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A PROSPECTIVE COMPARISON OF NIFEDIPINE AND ISOXSUPRINE FOR TOCOLYSIS

Kedar M Ganla*, Safla A Shroff**, Shyam DesaiI***, Amar G Bhinde****
*Lect; **Med off; ***Asst Hon; ****Unit Head; Nowrosjee Wadia Maternity Hospital, Parel, Mumbai.

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Objective : To compare the tocolytic efficacy and side effects of parenteral and oral isoxsuprine with sublingual and oral nifedipine.

Method : Hundred patients in labour between 26-36 weeks were prospectively entered into a randomised controlled trial of sublingual and oral nifedipine v/s parenteral and oral isoxsuprine. Outcomes include gestational age at delivery, prolongation of pregnancy, maternal and foetal side effects were noted.

Results : Both the groups were well matched regarding their demographic status. Delivery was prolonged for 22.4 + 15.6 days by nifedipine as compared to 16.5 + 14.5 days by isoxsuprine. Maternal effects were more common and more serious in the group which received isoxsuprine as compared to those which received nifedipine. However foetal and neonatal outcome appeared to be similar.

Conclusion : Nifedipine is a better tolerated, more effective and safe tocolytic agent than isoxsuprine with few maternal complications.

INTRODUCTION

Preterm delivery is a major obstetrics problem associated with high perinatal mortality and morbidity. The challenge of treating preterm labour clearly illustrates one of the central dilemma in obstetrics. Tocolysis, the pharmacologic inhibition of uterine contractions, is currently the principal preterm birth preventive measure and will remain so until the aetiology of preterm labour is better understood.

The tocolytic drugs most frequently used in India 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. The b-sympathomimetic drugs, however, have significant and potentially serious maternal and foetal side effects. [1, 2, 3]

Nifedipine, a calcium channel-blocker, has emerged as a potentially safer and better tolerated tocolytic agent. [4,5,6] Nifedipine inhibits smooth muscle contraction by impeding the flow of calcium across the muscle cell membrane. [7] Successful treatment of preterm labour with nifedipine has been reported. [8, 9]

We at the Nowrosjee Wadia Maternity Hospital decided to tackle preterm labour by using nifedipine, a dihydropyridone calcium channel blocker and comparing its tocolytic effectiveness and also maternal, neonatal effects with a known tocolytic, isoxsuprine, which is widely used in India.

MATERIAL AND METHODS

This randomised and prospective study was conducted at the Nowrosjee Wadia maternity Hospital during March 1997 to March 1998. One hundred cases of preterm labour with a gestational age between 26-36 weeks were randomly alloted to two groups. The patients’ detailed history was taken, followed by a thorough examination including general examination and obstetrics examination was carried out.

Inclusion criteria

• Gestational age less than 36 wks.
• Painful regular uterine contractions occurring at interval of less than 10 minutes recorded for atleast 30 minutes.
• No previous administration of tocolytics for 7 days.
  

To patients receiving nifedipine, an intravenous infusion of ringer lactate solution at the rate of 100 ml/hr was continued only till sublingual nifedipine was administered. Nifedipine was given 5 mg sublingual. If uterine contractions persisted after 15 minutes, 5 mg sublingual nifedipine was repeated upto a maximum of 8 doses (40 mg) during the first two hours of treatment, if uterine activity did not cease after two hours, the patient was deemed as a failure and treatment stopped. If Sub-lingual nifedipine ceased the uterine activity than oral nifedipine of 10 mg was initiated 3 hrs after the last sublingual dose. Oral nifedipine was then continued as 10 mg 8 hrly for next 48 hrs. Nifedipine retard tablet 10 mg or 20 mg was then started 12 hrly and continued till 36 weeks. Before each sublingual or oral dose, maternal vital parameters and foetal heart rate was also monitored along with the uterine activity. If the maternal pulse, BP were not within the normal range, the next dose was withheld and symptomatic treatment started. Patient was examined every 5 minutes until she was settled. If the foetal heart rate was not within 110-150 beats/min., therapy was withheld and patient was subjected to an NST and treated accordingly.

Those patients to be treated with isoxsuprine were given with 5% Dextrose. 60 mg of isoxsuprine was added in 5% Dextose and was initially started at the rate of 0.5 mg/min and increased upto 10 mg/min and after cessation of uterine activity drip was continued for 12 hours. Subsequently patients received isoxsuprine injectable 10 mg im 8 hrly for 48 hrs followed by oral 10-20 mg, 8 hrly till 36 weeks.

Antibiotic prophylaxis is given in the form of erythromycin to patients in both the groups. [10] Patients in both groups were given head low position and injection dexamethasone 12 mg im 12 hrly for two doses followed by weekly injections upto 36 weeks. [11] Patients who had recurrent preterm labour in both groups were treated with the same drug used initially as per the schedule followed earlier.

In both groups, our goal for tocolysis was to delay delivery till 36 completed weeks of gestation or at least 48 hrs till dexamethasone given would help to decrease hyaline membrane disease. Treatment failure was said to exist if, despite maximal dose mentioned for both groups, uterine relaxation was not achieved or patient / foetus developed some significant side effect that necessitated discontinuation of therapy and side effect were noted. Further data regarding mean prolongation of pregnancy, side effects, failure of treatment, gestational age, at delivery weight, apgar score and neonatal details were recorded.

RESULTS

The patients in both groups were well matched regarding age, antenatal care, gravidity, previous obstetrics history and socio economic status (Table 1).

Mean prolongation of pregnancy and good success rate was noted in nifedipine groups as compared to isoxsuprine group.

As regards the side effects of both tocolytics, nifedipine patients experienced much fewer side effect as compared to isoxsuprine group (Table 3). Although both group patients experienced hypotension, it was very significant (average 10 mm Hg diastolic) in isoxsuprine group. Nifedipine caused mild to moderate headache in 30% of patients. The more common side effects of isoxsuprine were chest pain, nausea and vomiting seen in more than 30% of the patients. Only 5 patients required stopping the infusion to alter the symptoms. Rest were relieved by reducing the infusion rate. In no instance did maternal side effects necessitated discontinuation of nifedipine.

Table 3
Side Effects	Nifedipine	Isoxsuprine
Tachycardia	23 (46%)	28 (56%)
Hypotension	10 (20%)	18 (36%)
Nausea and vomiting	5 (10%)	17 (34%)
Chest pain	2 (4%)	5 (10%)
Pulm. oedema	0	1 (2%)
Hot flushes	20 (40%)	17 (34%)
Headache	15 (30%)	6 (12%)

There was no significant difference in Apgar scores of babies in both groups. Two babies developed respiratory distress syndrome in Nifedipine group as compared to 6 babies in isoxsuprine group.

COMMENTS

Beta sympathomimetic drugs although proved useful, have been proved not to have any theraputic value in light of high incidence of side effect also they were not suitable for women with significant cardiovascular disease or diabetes. [12]

Activity in uterine muscle, in vitro, is depended upon extracellular calcium. [13] So that it would be anticipated that contraction would be inhibited by calcium antagonist. Nifedipine has a well known relaxing effect on the myometrium and it exhibits greater selectivity for inhibition of uterine activity with very minimal effect on maternal cardiovascular and metabolic changes. [14] Administration in retard form which makes the dosage convenient to take was found to be equally effective. [15] The side effect reported most frequently with nifedipine were headache, constipation and hypotension. When one considers that the potentially fatal cordiorespiratory complications seen with b sympathomimetic therapy are often preceded by side effect such as tachycardia, dyspnoea, and chest pain. [16]

Thus our study shows that nifedipine is a better tolerated and safer tocolytic agent than isoxsuprine with fewer maternal and foetal complications.

We conclude that i) Orally administered nifedipine is effective in the management of preterm labour, ii) Perinatal mortality is much reduced, iii) Side effects are mild and self limited. Larger series with comparative evaluation with other tocolytic agents is required.

REFERENCES

1. Benedetti TJ. Maternal complications of parenteral beta Sympathomimetic therapy for premature labour. Am J Obstet Gynecol 1983; 145 : 1-6.
   
2. Ferguson II, Holbrook RH, Stevenson DK, Hensleigh PA, Krednester D. Adjunctive magnesium sulfate does not alter metabolic changes associated with ritodrine tocolysis. Am J Obstet Gynecol 1987; 156 : 103-7.
3. Katz VL, Seeds JW. Fetal and neonatal cardiovascular complications from B-sympathomimetic therapy for tocolysis. Am J Obstet Gynecol 1989; 161 : 1-4.
4. Ulmsten U. Treatment of normotensive and Hypertensive patients with preterm labour using oral nifedipine, a calcium Antagonist. Arch Gynecol 1984; 236 : 69-72.
5. Read MD, Weilby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br J Obstet Gynecol 1986; 93 : 933-7.
6. Ferguson JE, Dyson DC, Holbrook RH, Schutz T, Stevenson DK. Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis. Am J Obstet Gynecol 1989; 161 : 788-95.
7. Forman A. Calcium entry blockade as a therapeutic principle in the female urogenital tract. Acta Obstet Gynecol Scand Suppl 1984; 121 : 1-26.
8. Ulmsten U, Anderson KE, Wingerup I. Treatment of premature labour with the calcium anatagonist nifedipine. Arch Gynecol 1980; 229 : 1-5.
9. Kaul AF, Osathanondh F, Safon LE, Frigoletto FD, Friedman PA. The management of preterm labour with the calcium channel blocking agent nifedipine combined with the beta-mmetic terbutaline. Drug Intell Clin Pharm 1985; 19 : 369-71.
10. Morales WJ, Angel JL, O’Brien WF, Knuppel RA, Fimzzam A. Randomized study of antibiotic therapy in idiopathic preterm labour Obstet Gynecol.
11. Liggins FC, Howie RN. Paedia 1972; 50 : 515.
12. Hemminki E, Starfield B. Br J Obstet Gynecol 1978; 85-411.
13. Bolton TB. Physio Rev 1979; 59 : 606.
14. James E Ferguson II, Donald CD, Harold Holbrock, Schutz T, David K Stevenson. Cardiovascular and metabolic effects associated with nifedipine and ritrodrine tocolysis. Am J Obstet Gynecol 1989; 161 : 78-95.
15. Long term treatment with nifedipine retard to suppress the preterm labour. Clinic Exp Obstet Gynecol 1991; 18 (1) : 35-7.
16. Murray C, Haverkamp AD, Orlenans M, Sally Berga. Depecth Nifedipine for treatment of preterm labour; a historic prospective study. Am J Obstet Gynecol 1992; 167 : 52-6.

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