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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 2  |  Page : 458-464

Comparison study between nifedipine and progesterone as maintenance tocolysis after arrested preterm labor


1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Family Planning, Met Khakan Health Center, Menoufia Governorate, Menoufia, Egypt

Date of Submission04-Jan-2018
Date of Acceptance03-Mar-2018
Date of Web Publication25-Jun-2019

Correspondence Address:
Elham F El-Sisi
Shebin El-Khom City, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_915_17

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  Abstract 


Objective
The aim was to compare the efficacy and safety of nifedipine and progesterone for maintenance tocolysis after arrested preterm labor and their perinatal outcomes.
Background
Preterm birth (before 37 completed weeks of gestation) is a 'major cause of death' and a significant cause of long-term loss of human potential. Maintenance tocolysis is continued tocolysis after arrested preterm labor to prevent the recurrence of preterm labor pains.
Patients and methods
A prospective randomized comparative clinical study was carried out on 66 pregnant women who had preterm labor (six cases lost to follow-up) and attended the Obstetrics and Gynecology Outpatient Clinic at Menoufia Teaching Hospital during the period from March to August 2017. Detailed history, laboratory investigations, obstetric, and ultrasound follow-up study were performed.
Results
There was no significant difference (P > 0.5) between nifedipine and progesterone groups regarding maternal age and gestational age on admission (weeks), mode of delivery, and neonatal birth weight. However, there was a statistically significant difference (P ≤ 0.05) regarding mean blood pressure before and after treatment in nifedipine group. Moreover, there were less occurrences of neonatal respiratory distress and neonatal ICU admission in the nifedipine group. Additionally, onset of labor between 24 and 34 and between 34 and 37 weeks was significantly less frequent in progesterone group than in nifedipine group.
Conclusion
We found a superiority of progesterone over nifedipine for maintenance tocolysis. We would only comment that progesterone looks like a promising drug in this regard, and further large studies are required to establish this fact.

Keywords: maintenance tocolysis, nifedipine, perinatal outcome, preterm, progesterone


How to cite this article:
Abdelgaied AM, Dawood RM, Nofal AM, El-Sisi EF. Comparison study between nifedipine and progesterone as maintenance tocolysis after arrested preterm labor. Menoufia Med J 2019;32:458-64

How to cite this URL:
Abdelgaied AM, Dawood RM, Nofal AM, El-Sisi EF. Comparison study between nifedipine and progesterone as maintenance tocolysis after arrested preterm labor. Menoufia Med J [serial online] 2019 [cited 2019 Sep 21];32:458-64. Available from: http://www.mmj.eg.net/text.asp?2019/32/2/458/260942




  Introduction Top


Preterm birth (before 37 completed weeks of gestation) is a 'major cause of (postnatal) death' and a significant cause of long-term loss of human potential[1]. There is a substantial long-term health effect from preterm birth owing to increased risk of both death and developing a wide range of chronic physical and neurological disabilities compared with full-term births[2]. Approximately 70% of neonatal deaths, 36% of infant deaths, and 25–50% of cases of long-term neurologic impairment in children can be attributed to preterm birth[3]. The estimated cost of preterm births exceeds $26.2 billion annually, with an average cost of care for a preterm birth being 10 times greater than that of a full-term birth, $32 325 in comparison with $3325. In 2015, preterm birth occurred in 9.6% of ∼4 million births in the USA and 11.7% of 59 632 births in the state of Alabama[4]. The preterm birth rate in Alabama has increased slightly over the past year (11.66% in 2014 to 11.73% in 2015), and Alabama has the third highest preterm birth rate in the nation[4]. Despite some severely low-income and middle-income countries have halved their preterm deaths within a decade, many countries have made minimal progress, creating a wide survival gap for preterm babies in different countries, with more neonatal deaths in African babies[5]. The percentage of under-5 deaths from preterm birth complications is still high in Egypt, and our country is ranked as 144 worst on the list of 162 countries with prematurity-related deaths, comprising ∼28.5% of all under-5 deaths in Egypt[6].

Tocolysis is the pharmacological inhibition of uterine contractions and is currently the principal preterm birth preventive measure and will remain so until the etiology of preterm labor is better understood. Acute tocolysis delays preterm birth by 48 h, the critical period of antenatal steroid administration for fetal lung maturity[7]. A major effect on the associated neonatal mortality and morbidity will be achieved only with effective maintenance tocolysis to prolong pregnancy to term[8]. Maintenance tocolysis is continued tocolysis after arrested preterm labor to prevent the recurrence of preterm labor pains. The oral route of administration has low cost and a possible efficacy in reducing neonatal morbidity favoring the use of calcium channel blockers. Nifedipine is found to be a safe and effective drug for acute tocolysis, with minimal adverse effects. However, its use for maintenance tocolysis has yielded conflicting results[9].

Progesterone is an important agent for maintaining uterine quiescence. It is increasingly used in women at high risk for preterm labor and for maintenance tocolysis[2]. Nifedipine was first reported in 1980 in an observational study to be an effective tocolytic agent with minimal adverse effects[10]. It is an efficient tocolytic agent, with an easy oral route of administration, few adverse effects, and a low neonatal complications rate. However, it should be used with caution in patients with compromised cardiovascular condition as they may be at risk of pulmonary edema and cardiac failure[11]. The efficacy of maintenance tocolytic therapy after successful arrest of preterm labor remains controversial.

The aim of this study was to compare the efficacy and safety of nifedipine and progesterone for maintenance tocolysis after arrested preterm labor and their perinatal outcome.


  Patients and Methods Top


A prospective randomized comparative clinical study was carried out on 66 pregnant women who had preterm labor (six cases lost to follow-up) and attended the Obstetrics and Gynecology Outpatient Clinic at Menoufia Teaching Hospital during the period from March to August 2017.

Ethical consideration

All participants were volunteers. All of them signed a written informed consent and were explained the aim of study before the study initiation. Approval was obtained from ethical committee in Faculty of Medicine, Menoufia University.

Sampling methods

Sample size was calculated using computer sample block randomization type. During the preselection visit, exclusion and inclusion criteria were applied, with recording of full medical history, findings on abdominal and local examination, and results of ultrasonographical examination, along with results of investigations.

Participants included in the study were randomly divided into two groups as follows:

  1. Group A included 30 pregnant patient who presented with preterm labor signs and received nifedipine 20-mg tablets (Epilat Retard; Eipico, Cairo, Egypt) twice daily, starting 12 h after the arrest of preterm labor
  2. Group B included 30 pregnant patients who presented with preterm labor signs and received 400 mg of micronized progesterone vaginally at bed time (Prontogest; Marcyl, Marcyrl Factory, El Obour City, Cairo, Egypt), starting 12 h after the arrest of preterm labor.


Inclusion criteria

The study included patients with preterm labor or threatened preterm labor signs. Preterm labor was defined as occurrence of regular uterine contractions greater than or equal to 4 in 20 min and cervical changes, effacement greater than or equal to 80%, and cervical dilatation greater than or equal to 1 cm, whereas threatened preterm labor was defined as signs of preterm labor but without any appreciable cervical changes[3] in women with intact membranes, singleton pregnancy, and gestational age (GA) between 24 and 37 weeks of gestation.

Exclusion criteria

Antepartum hemorrhage, lethal fetal anomaly, intrauterine growth restriction, contraindication for tocolysis (intrauterine fetal death, cardiovascular diseases, diabetes mellitus, and bronchial asthma), multiple pregnancy, cervical dilatation greater than 4 cm, and ruptured membranes were the exclusion criteria.

All pregnant women who fulfill the eligibility criteria were subjected to the following.

History taking

History taking included the following: personal history, with emphasis on name, age, occupation, residency, and special habits; present history, with emphasis on history of onset, course and duration of labor pains, vaginal gush of fluid, vaginal discharge, vaginal bleeding, or febrile illness; past history, with particular emphasis on history of medical disorders, abdominal surgeries, drug therapy, or allergy or history of intake of other tocolytic drugs; family history for any similar condition; obstetric history, with emphasis on history of previous preterm labor, previous abortion, previous full-term deliveries, mode of delivery, and fetal outcome; and menstrual history, for estimation of GA using Naegeles rule, provided that she had regular cycles for the last 3 months before she got pregnant and was not taking contraceptive pills during this period and was sure of her dates.

General examination

General examination was done to exclude any medical diseases, with special attention to blood pressure, pulse, and temperature.

Abdominal examination

Abdominal examination was conducted with emphasis on the fundal height, clinically estimated fetal weight, and presence of uterine contractions.

Pelvic examination

Pelvic examination was done to assess the state of membranes and exclude their rupture through examination with a sterile Cusco speculum and to exclude vaginal bleeding.

Cervical status

Cervical status was recorded to assess the state of the cervix and measure the bishop score (dilatation, length, consistency, and position).

Sonographic assessment

Sonographic assessment was done to estimate the GA and amount of liquor and to exclude placenta previa, placental abruption, and major fetal congenital anomalies. Several ultrasound parameters were used to estimate GA including biparietal diameter, head circumference, femur length, and cervical length.

Nonstress test was done for reassuring fetal well-being.

All patients included in the study were admitted to hospital and preterm labor was arrested by acute tocolysis within 48 h. Administration of tocolytic agent was done in the form of oral nifedipine (20 mg) tablet twice daily or vaginal progesterone (400 mg) at bed time as maintenance tocolysis.

Statistical analysis

Results were analyzed and tabulated using Microsoft Excel version 7 (Microsoft Corporation, New York, USA) and SPSS v. 16. (SPSS Inc., Chicago, Illinois, New York, USA). Two types of statistics were done: descriptive, for example, percentage, mean, median, and SD, and analytical, which included χ2, Wallis analysis of variance for comparing categorical data, and Person's correlation coefficient (r) for correlation between two dependents quantitative not normally distributed variable. A value of P less than 0.05 was indicated statistically significant.


  Results Top


Maternal age (years) of the studied patients ranged from 21 to 35 years, with mean of 28.27 ± 2.31 years, in the nifedipine group, and from 19 to 38 years, with mean of 30.63 ± 5.21 years, in the progesterone group. Moreover, there was statistical no significant difference (P > 0.5) between the two studied group (nifedipine and progesterone) regarding maternal age and GA on admission (weeks). However, there was statistically significant difference (P ≤ 0.5) between the two studied groups regarding parity and previous preterm labor [Table 1].
Table 1: Comparative study between the studied groups regarding maternal age, parity, previous preterm labor, and gestational age on admission (weeks)

Click here to view


Additionally, there was statistically significant difference (P ≤ 0.05) regarding the mean maternal heart rate (beats/min) before and after treatment in nifedipine group. Maternal heart rate increased significantly after treatment than before treatment. However, no statistically significant difference was observed regarding maternal mean blood pressure in nifedipine group and in mean blood pressure and maternal heart rate in progesterone group before and after treatment [Table 2].
Table 2: Comparative study between the studied groups regarding change in the maternal heart rate (beats/min) and blood pressure (mmHg) before and after treatment

Click here to view


Furthermore, there was a significant difference (P < 0.05) between the two studied groups regarding onset of labor between 24 and 34 weeks and greater than 37th week of GA, which were significantly higher in nifedipine group than progesterone group. On the contrary, there was no statistically significant difference (P > 0.05) between nifedipine and progesterone groups regarding onset of labor at 34–37 weeks, mode of delivery, and cervical dilatation [Table 3].
Table 3: Comparative study between two studied groups regarding onset of labor at 24-34, 34-37, and greater than 37th week of gestational age, mode of delivery, and cervical dilatation

Click here to view


Moreover, there were statistical significant differences (P < 0.05) between nifedipine and progesterone groups regarding neonatal respiratory distress and neonatal ICU admission. Neonatal ICU admission was less frequent in progesterone group than nifedipine group. In addition, there were no statistical significant differences (P > 0.05) between nifedipine and progesterone groups regarding neonatal birth weight [Table 4].
Table 4: Comparative study between patient and control regarding neonatal respiratory distress, ICU admission, and birth weight

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  Discussion Top


The current study showed that there was no statistically significant difference between the nifedipine and progesterone groups regarding maternal age (years). The same finding was supported by Rabei et al.[12]who compared nifedipine and progesterone in inhibiting threatened preterm labor and found that there was no statistically significant difference between nifedipine and progesterone groups regarding the maternal age. In addition, Kamat et al.[13]compared the efficacy and safety of nifedipine and progesterone for maintenance tocolysis after arrested preterm labor, and they found that there was no significant difference in maternal age between the two groups.

The current study showed that there was a statistically significant difference between the nifedipine and progesterone groups regarding parity. The same finding was supported by Kamat et al.[13], asthey found that there was significant difference between the nifedipine and progesterone regarding parity. Our results disagree with Rabei et al.[12]and Chawanpaiboon et al.[14], as they found that there was no statistically significant difference between nifedipine and progesterone groups regarding parity.

The current study showed that there was a statistically significant difference between the nifedipine and progesterone groups regarding previous preterm labor. This result is in agreement with Eldesouky et al.[6]who found a significant difference between placebo and progesterone groups with respect to history of preterm delivery. Our results disagree with Kamat et al.[13]who found that there was no significant difference in the previous preterm deliveries between the nifedipine and progesterone groups. Moreover, Rabei et al.[12]showed no statistically significant difference between the progesterone and nifedipine groups regarding the previous preterm.

The current study showed that there was no statistical significant difference between the nifedipine and progesterone groups regarding GA on admission (weeks). The same results were supported by Rabei et al.[12]who found that there was no statistically significant difference between nifedipine and progesterone groups regarding GA. The mean GA at the time of delivery in nifedipine group was 36.9 ± 1.7 weeks and in progesterone group was 36.3 ± 2.1 weeks. Similar findings were obtained by Suhag et al.[15] and Klein et al.[16]. In contrast to our results, Eldesouky et al.[6]found that GA/week ranged from 25 to 40 weeks, with a mean of 36.10 ± 3.27 weeks, and there was statistically significant increase in GA at delivery in the progesterone group in comparison with placebo group (37.16 ± 1.81 versus 35.04 ± 4.03 weeks, respectively).

The current study showed there were no statistical significant differences between nifedipine and progesterone groups regarding cervical dilatation. These findings agree with Kamat et al.[13]who found that there was no significant difference in cervical dilatation and effacement at admission between nifedipine and progesterone groups. On the contrary, these findings disagree with Fonseca et al.[17]who found that in women with short cervix treatment with progesterone, it reduces the rate of spontaneous early preterm delivery when compared with placebo.

The current study showed that there was a highly significant difference between the two studied groups regarding preterm labor after one, 32–34, and 37th week of GA. Preterm labor after one and 32–34 weeks was significantly less frequent in progesterone group (33.3 and 6.7%) than nifedipine group (16.7 and 20%). However, preterm labor after 37th week was higher frequent in progesterone group (83.3%) than nifedipine group (63.3%). These results confirmed by Ding et al.[18]who showed that progesterone was more significantly effective than nifedipine in maintenance tocolysis therapy after arrested preterm birth. Conversely, these results are in contradiction to that reported by several studies. O'Brien et al.[19] reported that the rate of preterm birth at less than or equal to 32 + 0 weeks of gestation was not significantly different. In the present study groups, no differences between groups 10.0% (n = 31) in the progesterone group and 11.3% (n = 34) in the nifedipine group. However, Rabei et al.[12]found that the percentage of full term in nifedipine group and progesterone group was 78.7 and 82.7%, respectively. The percentage of preterm birth in nifedipine group and progesterone group was 21.3 and 17.3%, respectively, and the difference between the two groups did not reach significance level.

Regarding mode of delivery, the current study showed that vaginal delivery occur in 46.7 and 60% in nifedipine and progesterone, respectively, whereas cesarean birth occurred in 53.3 and 40% in nifedipine and progesterone, respectively, which was statistically not significant in both studied groups. These results matched with a study of Rabei et al.[12] who showed that there was a statistically insignificant difference between progesterone and nifedipine groups regarding the mode of delivery. Vaginal delivery occurred in 53 (70.7%) cases and 60 (80%) cases in nifedipine and progesterone, respectively, whereas, cesarean birth occurred in 22 (29.3%) cases and 15 (20%) cases in nifedipine and progesterone, respectively. Additionally, Kamat et al.[13]found that there was no significant difference in the mode of delivery between the nifedipine and progesterone groups. Overall, 40% of the patients in the nifedipine group and 71% of the patients in the progesterone group delivered vaginally, whereas 60 and 29% of patients delivered by cesarean birth in nifedipine and progesterone groups, respectively, which was nonsignificant.

The current study showed that there were statistical significant differences between nifedipine and progesterone regarding neonatal respiratory distress. It was significantly less frequent in progesterone group than nifedipine group. Our results are consistent with Carolien et al.[20]who found that infant respiratory distress syndrome (RDS) treated with surfactant occurred in 12 (6.0%) of 201 pregnancies in the progesterone group and in 14 (6.8%) of 205 in the nifedipine. Moreover, Romero et al.[21]concluded that vaginal progesterone administration was associated with a significant decrease in neonatal RDS compared with nifedipine. However, according to Ding et al.[18]both nifedipine and progesterone groups had no significant influences on incidence of RDS.

Additionally, the current study revealed that neonatal ICU admission was less frequent (33.3%) in progesterone group than nifedipine group (13.3%), and the difference between reached significance level. Our results disagree with the study conducted by Papatsonis et al.[22]who found that neonatal ICU admission decreased in progesterone compared with nifedipine, which associated with lower admission rates to the ICU compared with ritodrine, and lower incidences of RDS (21 vs. 37%; 0.46, 0.24, 0.89). However, Ding et al.[18]reported that the outcomes of the proportion of neonatal ICU admissions, and neonatal ICU stay were not significantly different, based on the comparison of progesterone versus placebo or no treatment, and the comparison of nifedipine versus placebo or no treatment. Additionally, the current study indicated that neonatal birth weight was higher in progesterone group (3.4 ± 0.4 kg) than nifedipine group (3.2 ± 0.2 kg) but the difference between them did not reach significance level. These results agreed with the results of Chawanpaiboon et al.[14]who found that the mean fetal birth weight in nifedipine group was 2.856 ± 351 kg, and whereas in the progesterone group was 2.685 ± 456 kg, and the difference was statistically not significant. Moreover, Rabei et al.[12]found that the nifedipine group had higher frequency of adverse effects than in the progesterone group, with highly statistically significant difference between the two groups. There was no statistically significant difference between the two groups about the fetal birth weight. Conversely these results disagree with Dodd et al.[23]and Lyell et al.[24]who reported that women who received progesterone were statistically significantly less likely to give birth before 37 weeks, to have an infant with birth weight of 2.5 kg, or to have an infant diagnosed with intraventricular hemorrhage. Moreover, Eldesouky et al.[6]found that birth weight ranged from 1.250 to 3.600 kg, with a mean of 2907 ± 0.58, with statistically significant increase in birth weight in the study group in comparison with the placebo group (3.026 ± 0.570 versus 2.788 ± 0.749, respectively). The difference in birth weight between the current study and the others may be attributed to the use of progesterone in threatened phase of preterm whereas in others after tocolysis in established preterm labor and number of the patients in each study.

Regarding maternal heart rate before and after treatment, it was statistically significant in nifedipine group versus in progesterone group, which was not statistically significant. This is similar to the result of the study conducted by Ahtisham et al.[25]who found increase in maternal heart rate following each dose of nifedipine, but this was transient and less pronounced. However, no significant changes were noted in the fetal heart rate. Moreover, Abdel Hak and Gafaar[26] concluded that there a was statistically significant decrease of maternal heart rate; however, this change was clinically insignificant.

The current study revealed that there were statistically significant differences between studied groups regarding maternal mean blood pressure (mmHg) before and after treatment. Maternal mean blood pressure decreased significantly after treatment as compared before treatment. This agreed with Ahtisham et al.[25]who indicated that mean systolic blood pressure before treatment was 114.4 ± 5.3, whereas after treatment was 100.1 ± 3.6 which shows a decrease is systolic blood pressure of 14 mmHg, which is statistically significant. The mean diastolic blood pressure before treatment with nifedipine 75.5 ± 5.4, whereas after treatment was 67.4 ± 4.9. This decrease in blood pressure was significant but was not accompanied with any clinical symptoms of hypotension. Moreover, Haas et al.[27]studied tocolytic therapy for preterm delivery. They found that prostaglandin inhibitors and calcium channel blockers had the highest probability of delaying delivery and improving neonatal and maternal outcomes. In contrast to our study, Abdel Hak and Gafaar[26] found that hemodynamic studies proved nonsignificant changes in maternal blood pressure and fetal heart rate and clinically insignificant decrease in maternal heart rate.


  Conclusion Top


To conclude, the present study has clearly shown the superiority of progesterone over nifedipine for maintenance tocolysis. We would only comment that progesterone looks like a promising drug in this regard, and further large studies are required to establish this fact.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Chawanpaiboon S, Pimol K, Sirisomboon R. Comparison of success rate of nifedipine, progesterone and bed rest for inhibiting uterine contractions in threatened preterm labor. J Obstet Gynecol Res 2014; 7:787–791.  Back to cited text no. 14
    
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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