Oral nifedipine versus intravenous labetalol for hypertensive emergencies during pregnancy: a systematic review and meta-analysis

Abstract Aim: The optimal drug management strategy for severe hypertension during pregnancy remains inconclusive. Some randomized controlled trials found that oral nifedipine was more effective than intravenous labetalol in hypertensive emergencies during pregnancy, while others found otherwise. As a result, we conducted a meta-analysis to assess the effectiveness of oral nifedipine versus intravenous labetalol for hypertensive emergencies during pregnancy. Methods: We searched PubMed, Embase, and the Cochrane Library for randomized controlled trials that compared oral nifedipine versus IV labetalol in hypertensive emergencies during pregnancy. Results: 12 RCTs enrolling 1151 participants (573 in the labetalol group and 578 in the nifedipine group) were included in the meta-analysis. Patients who received oral nifedipine reached their target blood pressure more rapidly than those who received intravenous labetalol (MD 7.64, 95%CI 4.08–11.20, p < .0001). The nifedipine group required fewer doses to achieve the target blood pressure (MD 0.62, 95%CI 0.36 to 0.88, p < .00001). There were no meaningful differences on the maternal complications between the two groups, mainly including eclampsia (OR 1.51; 95% CI, 0.75–3.05; p = .25), headache (OR 0.86; 95% CI, 0.52–1.44; p = .57), nausea/vomiting (OR 1.50; 95% CI, 0.76–2.93; p = .24), hypotension (OR 0.49; 95% CI, 0.12–1.99; p = .32), dizziness (OR 2.01; 95% CI, 0.77–5.25; p = .16), HELLP (OR 0.27; 95% CI, 0.05–1.64; p = .16), palpitations (OR 0.63; 95% CI, 0.32–1.27; p = .20), flushing (OR 0.77; 95%CI, 0.18–3.22; p = .72). There were no significant difference in the neonatal complications, including NICU admission (OR 1.24; 95% CI, 0.87–1.77; p = .23), 5 min Apgar score < 7 (OR 1.07; 95% CI, 0.82–1.39; p = .63), neonatal deaths (OR 1.08; 95%CI, 0.66–1.76; p = .77), FHR abnormality (OR 0.94; 95%CI, 0.47–1.88; p = .86). Conclusion: In conclusion, oral nifedipine could achieve target blood pressure more rapidly and required fewer doses than intravenous labetalol in the management of hypertensive emergencies during pregnancy.


Introduction
Hypertensive disorders of pregnancy (HDP) are prevalent in the field of obstetrics and have a profound impact on the health of both mothers and infants.HDP remains one of the leading causes of maternal and perinatal death worldwide.Increased adverse perinatal outcomes have been reported to be related to severe hypertension rather than proteinuria [1] .Severe pregnancy hypertension is defined as systolic blood pressure (SBP) !160 mmHg and/or diastolic blood pressure (DBP) !110 mmHg.The American College of Obstetricians and Gynecologists (ACOG) recommends initiating antihypertensive treatment promptly for persistent and severe HDP with clinical management guidelines recommending intravenous hydralazine/labetalol or oral nifedipine for urgent blood pressure control for pregnant patients [2].However, due to manufacturing shortages, hydralazine is unavailable in many countries.Moreover, in the past decade, there have been frequent reports of maternal and fetal adverse effects associated with hydralazine [3].In recent years, labetalol and nifedipine have emerged as commonly used medications in clinical practice for controlling severe HDP.
Various professional associations recommend labetalol, an adrenaline receptor blocker with combined aand bblocking activity, as first-line treatment for severe hypertension during pregnancy [4,5].Multiple studies have demonstrated the efficacy and rapid response of repeated intravenous injections of labetalol in managing hypertensive emergencies during pregnancy.One advantage of labetalol is its ability to be administered intravenously, making it suitable for use even in cases where the patient is unconscious.Nifedipine, a dihydropyridine calcium antagonist, is also effective in treating severe hypertension.It exhibits an oral bioavailability ranging from 45% to 70% and has a half-life of approximately 4 h [6] .Nifedipine exerts its antihypertensive effects by inhibiting calcium influx into arterial smooth muscle cells, thereby reducing peripheral vascular resistance and blood pressure.Previous studies have shown that nifedipine can control severe hypertension in pregnant women without reducing uteroplacental blood flow, and no significant maternal or fetal adverse effects have been reported to date [7][8][9] .Additionally, the ease of administration and storage make oral nifedipine a frequently used option in managing hypertensive emergencies during pregnancy.
Numerous randomized controlled trials (RCTs) have compared the efficacy and safety of oral nifedipine and intravenous labetalol in hypertensive emergencies during pregnancy.Nonetheless, the findings from these studies have yielded controversial conclusions and the optimal drug management strategy for severe hypertension during pregnancy remains inconclusive.To that end, we conducted a meta-analysis to assess the effectiveness of oral nifedipine versus intravenous labetalol in terms of the time required to achieve blood pressure control, the number of doses needed, and the occurrence of adverse outcomes in hypertensive emergencies during pregnancy.

Search strategy and criteria
A systematic search was conducted using PubMed, Embase, and the Cochrane Library to identify all relevant studies published up to December 2021.The following terms were combined for the search: nifedipine, labetalol, pregnancy, and randomized controlled trial.
The inclusion criteria were: a. Randomized controlled trials; b.Studies where pregnant women with severe hypertension (systolic BP !160mmHg or diastolic BP !105mmHg) were the study subjects;    Three authors independently screened and read all searched articles, and the final list of included articles was decided through a consensus discussion.

Data extraction
Data information was performed independently by three authors.In cases where the original articles did not provide means and standard deviations (SDs), we estimated these values using the median, range (smallest value, largest value), and sample size [10].Any disagreements were resolved through consensus among all authors.The final results achieved unanimous agreement among the authors.The basic characteristics of the included studies are shown in Table 1.Table 2 lists the raw data of the included RCTs.

Statistical analysis
RevMan 5.3 (Cochrane Collaboration) was used for data analysis.Variables were pooled when more than three studies were evaluated.Continuous data were analyzed using the mean difference (MD) with 95% confidence intervals (CIs), while dichotomous data were analyzed using the odds ratio (OR) with 95% CIs to compare the different groups.We considered there were statistically significant differences in the results between the two groups if p < .05. High heterogeneity among the enrolled studies was defined as I 2 > 50%.The randomeffects model was utilized when I 2 > 50%.Publication bias was evaluated using a funnel plot and Egger's test, performed using Stata 17 software.

Quality assessment
We employed the Cochrane risk of bias assessment tool to evaluate the risk of bias in the included studies [23].Each study was assessed for low, high, or unclear risk of bias. Figure 1 and Figure 2 demonstrate an overview of the risk of bias.All authors were involved in the quality assessment of included articles, and a consensus was reached regarding the outcomes.

Results
After a thorough review of the full texts, we finally identified a total of 12 relevant RCTs [11][12][13][14][15][16][17][18][19][20][21][22] in this meta-analysis.Figure 3 summarizes the total flowchart.A total of 1151 pregnant women were involved in the meta-analysis (573 in the labetalol group and 578 in the nifedipine group).Among the twelve included studies, nine were conducted in India, one in China, one in the USA, and one in Malaysia.The classification of HDPs was as follows: five studies investigated severe preeclampsia (PE), five studies focused on severe gestational hypertension, and two were on severe hypertension during pregnancy.Five articles [11,14,15,17,20] investigated short-acting nifedipine, while the other seven articles did not specify which type of nifedipine was used.In all studies, nifedipine was given orally and never sublingually.

Characteristics of patients
The baseline characteristics of patients in the two groups were comparable in terms of maternal age

Time taken to control BP
A total of 12 studies involving 1151 participants (573 in the labetalol group and 578 in the nifedipine group) were pooled to compare the time taken to achieve the target blood pressure.High heterogeneity was observed among the studies (I 2 ¼ 82%).Patients who received oral nifedipine reached their target blood pressure more rapidly than those who received intravenous labetalol (MD 7.64, 95%CI 4.08-11.20,p < .0001)(Figure 4).

Number of doses required
Ten studies involving 951 participants (473 in the labetalol group and 478 in the nifedipine group) were pooled to compare the doses required to achieve the target BP.Our analysis revealed that significantly fewer doses of nifedipine were required to achieve the target blood pressure (MD 0.62, 95%CI 0.36-0.88,p < .00001)(Figure 5).

Sensitivity analysis, publication bias and meta-regression analysis
A sensitivity analysis was conducted by removing each article individually, and it was found that the heterogeneity did not significantly change, indicating that the results were relatively stable.Given the high heterogeneity, we used a random effect model for our meta-analysis.To assess the risk of publication bias, we included a funnel plot (supplement 1) and performed Egger's test.The results of Egger's test for the time taken to control BP did not find evidence of publication bias (supplement 2).However, Egger's test for the number of doses required suggested possible publication bias (p ¼ .02).Meta-regression analysis was conducted to identify potential factors contributing to high heterogeneity.Univariate and multivariate metaregression models were used to assess the impact of confounding factors, including gestational age, country, preeclampsia vs high BP, maternal age, use of magnesium sulfate, which may potentiate the effect of nifedipine, patient being on other concomitant antihypertensives at time of using nifedipine or labetalol for a hypertensive crisis.However, all of these confounders were not identified as potential sources of heterogeneity.

Safety
Reported maternal and neonatal side effects are shown in Figure 6.There was no obvious heterogeneity among studies (I 2 ¼ 0$38%).A summary of maternal and neonatal outcomes is detailed in Table 3.

Discussion
HDP affects about 10% of pregnant women [24].A severe increase in blood pressure can lead to preeclampsia, eclampsia, cerebrovascular hemorrhage, and  hypertensive encephalopathy, all of which are common causes of maternal death.Both oral nifedipine and intravenous labetalol are recommended in the clinical management guidelines for obstetricians and gynecologists.However, the guidelines did not provide sufficient evidence to support the prioritization of either drug.
Previously, several meta-analyses have been conducted to evaluate the effectiveness of antihypertensive drugs for the management of severe hypertension during pregnancy.Duley et al. [5] reviewed 35 RCTs with 15 drug comparisons.While their main findings indicated that hydralazine, labetalol, and nifedipine are commonly recommended for women with severe hypertension during pregnancy, there was insufficient evidence to determine which antihypertensive drug is the most effective.Moreover, an alternative analysis of this topic showed that the data do not support hydralazine as a first-line treatment for severe hypertension during pregnancy [25] and recommended further research to compare the effectiveness of labetalol and nifedipine.
In a systematic review conducted by Firoz et al. [26], oral antihypertensive agents for the treatment of severe hypertension during pregnancy and postpartum was investigated.The review identified 15 RCTs involving 915 women during pregnancy, as well as one trial conducted postpartum.The results indicated that a single oral agent could adequately lower BP when compared with parenteral hydralazine or labetalol.Among the oral antihypertensive agents, nifedipine was the most effective for managing severe hypertension during pregnancy and the postpartum stage.However, this review had a limited number of included literature.Less than three included studies compared oral nifedipine to intravenous labetalol, and a meta-analysis was thus not conducted.
Our meta-analysis revealed that oral nifedipine could achieve target blood pressure more rapidly and significantly fewer doses are required compared to intravenous labetalol in hypertensive emergencies during pregnancy.In terms of safety, the nifedipine group had a tendency to higher rates of hypotension, headache, flushing, HELLP, and palpitations, while the labetalol group had a tendency to higher rates of nausea/vomiting, dizziness, and eclampsia.But these rate differences did not reach significant statistical differences.In addition, although not statistically significant, the meta-analysis of neonatal outcomes showed a favorable trend toward nifedipine.
A meta-analysis by Shekhar et al. [27] also compared oral nifedipine and intravenous labetalol for severe hypertension during pregnancy.Only seven studies, including 363 pregnant women, were included in the meta-analysis.Their primary outcome was persistent hypertension and demonstrated that oral nifedipine reduced the risk of persistent hypertension significantly.Although the heterogeneity was significantly reduced when participants were categorized according to the dosage, only one or two studies were included in the subgroup analysis.We believe that the quality of evidence is low.Moreover, they did not report publication bias because the included studies were less than ten.
The strength of our meta-analysis lies in the inclusion of a large sample size, comprising 1151 pregnant women from 12 high-quality RCTs, which enhances the robustness of our findings.Moreover, we conducted sensitivity analysis and publication bias and found no evidence of publication bias in terms of the time taken to control BP.In addition, we had another interesting finding.Three studies included in our analysis (Vermillion [11], Dhali [15] , and Zulfeen [20]) demonstrated that the nifedipine group had significantly higher mean urine output, which may provide additional support for its use for severe hypertension in pregnancy.Because preeclampsia is associated with   intravascular volume depletion and decreased renal perfusion, the ability of nifedipine to preserve urinary output and renal perfusion via selective renal artery vasodilation could be beneficial for preeclampsia [28].
Preeclampsia is a multiorgan disease with a common pathology denominator being a microangiopathy in the mother and placenta.Notably, the existing literature does not address whether nifedipine or labetalol actually modify the above noted microangiopathy.However, guidelines emphasize that severe hypertension during pregnancy (SBP !160mmHg or DBP !110mmHg) requires urgent antihypertensive therapy in a monitored setting(strong).Consensus has been reached among guidelines that when blood pressure is severely elevated, lowering blood pressure to the target value within 60 min may reduce the risk of severe maternal morbidity.Although it does not mean that lowering the BP faster is better, the ability to achieve lower blood pressure in shorter time does establish the efficacy of nifedipine as an antihypertensive drug in the management of severe hypertension during pregnancy.
Nevertheless, there were several limitations to this study.Firstly, the study heterogeneity was very high.Unfortunately, we could not find the source of heterogeneity because of insufficient data.Secondly, the enrolled studies did not include a wide ethnic group.In our opinion, the limited number of clinical trials conducted in developed countries may be attributed to various factors, including advanced maternal care practices, as well as ethical, legal, and practical considerations that often hinder the inclusion of pregnant women in clinical trials.Despite these limitations, we believe that our meta-analysis is still meaningful and can provide valuable insights and reference for clinicians, while also highlighting the need for higher-quality RCTs.
In all enrolled studies of this article, the side effects were transient and mild.No serious adverse reactions with nifedipine were reported.Our article demonstrated that nifedipine was as safe as labetalol.However, the evaluation of the rare outcomes in drug safety should be viewed with caution.Because some rare outcomes such as seizures, HELLP, neonatal deaths, are affected by many factors, they may not necessarily reflect comparative efficacy of the drug when used as an acute intervention.Additionally, oral nifedipine isconvenient to use and is inexpensive.Considering these factors, oral nifedipine may present additionaladvantages in regions with limited medical resources due to its convenience of administration and cost-effectiveness.
At present, many international clinical guidelines recommend oral nifedipine as one of the first-line agents for the treatment of severe hypertension [29,30].According to the Society of Obstetrician and Gynecologists of Canada (SOGC) guidelines [30], oral nifedipine at a reasonable treatment interval is unlikely to cause maternal hypotension.It is important to note that the recommended administration of nifedipine is through swallowing the tablet whole, without biting or puncturing it.However, it is worth mentioning that the use of short-acting nifedipine has raised concerns in some countries due to reports of myocardial infarctions and rare instances of severe hypotension in the non-pregnant population.Consequently, its use in obstetrics may be restricted or even discontinued in certain regions.Similarly, the availability of intravenous labetalol may be limited in some settings.In summary, we also have to say that the choice of antihypertensive agent for managing severe hypertension during pregnancy is influenced by various factors, including the clinical situation, local availability of medications, and clinician's experience and expertise [31].In cases of severe hypertension crises, the healthcare workers can use any antihypertensive available to them including nifedipine oral in any of its formats, labetalol IV or oral, methyldopa oral, and others.The bottom line is to effectively lower blood pressure using the available options.

Conclusion
Our meta-analysis revealed that oral nifedipine could achieve target blood pressure more rapidly and required fewer doses than intravenous labetalol in the management of hypertensive emergencies during pregnancy.
110 150/100 168.13 ± 10.01 166.2 ± 11.85 115.4 ± 3.53 112.07 ± 6 ± 13.5 22.09 ± 11.7 2.36 ± 1.5 2.28 ± 1.58 L: labetalol; N: nifedipine; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure.THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE c.Studies comparing oral nifedipine and intravenous labetalol for hypertensive emergency during pregnancy; d.The primary study outcome is the time taken to achieve a target BP, and secondary outcomes included the number of doses required and adverse maternal and neonatal effects; e. Full text and related data can be available;

Figure 4 .
Figure 4. Time taken to control BP.

Figure 5 .
Figure 5. Number of doses required.

Figure 6 .
Figure 6.Forest plot of adverse events.

Table 1 .
The characteristics of included studies.
--Inclusion criteria: All antenatal women of gestational age >28weeks with severe hypertension with systolic BP of 160mmHg or higher and/or diastolic BP of 110 mmHg or higher on two separate occasions, 30min apart in lateral recumbent position with maternal heart rate between 60 and 120 beats per minute and re-assuring fetal heart rate.Excluding criteria: Patients with history of cardiac disease, bronchial asthma, hematological disorder, allergy to either drug, liver disorders, exposure to any antihypertensive medications in the past 24 h, Inclusion criteria: Pregnant women aged 18 years to 40 years at a gestation of 28 weeks or higher with severe hypertension as defined by systolic blood pressure (SBP) of 160 mm of mercury or higher and or diastolic blood pressure (DBP) of 110 or higher (measured on two occasions 15 minutes apart with women in a sitting position and arm cuff at the level of heart and disappearance of Korotkoff's sound as indicative of diastolic blood pressure) were approached for inclusion into the trial.Excluding criteria: Women who had taken anti hypertensive drug in preceding 24 hours, who had structural or rhythm disorders of heart, heart failure, asthma or those not in a position to swallow tablets L: labetalol; N: nifedipine; PIH: pregnancy induced hypertension; HDP: Hypertensive disorders during pregnancy; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure.

Table 2 .
Outcomes of randomized controlled trials.

Table 3 .
Summary of side effects.
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