivery after 24 weeks and before 34 weeks of gestation. Patients excluded from the study were those who developed preterm premature rupture of membrane (PPROM) but who subsequently delivered at term and patients who presented with placental abruption. We identified all cases corresponding to the above criteria from the year 2007 to 2012 through our hospital electronic medical archive system. The controls were matched to cases on 5-year age brackets and to gestational age by week. We identified a total of 28 cases and matched them to 122 controls for a ratio of 1:4. Individual charts of selected patients were reviewed using Chartmaxx (Quest Diagnostics, NJ, USA), the electronic patient record database used in our hospital. We collected data on maternal characteristics such as age ( 100 bpm), fetal tachycardia ( > 160 bpm), uterine tenderness, or foul-smelling amniotic fluid. Patients presenting with preterm labor with unknown status of vaginal group B streptococcus were treated with intravenous ampicillin. Patients presenting with PPROM were treated with intravenous ampicillin and erythromycin/azithromycin for 48 h followed by oral amoxicillin and erythromycin for 5 days. Nifedipine (Adalat, Bayer, ON, Canada) protocol for tocolysis at the Jewish General Hospital starts at 20 mg orally, followed by two doses of 10 mg, 20 min apart, and 20 min after the initial dose if contractions persist. Patients can then receive nifedipine 20 mg every 8 h for a total of 48 h. The medication was withheld if a patient’s blood pressure was
ChengWei Xiao, Mihnea Gangal and Haim A. Abenhaim*
Effect of magnesium sulfate and nifedipine on the risk of developing pulmonary edema in preterm births Abstract Objective: To evaluate the risk of developing pulmonary edema in women exposed to nifedipine, magnesium sulfate (MgSO4), or both in a preterm setting. Study design: We carried out a retrospective case-control study at a large tertiary care center from 2007 to 2012. Cases of pulmonary edema were age, and gestational age matched to controls at a ratio of 1 case to 4 controls. Logistic regression analysis was used to estimate the effect of nifedipine and/or MgSO4 on the development of pulmonary edema while controlling for predetermined confounding variables. Stepwise logistic regression analysis was used to evaluate additional risk factors of pulmonary edema. Results: A total of 150 charts were reviewed (28 cases and 122 controls). Nifedipine did not increase the odds of developing pulmonary edema [adjusted odds ratio (OR) = 1.22 (confidence interval (CI) 0.50, 3.01), P = 0.67], whereas exposure to MgSO4, or both MgSO4 and nifedipine, significantly increased the risk of developing pulmonary edema [adjusted OR = 3.91 (CI 1.44, 10.65), P = 0.008 and adjusted OR = 4.75 (CI 1.15, 19.71), P = 0.032, respectively]. In the stratified analysis, this association persisted even in nonpreeclamptic women [nifedipine: adjusted OR = 0.91 (CI 0.33, 2.52), P = 0.852; MgSO4: adjusted OR = 3.51 (CI 1.26, 9.76), P = 0.016; both: adjusted OR = 3.39 (0.76, 15.07), P = 0.108]. Other independent risk factors for pulmonary edema were multi-fetal pregnancy, azithromycin, and erythromycin administration. Conclusion: MgSO4 treatment is strongly associated with the development of pulmonary edema when used either as a tocolytic agent or for seizure prophylaxis. In light of the availability of safer alternatives, MgSO4 should be used for tocolysis only in cases whereby the benefits clearly outweigh the risks. Keywords: Preterm birth; pulmonary edema; tocolytics. *Corresponding author: Haim A. Abenhaim, MD, MPH, Department of Obstetrics and Gynecology, Jewish General Hospital, 5790 Cote-des-Neiges, H412, Montreal, QC, H3T 1E2 Canada, Tel.: +(514) 340-8222x5488, Fax: +(514) 340-7941, E-mail: [email protected]
ChengWei Xiao and Mihnea Gangal: Department of Obstetrics and Gynecology, Jewish General Hospital, McGill University, Montreal, QC, Canada Haim A. Abenhaim: Department of Obstetrics and Gynecology, Jewish General Hospital, McGill University; and Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, Montreal, QC, Canada
Introduction Preterm birth is the leading cause of neonatal morbidity and mortality worldwide, with an estimated incidence of 11.54% in North America [11]. Tocolytics have been used to delay preterm labor, allowing sufficient time to transfer patients to tertiary care facilities and to administer antenatal corticosteroids, which have shown to improve neonatal outcomes [2, 22]. Clinical indications for magnesium sulfate (MgSO4) and calcium channel blockers (CCBs) now include tocolysis in addition to treatment of gestational hypertensive disorders [5, 24]. Rare and severe side effects such as pulmonary edema, associated with the use of MgSO4 and CCBs, have emerged as the number of patients taking these medications has increased. The first case series to report pulmonary edema following administration of CCBs for tocolysis dates back to 2004. Several case reports suggesting the same association have been published [1, 3, 10, 13, 17, 19, 28] since. More recent reviews conducted on the safety profile of CCBs have also reported pulmonary edema as a serious adverse event, with an incidence of approximately 1% in patients treated with CCBs [8, 14]. The literature on MgSO4 as a cause of pulmonary edema is, however, conflicting [6, 15, 23, 25]. A 2006 case-control study assessing risk factors for pulmonary edema during pregnancy demonstrated an odds ratio (OR) of 4.3 for tocolytic administration, particularly for MgSO4 and nifedipine [21]. The Montreal Jewish General Hospital is a tertiary level referral center where an estimated 4200 deliveries occur per year among which 10% are preterm births. In our institution, CCBs have emerged as first-line tocolytic agents; however, MgSO4 is still commonly used. To evaluate the safety of these medications on the risk of pulmonary edema, we carried out a retrospective case-control study evaluating the effect of these agents on the development of pulmonary edema.
586 Xiao et al., Effect of magnesium sulfate and nifedipine on risk of pulmonary edema
Materials and methods We carried out a retrospective case-control study within the Department of Obstetrics and Gynecology of the Jewish General Hospital, an associate teaching hospital of McGill University, Montreal, Quebec, Canada. The study was approved by the Research Ethics Committee of the Jewish General Hospital. The main study inclusion criteria were development of labor and/or delivery after 24 weeks and before 34 weeks of gestation. Patients excluded from the study were those who developed preterm premature rupture of membrane (PPROM) but who subsequently delivered at term and patients who presented with placental abruption. We identified all cases corresponding to the above criteria from the year 2007 to 2012 through our hospital electronic medical archive system. The controls were matched to cases on 5-year age brackets and to gestational age by week. We identified a total of 28 cases and matched them to 122 controls for a ratio of 1:4. Individual charts of selected patients were reviewed using Chartmaxx (Quest Diagnostics, NJ, USA), the electronic patient record database used in our hospital. We collected data on maternal characteristics such as age ( 100 bpm), fetal tachycardia ( > 160 bpm), uterine tenderness, or foul-smelling amniotic fluid. Patients presenting with preterm labor with unknown status of vaginal group B streptococcus were treated with intravenous ampicillin. Patients presenting with PPROM were treated with intravenous ampicillin and erythromycin/azithromycin for 48 h followed by oral amoxicillin and erythromycin for 5 days. Nifedipine (Adalat, Bayer, ON, Canada) protocol for tocolysis at the Jewish General Hospital starts at 20 mg orally, followed by two doses of 10 mg, 20 min apart, and 20 min after the initial dose if contractions persist. Patients can then receive nifedipine 20 mg every 8 h for a total of 48 h. The medication was withheld if a patient’s blood pressure was
