Comparison of outcomes following intravenous magnesium compared with intravenous labetalol and oral nifedipine in 355 pregnant Han Chinese women with preeclampsia

At EL women of MS (142.56 ± 0.74 mm Hg vs 116.47 ± 0.35 mm Hg, P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons tests), LB (140.5 ± 0.51 mm Hg vs 166.18 ± 0.36 mm Hg, P < .001, Kruskal–Wallis’ test/ Dunn multiple comparisons tests), and NF (141.08 ± 0.68 mm Hg vs 165.51 ± 0.33 mm Hg, P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons test) cohorts were successfully decreased systolic blood pressure as compared to their BL condition. At EL systolic blood pressure of women of the LB, cohort was decreased than those of women of the MS ( P < .05, Kruskal–Wallis’ test/Dunn multiple comparisons test) and the NF ( P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons test) cohorts. At EL systolic blood pressure of women of the MS, cohort was decreased than those of women of the NF cohort ( P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons test). The details of systolic blood pressure of women of different cohorts at BL and EL are presented in Figure 2 . Systolic blood pressure before therapy and after maximum dosage of therapy of women of different cohorts. * Fewer than that of before therapy. MS cohort: Women received 4 g intravenously over 15 min magnesium sulfate in 100 mL normal saline then the maintenance dose of 1 g/h intravenous magnesium sulfate in 500 mL normal saline was maintained for 24 hours (even for 1 day after delivery if required), LB cohort: Women received 20 mg intravenously over 2 minutes initially, then 40–80 mg intravenous after 10 min intervals labetalol; the total dose of labetalol did not exceed 200 mg/day, NF cohort: Women received 20 mg extended-release nifedipine 3 times a day for a maximum of 7 days. At EL women of MS (91.77 ± 0.7 mm Hg vs 114.27 ± 0.29 mm Hg, P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons tests), LB (88.6 ± 0.51 mm Hg vs 114.16 ± 0.34 mm Hg, P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons tests), and NF (92.5 ± 0.66 mm Hg vs 114.99 ± 0.29 mm Hg, P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons test) cohorts were successfully decreased diastolic blood pressure as compared to their BL condition. At EL diastolic blood pressure of women of the LB, cohort was decreased than those of women of the MS ( P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons test) and the NF ( P < .001, Kruskal–Wallis’ test/Dunn multiple comparisons test) cohorts. At EL diastolic blood pressure of women of the MS cohort was not decreased than those of women of the NF cohort ( P = .1883, Mann–Whitney U -test). The details of the diastolic blood pressure of women of different cohorts at BL and EL are presented in Figure 3 . Diastolic blood pressure before therapy and after maximum dosage of therapy of women of different cohorts. * Fewer than that of before therapy. MS cohort: Women received 4 g intravenously over 15 min magnesium sulfate in 100 mL normal saline then the maintenance dose of 1 g/h intravenous magnesium sulfate in 500 mL normal saline was maintained for 24 hours (even for 1 day after delivery if required), LB cohort: Women received 20 mg intravenously over 2 minutes initially, then 40–80 mg intravenous after 10 min intervals labetalol; the total dose of labetalol did not exceed 200 mg/day, NF cohort: Women received 20 mg extended-release nifedipine 3 times a day for a maximum of 7 days. Therapy was successful in 89 (86 %), 107 (93 %), and 112 (82 %) women of the MS, the LB, and the NF cohorts, respectively. Therapy was more successful in women of the LB cohort than those of the NF cohort ( P = .0132, 95% Cl: 1.156 to 1.861 [using the approximation of Katz.], Fisher exact test). Therapy was more successful in women of the LB cohort than those of women of the MS cohort but was statistically not significant ( P = .0809, 95% Cl: 1.027 to 2.009 [using the approximation of Katz.], Fisher exact test). Therapy was also statistically the same among women with successful therapies ( P = .5972, 95% Cl: 0.5671 to 1.330 [using the approximation of Katz.], Fisher exact test) between women of the MS and the NF cohorts. A total of 35 (34 %), 75 (65 %), and 21 (15 %) women of the MS, the LB, and the NF cohorts, respectively reduced blood pressure (desired systolic blood pressure: 140 mm Hg and diastolic blood pressure: 90 mm Hg) after 1 day of therapy. More numbers of women were reduced blood pressure (desired systolic blood pressure: 140 mm Hg and diastolic blood pressure: 90 mm Hg) after 1 day of therapy from the LB cohort than those of the NF ( P < .0001, 95% Cl: 2.272 to 4.035 [using the approximation of Katz.], Fisher exact test) and MS ( P < .0001, 1.541 to 2.716 [using the approximation of Katz.], Fisher exact test) cohorts. A total of 79 (76 %), 81 (70 %), and 102 (75 %) women of the MS, the LB, and the NF cohorts, respectively delivered children through vaginal delivery ( P = .5986, chi-square test). All women who received therapies faced adverse effects of headache, nausea, vomiting, and dizziness. Labetalol-induced flushing, tachycardia (>100 beats/min), bradycardia (<60 beats/min), intracranial hemorrhage, abruptio placentae, lethargy, shortness of breath, and peripheral edema. Magnesium sulfate-induced toxicity with reduced tendon reflexes, wound hematoma, and urinary tract and/ or chest infection(s). Nifedipine-induced urinary tract and/or chest infection(s) and gastroenteritis. A total of 77, 120, and 114 total therapy-related adverse outcomes were reported in women of the MS, the LB, and the NF cohorts, respectively. Therapy-related adverse outcomes in women within therapy before delivery and after delivery are reported in Table 2 . Therapy-related adverse outcomes in women within therapy, before delivery, and after delivery. Women had 1 or more adverse effects. variables presented as frequencies (percentages). χ 2 -test was used for statistical analysis. A P -value <.05 is considered significant. Magnesium sulfate-emergent adverse effects. #Labetalol-emergent adverse effects. $Nifedipine-emergent adverse effects. Three neonatal deaths occurred in the LB cohort. Labetalol-induced respiratory distress syndrome, need for additional respiratory support, necrotizing enterocolitis, and hypoglycemia in neonates. Nifedipine-induced respiratory distress syndrome, need for additional respiratory support, necrotizing enterocolitis, hypoglycemia, sepsis, and congenital anomalies in neonates. Magnesium sulfate-induced ventilation in neonates. A total of 20, 61, and 124 therapy-related adverse outcomes were reported in neonates of women of the MS, the LB, and the NF cohorts, respectively. Therapy-related adverse outcomes in neonates after delivery are presented in Table 3 . Therapy-related adverse outcomes in neonates after delivery. Neonates had 1 or more adverse effects. Variables presented as frequencies (percentages). χ 2 -test was used for statistical analysis. A P -value <.05 is considered significant. Magnesium sulfate-emergent adverse effects. #Labetalol-emergent adverse effects. $Nifedipine-emergent adverse effects.

Blood pressure higher than 140/90 mm Hg (systolic/diastolic blood pressure) in the 2nd half of pregnancy is considered preeclampsia. [ 1 ] However, the “second half of pregnancy” typically refers to the period from 20 weeks of gestation until birth, and the diagnosis of preeclampsia is not limited to this period. This is often associated with proteinuria. [ 2 ] Eclampsia, hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome), hemorrhagic stroke, renal failure, and pulmonary edema are associated with preeclampsia. [ 1 ] Severe hypertension is necessary to prevent in pregnancy to overcome fetal–maternal morbidity and mortality. [ 3 ] The current clinical management of preeclampsia is preferring labetalol (combined α -blocker and β -blocker) and magnesium sulfate. Magnesium sulfate slows the progression of preeclampsia, prevents maternal seizures, and prolongs pregnancy. [ 1 ] Magnesium sulfate is the preferred anticonvulsant agent for pregnant women with preeclampsia than diazepam, phenytoin, and lytic cocktails. [ 4 ] Understanding of the association between magnesium status in organisms and women’s reproductive and mental health, such as the link between magnesium, anxiety, and endometriosis has been previously established. [ 5 ] Furthermore, symptoms of distress (anxiety, depression, physical and mental health, and worry) present in everyday life are preeclampsia risk factors for those women who will achieve pregnancy. [ 6 ] Besides these, magnesium supplementation reduces subjective anxiety and stress. [ 7 ] As per the American College of Obstetricians and Gynecologists in 2013, magnesium sulfate is the gold standard for the management of preeclampsia [ 8 ] but it has a short action time that does not provide stable maintenance of blood pressure. [ 9 ] Labetalol is currently recommended as first-line treatment by the national UK guidance. [ 10 ] However, the treatment of preeclampsia is effective when it would be tailor-made according to race, obesity, ethnicity, age, and hemodynamic profiles. [ 11 ] Han Chinese women may react differently from other ethnic groups because of hereditary variability. [ 12 ] In addition, there is a causal association between labetalol and nipple pain in pregnant women. [ 13 ] The management of preeclampsia is a balance between risk and associated therapy-related toxic effects in cardiovascular diseases. [ 12 ] Oral nifedipine is generally used by obstetricians in pregnant women for the management of hypertension in preeclampsia but it has slower management of hypertension and the effects are not last long. [ 14 ] Therefore, this study included 355 pregnant Han Chinese women with preeclampsia and aimed to compare the effectiveness of different drug treatments in Han Chinese women with preeclampsia, including aspects like blood pressure control and prevention of complications following intravenous magnesium compared with intravenous labetalol and oral nifedipine.

Conceptualization: Zhouli Peng. Data curation: Zhouli Peng. Formal analysis: Zhouli Peng. Investigation: Zhouli Peng. Methodology: Zhouli Peng, Jidong Zhang, Yuhui Xiao, Weiyan Dong. Project administration: Zhouli Peng. Resources: Zhouli Peng. Software: Zhouli Peng, Jidong Zhang, Yuhui Xiao, Weiyan Dong. Supervision: Jidong Zhang, Yuhui Xiao, Weiyan Dong. Writing – original draft: Zhouli Peng. Writing—review & editing: Zhouli Peng.

The designed protocol of the study (Approval number: BSH14eg dated April 5,2021) was approved by the Beijing Shunyi Hospital review board and the Obstetrics Society of China. The study follows the law of China and the v2008 Declarations of Helsinki. Being a retrospective study registration in the Chinese clinical trial registry and consent to participate were waived by the Beijing Shunyi Hospital review board and the Obstetrics Society of China. Pregnant Han Chinese women (age > 18 years) with preeclampsia diagnosed as per the American College of Obstetrics and Gynecology guidelines [ 15 ] (systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg with proteinuria [>300 mg/d protein in urine] after 20 weeks gestation) were included in the analysis. Han Chinese women with heart failure, proteinuria before pregnancies, elevated blood pressure before pregnancies, and women who were on aspirin prophylaxis (in the last 20 weeks gestation) were excluded from the study. Han Chinese women with serious basic diseases (e.g., heart valve diseases, kidney diseases) and drug allergies were excluded from the study. The study assumed that intervention(s) would decrease blood pressure by at least 20 mm Hg after the maximum dosage of therapy (EL) was reached compared to before therapy condition (BL). Based on this assumption, α = 0.05, and β = 0.1, and 90 % of power calculation, the sample size (minimum pregnant women required in each cohort) was found to be 100. [ 16 ] A total of 104 women received 4 g intravenously over 15 min magnesium sulfate in 100 mL normal saline then 1 g/h intravenous magnesium sulfate in 500 mL normal saline (the maintenance dose) was maintained for 24 hours (even for 1 day after delivery if required [ 12 , 17 ] ; magnesium sulfate [MS] cohort). If the urinary output of magnesium sulfate was <120 mL in 4 h then 10 % calcium gluconate was administered or 1 g/h magnesium sulfate infusion was discontinued. [ 17 ] A total of 115 women received 20 mg intravenously over 2 minutes initially, then 40–80 mg intravenous after 10 min intervals labetalol; the total dose of labetalol did not exceed 200 mg/day (labetalol [LB] cohort). [ 12 ] A total of 136 women received 20 mg extended-release nifedipine 3 times a day for a maximum of 7 days (nifedipine [NF] cohort). [ 8 ] The choice of intravenous magnesium sulfate, intravenous labetalol, or oral extended-release nifedipine therapy was at the discretion of the attending obstetrician(s) but therapy follows institutional protocol (not published yet) for the management of preeclampsia in the pregnant women. Pregnant women received other normal treatment(s) as prescribed by the attending obstetrician(s) (vitamins, proteins supplements, etc) during the treatment for preeclampsia. Women with reduced blood pressure (desired systolic blood pressure: 140 mm Hg and desired diastolic blood pressure: 90 mm Hg) after 1 day of therapy. In addition, the number of women who did successfully control systolic blood pressure (~140 mm Hg) and diastolic blood pressure (~90 mm Hg) after therapy. A Mercury sphygmomanometer was used for the evaluation of systolic blood pressure and diastolic blood pressure. Treatment failure (therapy failure) was defined as persistent systolic blood pressure ≥ 160 or diastolic blood pressure ≥ 110 mm Hg at EL or women switched to second-line medication according to the institutional protocol (not published yet) because of undesired effects during therapy by attending obstetricians. [ 12 ] Therapy-related adverse outcomes within therapy, those of before delivery and after delivery. Instat 3.01 GraphPad Software, San Diego, CA was used for statistical analysis purposes. Categorial variables are depicted as frequencies (percentages) and continuous variables are depicted as mean ± standard error of the mean. The chi-square test of independence or Fisher exact test was used as statistical analysis for categorical variables. The Kolmogorov–Smirnov test was used to check the linearity of continuous variables. A one-way analysis of variance or unpaired t -test was performed for statistical analysis of the normal continuous variables. Kruskal–Wallis’ test or Mann–Whitney U -test was performed for statistical analysis for the non-normal continuous variable. The distribution of standard deviation values between/among continuous variables was checked whether distributed equally or not using the Bartlett test. If standard deviation values were not distributed equally between the columns, then an unpaired t -test with Welch correction was performed for statistical analysis. The Tukey–Kramer or Dunn multiple comparisons test was used for post hoc analysis. All results were considered significant at a 95% confidence interval of the difference (Cl).

From January 15, 2019 to March 14, 2021, a total of 402 pregnant women (age > 18 years) were diagnosed with preeclampsia as per the American College of Obstetricians and Gynecologists guidelines (systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg with proteinuria [>300 mg/ day protein in urine] after 20 weeks gestation age) at the department of Obstetrics, Beijing Shunyi Hospital, Beijing, China, and the referring hospitals. Among them 1 woman with heart failure, 3 women had proteinuria before pregnancy, 7 women had elevated blood pressure before pregnancy (because of the other reason(s)), and 36 women who were on aspirin prophylaxis in the past 20 weeks of gestation age by attending obstetricians. Therefore, these women (47 women) were excluded from the study. Therapy success, therapy failure, and therapy-related adverse outcomes of a total of 355 women were included in the analysis. The summary chart of the study is presented in Figure 1 . The summary chart of the study. Women with preeclampsia available at the hospital had 19 to 37 years of age and 29 to 37 weeks gestational age. Age, gestational age, body mass index, education level, residence, blood pressure, and symptoms of pregnant women at BL were comparable among cohorts ( P > .05 for all, Table 1 ). Demographic and clinical parameters of women before therapy. Continuous linear variables are presented as mean ± standard deviation (SD). Continuous not linear variables are presented as interquartile (range). Constant variables are presented as frequencies (percentages). N/A: not applicable, df: degree of freedom. Test value (χ 2 -value for χ 2 -test; F -value for one-way ANOVA; Kruskal–Wallis’ statistics for Kruskal–Wallis’ test). A P -value <.05 is considered significant.

Results of the current study suggested that intravenous labetalol is more effective than intravenous magnesium sulfate or oral nifedipine for acute therapy of severe hypertension in pregnant Han Chinese women. The reduction of blood pressure due to intravenous labetalol in the current study is consistent with those of the retrospective study of Thai women, [ 12 ] the phase IV trial on English women, [ 10 ] and a trial on Egyptian women. [ 18 ] Intravenous labetalol provides proper reduction of blood pressure in Han Chinese women with preeclampsia. Intravenous magnesium sulfate had fewer effects on the reduction of blood pressure than intravenous labetalol. In addition, intravenous magnesium sulfate decreased systolic blood pressure but did not decrease diastolic blood pressure as compared to those of women who received oral nifedipine. The primitive reduction in blood pressure in the MS cohort suggests that magnesium sulfate is not the primary hypertensive agent and antihypertensive effect is due to a reduction in the action of circulating calcium-dependent vasoconstrictors. [ 12 ] The results of primitive reduction in blood pressure due to intravenous magnesium sulfate in the current study are consistent with those of the retrospective study of Thai women [ 12 ] and an observational study [ 19 ] but are not consistent with those of the prospective descriptive study. [ 17 ] Genetic polymorphisms are responsible for the different responses of individuals to antihypertensive drugs. Labetalol and magnesium sulfate both had high plasma protein binding (~50%). The drugs that have high first-pass metabolism and high plasma protein binding exhibit racially diverse responses. [ 20 ] Intravenous magnesium sulfate provides a primary reduction of blood pressure in Han Chinese women with preeclampsia. Intravenous labetalol had high maternal and neonatal therapy-emergent adverse effects than those of intravenous magnesium sulfate and oral nifedipine. Fewer adverse effects of intravenous magnesium sulfate in the current study are consistent with those of the prospective descriptive study. [ 17 ] The Royal College of Obstetricians and Gynecologists’ evidence-based guidelines for the management of eclampsia [ 21 ] were used for the administration of intravenous magnesium sulfate. Loading followed by the maintenance dose decreases maternal and neonatal therapy-emergent adverse effects of intravenous magnesium sulfate. [ 17 ] Intravenous magnesium sulfate is a safer approach for the management of preeclampsia in Han Chinese women than intravenous labetalol and oral nifedipine. Therapy was less failure in women of the LB cohort than those of the NF and the MS cohorts. The short action time of magnesium sulfate [ 9 ] and nifedipine [ 22 ] do not provide stable maintenance of blood pressure. Intravenous labetalol is successful therapy than intravenous magnesium sulfate and oral nifedipine for the management of preeclampsia in Han Chinese women. Therapy was more successful in women of the LB cohort than those of women of the MS cohort but was statistically not significant. Magnesium sulfate and labetalol both are successful in reduction of blood pressure systolic blood pressure ~140 mm Hg and diastolic blood pressure ~90 mm Hg from initial values. Therefore, the LB and MS cohorts have statistically same women with therapy success. The study has a significant sample size, covering 355 Han Chinese pregnant women, which is an important strength. However, there are some limitations of the study, for example, retrospective analysis and lack of randomized trial. Individual risk factors for preeclampsia and adverse effects were not evaluated. Therefore, it is suggested to consider these potential confounding factors in future research and conduct a more systematic exploration and analysis. In the LB cohort, women reported labetalol-induced intracranial hemorrhage, but labetalol has not caused intracranial hemorrhage clinically. Women with respiratory distress syndrome at BL have some complications of pregnancy-induced hypertension. However, the current study has not evaluated the independent parameter of women for preeclampsia.

Intravenous labetalol provides a proper and reduction of blood pressure in Han Chinese women with preeclampsia but has the risk of therapy-related maternal and neonatal adverse effects. Intravenous magnesium sulfate is a safer approach but provides a primary reduction of blood pressure for the management of preeclampsia in Han Chinese women than intravenous labetalol and oral nifedipine. Intravenous labetalol is successful therapy than intravenous magnesium sulfate and oral nifedipine for the management of preeclampsia in Han Chinese women. This study has clinical significance in comparing treatment options for preeclampsia.

The authors are thankful for the medical and nonmedical staff of the Beijing Shunyi Hospital, Beijing, China.