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Preterm birth is the most important single determinant of adverse infant outcome, in terms of both survival and quality of life. Although preterm birth is defined as being before 37 completed weeks, most mortality and morbidity is experienced by babies born before 34 weeks. Prevention and treatment of preterm labor is important, not as an end in itself, but as a means of reducing adverse events for the child. Postponement of preterm birth can help improve outcomes for babies, as the mother can be given steroid drugs which help develop the baby's lungs in a short time.
Several classes of medications are used for tocolysis to inhibit preterm labor in order to allow time for such co-interventions to occur. Multiple Cochrane systematic reviews exist for individual tocolytic medications, but there has been no rigorous, quantitative synthesis of the data comparing tocolytic drug classes.
There is a growing body of evidence that Nifedipine, a dihydropyridone calcium channel blocker has emerged as an effective, potentially safer and better-tolerated tocolytic agent with no known fetal side effects. The Cochrane review claimed a markedly reduced risk of cessation of treatment for maternal adverse drug reactions Successful treatment of preterm labor with Nifedipine has been reported. Pharmacoeconomics involving the cost of Nifedipine and Isoxsuprine in 3 day treatment duration is in 1:4 ratios.
II. Relationships of research objectives, data substrates, operationally-defined variables and data analyses
To compare the effectiveness and safety of Oral Nifedipine as compared to Parenteral and Oral Isoxsuprine
Data Collection Form
- mean delay of delivery (in days) of patients given Oral Nifedipine and of patients given Parenteral and Oral Isoxsuprine
- cervical status determination (by cervical length in centimeters and funneling in percentages)
- effectiveness in suppressing contractions ( by EFM)
- symptoms or adverse effects
Comparison of means
Spontaneous preterm birth is pathophysiologically a heterogeneous syndrome. The cascade of events that eventually culminate in spontaneous preterm birth has several possible underlying pathways. Possible pathways include excessive myometrial and fetal membrane overdistention, decidual hemorrhage, precocious fetal endocrine activation, and intra-uterine infection or inflammation.1 These pathways may be initiated for weeks or months before clinically apparent preterm labor. The processes leading to preterm parturition may originate from one or more of these pathways; for example, intrauterine infection or inflammation and placental abruption often coexist in preterm births.2 Apparently, decidual hemorrhage and intra-uterine infection share several inflammatory molecular mechanisms that contribute to parturition. The etiologic heterogeneity of preterm birth complicates therapeutic approaches. Although the ultimate clinical presentation of women with preterm labor may appear to be homogeneous, the antecedent contributing factors probably differ considerably from woman to woman.
Preterm birth affects 8-10% of pregnancies and after exclusion of genetic and anatomic defects, it accounts for 75-80% of perinatal morbidity and mortality and 50% of childhood neurological morbidities.3 It is also associated with high immediate and long-term costs after discharge from the hospital. Infants born at less than 28 weeks spend 85 times as long in hospital as term babies in the first five years of life, with substantial healthcare costs.4 Over the last decades, the frequency of preterm birth in most western countries seems to be increasing rather than decreasing. An increase not only to be explained by an increase in assisted conceptions, multiple pregnancies and elective deliveries. Perinatal death and morbidity are not only strongly related to early gestational age but also to whether or not steroids had been administered antenatally and whether a preterm infant had been transferred to a tertiary care center in- or ex-utero. Therefore, postponing delivery for 48 hours in order to allow maximal effect of maternal parenteral steroid administration and transportation of the mother to a center with neonatal intensive care unit facilities are the primary indications for treatment of women with the diagnosis of threatening preterm delivery.
Because the contracting uterus is the most frequently recognized antecedent of preterm birth, stopping contractions has been the focus of therapeutic approaches.5 However, no one tocolytic has been identified as the best first-line option.6 Risks and benefits of all tocolytic options for both the fetus and the mother must be considered. Several classes of medications are used for tocolysis to inhibit preterm labor in order to allow time for such co-interventions to occur. These include Beta adrenergic agents or Betamimetics, Calcium Channel Blockers and Prostaglandin synthesize inhibitors such as Indomethacin and Magnesium Sulfate. Multiple Cochrane systematic reviews exist for individual tocolytic medications, but there has been no rigorous, quantitative synthesis of the data comparing tocolytic drug classes.
Pharmacoeconomics involving the cost of Nifedipine and Isoxsuprine in 3 day treatment duration is in 1:4 ratios. The cost involved in the treatment with Isoxsuprine ranged from P660.50 to P700.00 as compared to Nifedipine treatment of P168.00-180.00. The cost of therapy doesn't include other expenses such as syringes and solusets used in delivering the treatment.
This study compares in a prospective design, the efficacy, maternal and neonatal effects and safety of Nifedipine with that of Isoxsuprine in the management of preterm labor.
Review of Related Literature
Preterm labor remains a major obstetrics problem associated with high perinatal mortality and morbidity. It is defined as the occurrence of regular contractions every 5-8 minutes or less, lasting 30 seconds or more, with progressive cervical change, after 28 and before 37 weeks of pregnancy. The challenge of treating preterm labor clearly illustrates one of the central dilemmas in obstetrics.7 Most review articles on preterm labor point out that preterm birthrates are not declining but are, in fact, slowly increasing. Tocolysis is the use of medication to prevent preterm delivery.
Throughout the years, a variety of drugs with different pharmacologic principles have been used to suppress preterm labor. However, the choice is limited by their efficacy, safety and side effects thus necessitating a continuous search for effective drugs with minimal side effects. The tocolytic drugs most frequently used are the B-sympathomimetic agents usually Isoxsuprine. Intravenous administration of these agents has a rapid tocolytic effect, and oral administration, may be used for maintenance therapy. Isoxsuprine inhibits spontaneous and oxytocin induced uterine activity both in vitro and in vivo during term labor. An efficacy rate of 72% of preterm labor being postponed by more than seven days was reported in two uncontrolled studies.8 Side effects of Isoxsuprine include maternal tachycardia, hypotension, nausea, sweating, drowsiness and headaches. An increase of fetal heart rate by 10 to 20 beats per minute has been observed.
There is a growing body of evidence that Nifedipine, a dihydropyridone calcium channel blocker has emerged as an effective, potentially safer and better-tolerated tocolytic agent with no known fetal side effects. It inhibits smooth muscle contraction by impeding the flow of calcium across the muscle membrane. Successful treatment of preterm labor with Nifedipine has been reported. It easily crosses the placenta with a ratio of 0.93 between umbilical cord blood and maternal serum concentrations.9 Some animal studies report changes in uterine blood flow and fetal acidosis after CCB administration.10 Harake and co-workers found decreased uterine blood flow and lower fetal arterial oxygen content in instrumented pregnant sheep treated with Nifedipine infusion.11 They suggested that fetal acidosis after CCB infusion is primarily due to a decrease in uterine blood flow rather than a direct fetal effect of the drug. However, Blea and co-workers infused instrumented sheep with low dose Nifedipine corresponding with human concentrations.12 They found hypoxia and acidosis in the sheep fetus, without persistent decreases in uteroplacental or fetoplacental blood flows or blood pressures.
Most studies in humans show no decrease in uterine blood flow after Nifedipine administration to pregnant women. Moretti et al. and Hanretty et al. found no changes in uterine and fetal Doppler flow velocity waveforms after oral Nifedipine therapy in hypertensive pregnant women. Several studies have reported on short-time effects (15 min.,1 hr., 3 hrs. and 5 hrs.) of oral Nifedipine administration on fetal Doppler flow velocity waveforms in normotensive women.13 One study found a transient decrease in umbilical artery pulsatility index (PI) 15 min. after 10 mg sublingual Nifedipine. The other studies found no changes in the fetal or uteroplacental circulation.14
A recent study by Guclu et al. was the first to study fetal Doppler parameters during 48 hours of Nifedipine tocolysis. They found no changes in umbilical artery PI during treatment, but found decreased fetal middle cerebral artery PI and maternal uterine artery PI at 24 hours and 48 hours of treatment.15 A Cochrane review of CCB for inhibiting preterm labor concluded that neonatal outcome was improved compared to betamimetics.16 Houtzager and coworkers followed up 48 children at the age of 9-12 years who were in utero exposed to nifedipine.14 They found no negative effects on psychosocial and motor functioning. Although animal studies show conflicting results regarding fetal safety with the use of CCB, data from human studies show only very limited adverse fetal effects.
Maternal effects of Nifedipine exert both vascular and cardiac effects. It vasodilates the vessels and exerts negative inotropic and chronotropic effects depressing the heart. 16 The cardiodepressant effect of Nifedipine in vivo is counteracted by a vasodilatation-triggered and baroreceptor mediated reflex increase in sympathic tone resulting in indirect cardio-stimulation. The increase in sympathic tone compensates for the negative inotropic and chronotropic action by Nifedipine on the heart. These mechanisms are most likely the basis for the adverse events and side effects seen with Nifedipine tocolysis. The Cochrane review by King et al., reviewing 11 trials, claimed a markedly reduced risk of cessation of treatment for maternal adverse drug reactions when comparing calcium channel blockers with mainly Î²-adrenergic-receptor agonists (RR 0.14; 95% CI 0.05 to 0.44).13
The number needed to treat for drug reaction requiring cessation of treatment was 14 (95% CI 10 to 25).15 Translation of these numbers to the general population of women with preterm labor appears to be difficult due to the exclusion criteria used in most trials (twin pregnancy, PPROM, blood loss or history of cardiovascular disease). Most common side effects due to the vascular and cardiac effects of Nifedipine are hypotension, tachycardia, flushes, headache, increased liver enzymes, nausea and dizziness.
Most of the randomized controlled trials on Nifedipine for tocolysis have started with immediate-release tablets or capsules up to a maximum dose of 40 mg during the first hour. The extended-release medication varied from 60 to 160 mg daily.15 These trials report only minor or no reductions in diastolic or systolic blood pressure in normotensive pregnant women during tocolysis extended-release regimen. Two studies focusing on the short term effects of Nifedipine in normotensive pregnant women found hypotension accompanied with tachycardia 45 minutes after Nifedipine administration.7 Concerns on the possible effects of Nifedipine on the maternal cardiovascular circulation remain, because only limited information is available. Furthermore, most trials have excluded patients with multiple pregnancies, diabetes mellitus, cardiovascular disease, preeclampsia, and hyperthyroidism.
Several papers were done comparing Nifedipine and Isoxsuprine in the suppression of preterm labor. In a study "A comparative study between Nifedipine and Isoxsuprine in the suppression of preterm labor by Raymajhi, R. et al, 81.25% of patients receiving Nifedipine and 70% of those receiving Isoxsuprine achieved successful tocolysis.17 The mean prolongation of pregnancy with Nifedipine was 25+19.85 days and with Isoxsuprine it was 19.18+17.82 days. Maternal side effects were similar in both groups with hypotension and tachycardia being the commonest.
In a randomized study by Kedar, MG conducted at the Nowrosjee Wadia Maternity Hospital showed delivery was prolonged for 22.4 + 15.6 days by sublingual and oral Nifedipine as compared to 16.5 + 14.5 days by parenteral and oral Isoxsuprine. 18 Maternal effects were common and more serious in the group which received Isoxsuprine. However fetal and neonatal outcome appeared to be similar.
After Nifedipine was first reported in 1980 in an observational study to be an effective tocolytic agent with minimal side effects it has not replaced the betamimetics as the most commonly used tocolytic agent in clinical practice. Concerns arose from animal studies9 that Nifedipine may have adverse effects on the fetal and placental circulation, and although there have been subsequent studies which failed to confirm this, it is necessary to review the evidence for the safety and efficacy of this treatment.
Are the efficacy and safety of Oral Nifedipine and Parenteral and Oral Isoxsuprine the same?
Significance of the Study
Calcium channel blockers have fewer adverse effects for women in preterm labor than betamimetics drugs, and appear at least as good at postponing preterm birth. Even short-term postponement of preterm birth (before 37 weeks) can help improve outcomes for babies, as the mother can be given steroid drugs which help develop the baby's lungs in a short time. The most common drugs to try and stop preterm labor are betamimetics. Calcium channel blocker drugs are another option. They are commonly used for high blood pressure, but might also relax uterine contractions. The review found that calcium channel blockers seem to be at least as good as betamimetics, and maybe better, for postponing preterm labor. Calcium channel blockers have also fewer adverse effects on the mother.
Objective of the Study
To compare the efficacy and safety of Oral Nifedipine with Parenteral and Oral Isoxsuprine.
To describe the patient's profile.
To evaluate the tocolytic effectiveness of Oral Nifedipine as compared to Parenteral and Oral Isoxsuprine in terms of:
Prolongation of pregnancy (by number of days)
Cervical status (by cervical length and funneling determination)
Efficacy in suppressing preterm labor ( by uterine contractions)
To study the incidence of common side effects of Oral Nifedipine and Parenteral and Oral Isoxsuprine and compare them in this aspect.
The study will use a randomized controlled trial.
This prospective study will be conducted at Southern Philippines Medical Center, a Local Tertiary Government Hospital from March 2011 to December 2011.
The study will include 96 cases of Filipino pregnant women with preterm labor with a gestational age between 26-35 weeks.
Gestational Age less than 35 weeks (Gestational age is based on the last menstrual period with a reliable menstrual history and/or an ultrasound before 20 weeks gestation)
Minimal cervical changes in the form of effacement and dilatation (not exceeding 4 cm)
Painful regular uterine contractions occurring at least once every 10 minutes recorded for at least 30 minutes
No previous administration of tocolytics
Cervical Dilatation of > 4cm
Severe IUGR (below 10th percentile based on Colorado chart)
Fetal Anomaly incompatible with life
Interventions and Comparisons
The intervention will be those given Nifedipine tocolysis (Group A) while the comparison group are those given with Isoxsuprine tocolysis (Group B).
All the patients presented with the preterm labor will be scrutinized to select the patients for tocolysis. Those patients who fulfilled the selection criteria will be randomly assigned to the two treatment groups using electronic number generator by the investigator. The patients receiving these two drugs will be matched for age, parity, socioeconomic status, previous obstetrics history, previous risk factors, gestational age and cervical status before tocolysis.
Data Gathering and Intervention Protocol
The independent variable is the treatment group while the dependent variables are the prolongation of pregnancy and cervical status (cervical length determination and funneling), efficacy, perinatal outcomes, adverse effects and economic outcomes.
After giving their informed consent, the patients will be allocated to one of the two groups.
The patients who are in Group A will receive NIFEDIPINE tocolysis:
Patient is started IV infusion with 500 mL 5% Dextrose at KVO rate and given a 10 mg tablet of Nifedipine, crushed between teeth before swallowed. If uterine contraction continued, same dose is repeated every 15 min with a maximum of 40 mg Nifedipine within the first hour of treatment. After completing the first hour, Oral Nifedipine is continued as 10mg every 6 hours consecutively to complete 7 days.
Those in Group B will receive ISOXSUPRINE tocolysis.
Patient is given with 500 mL 5% Dextrose. 50 mg of Isoxsuprine is added in 5% Dextrose and started at the rate of 20ugtts/min (0.03mg/min) with increasing increments of 5ugtss/min every 20-30 minutes up to 60 ugtss/min (0.1mg/min) with regular monitoring of blood pressure, maternal and fetal heart rate. After cessation of uterine activity, drip is discontinued for 12 hours. After discontinuation of IV infusion, patients are maintained on oral Isoxsuprine 10mg 8 hourly for up to 7 days.
In both groups, dosage schedule could be modified according to the patient's clinical symptoms and vital signs. Before each oral dose, maternal vital parameters and fetal heart rate will be monitored along with the uterine activity. If the maternal pulse, BP is not within the normal range, the next dose is withheld and symptomatic treatment will be started. Patient is examined every 30 minutes until she is settled. If the fetal heart rate is not within 110-150 beats/minute, therapy is withheld and patient is subjected to NST and treated accordingly.
To enhance fetal lung maturation, which improves gaseous exchange and lung compliance, patients with gestational age <34 weeks are given 6mg Dexamethasone, intramuscularly every 12 hours for 4 consecutive doses. Patients who had recurrent preterm labor in both groups will be treated with the same drug used initially as per the protocol followed earlier.
All patients included in the study will undergo transvaginal ultrasound measurement of cervical length with funneling on admission by the investigator. An official result of transvaginal ultrasound measurement of cervical length with funneling will be done by a Perinatologist and an intra and inter observer results will be gathered.
The goal for tocolysis in both groups is to delay delivery until 7 days from the time of admission until Dexamathasone given would help to decrease Hyaline Membrane Disease. The main outcomes of interest in arresting preterm labor are the effectiveness and safety of Nifedipine and Isoxsuprine. Tocolytic effectiveness is assessed in terms of the total number of women in the intent-to-treat population who had not been delivered after beginning the treatment up to 7 days. The most important factor determining efficacy is cervical status determined by cervical length and funneling using transvaginal ultrasonography. Treatment failure is said to exist if uterine relaxation was not achieved in 7 day treatment, cervix dilated >4cm or patient and fetus developed some significant side effect that necessitated discontinuation of therapy and side effect are noted. If spontaneous rupture of membranes occurred, fetal distress, placental abruptio and unexplained bleeding occurred, delivery is considered.
Definition of Variables
In order to unlock difficulties, the following variables are defined as they appear in the study. Data will be recorded by the Obstetricians. All will be trained about data collection before starting the study.
AGE - the number of years from birth up to present.
GESTATIONAL AGE - time elapsed since the first day of the last menstrual period.
PARITY - determined by the number of pregnancies reaching 20 weeks.
CERVICAL DILATATION - cervical distention, determined by transvaginal ultrasonography determining cervical length and funneling
CERVICAL EFFACEMENT - manifest clinically by shortening of cervical canal.
PRIMARY OUTCOME - who had not been delivered at 7 days
ADVERSE EFFECTS - In mothers, other adverse effect are the changes from baseline of systolic blood pressure, flushing, nausea and vomiting, chest pain, heart rates, headache and tremors, etc. Fetal heart rates are recorded hourly.
ECONOMIC OUTCOME - measurement of direct medical costs including the total costs of the medicine and nonmedical products required for drug administration
Sample Size Computation
This is a study of independent cases and controls with 1 control per case. Prior data indicated that the failure rate among controls is 0.3. If the failure rate for experimental subjects is 0.185, 217 experimental subjects and 217 control subjects is needed in the study to be able to reject the null hypothesis that the failure rates for experimental and control subjects are equal with probability (power) 0.8. The type I error probability associated with this test of this null hypothesis is 0.05. Uncorrected chi-square statistic is used to evaluate the null hypothesis.
The software used was PS Power and Sample Size Calculations Version 3.0.34.
Data Handling and Analysis
Data will be encoded using Epi Info. The same software is used to analyze the data. Descriptive and Analytical Statistics will be computed. For qualitative variables, proportions will be used. Mean and Standard Deviation will be used for quantitative variables. In order to determine the relationship between the type of treatment and treatment outcome, chi square test will be used. The level of significance is set at 0.05.
Approval from the Research Committee and Ethics Committee
A research proposal will be submitted and presented to the Research Committee and Ethics Committee for review. When approved, data gathering will ensue.
Permission to Conduct Study
A letter will be sent to the Chief of Hospital that a study will be conducted among patients with preterm labor in the Department of Obstetrics and Gynecology. When granted, written informed consent will be obtained from all patients.
Table 1. Age variations among the two groups
Age in Year
Gestational Age in weeks
26 - 28 6/7
29 - 31 6/7
32 - 34 6/7
Data presented as n (%)
Where n = No. of patients in the study groups
Table 2. Clinical Characteristics of two groups
Gestational Age (week)
Cervical Dilatation (cm)
Cervical Effacement (%)
Cervical Length (cm)- On admission
Cervical Funneling (%)- On admission
Data presented as mean + S.D.
Table 3.Prolongation of Pregnancy and Tocolytic Effectiveness
Delivery within 7 days of treatment
Cervix dilated >4cm
Developed fetal side effects
Others (fetal distress, placental abruptio and unexplained bleeding)
*Data are presented as mean + S.D.
Table 4. Adverse Effects in Mothers treated with tocolytic agents
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