https://doi.org/10.1007/s00404-022-06504-5 REVIEW
Nifedipine or amlodipine? The choice for hypertension during pregnancy: a systematic review and meta‑analysis
Jinjin Yin1 · Zhengrong Mei1 · Shengying Shi1 · Peili Du2 · Shumin Qin3
Received: 14 September 2021 / Accepted: 1 March 2022 / Published online: 19 March 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022
Abstract
Background There is a lack of sufficient evidence regarding efficacy and safety of amlodipine on treating hypertension during pregnancy.
Objective To compare antihypertensive efficacy, pregnancy outcome and safety of amlodipine with nifedipine on hyperten- sion during pregnancy.
Methods A systematic search of PubMed, Embase, Cochrane Library, clinicaltrials.gov, Chinese National Knowledge Infra- structure, Wanfang Database and China Biology Medicine disc of randomized controlled trials (RCTs) up to April l5, 2021 was conducted on RCTs comparing amlodipine to nifedipine for the treatment of hypertension during pregnancy. Screening, data extraction, and quality assessment were done by two independent reviewers. To estimate relative effects from all avail- able evidence, a meta-analysis was conducted.
Results Seventeen RCTs were included. Amlodipine was found the efficacy is slightly superior to nifedipine on treating hypertension during pregnancy (RR 1.06, 95% CI 1.01 to 1.10) with a decreased risk for maternal side effects (RR 0.42, 95% CI 0.29 to 0.61). Subgroup analysis found amlodipine can get a better control on SBP (RR − 11.68, 95% CI − 17.98 to
− 5.37) and DBP (RR − 7.44, 95% CI − 13.81 to − 1.06) compared with intermediate-/long-acting nifedipine. In addition, there was no difference between amlodipine and nifedipine on pregnancy outcomes including caesarean section, premature labour, placental abruption, FGR, fetal distress, neonatal asphyxia.
Conclusions Given the results of this systematic review and meta-analysis, amlodipine can be effectively and safely used for hypertension during pregnancy.
Keywords Amlodipine · Nifedipine · Hypertension during pregnancy · Meta-analysis
Introduction
Hypertension is one of the most common maternal prob- lems in pregnancy and is the second leading direct cause of global maternal mortality behind maternal hemorrhage [1].
Antihypertensive drug therapy for elevated blood pressure in pregnancy reduces the risk of the development of severe hypertension which is considered to be a risk factor for maternal end-organ complications (such as stroke), although it does not prevent the development of preeclampsia [2, 3].
Nifedipine is the first generation calcium antagonist which is recommended as a first-line antihypertensive drug for pregnant women by most of the authorities [4, 5]. There are three formulations of this drug based on their delivery system [6]: (1) immediate-release nifedipine (nifedipine IR, short-acting) with peak effect in 30 min; (2) intermediate- acting nifedipine (delayed-release; in some countries, this is known as nifedipine retard) with peak onset within hours;
and (3) long-acting nifedipine (extended-release; this is known as nifedipine XL or CR or ER or GITS) that releases nifedipine over 24 h and is usually given once daily. The immediate-release nifedipine formulations are easy to cause
* Shumin Qin [email protected]
1 Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of China
2 Department of Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of China
3 Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China
rapid vasodilation followed by reflex sympathetic activa- tion, resulting in side effects such as headaches, palpita- tions, and flushing, which is now recommended only for emergency hypertension when IV access is not available [7, 8]. Instructions of intermediate-/long-acting nifedipine formulations from lots of Chinese manufacturer clearly marked that the drug is contraindicated in pregnant women, or contraindicated in pregnant women within 20 gestational weeks. Therefore, in order to avoid off-label use of nifedi- pine, immediate release formulations are commonly used on pregnant women in china. Amlodipine is a long-acting calcium antagonist which is used first line to manage hyper- tension in many settings outside pregnancy [9]. The drug’s long half-life, infrequent dosing, low cost and positive side- effect profile make it an ideal candidate for treatment of hypertension during pregnancy [10]. It is worth mentioning that the instructions for amlodipine have no pregnancy pro- scribing cautionary usage. Patients with chronic hyperten- sion who take amlodipine for better blood pressure control often continue to take amlodipine after pregnancy. There are many comparative randomized controlled trials on the efficacy and safety of amlodipine and nifedipine in reduc- ing hypertension during pregnancy in China [11–15], but the results are not entirely consistent. As a result, we con- ducted a meta-analysis of RCTs to compare antihypertensive efficacy, pregnancy outcome and safety of amlodipine with nifedipine on hypertension during pregnancy.
Methods
The review was registered with the PROSPERO Interna- tional Prospective Register of Systematic Reviews (Reg- istration No: CRD42021250406) following the PRISMA guidelines for protocols.
Systematic search
We searched the electronic databases of PubMed, Embase, Cochrane Library, clinicaltrials.gov databases, Chinese National Knowledge Infrastructure Database, Wanfang Database and China Biology Medicine disc, without date and language limitations (last search was updated April l5, 2021). In addition, we searched reference lists of included studies. We developed a search strategy using the following search terms and their associated medical subject headings to identify all the relevant studies: ‘nifedipine’, ‘amlodi- pine’, ‘hypertension during pregnancy’, ‘hypertension and pregnancy’ and ‘gestational hypertension’. We modified the search strategy in accordance with different electronic databases.
Study selection and data extraction
Studies were included if they met the following crite- ria: (1) participants were patients with hypertension dur- ing pregnancy (defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg), (2) the study design was a RCT, (3) patients were randomized grouped in to amlodipine therapy group (with or without additional medication) and nifedipine therapy group (with or without the same additional medi- cation), (4) at least one outcome of interest (effective rate, post-treatment blood pressure, pregnancy outcome, reported maternal side effects) was reported. Duplicate studies were removed and the papers were excluded if they were patients with hypertension complicated with other organ damage.
And studies with obvious randomization mistakes are also removed.
Two independent investigators (Yin JJ and Qin SM) reviewed study titles and abstracts, and studies that satis- fied the inclusion criteria were retrieved for full-text evalu- ation. Data extraction was carried out by one researcher and checked by another. Any disagreements were resolved through discussion. Primary outcomes for which data was extracted were: antihypertensive efficacy (effective rate, SBP and DBP after treatment). Effective rate was defined as the ratio of the number of pregnant women who achieved effec- tive blood pressure control to the total number of pregnant women in each group (effective blood pressure control refers to SBP less than 140 mmHg and DBP less than 90 mmHg for three consecutive days after antihypertensive therapy).
Secondary outcomes studied were: pregnancy outcome (cae- sarean section, premature labour, placental abruption, fetal growth restriction (FGR), fetal distress, neonatal asphyxia), reported maternal side effects (dizziness, headache, lower limb edema, and flushing).
Study quality assessment
Two authors (Yin JJ and Qin SM) worked independently to search for and assess studies for their methodological quality for inclusion in the review. Studies were assessed with the Cochrane Risk of Bias tool and classified to be low, high or unclear by taking into account the following criteria: ran- dom sequence generation, allocation concealment, blinding, incomplete outcome and selective reporting. We resolved any disagreement by consensus.
Statistical analysis
The meta-analysis was performed on Revman Manager 5.3 software (Copenhagen, Denmark) for statistical calculations.
Weighted mean difference (WMD) was given for blood
pressure outcome variable with 95% confidence interval (CI), while risk ratio (RR) or rate difference (RD) was given for other outcome variable with 95% CI. We tested hetero- geneity using the I2 statistic and the Chi2 statistic. An I2 value > 50% and a p value < 0.10 were considered statistical heterogeneity, prompting a random effect modeling estimate.
Otherwise the fixed-effect model was used. Inverted funnel plot analysis was used to identify publication bias when the included study was ≥ 10. In Addition, in order to eliminate the clinical heterogeneity between studies, We intended to do subgroup analysis of some outcomes which there are het- erogeneity between studies according to nifedipine formula- tion used.
Results
Study selection and characteristics
The outcomes of literature search are described in Fig. 1.
177 studies were identified and 139 of them were screened after removal of duplicates. The majority of them were excluded after reading their title and abstract and thus a total of 28 articles were retrieved as full-texts. 11 articles were
excluded for not meeting the inclusion criteria. As a result, 17 studies [11–27] were included in the present review, comprising a total of 1319 women. The characteristics of included studies are summarized in Table 1. Information regarding the formulation of nifedipine was available for all trials. Twelve trails used immediate release nifedipine tablet while four trials used nifedipine retard and one trial used nifedipine GITS.
Risk of bias in included studies
Most of the included trials were small. Only three studies recruited more than 100 women; Hu [14] which recruited 110 women, Wang [20] 102 women, Xin [23] 114 women.
Summaries of 'Risk of bias' assessments in included trials are shown in Fig. 2. Additionally, the funnel plots of out- comes (post-treatment SBP, DBP and reported maternal side effects) showed asymmetries, indicating there was some publication bias. These funnel plots are shown in Fig. 3.
Antihypertensive efficacy
All included studies analyzed the antihypertensive efficacy of the two drugs. Effective rate was used in nine studies
Fig. 1 Selection of studies for the inclusion in the meta- analysis
[11–14, 17, 18, 21, 23, 24] and post-treatment blood pres- sure [12–27] was used in sixteen studies. The overall analy- sis showed that effective rate of the amlodipine group were significantly higher than the nifedipine group (RR = 1.06, 95% CI 1.01 to 1.10, P = 0.02, Fig. 4a), and there was lit- tle heterogeneity of results among the studies (I2 = 9%;
P = 0.36). Furthermore, amlodipine therapy induced a greater reduction of post-treatment SBP (mean difference
− 3.35, 95% CI − 6.6 to − 0.11, P < 0.00001; Fig. 4b.) than nifedipine therapy, but not post-treatment DBP (mean differ- ence − 2.19, 95% CI − 4.53 to 0.15, P = 0.07; Fig. 4c). How- ever, significant heterogeneity were observed among trials.
So we did a subgroup analysis based on different nifedipine formulations. Subgroup analysis found a significant differ- ence in post-treatment SBP and DBP between amlodipine and nifedipine amongst various formulation groups (Fig. 4b, c). Compared with intermediate-/long-acting nifedipine
but not nifedipine IR, amlodipine therapy can induced a greater reduction post-treatment SBP (mean difference
− 11.68, 95% CI − 17.98 to − 5.37, P = 0.0003; Fig. 4b) and DBP (mean difference − 7.44, 95% CI − 13.81 to − 1.06, P = 0.02, Fig. 4c).
Pregnancy outcome
The results showed that there was no difference between amlodipine and nifedipine on caesarean section (RR 0.96, 95% CI 0.82–1.12), premature labour (RR 0.96, 95%
CI 0.67–1.39), placental abruption (RR 0.96, 95% CI 0.30–1.54), FGR (RR 0.70, 95% CI 0.14–3.51), fetal dis- tress (RR 1.01, 95% CI 0.72–1.43), neonatal asphyxia (RR 1.19, 95% CI 0.64–2.20). These results did not vary across studies (I2 = 0%).The detailed results are shown in Table 2.
Table 1 Characteristics of included studies
① Effective rate; ② blood pressure after treatment; ③ pregnancy outcome; ④ reported maternal side effects A Amlodipine, N Nifedipine, IR immediate-release, GITS gastrointestinal therapeutic system
Study Gesta- tional week
Age (A/N) No. of par-
ticipants (A/N)
Baseline blood pressure Treatment Type of
Nifedipine used
Outcome
A(mmHg) N
(mmHg) A
(mg/day) N (mg/day)
Chen 2015 – 32.7/32.2 21/21 176 ± 8/108 ± 4 175 ± 9/106 ± 6 5 mg, qd 10 mg, tid Nifedipine
IR ①③④
Gan 2013 > 20 28–43 40/38 172 ± 10/108 ± 7 172 ± 9/108 ± 6 5 mg, qd 10 mg, tid Nifedipine
IR ①②③④
Guan 2015 – 33.8 (24–39)/33.6(25–29) 24/24 172 ± 9/108 ± 5 173 ± 8/107 ± 6 5 mg, qd 10 mg, tid Nifedipine
IR ①②③
Hu 2015 > 24 28.5 (3.1)/27.6 (2.3) 55/55 170 ± 11/110 ± 6 170 ± 11/109 ± 5 5 mg, qd 10 mg, tid Nifedipine
IR ①②③④
Jin 2018 > 28 25.6 ± 2.8/26.1 ± 2.4 43/43 162.1 ± 10.5/105.7 ± 5.9 163.2 ± 10.7/105.3 ± 9.2 5 mg, qd 10 mg, bid Nifedipine retard ②④ Li 2016 – 31.22 ± 5.85 /31.54 ± 6.12 47 / 47 172 ± 9 / 108 ± 7 172 ± 8 / 108 ± 6 5 mg, qd 10 mg, tid Nifedipine
IR ②③
Liu 2015 – 29.6 ± 4.6/31.2 ± 5.3 48/48 172 ± 9/107 ± 6 172 ± 8/107 ± 7 5 mg, qd 10 mg, tid Nifedipine
IR ①②
Ruan 2014 – 25–40 45/45 171 ± 11/109 ± 6 171 ± 10/109 ± 5 5 mg, qd 10 mg, tid Nifedipine
IR ①②③
Wang FJ
2016 – 32.7 ± 3.81/32.63 ± 3.85 20/20 176 ± 9/106 ± 8 175 ± 10/107 ± 6 5 mg, qd 10 mg, tid Nifedipine
IR ②③④
Wang H
2018 – 31.94 ± 5.1/32.44 ± 4.7 51/51 171.6 ± 9/106.7 ± 3.8 172.5 ± 9/105.7 ± 3.5 5 mg, qd 10–20 mg,
bid Nifedipine retard ②③④ Wang ZF
1997 > 32 25.3 ± 3.6/26.1 ± 3.4 45/34 153 ± 11.3/108 ± 5.3 150.8 ± 9.8/106.5 ± 3.8 5–10 mg,
qd 10–20 mg,
tid Nifedipine
IR ①②③④
Xiang
2016 > 20 30 ± 1.1/31 ± 1.7 30/30 168 ± 12 /98 ± 9 167 ± 13/98 ± 12 5 mg, qd 10 mg, bid Nifedipine retard ②④ Xin 2017 > 25 25.48 ± 2.36/25.45 ± 2.15 72/72 174.4 ± 15.2/104.0 ± 10.4 173.8 ± 15.3/103.6 ± 10.4 5 mg, qd 30 mg, qd Nifedipine
GITS ①②③
Yuan 2016 – 29.3 ± 44/30.8 ± 5.1 24/24 171.7 ± 8.5/106.3 ± 5.5 171.4 ± 7.3/106.5 ± 8.5 5 mg, qd 10 mg, tid Nifedipine
IR ①②
Zhang JS
2018 – 28.63 ± 5.36/28.74 ± 5.42 19/19 171.0 ± 8.4 / 105.5 ± 5.7 170.9 ± 8.3 / 105.4 ± 5.7 5–10 mg,
qd 10 mg, tid Nifedipine
IR ②④
Zhang Y
2019 > 20 26.3 ± 1.9/26.6 ± 1.8 35/35 168 ± 12/98 ± 10 167 ± 13/98 ± 11 5 mg, qd 10 mg, bid Nifedipine retard ②④ Zhou 2017 – 35.6 ± 2.7/34.5 ± 2.6 47/47 172 ± 10/105 ± 5 171 ± 9/106 ± 10 5 mg, qd 10 mg, tid Nifedipine
IR ②③④
Reported maternal side effects
For comparative analysis of reported maternal side effects, eleven trials [11, 12, 14, 15, 19–22, 25–27] (799 women) were included. Meta-analysis demonstrated significantly fewer side effects with amlodipine (RR 0.42, 95% CI 0.29–0.61, Fig. 5).
Minimal heterogeneity was observed (I2 = 21%). The results varied minimally between studies (I2 = 48%) when RD was used as the summary statistic (RD − 0.11, 95% CI − 0.16 to
− 0.07). Subgroup analysis did not find any significant dif- ference between amlodipine and nifedipine amongst various formulation groups. As for dizziness, headache, lower limb edema, and flushing, which are commonly reported in calcium channel blockers, some studies report these events in detail, so we compared the rates of these events. The results showed that amlodipine therapy significantly reduced dizziness events (RR 0.49, 95% CI 0.26–0.94) and headache events (RR 0.26, 95%
CI 0.08–0.81) compared with nifedipine. However, there was
Fig. 2 Risk of bias in included studies
no significant difference in the lower limb edema events (RR 0.59, 95% CI 0.26–1.33) and flushing events (RR 0.62, 95%
CI 0.25–1.56) with use of either drug. The detailed results are shown in Table 2.
Discussion
Main findingsOur meta-analysis found that amlodipine can be effectively used for hypertension during pregnancy. A little larger percentage of pregnant women with amlodipine could get their target blood pressure compared with nifedipine. And amlodipine therapy induced a greater reduction of post- treatment SBP and DBP compared with intermediate-/
long-acting nifedipine. In addition, there was no difference
Fig. 3 a Funnel plot- post-treatment SBP. b Funnel plot- post-treatment DBP. c Funnel plot-reported maternal side effects
Fig. 4 a Forest plot-effective rate. b Forest plot- post-treatment SBP. c Forest plot post treatment DBP
in pregnancy outcomes with amlodipine and nifedipine, including caesarean section, premature labour, placental abruption, FGR, fetal distress, neonatal asphyxia. Further- more, amlodipine have fewer totel side effects compared with nifedipine. There results suggest that amlodipine can be a good choice for hypertension during pregnancy.
Strengths and limitations
The major strength of our study is the first meta-analysis comparing efficacy and safety of amlodipine with nifedipine on hypertension during pregnancy. And this meta-analysis is the strict methodology, which followed the recommenda- tions of PRISMA statement. Additionally, we have done a comprehensive search of both English and Chinese language biomedical databases.
There are also several limitations in our meta-analysis.
First, although 17 RCTs are included, the overall participants
Table 2 Summary of findings
Outcome Studies Participants Amlodipine
events/total Nifedipine
events/total Statistical method Effect estimate Caesarean section 11 921 180/467 185/454 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.82, 1.12]
Premature labor 10 827 49/420 50/407 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.67, 1.39]
Placental abruption 8 706 31/354 32/352 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.30, 1.54]
FGR 3 270 2/136 3/134 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.14, 3.51]
Fetal distress 9 839 55/426 53/413 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.72, 1.43]
Neonatal asphyxia 7 593 21/303 17/290 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.64, 2.20]
Total adverse reactions 11 799 33/406 76/393 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.29, 0.61]
Dizziness 8 559 13/286 25/273 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.26, 0.94]
Headache 4 295 2/153 11/142 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.08, 0.81]
Peripheral edema 6 394 8/198 14/196 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.26, 1.33]
Flushing 7 517 5/265 9/252 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.25, 1.56]
Fig. 5 Forest plot-reported maternal side effects
involved is still relatively small. Second, though all of 17 included trials reported randomization, only 5 trials had the random number table, the rest of the studies randomness was not clear. Finally, nifedipine IR are mostly used in the con- trol group, only four studies used nifedipine retard and one study used nifedipine GITS. However, in the other countries except China, nifedipine IR is rarely used except emergent therapy for severe hypertension during pregnancy. There- fore, in our meta-analysis, we had done subgroup analysis for different nifedipine formulations to increase the appli- cability of our results to pregnant women in all countries.
Interpretation
Antihypertensive treatment is very important for hyperten- sion during pregnancy. Calcium channel blockers are often used [28]. Among them, nifedipine is commonly used and recommended by many guidelines as a first-line antihyper- tensive agent in pregnancy [29, 30]. Amlodipine is long- acting and causes relatively few adverse drug reactions associated with vasodilation [31], which is recommended for hypertension during pregnancy in Brazilian Guideline [32] and is mentioned that it is not contraindicated during pregnancy in ISSHP Guideline [33], but has not yet been mentioned in other main guidelines, including the Euro- pean Society of Cardiology (ESC) [34], National Institute for Health and Care Excellence (NICE) [35] and American College of Obstetricians and Gynecologists (ACOG) [4], etc.
And because of these advantages, amlodipine is frequently used for the treatment of hypertension. Selection of drugs during pregnancy should also consider the safety of drugs to the fetus. A few studies reported that amlodipine may not pose a significant teratogenic risk even in early pregnancy [10, 36]. Our meta-analysis suggests that amlodipine should be considered in hypertension during pregnancy, given that it can effectively reduce blood pressure with few adverse reaction. And its long half-life can increase the patient's medication compliance. Nonetheless, It's worth mention- ing that pregnant women's blood pressure is not the lower the better. Some guidelines of different countries indicate that the blood pressure of pregnant women should not be too low (e.g., < 110/70 mmHg) in order to ensure adequate placental perfusion [4, 5, 33, 35]. Therefore, our findings should be interpreted cautiously because of the particularity of antihypertensive therapy during pregnancy, the marginal confidence intervals in some analyses and the small-study size in most studies included.
Conclusion
The result suggested that amlodipine therapy was safe and could gain better outcomes in clinical therapeutic efficacy with fewer side effects compared with nifedipine for hyper- tension during pregnancy. Amlodipine can control blood pressure continuously and stably for a long time, and has good clinical practicability, so it can be used as the preferred drug for the treatment of hypertension during pregnancy.
This may be particulally important for pregnant women with chronic hypertension who use amlodipine before pregnancy to get better blood pressure control. Until more, higher qual- ity RCTs are performed to evaluate the efficacy and safety of amlodipine for hypertension during pregnancy, this meta- analysis provides a useful and comprehensive comparative analysis of efficacy and safety outcomes, when amlodipine are used to lower blood pressure in pregnant women.
Author contributions YJ, QS wrote the protocol. YJ performed the search. YJ and QS independently selected eligible studies and extracted data. Differences of opinion were registered and resolved by consensus with DP, SS. YJ and QS performed the meta-analyses. YJ, MZ, DP, SS, QS participated in the interpretation of the data and writing of the review.
Funding This study was supported by Guangdong Medical Science and Technology Research Foundation (A2020161).
Declarations
Conflict of interest None declared. Completed disclosure of interests form available to view online as supporting information.
Ethical approval Ethical approval was not needed for this meta-anal- ysis.
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