Nifedipine versus magnesium sulfate in the management of preterm labour- A randomised controlled trial

Introduction

Every year, an estimated 15 million babies are born preterm (before 37 completed weeks of gestation). Preterm birth complications are the leading cause of death among children less than 5 years of age, responsible for nearly 1 million deaths in 2015. Three-quarters of them could be saved with current, cost-effective interventions. Across 184 countries, the rate of preterm birth ranges from 5% to 18% of babies born.^[1]

Preterm labour is defined by WHO as the onset of labour prior to the completion of 37 weeks of gestation, in pregnancy beyond 28 weeks of gestation with sub-categories like extremely preterm (less than 28 weeks) very preterm (28 to 32 weeks) moderate to late preterm (32 to 37 weeks). India has the highest number of preterm births 35,19,100. Preterm birth rate (per 100 live births) in 2010 is 13.^[2] World Prematurity Day is observed on 17 November each year to raise awareness of preterm births since 2011. It was first created by European parent organizations in 2008. Currently, cost-effective interventions like essential hospital care during childbirth and in the postnatal period for every mother and baby, including antenatal steroid injections, kangaroo mother care and antibiotics to treat new-born infections.

The aetiology of preterm labour is multi-factorial and can be divided into three groups. Socio-biological variables like low maternal age,^[3] marital status, race and ethnicity,^[4] (more common in African-American women), cigarette smoking,^[5] environmental stress,^[6] short inter-pregnancy interval,^[7] alcohol, coffee, and substance abuse.^[8] Past obstetric history like previous preterm delivery,^[9] previous abortion,^[10] multiple dilatation and curettage,^[11] cervical surgery like cone biopsy, large loop excision of transformation zone (LLETZ).^[12] Complications of current pregnancy like elective preterm birth for a number of maternal and foetal reasons such as preeclampsia, placenta previa, abruption placenta,^[4] multiple gestations due to Artificial reproductive techniques and infection.^[13]

Materials and Methods

Results

In the present study, majority of women were in the age group 21-25 years constituting 24 (60%) in nifedipine group and 23 (57.5%) in MgSO4 (Magnesium Sulfate) group. Women with age 18-20 years were 6 (15%) in group 1 and 2 (5%) in group 2. Women between 26-30 years were 7 (17.5%) in nifedipine group and 8 (20%) in MgSO4 group. Only 3 (7.5%) of nifedipine group and 7 (17.5%) of MgSO4 group were aged more than 30 years. The mean maternal age was 23 years in group 1 and 25 years in group 2 as shown in the [Table 1].

The majority of women belonged to socio-economic status (SES) III, i.e., 26 (65%) in group 1, 24 (60%) in group 2 whereas women belonging to SES IV comprised 9 (22.5%) in group 1 and 14 (35%) in group 2. A small group of 3 (7.5%) belonged to SES 2 in group 1 and 2 (5%) in group 2 as mentioned in the [Table 1].

Majority of women completed their secondary education i.e., 27 (67.5%) in nifedipine group whereas majority of women were graduates in MgSO4 group i.e., 25 (62.5%) as shown in [Table 1]. Majority of women were 31-33 weeks of gestational age i.e., 20 (50%) in nifedipine group and 21 (52.5%) in MgSO4 group. Mean gestational age is 32 weeks in nifedipine group and 31weeks in MgSO4 group as represented in [Table 2].

Most of patients in Nifedipine group are multipara (22) 55% and MgSO4 group are primigravida (21)52.5% using chi-square test with p-value 0.502 (not significant) as shown in [Table 2]. Most of the women were singleton pregnancies 37(92.5%) in both the groups and only 3 (7.5%) were multiple pregnancies as mentioned in [Table 2]. The interpregnancy interval among multigravida in both groups has no showed significance with p-0.540 value. Majority of multigravida women are with interpregnancy interval less than 2 years i.e., 15 (37.5%) in nifedipine group and 15 (37.5%) in MgSO4 group as represented in the [Table 2].

Only 2 (5%) of women in nifedipine group and 9 (22.5%) are with previous history of curettage. Majority of women i.e., 38 (95%) in nifedipine group and 31 (77.5%) in MgSO4 group didn’t have previous history of curettage as shown in the [Table 2].

Most of the pregnant women are anaemic i.e., 31 (77.5%) in nifedipine group and 29 (72.5%) in MgSO4 group (not significant at p<0.05) as mentioned in [Table 2]. Majority of women 33 (82.55%) in nifedipine group and 36 (90%) in MgSO4 group didn’t had previous preterm birth. Only 7 (17.5%) of pregnant women had previous preterm birth in nifedipine group and 4 (10%) in MgSO4 group as mentioned in [Table 2].

Most of the pregnant women i.e., 39 (97.5%) in nifedipine group and 39 (97.5%) in MgSO4 group are with adequate liquor. Only 1 (2.5%) of women in both groups had polyhydramnios. Fourteen patients (35%) had urinary tract infection in nifedipine group and 9 (22.5%) in MgSO4 group. Majority of women i.e., 26 (65%) in nifedipine group and 31 (77.55%) in MgSO4 group didn’t have urinary tract infection as shown in [Table 2].

Only 8(20%) of nifedipine group and 11 (27.5%) in MgSO4 group had growth in urine culture. Majority of pregnant women had no growth in urine culture i.e., 32 (80%) in nifedipine group and 29 (77.5%) in MgSO4 group. Most of the women had no complaints of vaginal discharge i.e., 39 (97.5%) in nifedipine group and 39 (90%) in MgSO4 group as shown in [Table 2]. Only 5 (12.5%) in nifedipine group and 7 (17.5%) in MgSO4 group had growth in vaginal culture. Majority of pregnant women i.e., 35 (87.5%) in nifedipine group and 33 (82.5%) in MgSO4 group had no growth in vaginal culture as represented in table.2.

As mentioned in the [Table 2], majority of women i.e., 37 (92.5%) in nifedipine group and 39 (97.5%) in MgSO4 group didn’t have side effects. Only 3 (7.5%) of nifedipine group, of which 2 women had hypotension which was corrected by intravenous fluids and one women had headache and 1 (2.5%) of MgSO4 group had flushing. These side effects did not cause drug discontinuation.

Patients with cervical dilatation less than 4cm were included in this study. When change in bishops score before and after administering of nifedipine and MgSO4 was compared, there is no significant difference between the two groups with p value 0.868 as shown in [Table 3].

In the present study, the [Table 2], if patient delivers within 48 hours after the initiation of the treatment, then the treatment is ineffective or treatment failure. In this study, Nifedipine was successful in inhibiting preterm labour in 34 (85%) patients and MgSO4 in 32 (80%) patients and did not deliver within 48 hours (primary tocolytic effects). Six women (15%) of nifedipine group and eight (20%) of MgSO4 group delivered within 48 hours and considered as treatment failure.

Three patients (7.5%) within 24 hours, 3 patients (7.5%) between 24-48 hours, 2 patients (5%) between 48 hours- 7days and 32 patients (80%) after 7 days had delivery in the nifedipine group and 6 patients (15%) within 24 hours, 2 patients (5%) within 24-48 hours, 5 patients (12.5%) between 48 hours-7 days and 27 patients (67.5%) after 7 days had delivery in the magnesium sulfate group. This characteristic was not statistically different between the two groups as shown in [Table 2].

Nifedipine group didn’t require alternative tocolysis within 48hours. 2(5%) required alternative type of tocolysis within 48-72hours. Thirty (75%) patients didn’t require any tocolysis. 6(15%) of patients delivered before it required alternative tocolysis. Among MgSO4 group, 1(2.5%) required alternate tocolysis within 48hours. 4(10%) required alternate tocolysis within 48-hours, 1(2.5%) within 72hours. 26(65%) didn’t require any other tocolysis. 8(20%) delivered before it required alternative tocolysis as represented in [Table 4].

When risk factors of preterm labour are considered, treatment failure i.e., delivery couldn’t be delayed for 48 hours in anaemic women of nifedipine and MgSO4 groups 12.9% vs 24.1%, urinary tract infection 21.4% vs 11.1%, high vaginal growth culture 20% vs 14.3%, dilatation and curettage 50% vs 33.3%, multiple pregnancy 33.3% in both the groups. Only one patient in nifedipine group and 1 out of 4 patients in MgSO4 group had vaginal discharge whose delivered within 48 hours. One patient had polyhydramnios in both groups whose delivery couldn’t be delayed for 48 hours. One out of seven patients (14.3%) in nifedipine group with previous preterm birth had treatment failure as shown in [Table 5].

In our study, 23 (57.5%) of nifedipine group and 28 (70%) of MgSO4 group delivered in our hospital, others lost follow up or delivered elsewhere. Out of which, when neonatal outcomes are compared, APGAR at 1 minute was more than 7 for 13 neonates (56.5%) of nifedipine group and 14 (50%) of MgSO4 group. P value not significant 0.642 as in [Table 6].

When APGAR score at 5 minutes are compared among neonates, it is more than 7 for 15 (65.2%) for nifedipine group and 16 (57.1%) for MgSO4 group. P-value not significant 0.557 as shown in [Table 6]. Respiratory distress among neonates was more for MgSO4 group than nifedipine, 12(42.9%) vs 8(34.8%) respectively. P value-0.557 is not significant as in [Table 7]. Patients of MgSO4 group 16(57.1%) had more NICU admission when compared to 7(30.4%) of nifedipine group which is a significant difference (p value 0.049) as represented in [Table 8].

Discussion

Tocolytics are an accepted component of the obstetric management of women with preterm labour and research continues to identify new tocolytic agents. In our study, maternal outcome was assessed in terms of successful prolongation of pregnancy who had not been delivered at 48 hours (primary tocolytic effects) and at more than 7 days (secondary tocolytic effects) after beginning the treatment.

Among 80 study subjects who were in preterm labour, nifedipine was more effective in inhibition of contractions for 24 hours in 92.5% of patients when compared to MgSO4 (magnesium sulphate) which was effective in 85% of patients. Nifedipine was successful in prevention of labour for 48 hours (primary tocolytic effects) in 85% of patients and MgSO4 in 80% patients.

Nifedipine was efficient in delaying delivery up to 7 days (secondary tocolytic effects) in 80% of patients and MgSO4 was efficient in 67.5% of patients. Although from the above, nifedipine appears to be a better tocolytic when compared to MgSO4, statistically, it is not significant (p value is 0.854). Nikbakht et al. 2014 conducted a similar study and both drugs were equally effective in prevention of labour and delaying delivery >7 days, 56% vs. 64% in the nifedipine and magnesium sulphate groups, and the days gain in utero was no statistically different in two groups.^[14]

Khooshideh M et al 2017 concluded that there were no differences in suppression of labour pain in 24 hours and 48 hours.^[15] Tabassum S et al 2016 observed that preterm labour was prevented for 48hrs in MgSo4 group (88.80% patients) while in nifedipine group, it was prevented 74% patients with p-value of 0.003 and concluded that magnesium sulphate is associated with higher efficacy for prevention of preterm labour as compared to oral nifedipine.^[16] In a study conducted by Lyell et al 2007, primary outcome was arrest of preterm labour, defined as prevention of delivery for 48 hours with uterine quiescence which was achieved by MgSO4 when compared to Nifedipine (87% compared with 72%, P=.01). In our study, when change in Bishops score before and after administering of nifedipine and MgSO4 was compared (-0.45 vs. -0.5), there is no significant difference between the two groups with p value 0.868.^[17]

In our study, all pregnant women with gestational age between 28-37weeks with preterm labour are treated with Nifedipine or magnesium sulphate on randomised basis. Characteristics such as age, parity, religion, socio-economic status, and gestational age were comparable between the two groups. Mean age in Nifedipine group is 23 years and MgSO4 is 25 years. In a study conducted by Tabassum S et al 2016, the mean age of women in nifedipine group was 29 years and in MgSO4 was 30 years. Sixty-five percent of women belong to socio-economic status (SES) III in nifedipine group, 60% in MgSO4 group. Most of the women i.e., 67.5% completed their secondary education in nifedipine group whereas 62.5% were graduates in MgSO4 group. Mean gestational age in nifedipine group was 32 weeks and MgSO4 group was 31 weeks. In a study by Khooshideh M et al 2017, mean gestational age was 31weeks. Primigravida and multigravida was equally distributed in both the groups.^[15], ^[16]

Singleton and multiple pregnancies were equally distributed between the two groups. Kurdi AM et al 2004) stated that premature labour in multiple pregnancies was 7 times greater than singletons (42% versus 6.4%).^[18] In our study, there were three twin pregnancies in both groups of which delivery was delayed for 48 hours in (66%) two patients. Pregnancy with polyhydramnios increased chances of preterm labour. Pri-Paz et al 2012 reported significantly higher rates of preterm (<37 weeks) and early preterm (<34 weeks) deliveries in their polyhydramnios group compared with controls.^[19] In our study, multiple pregnancies and polyhydramnios were equally distributed where 1 out of 3 patients with multiple pregnancies and the one polyhydramnios pregnancy, delivered within 48 hours.

Aboushamat & Nanu 2015 observed that the lower the haemoglobin in pregnant women, the greater percentage of preterm labour. Anaemia is an important risk factor for preterm labour; most of the pregnant women in our study i.e., 77.5% in nifedipine group and 72.5% in MgSO4 group were anaemic. Among anaemic patients, 12.9% of nifedipine group and 24.1% of MgSO4 group, uterine quiescence could not be achieved and delivered within 48 hours (p value 0.215).^[20]

Visintine et al. 2008, observed women with multiple prior induced abortions and a short cervix have a 3.3-fold greater chance of spontaneous preterm birth compared with those with normal cervical length (> or = 25mm).^[11] But, in our study, two patients (5%) of nifedipine group, nine patients (22.5%) of MgSO4 group had history of dilatation and curettage. Out of which one patient of nifedipine group and three patients of MgSO4 group went into labour. Previous preterm delivery is considered as a risk factor for preterm labour in the current pregnancy.^[10] Most of the patients of both nifedipine and MgSO4 group (90% vs. 82.5%) do not have a history of preterm birth. Similar to our study, Lyell et al 2007, also concluded there is no significant difference in the distribution of previous preterm birth in both the groups in his study.^[17]

Most of the multigravida women in both the study groups are with inter-pregnancy interval <2years (79% vs. 83.3%). Similarly, Smith et al 2003, observed that a short inter-pregnancy interval is an independent risk factor for preterm delivery and neonatal death in the second birth.^[7]

Varma et al 2014 states that recognising and treating the women having urogenital infections at a stage, when it has not become clinically evident, will decrease the percentage of women going into preterm labour and will improve the perinatal outcome. In our study, urinary tract infection lead to preterm labour in 35% of nifedipine group with 20% of positive urine culture and 22.5% of MgSO4 group with 11% of positive urine culture. High vaginal swab showed growth only in 12.5% vs 17.5% of nifedipine and MgSO4 groups respectively. Positive urine (p value 0.42) and vaginal culture (p value 0.68) which lead to treatment failure is not significant in our study. As per the culture report and sensitivity, antibiotics were started. ^[21]

Serious adverse effects like shortness of breath, pulmonary oedema which is caused by MgSO4 and significant hypotension which is seen with nifedipine is not seen in our study. But 3 patients of nifedipine group had hypotension which was corrected by intravenous fluids and one had headache and one patient of MgSO4 group had flushing. These side effects did not cause drug discontinuation. Khooshideh et al 2017, concluded that maternal hypotension was higher in the nifedipine group in his study, but the difference was not significant. Dyspnoea and minor maternal side effects (P ≤ 0.001) were significantly higher in the MgSO4 group than the nifedipine group. Nikbakht et al 2014, stated that 6% of nifedipine group and 2% of magnesium sulphate group required drug discontinuation due to severe symptoms.^[14], ^[15]

Uterine quiescence was better achieved in all patients of nifedipine group for 48 hours and didn’t require alternate tocolysis in 75% of patients till delivery or discharge when compared to MgSO4 group (65%). Few patients went into active labour and delivered, where other tocolytics couldn’t be given (15% vs 20%).

In our study, 57.5% of nifedipine group and 70% of MgSO4 group delivered in our hospital, others lost follow up or delivered elsewhere. Out of which when neonatal outcomes were compared, neonates who were exposed to MgSO4 in utero had more NICU admission when compared to nifedipine group (57.1% vs 30.4%) with p value-0.049 which is significant. Similar to our study, Lyell et al 2007, described new-borns in the magnesium sulphate group had more NICU admissions and spent longer in the neonatal intensive care unit (8.8±17.7 days compared with 4.2±8.2 days, P=.007).^[17] In our study, there were no statistically significant differences in one-minute and five-minute Apgar scores in neonates although majority of neonates with reassuring Apgar score (i.e., >7) at 1 minute and 5 minute belong to nifedipine group when compared to MgSO4 group (Apgar >7 at 1 minute is 56.6% vs. 50% with p value 0.642 & Apgar >7 at 5 minutes is 65.2% vs. 57.1% with p value 0.557 respectively) which is not significant. Neonates of MgSO4 group had more respiratory distress when compared to nifedipine group (42.9% vs. 34.8% respectively) with p value 0.557. Similar to our study, Khooshideh et al 2017, also observed that there were no statistically significant differences in one-minute and five-minute Apgar scores in neonates. Also, there were not any statistically significant difference in neonatal respiratory distress syndrome and NICU admission between the two groups in the same study. Singh et al 2015, observed that maximum number of babies had Apgar score between 8 and 10 at 5 minutes. Mean Apgar score at 5 minute was 8.1 ± 2.20, 8.2 ± 2.00, 7.9 ± 2.39, 7.9 ± 2.39, 7.6 ± 2.34 in ritodrine, isoxuprine, nifedipine, glycerlynitrate and magnesium sulphate group respectively.^[22]

Many studies reported that nifedipine is a superior drug compared to MgSO4 in decreasing the rate of respiratory distress syndrome^[23], ^[24] and NICU admission in preterm and very preterm neonates.^[25] Some authors reported that MgSO4 may lead to respiratory suppression in neonates.^[26], ^[27] In the present study, although neonates who were exposed to MgSO4 in utero had more NICU admission when compared to nifedipine group which is significant, we have not found any significant difference in the incidence of respiratory distress syndrome and 1- and 5-minute Apgar scores between the two groups.

On the other hand, other factors which have led to the growing interest in nifedipine as a tocolytic are the availability of a wide range of immediately acting and extended-release preparations, easy availability, ease of administration and low cost. MgSO4 must be used by only the infusion route and requires special monitoring and close observation. Patients taking magnesium sulphate should be monitored for toxic side effects such as respiratory depression or even cardiac arrest. Magnesium crosses the placenta and can cause respiratory and motor depression of the neonate. Moreover, Grimes and colleagues showed that the risk of total paediatric mortality was significantly higher for infants exposed to magnesium sulphate and it should not be used for tocolysis.^[28] But evidence suggests that magnesium sulphate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants.^[29] When selecting a tocolytic, patient-specific characteristics must be considered. In patients who require magnesium sulphate for neuro-protection, it may be suitable to use this therapy at tocolytic doses because it can serve both purposes.^[30]

Conclusion

In conclusion, our data in this study showed that oral nifedipine is as effective as magnesium sulfate with regard to inhibition of preterm labour. Although, nifedipine is better than MgSO4 when their primary tocolytics effects (who has not delivered till 48 hours) and secondary tocolytic effects (who has not delivered till 7 days) are compared but it is not statistically significant. Although neonates who were exposed to MgSO4 in utero had more NICU admission when compared to nifedipine group which is significant, we have not found any significant difference in the incidence of respiratory distress syndrome. We conclude that as nifedipine with its easy availability, least side effects profile, low cost, ease of administration and with less intensive monitoring, can be considered as better option for management of preterm labour. No matter which tocolytic agent the clinician chooses, the evidence supports the use of short-term tocolytic drugs to prolong pregnancy for at least 48 hours to allow for administration of antenatal steroids and to allow for transport of the mother to a tertiary care facility. As this study comprised a small sample, large randomised studies are required to prove the efficacy of the tocolytics.

Source of Funding

None.

Conflict of Interest

None.